Highly correlated yet independently-derived reductions in productivity from sun-induced fluorescence, vegetative near-infrared reflectance, and GPP simulated by the Simple Biosphere model version 4 (SiB4) suggest a 130–340 TgC GPP reduction in July–August–September (JAS) of 2018. This occurs over an area of 1.6 × 106 km2 with anomalously low precipitation in northwestern and central Europe. In this drought-affected area, reduced GPP, TER, NEE and soil moisture at ICOS ecosystem sites are reproduced satisfactorily by the SiB4 model. We found that, in contrast to the preceding 5 years, low soil moisture is the main stress factor across the affected area. SiB4’s NEE reduction by 57 TgC for JAS coincides with anomalously high atmospheric CO2 observations in 2018, and this is closely matched by the NEE anomaly derived by CarbonTracker Europe (52 to 83 TgC). Increased NEE during the spring (May–June) of 2018  largely offset this loss, as ecosystems took advantage of favourable growth conditions.We analysed gross primary productivity (GPP), total ecosystem respiration (TER) and the resulting net ecosystem exchange (NEE) of carbon dioxide (COThis article is part of the theme issue ‘Impacts of the 2018 severe drought and heatwave in Europe: from site to continental scale’. Decreased precipitation in combination with record-high temperatures led to strong reductions in soil moisture availability and decreased atmospheric humidity ,4. On thactivity ,6. The net al. [2 uptake from the atmosphere between 0.135–0.205 PgC yr−1 based on both land-based and atmosphere-based estimates. Luyssaert et al. [−1 for 2001–2005 following from a combination of atmospheric inverse, inventory and flux measurement-based approaches. Peters et al. [−1 on average in the period 2001–2007 using the atmospheric inverse system CarbonTracker Europe. Monteil et al. [−1 during the 2006–2015 period.The terrestrial ecosystems of Europe have been estimated to act as a net sink of carbon. The annual budget comprises a large seasonal cycle of summer uptake and winter loss that is highly sensitive to large-scale weather patterns, and therefore interannual variability is high. Janssens et al.  estimatet et al.  derive as et al.  find a nl et al.  use a coet al. [−1 source of carbon. Peters et al. [−1 over the year 2003, largely neutralizing the carbon sink. Vetter et al. [−1. Recently, Buras et al. [This small net European sink can reduce and even turn into a carbon source during droughts and heatwaves. Ciais et al.  estimates et al.  suggest r et al.  estimates et al.  have sugSevere droughts and heatwaves are expected to occur more frequently in Europe under likely climate change scenarios . It is, 2 fluxes and atmospheric CO2 mole fractions at the stations of the spatially dense Integrated Carbon Observation System (ICOS) [et al. [2 fluxes as a starting point in the data assimilation system CarbonTracker Europe (CTE) [2 mole fraction observations to derive an atmospheric view of the reduction in the carbon uptake over Europe during the 2018 drought.We use observations of eddy-covariance COm (ICOS)  togetherm (ICOS)  and vegem (ICOS) , which hm (ICOS) , for exam (ICOS) . Besidesm (ICOS) ) to undem (ICOS) ,22. We w [et al. , in whic [et al. . Finallype (CTE)  and we u2.σ anomaly in precipitation over the period May–September of 2018 relative to the 2000–2017 period. This covers an area of 1.6 × 106 km2 over land and corresponds to the ‘extreme drought’ threshold that we are primarily interested in under the system proposed by Quiring [et al. [In this section, we describe the observations and methodologies used for this study, throughout which we consider the drought to have had the highest impact during the months July–September of 2018 [ Quiring . Using t [et al. , the sam(a)2 mole fractions are measured at the atmospheric sites (see http://www.icos-ri.eu). The current ICOS network consists of 81 ecosystem stations (22 of which have completed the ICOS labelling process) and 36 atmospheric stations (23 fully ICOS-labelled) in 12 countries. In our study, we use the local carbon flux measurements and partitioning thereof into NEE, GPP and TER and compare these with the simulated values from the biosphere model SiB4 , and tall tower sites. [2 mole fractions to infer carbon fluxes at the surface using the data assimilation system CTE SIF is the small percentage of incident radiation that is re-emitted by chloroplasts during photosynthesis at higher wavelengths, and this signal correlates well with GPP . The retet al. [Recently, Badgley et al.  introducet al. . We use et al. . NIRv isin situ observations of GPP from the ICOS network We use the Simple Biosphere model v.4 (SiB4) to simulate biosphere fluxes of carbon during the drought period and preceding years. The SiB model was developed in the ′80s and ′90s with the aim of simulating the land–atmosphere exchange of energy, water and carbon ,36). TheSiB4 simulates the leaf photosynthesis rate as a minimum of three limiting assimilation rates: that is, (1) limited by the capacity of the RuBisCo enzyme, (2) limited by light, and (3) limited by storage and export in the photosynthesis process ,40,41. T2 fertilization to the carbon pools following the observed increase in atmospheric CO2 mole fractions [Meteorological data that are used as forcing for the SiB4 model are taken from the Modern-Era Retrospective Analysis for Research and Applications 2 (MERRA-2) and are available from 1980 onwards . For iniractions ,43. The ractions  and soil(d)et al. [et al. [et al. [et al. [et al. [Previous work has shown that the carbon cycle drought response to soil moisture stress is often not well captured in biosphere models ,23,45. Wet al. ), we see [et al. ). Furthe [et al. . Secondl [et al. . We have [et al. .(e)2, described in full in van der Laan-Luijkx et al. [2 concentrations from the GLOBALVIEWplus v.5.0 ObsPack product [CTE is a global atmospheric inverse system that estimates the biosphere and oceans’ fluxes of COx et al. . Here, w product  and the  product ,30, made product  on a 3°  product .et al. [Two inversions are carried out following this setup: one with prior fluxes for Europe’s terrestrial biosphere taken from SiB4 § and one et al. . Scalinget al. ).Fossil fuel and biomass burning emissions are taken from the EDGAR 4.0  and SiBC3.(a)a) SIF, (b) NIRv and (c) SiB4 GPP across Europe relative to the 2013–2017 baseline period, with similar patterns of reductions. Strong reductions in SIF and NIRv in northwestern Europe correspond to the area of reduced precipitation (green contour) and high temperatures, contrasting with increases in productivity in eastern Europe and the Iberian peninsula that are also noted in Longdoz et al. [σ reductions in precipitation over land, we estimate the drought-affected area at 1.6 × 106 km2, and based on 1σ reductions in SIF as well as NIRv, we derive an affected area of 1.9 × 106 km2, each with a slightly different spatial distribution. The integrated anomalies for SIF and NIRv are just above 1σ in May, become negative starting in June, and drop well below the −1σ range in the summer months July–September (JAS).The carbon cycle impact of the 2018 summer drought was recorded in productivity independently across the network of ICOS eddy-covariance observations as well as in remotely sensed SIF and NIRv. z et al. . Based oN=10 out of 16) and for each of the PFTs, concomitant reductions in TER and (of higher magnitude) GPP lead to overall reduced NEE. Although there is an important role for vegetation stress due to high temperatures, high vapour pressure deficit, and low soil moisture, we find mixed signals of changes in water-use efficiency across sites (not shown) and only evergreen needleleaf forests (ENF) exhibit the clear increase that was demonstrated in Ciais et al. [et al. [Within the drought-affected area, 14 out of 16 selected eddy-covariance sites recorded reductions of monthly GPP and/or TER, as derived from the measured NEE in JAS. There was no clear separation of magnitudes across PFTs, nor a strong sign of GPP- or TER-dominated responses. Table 1 shows the changes in the monthly mean carbon balance averaged over PFTs. At most sites N = 7, grouped together because of their highly similar temporal anomalies) in Figure 2d shows this depletion to occur substantially earlier at the ICOS sites than SiB4 simulations suggest. The strongest GPP response consistently occurs once soil moisture goes outside its 1σ variability in July.The summer drought impacts on the carbon cycle were most severe in the July–August–September (JAS) period, and were preceded by favourable growth conditions in spring that increased productivity and net carbon uptake. This is partly visible in the anomalies in 2 (Ci/Ca), stomatal conductance (gs), and GPP, as well as increased intrinsic water-use efficiency. The same stress factor also scales down heterotrophic respiration (and maintenance respiration), representing reduced microbial activity in dry soils. This makes soil moisture levels, and ensuing stress, a key driver of the biospheric response to severe droughts as studied here. Simulations with an alternative soil moisture distribution derived from the PCR-GLOBWB hydrological model, which performed very well when we applied it to SiBCASA over the Amazon [e Amazon , now mai(c)R = 0.54–0.89 for SIF, and R = 0.70–0.97 for monthly NIRv versus eddy-covariance GPP; see electronic supplementary material, §SC) allows PFT-dependent upscaling of NIRv (and SIF) from figure 1c, which does not use any remotely sensed products to prescribe changes in vegetation phenology. SiB4’s total GPP anomaly integrates to −130 TgC over the same area and time period, as documented in Regression of the site-specific productivity  and 57 TgC, respectively, when averaged over the JAS period and the 1.6 × 102 mole fractions across the ICOS network. Through CTE, we derive a summertime reduction of NEE of 52–83 TgC during JAS, shown alongside the other numbers in et al. [The integrated NEE anomalies at local to regional scales derived with SiB4 agree well with large-scale constraints derived from atmospheric COn et al. , this an4.et al. [2 observations from an extensive tower network. As warm conditions persisted, and possibly fed by a positive land–atmosphere feedback discussed in various publications [et al. and Kowalska et al. [et al. [The contrasting carbon cycle anomalies between the spring and summer periods of 2018 strongly resemble the 2012 drought in North America described extensively in Wolf et al. . Similarications –63, soilications ,64. The a et al. ,65, as w [et al. , who hav6 km2, a factor of 2 larger). Also, the 2003 event was preceded by a weaker spring anomaly than in 2018. Sites impacted during both events include Loobos , Tharandt , Hainich  and Sorø , with needleaf forests showing comparable GPP reductions (approx. 10–15%), and the deciduous forests suggesting much larger reductions (approx. 20–50%) in 2018 than in 2003. The sample size of N=2 for both sets precludes strong conclusions on the 2003–2018 difference in drought response of each PFT though, which is more extensively evaluated in Fu et al. [increase in net carbon uptake. This contrasts strongly with the 2003 European summer anomaly, which led to a decreased European carbon uptake of 147 TgC [2 mole fractions presented in Thompson et al. [Compared with the 2003 drought in Europe, the 2018 impacts on GPP and NEE are large at the site level but integrate to smaller totals, partly because the 2003 event covered a much larger area  of any single PFT in the model while their NEE response is overestimated by SiB4. In agreement with earlier [figure 2a is best reproduced by the model, although it also results from a too late and too small decline in both GPP and TER, and appears to occur at a too small increase of water-use efficiency compared with the (quite noisy) eddy-covariance-derived inherent water-use efficiency. Underestimation of changes in water-use efficiency during droughts is common amongst biosphere models [et al. [Our SiB4 model-based analysis suggests that the largest contribution to the total drought anomaly (JAS) in western Europe came from grasslands (NEE: 28 TgC), which had a small measured NEE response per unit area across the ICOS sites in  earlier  and 2018 earlier ,76, grase models , for vare models . SiB4-dee models ,79. Like [et al.  are unde [et al.  is large2 mole fraction observations. This was confirmed by our simulation using the climatological SiB4 prior, as well as by two alternative inverse simulations with CTE, in which we (a) started from the SiBCASA biosphere model that simulated no 2018 drought anomaly, and (b) additionally removed the extra ICOS CO2 observations  to fall back on the standard set of sites over Europe. The posterior result of inversion (a) was similar in the timing of the anomaly compared with our CTE simulations shown in The SiB4 simulated biosphere flux has thereby already made a reasonable prior NEE estimate for the inversions we performed with CTE, but we stress that its outcomes are most strongly driven by the ICOS CO5.6 km2. This strong local response was offset on the European level owing to relatively high amounts of precipitation in southern and eastern Europe, which led to an increase in NEE in these regions. This resulted in a mean annual European net carbon uptake of −51 to −108 TgC, illustrating that there the event was concentrated on a smaller area than that of 2003.We estimate that the drought of the summer of 2018 caused a 52–83 TgC drop in the net amount of carbon absorbed by the most strongly affected region in northwestern Europe compared with the climatological mean for July to September. This was partly mitigated by above-average uptake in late spring–early summer and exacerbated by large releases of carbon during January–March, resulting in an annual mean reduction in carbon uptake of 20–49 TgC integrated across the most strongly affected region of 1.6 × 10Using the biosphere model SiB4, we have shown that this is primarily due to soil moisture stress, which limited productivity across even typically resilient ecosystems, like evergreen needleleaf forests. Improvements to the hydrological component of this model, as well as corroboration in our findings across remote sensing products, the hydrological model PCR-GLOBWB, and eddy-covariance measurements give us confidence in the NEE anomaly estimates of SiB4. Our subsequent use of it as a high-quality prior estimate in the inverse model CTE, along with constraints from a dense network of observations across the region of interest, confirm the anomaly from the largest perspective.


This study aims to review the evidence for the empirical validation of Frank et al.’s proposed concept definitions and to discuss evidence-based modifications.For the past quarter of a century, Frank et al.’s request for definition validation. Publications with data relevant for validation were included and checked for referencing other studies providing such data.A literature search of Web of Science and PubMed from 1/1/1991 to 08/30/2017 identified all publications which referenced Frank A total of 56 studies involving 39 315 subjects were included, mainly presenting data to validate the severity and duration thresholds for defining remission and recovery. Most studies indicated that the severity threshold for defining remission should decrease. Additionally, specific duration thresholds to separate remission from recovery did not add any predictive value to the notion that increased remission duration alleviates the risk of reoccurrence of depressive symptoms. Only limited data were available to validate the severity and duration criteria for defining a depressive episode.Remission can best be defined as a less symptomatic state than previously assumed  ⩽4 instead of ⩽7), without applying a duration criterion. Duration thresholds to separate remission from recovery are not meaningful. The minimal duration of depressive symptoms to define a depressive episode should be longer than 2 weeks, although further studies are required to recommend an exact duration threshold. These results are relevant for researchers and clinicians aiming to use evidence-based depression outcomes. Major depressive disorder (MDD) is a common, often chronic and recurrent condition, marked by persistent suffering and poor overall health and with deleterious effects on psychosocial, academic, vocational and family functioning. MDD is one of the most prevalent mental disorders and the leading cause of disability worldwide  should be chosen in such a way that they have optimal prognostic significance.In particular, it should be possible to distinguish remission from recovery (and therefore relapse from recurrence), which are different only in their duration, by a difference in prognosis. The hypothesis is that those in remission have not (yet) fully recovered from the latently present episode  and therefore have a relatively high relapse rate compared with those who recovered. Those who recovered have a low recurrence rate that is no longer dependent on the time since their last episode and equal to the incidence rate of a risk factor-comparable population who never experienced an episode. Similarly, in cancer research, ‘full remission’ is defined as the period during which any sign of the disease is lacking, but during which a patient is particularly vulnerable for a relapse of the tumour since latent disease might still be present. When the remission is of sufficiently long duration, the patient can be (retrospectively) considered to be recovered or ‘cured’ as the passing of even more time does not provide additional protection to disease recurrence, the risk of which is similar to the incidence risk of a comparable healthy population.Some of the clinical status concepts that are the subject of this review are also defined in the Diagnostic and Statistical Manual of mental disorders validate at least one of Frank's definitions. Because severity related criteria were necessarily instrument-specific we focused on articles determining cut-offs on the HAMD-17 and the Montgomery-Åsberg Depression Rating Scale (MADRS), which are the most widely used instruments  extracted data independently and resolved discrepancies through discussion and consensus. References of included articles were searched for additional relevant studies. The literature search was last updated on August 30, 2017.The 1570 identified papers  included 214 duplicates and 26 non-obtainable papers. The study selection criteria (as outlined above) reduced the number to 117 papers and yielded 49 additional records via reference checks. From these 166 papers, 110 were excluded based on the full-text assessment. Thus 56 studies covering 39 315 subjects were included, and summarised in et al.  population, in which the average HAMD-17 score is about 3.2  should be visible as an upward discontinuity in the survival curve slope.Survival curves  for asymptomatic individuals until relapse/recurrence or equivalent data were obtained from 31 studies see . There iet al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.et al.Several studies show some indication of a sudden drop in relapse/recurrence rate a certain time after remission/recovery was obtained  remission of depressive symptoms is relatively high when the onset of these symptoms is recent, especially during the first 12 weeks, but diminishes quickly thereafter. This provides some justification for the suggestion by Frank et al.  of requiet al.  does notet al.A substantial body of literature studying depressive relapse/recurrence risk over time has been obtained see , but comet al. . Moreover, a substantial part of the data had to be extracted from survival curves that only rarely showed confidence intervals and often did not possess a clearly labelled time axis, making it difficult to assess exactly when the measurement began.et al. (More than a quarter-century after the landmark paper in which Frank et al.  provided


Low temperature solder  has great advantages in aerospace and through-hole technology assemblies in IBM mainframe due to its unique low temperature characteristics. The review evaluates the effects of alloying elements, rare earth elements and nanoparticles on the wettability, microstructure, mechanical properties and oxidation resistance of the low-temperature solders.  HoweverAt present, the new type of lead-free solder mainly includes Sn-Cu, Sn-Ag, Sn-Bi binary solder and Sn-Ag-Cu ternary alloy solder. The melting point of Sn-Ag solder is high (221 °C), and the price of Sn-Ag lead-free solder is relatively high due to the presence of Ag, which limits the use of the solder . The cosX, Sn-Bi, Sn-Zn), and points out the potential problems and future research directions of low temperature lead-free solder.The review evaluates the effects of alloy elements , nanoparticles  and rare earth elements  on the wettability, mechanical properties, microstructure and oxidation resistance of low-temperature lead-free solder  are called ‘vitamins’ of metal elements, A small amount of rare earth elements can change the properties of solder . As a la2.3.2O3 oxide film, which hinders the flow of liquid solder. It may be due to the different addition proportion of Al element, resulting in two different results. Du et al. [Sn-Zn lead-free solder has a wide range of raw materials and a low melting point, which is close to the traditional Sn-Pb solder. It is one of the options to replace Sn-Pb solder at present. However, the use of Sn-Zn solder is limited due to its coarse structure, poor wettability and oxidation resistance . The effu et al.  added P u et al.  studied u et al. , the schWhere Zhang et al.  studied 3.3.1.11In9) when the soldering temperature is 85°C-200°C. The first form is a continuous layer formed on the Cu substrate, which contains 6 wt.% Bi elements. The second form is scallop like compound layer. The compound layer is penetrated by molten liquid solder. It is the main channel of atom diffusion. The Bi-rich Cu11In9 phase becomes CuIn2 phase with the increase of temperature. The diffusion channel is blocked due to the growth of IMC. The growth rate of intermetallics decreases, and the interface microstructure becomes uniform. Tian et al. [2 layers with tetragonal crystal structure, Cu2 sublayers with coarse grains and Cu2 sublayers with fine grains. The shape of Cu 2 grain is the block with the largest grain, the shape of Cu2 grain is rod with medium grain size, and the shape of Cu2 grain with the smallest grain size is shown. Cu 2 layers grow and consume Cu2 layers continuously because the diffusion rate of In and Sn atoms is higher than that of Cu atoms after aging at 40 °C. Jin et al. [3In5 was only detected in In-50Bi alloy solder, BiIn2 was detected in In-40Bi, In-33.7Bi and In-30Bi, which confirmed that In-Bi binary system contained stable mesophase: Bi3In5, BiIn2 and ɛ.Joanna et al.  investign et al.  studied n et al.  studied 3.2.The molten solder reacts with the base metal to forms the solder joint after cooling in the process of soldering. Whether the internal structure of the solder joint is uniform or there are too many intermetallic compound layers will directly affect the service life of the solder joint. The research on the internal microstructure of the solder joint is the basis of the research on the reliability of the solder joint . It is e6Sn5 compound in the liquid solder decreased due to the increase of Cu element content, and the thickness of IMC thickened. Miao et al. [Wang et al.  added pho et al.  obtainedo et al.  studied o et al.  that addo et al. . The reso et al.  found tho et al.  investigo et al. . The teso et al.  shows tho et al.  found tho et al. . More heo et al.  studied o et al.  also belxCe were refined. The rare earth elements belong to the surface-active elements. According to the adsorption theory of the surface-active elements [The microstructure can also be refined by adding rare earth elements. Shiue et al.  studied elements , the equ6Sn5 compounds in the microstructure of Sn-Bi-xCe solder will disappear, which will refine the microstructure. Xia et al. [xRE composite solder decreased from 20.13 μm to 8.13 μm after RE were added, so as to refine the microstructure.Where a et al.  also rep3Ag particles will be formed after the addition of nano Ag particles. They make the grains more difficult to grow, so as to refine the Bi-rich and Sn-rich phases. Liu et al. [6Sn5 nanoparticles can refine the microstructure of Sn-Bi solder. The melting point of Cu6Sn5 nanoparticles is high. It acts as a nucleation particle in the Sn-Bi solder after Cu6Sn5 nanoparticles was added in Sn-Bi solder. The nanoparticles can inhibit the coarsening of the Bi-rich phase. It has been pointed out in the literature [Sun et al.  studied u et al.  pointed terature  that aftterature  also shoterature  reported3.3.6Sn5, CuZn5 and Cu5Zn8 are formed after Cu element was added in it. The coarse needle-like Zn-rich phase gradually becomes fine needle-like or even disappears, and the Sn-Zn eutectic structure is gradually refined. Lin et al. [5Zn8 and Cn6Sn5 according to the comparison of Cu-Zn [3Sn4 intermetallic compound phase produced by Ni element. Temperature is one of the important factors that affect the metallurgical effect of solder in the process of soldering. Praphu et al. [4, Cu5Zn8) formed at the interface between Sn-Zn solder and Cu substrate. Na element and Zn react to form NaZn13 compound according to the following reaction equation. The compounds hinder the diffusion of Zn atom, and the activation energy of Cu5Zn8 phase is higher than that of eutectic Sn-Zn phase. Too much brittle IMC will be produced if excessive Na element is added, which will affect the reliability of solder joints.The effect of Ag on the microstructure of Sn-Zn solder was studied by Wu et al. . They fon et al.  investign et al.  added Crn et al.  found thof Cu-Zn , Cu-Zn cof Cu-Zn  also addof Cu-Zn  studied of Cu-Zn  investigof Cu-Zn . The resu et al.  investigu et al.  studied xCe/La composite solder is composed of rod-like Zn-rich phase and eutectic. These results can be explained by the equation of nucleation rate [Lin et al.  reportedion rate :(4)P(t)2 particles after repeated reflow when ZrO2 nanoparticles were added into Sn-Zn solder. It will reduce the possibility of Zn atom aggregation and roughen IMC layer, and achieve the purpose of refining IMC layer [2O3 nanoparticles on the microstructure of Sn-Zn solder. The results showed that the microstructure of Sn-Zn eutectic was more fine and uniform after adding micro nanoparticles into β-Sn matrix. Al2O3 nanoparticles can inhibit the growth of coarse dendrite Sn-Zn eutectic structure and refine the grains of composite solder. The literature [Where u et al.  pointed MC layer . Xing etMC layer  investigterature  shows th4.4.1.In electronic components, solder joints not only play the role of electrical connection, but also play the role of mechanical support . TherefoK represents a constant that depends on the material, d represents the size of grain. The grain size became smaller after trace amount of Ag was added to the In solder, which enhanced the strength of solder joints. Solid-state interface reactions between 50In-50Pb solder and a Cu-Fe alloy attached to an electroplated Au layer were investigated by Vianco et al. [2 compound. The compound is implanted at the interface and grows into intermetallic compound. It has good ductility and plays a role of dispersion strengthening in the solder joint. The mechanical properties of the solder joint got improved. With the increase of annealing time, the intermetallic compound layer began to thicken and other brittle compounds were formed, which reduced the mechanical properties of the solder joints. The mechanical properties of the solder joint of alloy In and Au substrate after low temperature bonding at 200 °C were studied by Won et al. [5Zn8 and Cu11In9 composite layer. On the In-Bi-Zn interface of Sn/Cu substrate, Cu5Zn8 phase was better than Cu6Sn5 phase. Jin et al. [Where o et al. . The annn et al. . The resn et al.  studied n et al.  investig4.2.3Sn compound in Sn-Bi/Cu solder joints, which lead to the brittle failure of the samples during the tensile process. It was found that the mechanical properties of Sn-Bi solder joints increased first and then decreased with the increase of Ag content [3Ag compound is formed in the filler metal when the content of Ag is less. The compound is granular or acicular. It is evenly distributed in the matrix, which can refine the structure, improve the tensile strength and play the role of fine-grain strengthening. However, Sn3Ag begins to segregate and grow into plate or block when the amount of Ag is more than 1 wt.%. The large size of Ag3Sn compound will decrease the tensile strength of the solder joint according to the hall match formula. Wang et al. [2 intermetallic compound produced as the second phase particles dispersed in the solder matrix. It impeded the grain boundary sliding and dislocation movement and improved the shear strength of the solder joint [6Sn5 phase with peculiar shape is wrapped in the Bi-rich phase, which can promote the refinement of Bi crystal branch and improve the tensile strength of the solder joint. The mechanical properties of Sn-Bi solder joints were studied by Roh et al. [Zhang et al.  found th content . It was g et al.  believedg et al.  studied g et al.  added Crer joint . Chen eter joint  reporteder joint  added hier joint  reportedh et al. . The resh et al.  studied It has been reported that rare earth elements can improve the mechanical properties of solder . It is fThe influence of nano particles on the mechanical properties of Sn-Bi solder joints is reported in the literatures ,113. The3Sn4 compound strengthen the composite material together, which makes the tensile strength of solder joint enhanced. The tensile strength and elongation decrease with the further increase of the content of Ni-CNTs due to the existence of CNTs clusters and the increase of brittleness. Lee et al. [The literature  shows the et al.  investige et al.  studied 4.3.5Zn2 compound layer, which inhibits the diffusion of Zn atom to the substrate. It can inhibit the growth of compound layer. Also, it will make IMC layer uniform and improve the mechanical properties of solder joints. Sharif et al. [3 intermetallic compound was formed during aging. The IMC layer gradually peels off with the increase of aging time, and a layer of Ni5Zn21 IMC layer is produced. The compound layer grows up gradually, which makes the shear strength of the solder joint decrease gradually. In order to prevent the decline of the mechanical properties of the solder joint, the peeling off of AuZn3 compound layer should be avoided as far as possible to ensure the reliability of Sn-9Zn/Au/Ni/Cu solder joint of the solder joint.The mechanical properties of eutectic Sn-9Zn solder and the properties of hypoeutectic Sn-4Zn and hypereutectic Sn-12Zn solder have been studied by Garcia et al. . The resf et al.  thought f et al. . It was 3 compound phase formed is a stable phase. The fine particles gathered at the grain boundary and played an obvious strengthening role. Hu et al. [5Zn8) layer more uniform, improve the air tightness of the joint surface and improve the mechanical properties.The oxidation activity of rare earth elements  is very high. The addition of trace RE elements can refine the structure of β – Sn phase rod-like Zn-rich phase. It is the main reason for rare earth elements to improve the mechanical properties of solder . Accordiu et al.  studied u et al. . The res2 nanoparticles was added. ZrO2 nanoparticles can be embedded in the solder matrix and play a role in pinning the grain boundary due to the small size of nanoparticles. It can prevent the occurrence of dislocation to a certain extent so as to improve the shear strength of the solder joint when the solder joint is subject to external force. The influence of Al2O3 nanoparticles on the mechanical properties of Sn-Zn solder joints was reported in the literature [2O3 nanoparticles is 1 -wt. %. It was pointed out that the tensile strength of the solder joint increased by about 10.9% compared with that of the common Sn-Zn solder joint when Al2O3 nanoparticles were added. The researchers attributed it to the use of Al2O3 nanoparticles, which made the pore size smaller and distributed uniformly. Therefore, the mechanical properties of solder joints got improved. It was found that the shear strength of Sn-9Zn solder joint increased after Ni nanoparticles were added. Nano Ni particles can refine the microstructure of solder and reduce the internal crack source of solder joint. The fracture mode of solder joint is mainly ductile fracture [Shen et al. studied the effect of nanomaterial addition on the mechanical properties of Sn-Zn solder joints . The resterature . The resfracture .6Sn5 compounds were produced at the interface after aging or reflowing, thus the reliability of solder joints got worse.5.5.1.In is an active element, but it does not react with oxygen under normal conditions. The literature shows that there is little research on the oxidation resistance of In solder.5.2.3+ accumulated on the surface of liquid solder and forms oxide film after Al were added, which prevent the further oxidation of SBZ. Teng et al. [Sn-Bi solder will not react with oxygen at room temperature, but oxidation may occur during the soldering. Little is known about the oxidation resistance of Sn-Bi solder. The effects of high-temperature aging on a novel hybrid bonding layer consisted of Cu nanoparticles and a eutectic Bi-Sn solder powder was studied by Usui et al. . The resg et al.  found th5.3.2, which makes the oxidation resistance of solder containing Zn very poor (Zn element easily reacts with Oery poor . It is a2O3) is formed by the rapid reaction of Nd element with oxygen. The oxide film is wrapped on the surface of the molten composite solder, which blocks the entry of oxygen. It reduced the contact between Zn and oxygen, and improved the oxidation resistance of the solder.Where Y represents weight gain ratio, X represents aging time. It can be seen from the above equation that with the increase of aging time, the growth rate of oxide film thickness is lower than that of Sn-9Zn solder when appropriate amount of Ag and In elements are added. The effect of Bi on the oxidation resistance of Sn-Zn solder was reported by Jiang et al. . They po6.The research status of low temperature lead-free solder is comprehensively evaluated. The alloy elements , rare earth elements , nanoparticle  are summarized. It is found that some alloy elements, rare earth elements and nano materials can refine the internal structure of solder. It can reduce the size of intermetallic compound particles and reduce the thickness of interface to some extent. The addition of reinforcement elements can improve one or the whole performance of low temperature solder, but the opposite view has been put forward, which is mainly related to the way and content of reinforcement phase. At present, there are very few reports on low-temperature In-based solders, especially on the solders containing nanomaterials and rare earth elements.


Figure 1 as published as Villanacci et al. (2011) was inadvertently not cited.In the original article, there was a mistake in the legend for FIGURE 1 | Histological features of microscopic colitis. Hematoxylin and eosin (A) and anti-CD3 (B) staining in lymphocytic colitis; black arrows indicate intraepithelial lymphocyte infiltration. Hematoxylin and eosin (C) and Masson's Trichrome staining (D) in collagenous colitis; arrows point to the subepithelial collagen band. All images also show surface epithelial injury and lamina propria increased cellularity . This figure was obtained from Villanacci et al. (i et al.  with perThe authors apologize for this error and state that this does not change the scientific conclusions of the article in any way. The original article has been updated.


Its actions are manifested on organs like the brain, heart and kidneys. High serum uric acid (SUA) escalates cardiovascular vulnerability in patients with systemic hypertension.a cross-sectional study was performed in 271  patients with systemic hypertension. Two hundred and seventy one healthy age and sex matched non-hypertensive persons obliged as controls. Left ventricular hypertrophy (LVH) was estimated by echocardiography. Blood samples were collected for measuring uric acid levels.mean SUA was significantly higher among the hypertensive patients (371±125μmol/L) than in the controls , and the prevalence of hyperuricemia was 46.9% among the hypertensives and 11.1% among the controls (P < 0.001). Independent predictors of SUA were class of systemic hypertension, left ventricular mass index (LVMI), body mass index (BMI) and age. However, class of hypertension was the best independent predictor of SUA levels in the multivariate regression model (β = 0.597). Linear regression revealed SUA levels ≥ 430μmols/l as a predictor of stage 2 hypertension . Among the hypertensive patients, LVH was present in 39.3% of those with hyperuricemia and in 28.0% of those with normal SUA levels (p = 0.003).results indicate serum uric acid is positively correlated with hypertension and a reliable indicator of LVH in study population. It et al. [et al. [et al. found that hypertensive patients with LV hypertrophy had higher uric acid levels and a greater prevalence of hyperuricemia than patients with a normal left ventricular mass [In the last decade, several well-grounded pieces of evidence showed that the elevation of uric acid often occurs prior to the development of hypertension or metabolic syndrome, thus suggesting a direct association between elevated SUA and these conditions . Moreoveet al. , indicatet al. , 34 This [et al. , 36 wherlar mass .et al. [et al. [et al. found 17% of the patients studied had concentric LV hypertrophy which is a geometric pattern associated with increased cardiovascular morbidity [et al. [In our study, there is a positive linear association between SUA ranges and LVMI  as shown in et al.  found th [et al.  assessin [et al.  where heorbidity  Comparab [et al.  also fouet al. [et al. [5H4N4O3) similar chemical structure to caffeine (C8H10N4O2) that stimulates organs and both have antioxidant properties that are neuroprotective [UA is the ultimate breakdown product of dietary or endogenous purines and is generated by xanthine oxidase (XO). A net release of urate in coronary heart disease  and the et al.  in a stu [et al.  that indotective  this preet al. elucidated that high-dose allopurinol regresses LVH, reduces LV end-systolic volume, and improves endothelial function in patients with ischemic heart disease (IHD) and LVH [et al. mentioned that SUA is positively associated with body mass index (BMI), blood glucose, blood pressure (BP), markers of inflammation, and altered lipid profile but concluded that in treated hypertensive patients, high levels of SUA normalized for major biological determinants and do not independently predict CV outcome [et al. reported a reduction of LV mass after weight reduction in young, obese hypertensive subjects [Losartan can cause uricosuria. The Losartan Intervention for Endpoint Reduction (LIFE) study outlined a 29% reduction in composite cardiovascular outcome  in the losartan (ARB) arm of the study suggesting that a decrease in serum uric acid levels can lead to reduction in adverse cardiovascular outcomes  Rekhraj  and LVH . This st outcome . The finsubjects . Previousubjects . Our stuThis study reveals that hyperuricemia is widespread in our study population with systemic hypertension and both are positively correlated. Hyperuricemia was associated with LVH. Thus, the study recommends a repetitive evaluation of serum UA in all hypertensive patients.Elevated serum uric acid (SUA) is a risk factor for Chronic Kidney Disease (CKD);Normal levels of SUA is also associated with systemic hypertension;Elevated SUA is associated with a high body mass index (BMI).Linear regression revealed SUA levels ≥ 430μmols/l is a predictor of stage 2 hypertension ;Class of hypertension was the best independent predictor of SUA levels in the multivariate regression model (β = 0.597);Among our hypertensive patients, LVH was present in 39.3% of those with hyperuricemia and in 28.0% of those with normal SUA levels (p = 0.003).


Fig. 1). Lichens were show-cases to introduce the concept of symbiosis ), which causes ‘vitrification', the transition of their cytoplasm to a ‘glassy' state and cease of metabolism. To find out what reactions may occur at different levels of desiccation in lichens, Candotto Carniel et al. [2O g–1 DW and enzymes were active in a ‘rubbery' state (0.17 g H2O g–1 DW) but not in a glassy state (0.03 g H2O g–1 DW). Therefore, desiccated tissues may appear to be ‘dry' in the conventional sense, but subtle differences in water content will have substantial consequences on the types of (bio)chemical reactions that can occur, with downstream effects on longevity in the desiccated state.Lichens have an outstanding ability to revitalize from dry stages. Lichens can endure extreme desiccation to water contents , as well as expanded fungal protein families  and expanded algal protein families (carbohydrate active enzymes and a specific subclass of cytoplasmic carbonic anhydrases). Horizontal gene transfer from prokaryotes played a likely role for acquisition of novel archaeal ATPases and Desiccation-Related Proteins by the algae. According to these results lichens evolved by accretion of many scattered regulatory and structural changes, which agrees with an independent origin of lichenized fungal lineages in the fungal kingdom. Kono et al. [Usnea hakonensis for transcriptomic analyses. By comparing resynthesized and natural thalli (symbiotic states) with that of isolated cultures (non-symbiotic state), they found evidence for various processes involved in symbiotic establishment, including cell wall remodeling, production of hydrophobins  and symbiosis-specific nutrient flow (including polyol transporters). Future transcriptomic approaches need to consider a side by side of life and death in lichens. Behind the growing thallus edges, even neighbouring cells can vary in vitality and fungal remnants are often part of protective surface layers or provide a scaffold for a fraction of living cells. In some lichens, these layers contain inflated algal cell walls as well, while in others, the remnant algal walls stay put and supposedly support the architectural integrity of thalli. New results, such as the detection of caspase-like activity as a marker of programmed cell death in lichens [Several attempts have recently been undertaken to achieve a better understanding of the genomic “hardwiring” for the lichen symbiosis. For example, Armaleo et al.  conducteo et al.  succeede lichens , opens mFig. 2), which is considered in a recently emended definition of the lichen symbiosis [et al. [Over the past decade it has also become increasingly clear that the living-together of fungi and algae is more complex than previously thought. Algal partners are not uniform and may switch with climatic parameters, while the lichen phenotypes also host associated microbiota (ymbiosis . While nymbiosis . With re [et al.  publishe [et al. . Despite [et al. . In addi [et al. .Nephromopsis pallescens revealed one of nine found type I PKS, Nppks7, as potentially involved in usnic acid biosynthesis [The varied colors of lichens are the result of accumulations of crystallized metabolites, which deposited on the outside of the fungal cells as light filters or herbivore deterrents. Thousands of compounds are known but only few are better characterized for antibiotic effects and other bioactive potentials . Researcynthesis . Nppks7 ynthesis . The dozynthesis , as wellynthesis .et al. [Aspergillus nidulans shields the alga Chlamydomonas reinhardtii from toxic azalomycin F produced by the bacterium Streptomyces iranensis. Whether similar effects could be part of the ecological success of lichen phenotypes in their natural environments still remains to be studied. Considering the high potential of compound production in lichens, science would be ready for further surprising discoveries. While the pocket-sized microbial ecosystems of lichens are still a challenge for research, new technological approaches provide bridgeheads for culture-independent functional studies.Cultivation of genuine lichens has remained difficult, but enhanced productivity of fungal-algal associations has been demonstrated also for co-cultures of faster-growing partners in the laboratory. Such studies also direct to hitherto unknown beneficial effects in the lichen symbiosis. As Krespach et al.  discover


IUCrJ, Roth et al.  analysis of scattering data from powder samples to investigate departures from perfectly crystalline order (Billinge & Kanatzidis, 2004 al. 2020 demonstret al., 2018et al., 2015et al., 2011Recent developments in instrumentation and computing have made the measurement of single-crystal diffuse scattering much easier than it was even ten years ago (Ye et al. (2020x1 − CoSb. These have proven challenging to understand via crystallographic techniques; while crystallographic solutions can confirm the concentration of vacancies on the Nb sites, the distribution of these vacancies is more difficult to discern. Electron diffraction data collected by Xia et al. (2018Roth  al. 2020 have pro al. 2018, 2019 ▸ et al. (2020SCATTY (Paddison, 2019Roth  al. 2020 approachx = 1/4 and x = 1/6, with intermediate compositions showing short-range combinations of the two. For concentrations with x < 1/6, broader wave-like scattering is seen. This entire range of compositions can be modeled and explained with self-avoiding vacancies.For a single ratio of energies, these models impressively reproduce published electron diffraction data over a range of vacancy concentrations (see Fig. 1et al. (2020These results provide a significant advance in the knowledge of the structure of these materials as well as a great example of how short-range ordering can be understood, modeled and described. Roth  al. 2020 have pro


Breast cancer (BC) is the most frequent cancer among women in the world and it remains a leading cause of cancer death in women globally. Among BCs, triple negative breast cancer (TNBC) is the most aggressive, and for its histochemical and molecular characteristics is also the one whose therapeutic opportunities are most limited. The REpurposing Drugs in Oncology (ReDO) project investigates the potential use of off patent non-cancer drugs as sources of new cancer therapies. Repurposing of old non-cancer drugs, clinically approved, off patent and with known targets into oncological indications, offers potentially cheaper effective and safe drugs. In line with this project, this article describes a comprehensive overview of preclinical or clinical evidence of drugs included in the ReDO database and/or PubMed for repurposing as anticancer drugs into TNBC therapeutic treatments. Breast cancer (BC) is the most frequent cancer among women in the world. Triple negative breast cancer (TNBC) is a type of BC that does not express oestrogen receptors, progesterone receptors and epidermal growth factor receptors-2/Neu (HER2) and accounts for the 16% of BCs approximatively , 4. TNBCet al [Drug repurposing is the application of an old drug to a new disease indication: this holds the promise of rapid clinical impact at a lower cost than de novo drug development . In oncoet al , point tet al .In line with this project, we searched in PubMed for published preclinical or clinical evidence of anticancer activity for all drugs included in the ReDO_DB for TNBC. Specifically, starting from each drug present in ReDO_DB, we searched in PubMed for published preclinical and clinical evidence of anticancer activity for TNBC. The strings were composed by the name of the drugs and specific keywords related to TNBC.An additional search string was used to investigate potential clinical evidence about drugs not included in ReDO_DB or references not retrieved in the first search. The string was composed by three blocks concerning keywords related to TNBC, repurposing and study type, respectively. Both strings are provided in the supplementary file . ObservaMoreover, clinicaltrials.gov  was searThe aim of this paper is to give to clinicians and scientists a comprehensive overview about preclinical and clinical studies, including clinical trials, present in literature on the repurposing of old-licensed drugs for TNBC.We found 188 preclinical studies references , 18 clinical references –26 and 1Using the PubMed database, we found preclinical evidence on TNBC models (cell lines and xenograft models of TNBC) for 84 out of 268 old drugs (31.3%) present in the ReDO_DB. For 42 of the 84 drugs, only one reference was retrieved . Thirteeet al analyses two different retrospective studies on beta blockers efficacy and safety on TNBC [et al [et al [ on TNBC , and theC [et al  and Ishil [et al  analysedl [et al , 25, 26,l [et al , 21, 23 l [et al   and hazard ratio of overall survival was 0.35  [et al [p = 0.02) and hazard ratio of metastasis and BC death were significant . The study of Spera et al [p = 0.002) but not in overall survival . The second study presented by Spera et al [p = 0.269; 0.73; 95% CI, 0.35–1.48; p = 0.38, respectively).BBs were evaluated on postmenopausal women with operated early primary TNBC, on women with invasive TNBC (receiving neoadjuvant chemotherapy), and on women with advanced or nodal positive TNBC. Study populations ranged from 35 patients to 1,417 patients. In the study of Melhem-Bertrandt et al , using m) [et al  using Brra et al , using dra et al  using alet al [p = 0.23). Overall survival was 67% in the metformin group, 69% in the non-metformin group and 66% in the non-diabetic group (p = 0.58). Recurrence free survival was 65% in the metformin group, 64% in the non-metformin group and 54% in the non-diabetic group (0.38). Also, after adjustments, no significant survival outcomes were obtained.The retrospective study of Bayraktar et al  using meet al [The primary endpoint of phase II open label single arm study of Chan et al  was to aet al [p = 0.112) when comparing neoadjuvant chemotherapy plus zoledronic acid (6/17 (35.3%) CI: 12.6–58.0) with chemotherapy alone (2/17 (11.8%) CI: 0.0–27.1). Also for the 3 years disease free survival, neoadjuvant chemotherapy plus zoledronic acid showed no significant benefit compared to the neoadjuvant treatment alone (p = 0.077) despite the fact that the percentage of patients in treatment with zoledronic acid was higher compared to the other arm (94.1% versus 70.6%).The articles of Hasegawa et al  and Ishiet al  referredet al [et al [Celecoxib was analysed in two studies: the first, a phase II randomised study of Pierga et al  performel [et al , analyseet al [p = 0.04; anti-platelet 8.8%, no anti-platelet 31.9%, HR: 0.310 (0.132–0.729); p = 0.007, respectively). Five years overall survival hazard ratio was not significant between the two arms (HR: 0.652 (0.343–1.239); p = 0.192). The second retrospective study of Williams et al [Aspirin was analysed in two retrospective studies. The first retrospective study of Shiao et al  that colms et al  performeet al [Finally, Retsky et al  showed tet al , in whicet al [The article of Tsubamoto et al  reportedet al [p = 0.011).The phase II, open label, randomised study of Wang et al  analysedIn the Phase I, randomised study of Nanda and colleagues performed in USA, four women with metastatic or locally advanced TNBC were analysed . Unfortunately, no information about patients allocation, nor any outcome information could be retrieved from this article .et al [p = 0.026, 95% CI: 0.01–0.76).The retrospective study of Shaitelman et al  used medet al [The retrospective study of Lacerda et al  using BrSearching the web site of clinicaltrials.gov , we found only 17 drugs out of 286 presented in the ReDo_DB with ongoing or completed clinical trials for TNBC. in silico modelling or other computational pharmacological approaches that, despite the interest for the research [This review presents an overview of all the evidences about the repurposing of old, licensed, non-cancer-drugs in the treatment of TNBC, starting from preclinical evidence and going through current clinical trials. ReDO is an ambitious project aiming to investigate the repurposing of non-cancer-drugs in oncology, and ReDO_DB is a powerful tool that need to be dynamically implemented with recent findings, by adding to the database new drugs for which there are preclinical evidence, and by giving visitors a specific PubMed search string for each tumour and tumour subtypes. The ReDO approach is based on published literature and does not aim to identify new active compounds against cancer. Thus, the database does not include potential repurposing candidates identified through research –31, unleBeta Blockers (BBs) seem to be the more promising drugs in the repurposing for the treatment of TNBC. Three articles showed significant benefits of these drugs in women with advanced TNBC and in early primary TNBC patients treated with the combination of chemotherapy plus BBs –13. Unfoet al [While BBs demonstrated to be beneficial in the treatment of TNBC, metformin, a promising molecule in preclinical studies, did not show any efficacy in the treatment of women with TNBC. Bayraktar et al  showed tet al [et al [et al [The articles of Shiao et al  and Willl [et al  showed cl [et al  did not et al [et al [Despite many studies trying to evaluate the use of statins in breast cancer treatment –36, in tet al  reportedl [et al  did not In vitro, proton pump inhibitors inhibit FASN activity and induce apoptosis in breast cancer cell lines. In this study, omeprazole in combination with anthracycline-taxane (AC-T) was administered to 42 patients until surgery, and pathologic complete response (pCR) was investigated. FASN positivity significantly decreased with omeprazole from 0.53 (SD = 0.25) at baseline to 0.38 , and the drug was well tolerated with no known grade 3 or 4 toxicities. Furthermore, the pCR rate was 71.4% (95% CI: 51.3–86.8) in FASN+ patients and 71.8 % (95% CI: 55.1–85.0) in all enrolled patients, demonstrating that the omeprazole in addition to neoadjuvant AC-T yields a promising pCR rate without adding toxicity.Other authors showed significant results on the survival of TNBC patients treated with esomeprazole. Recently, one phase II study on activity of omeprazole on patients with operable TNBC independent of baseline Fatty acid synthase (FASN) expression was presented at the ASCO meeting.  In vitroFor those drugs collected in ReDO_DB with favourable preclinical evidence or whose retrospective clinical trials were not so large to provide strong evidence, large retrospective cohort studies are needed to evaluate effectiveness. Further, as for BBs that have proven by retrospective studies to be effective in the treatment of TNBC patients, randomised clinical trials might be important to confirm the evidence of the repurposing.Drug repurposing is a highly interesting novel strategy for the oncology community and ReDO_DB is a powerful tool that can give authors the opportunity to investigate weather non-anticancer drugs might be effective in cancer treatment. Some precision medicine studies, based on omics data, have included repurposed drugs and have reported interesting case reports of responses from patients , 39, howFrom the literature retrieved, BBs seemed to be the more promising drugs for the repurposing, while evidence about other drugs as NSAIDs still need to be assessed or proven for the treatment of TNBC.The authors declare that they have no conflict of interestMZ and SC conceived the study. AS extracted the data. SD supervised the data extraction. MZ, SD, SC, AS, and PP contributed to the interpretation and discussion of study results. AS and SD drafted the manuscripts. All authors revised and approved the final version of the paper.This study was supported by Fondazione Decima Regio ‘Olga e Raimondo Curri’, Via Cimarra 44-B, Roma.


Visible light communications (VLC) (including LiFi) represent a subset of the broader field of optical wireless communications. Where narrow beams, typical of free space optical communications are largely free from interference. VLC encompasses use cases involving combined illumination and data access and supporting a wireless access point (AP) model. The use of many units provides scaling of spatial coverage for both lighting and data access. However, AP replication in close proximity creates many interference challenges that motivate the investigation embodied in this paper. In particular, we frame the interference challenge in the context of existing strategies for driving improvements in link performance and consider the impacts of multiple users, multiple sources and multiple cells. Lastly, we review the state of existing research in this area and recommend areas for further study.This article is part of the theme issue ‘Optical wireless communication’. These are typically served by narrow beams that are more easily isolated to single target receivers. The introduction of divergent sources permits the possibility to serve multiple receivers with a single signal but also encourages interference in the presence of multiple sources. The emergence of light-emitting diode (LED) lighting as a basis for OWC for multiple users exacerbates the need to understand the impact of each of these dimensions: source divergence and the existence of neighbours. Research in this area spans visible light communications (VLC) ,2 and liEarly research in VLC mainly focuses on the physical layer and single-link implementations to ensure successful point-to-point communication, isolating the transmitter and receiver link into a fixed system. This research improves link performance through signal processing and the introduction of novel modulation techniques. More recent works delve into the system level by deploying cells of multi-point-to-point or multi-point-to-multi-point communication. These multi-AP systems introduce neighbouring cells which naturally induce interference when signals from multiple APs are simultaneously received. Interference can also occur from multiple user transmissions; but little work has analysed interference in the context of OWC uplinks and the impact of in-band uplink on overhead (i.e. AP) signal distribution. This is primarily because many systems incorporate asymmetry by using an alternative medium for uplink. For this reason, our survey focuses on downlink interference, leaving the uplink interference analysis as an open research opportunity. Wireless capacity can be added to indoor spaces by increasing AP density; but doing so can increase interference. Fortunately, light, with its directional property, offers performance gains with respect to interference. In this paper, we explore the relationship of VLC with radio frequency (RF) models but mainly focus on the unique characteristics of VLC interference mitigation. We discuss recent techniques proposed to improve system performance and describe possible research opportunities.Note that we will henceforth use the term OWC rather than VLC or LiFi which imply the use of the visible spectrum. Other optical spectra such as ultraviolet (UV) or infrared (IR) are applicable as well as covered by the more general OWC label.The remainder of the paper is organized as follows: in §2.Interference is a critical parameter when deploying systems where multiple links are simultaneously active and within range of each other. In this section, we identify unique characteristics of the optical medium and OWC network deployments that distinguish OWC interference analysis from the traditional interference analysis techniques used for RF communications.(a)—Directionality of the medium. The transmitter’s illumination pattern/beam width, as well as the receiver’s FOV, establish the directionality property . —Optical power constraints. When the optical carrier is also expected to provide illumination, the optical signal must conform to lighting conventions and the nature of human perception including intensity, glare, flicker and colour quality. Also, intensity modulation with direct detection (IM/DD) signals have a different relationship between the constraint  and the signal current or voltage. For an electrical signal X(t), average optical power in IM/DD relates to a constraint on E[X], whereas average electrical power sets a constraint on the variance of X, or E[X2] assuming X(t) is a 0 mean signal ) in most RF systems; however, the relationship between the variance and the average optical power constraint (i.e. E[X]) depends on the modulation used.Interference is widely explored in the RF domain; however, there are differences exhibited due to the properties of the media at different operating points in the electromagnetic spectrum. RF models for interference are insufficient for characterizing light-based models ,13,14. I(c)A wireless network with multiple simultaneous transmissions can be analysed as a single-coordinated AP or as multiple-coordinated APs. For OWC, we expect that the scope of interfering devices is more constrained due to the directionality of light and the nearness of adjacent APs. This is in contrast to RF-based APs which have much larger spatial scope. Each of these models suffers from different types of interference. These include inter-cell interference: UDs share the same resources but are in different cells; intra-cell interference: UDs consume different resources but are within the same cell; cross-cell interference: UDs are in different cells and have different resources .Interference and its impact can be characterized by direct and indirect metrics. Of this list, we identify a subset as best for establishing and benchmarking the performance of multiple AP systems. These are (1) system throughput, (2) sustained link speed of a single user, and (3) system complexity. However, in practice, evaluating published work on multiple access OWC systems is challenging due to disparate assumptions and operating conditions. To help with this challenge, we break down the techniques into categories to help permit fair comparison. These are described next.3.Up to this point, we have discussed the challenges associated with OWC APs including the nature of the optical physical channel models. In this section, we survey and classify existing techniques intended to manage interference in the context of multiple access in OWC systems. We begin with a summary of nomenclature and classification and then relate key results from the literature onto this classification.rejection is the strictest term used to describe completely removing interference from a system. It is normally employed in physically isolated techniques that can effectively separate resources or channels. Coordination is done in systems that attempt to either use interfering signals to their advantage or arrange transmissions in a way to cause the least possible interference. Coordination is normally done in networked or synchronized systems. Interference alignment is a scheme developed for RF [Avoidance, mitigation, cancellation and suppression are ways to minimize interference. Although cancellation sounds as strong as rejection, most of the literature uses it to describe minimizing interference where some interference effect remains. These techniques are adopted in systems with fixed resources that deploy resource allocation or load balancing. Management is a term that is usually used broadly to describe each of the previous systems that aim to combat interference effects in any manner. Using the term ‘interference management’ to cover the range of nomenclature, we classify techniques in OWC into two main categories (—Multiple access (MA). This class consists of the techniques that allow an AP or set of APs to distribute defined resources across a set of users. It is divided into two further categories:(i)MA-signal processing (MA-SP). This class of techniques applies pre-processing at a transmitter to enable distinction of signals at the receiver, such as employing orthogonal multiple access. The received signal is the superposition of the intended signal and some number of interfering signals.(ii)MA-physical isolation (MA-PHY). This class of techniques isolates signals by using the physical characteristics of the channel such as using orthogonality of physical resources (e.g. wavelength division multiplexing) or by leveraging the properties that are distinct to OWC, such as directionality or receiver FOV.—Spatial diversity. This class encompasses both of the PHY and SP cases and is concerned with receiving data by many spatially unique channels or multiple PDs then performing signal processing to have them de-correlated.A review of the state-of-the-art related to OWC interference studies yields a range of terms similarly applied. These terms include the following: d for RF  that inctegories . These aNext we consider the state of the art for interference management in each of these classes and corresponding to the different system models . For eac(a)In the first instance Multiple access refers to how a set of resources can be distributed to serve multiple UDs. The characteristics of the medium used are reflected in the techniques applied towards sharing the channel. In the basic case, resource distribution provides fairness from a single AP to multiple users. The other case involves a receiver detecting multiple sources. Here the resolution can include more complex coordination among APs or more advanced coding techniques.et al. [Marsh et al.  provide et al. [Kim et al.  study fret al. ,20 focuset al. [For the visible spectrum, Jung et al.  analyse (ii)cooperative transmission or joint transmission (JT) which allows transmission from multiple transmitters to a single VLC receiver, similar to MP2P systems as shown in The techniques mentioned here employ et al. [An approach using synchronized time of arrival (TOA) from multiple sources was introduced by Prince et al. . This meet al. [Chen et al.  adapt JTet al. [Park et al.  study anet al. [et al. study robust MMSE linear precoding for MU-MISO VLC broadcast systems assuming imperfect CSI to create a more robust precoder in [et al. [Yu et al.  tackle Mcoder in . This sy [et al.  explore et al. [Li et al.  design tMU-MISO precoding can be very beneficial for users to help increase their data rates as well as the system throughput. However, there is much complexity on the transmit side that needs to be clarified. The transmitters are considered connected, synchronized and/or have channel information regarding the receivers in most works mentioned above. Some works assume transmit precoding as well. The backhaul network must be able to handle such overhead, and as more devices enter the system, the technique does not scale gracefully. While these systems appear promising, there needs to be more investigation to establish scaling limits with respect to number engaged transmitters UDs.(iii)NOMA permits the full use of the channel bandwidth by any transmitter, relying on superposition coding at the source and successive interference cancellation at each receiver. Many works have been published on the topic of NOMA in 5G networks ,30.et al. [Marshoud et al.  propose et al. , as wellet al. [et al. [et al. [et al. [Kizilirmak et al.  compare  [et al.  study NO [et al.  derive c [et al.  they ext [et al.  analyse et al. [et al. [et al. [There are works that opt for solutions other than SIC such as Guan et al. , who stu [et al.  use join [et al.  study SIet al. [et al. [A low complexity power control allocation that aims at fairness under optical intensity constraints by maximizing the sum log user rate is studied by Yang et al. . Chen et [et al.  study efWhile most works mention that NOMA is attractive for OWC systems, especially indoors, because the channel at a fixed location/orientation is nearly deterministic and the SNR is relatively high (in the absence of blockage), there is still a need for channel estimation as performance is impacted by shadowing, receiver mobility and orientation. NOMA has the advantage of allowing full resource usage and therefore best spectral efficiency. The main drawbacks of this approach are complexity, error propagation, and latency added due to the use of SIC. There is room for new solutions that find a trade-off between SIC and joint detection in terms of complexity while keeping a tolerable delay.(b)Here, we consider the implications of the physical layer characteristics on the nature of interference. This class includes sub-cases of (i) AP positioning, (ii) beam control and (iii) orthogonal multiplexing . Each is(i)The conventional model for an RF AP is a single omni-directional unit spanning multiple rooms in the service to a locale (e.g. an apartment). Coverage of a larger facility (building or campus) is realized by replication of APs. OWC APs, being primarily LOS-based, can service much smaller zones such as individual rooms, or can be replicated in larger rooms (e.g. open office seating). Clearly, there are important design considerations for the height, spacing and beam width of the OWC APs especially if they are also intended to provide lighting . Currentet al. [et al. [et al. [et al. [Wang et al.  investig [et al.  focus on [et al.  propose  [et al.  study opAP placement is an interesting topic with more to investigate, and in particular, the impacts of mobility and device density. The introduction of steerable APs also adds a new dimension to improving system performance.(ii)The aforementioned cases consider static lighting and AP scenarios in which the source intensity parameters are provisioned for a particular operating point. With the use of beam control including beam width (transmitter FOV) and beam steering , new optimizations result as well as options to support adaptive performance to varying device location and data traffic.et al. [Rahaim et al.  study SIet al. [Valagiannopoulos et al.  suggest Beam steering can also be used at the transmit side, either as a narrow or diffuse beam –50. By uet al. [Another MA-PHY technique is proposed by Chang et al.  involvinet al. [In addition to controlling the directionality of a source, the FOV and pointing angle of a receiver can be controlled to improve interference rejection. Abdalla et al.  propose (iii)This technique facilitates co-location of multiple non-interfering  signals that can be decoded selectively by independent receivers. .)et al. [et al. [−1 and 6.25 Mb s−1. Butala et al. [Liu et al.  demonstr [et al.  considera et al.  propose Exploiting WDM in OWC systems is an attractive means to gain capacity. However, it needs careful design to meet the relevant illumination requirements. These include (1) light distribution and intensity levels including minimizing glare, each dependent on the lighting use case; (2) providing satisfactory spectral power distributions for colour rendering, essential for humans; and (3) avoiding visible temporal discontinuities in colour or spatial distribution of light. Each of these is surmountable, but requires consideration when designing the modulation approach involving WDM or combinations of WDM with time division multiplexing (TDM).(c)Diversity techniques exploit the ability to simultaneously source multiple signals that can be combined at a receiver, the ability to receive sources from multiple detectors at a receiver, or some combination of the two techniques. The diversity class of interference management includes sub-cases of (i) space time block coding, (ii) multiuser-MIMO, (iii) angular diversity, (iv) interference alignment, (v) differential detection, and (vi) spatial light modulators .Figure (i)et al. [et al. [Space–time block coding (STBC), first introduced for RF communications, has been established as a method to allow diversity in a system to achieve very low BER while saving power . Ntogariet al.  analyse  [et al.  propose  [et al. ) and shoet al. [−1 adding that the free space transmission range can be extended to 5 m. BER is reported at less than 10−5. However, their system does not account for any mobility.Meanwhile Shi et al.  construcWhile STBC can be beneficial in achieving low BER, there is a relatively high complexity involved with this approach. This includes the complexity associated with achieving syncronization of distributed transmitters.(ii)et al. [−1 at a BER of 10−6 while 70° and 50° are considered for receiver FOV.Hong et al.  investiget al. [et al. [Pham et al.  also emp [et al.  investiget al. [Lian et al.  study anMIMO schemes support increases in system capacity and related performance but at a the cost of complexity. Some of the systems mentioned above employ precoding which helps in relieving interference but assumes transmitter connectivity and the availability of CSI which is not always the case nor is it necessarily accurate. In support of this scheme, indoor VLC channels tend to be more deterministic but only in a static study. When device mobility is introduced, CSI changes and any static precoding matrices quickly become obsolete.(iii)a,b) but other designs using masks suspended over array receivers can be used [Angle diversity receivers (ADRs) rely on the ability to discern the angle of arrival of an incident transmitted signal . They arfigure 9 be used .Figure et al. [Most works on this topic focus on using ADR receivers in MIMO settings and for optical channel decorrelation. ADRs can also be used to mitigate inter-cell interference (ICI). Haas et al.  explore et al. [a). Their results show that increasing the number of PDs (increasing diversity) improves the ability to reduce interference caused by reflections. And that the increased number of PDs degrades performance when reflections are not present due to the limited FOV of the PDs, all while assuming a fixed effective area.Chen et al.  propose et al. [ϕ (b). Results show promise in the ability to minimize SINR fluctuation through optimizing parameters such as number of detectors, inclination angle and the combining scheme for the signals received by the PDs. However from their description of their ADR, they do not optimize ϵ, which they define as the gap between the top detector and the side one although that area where ϵ presides is very useful and important for communication quality, they also do not study NLOS reflections. Most importantly, they do not study receiver orientation effects and so the proposed optimal inclination angle they reach through simulation is only optimized for a horizontally fixed receiver.Chen et al.  study SIet al.  §3bi). bi. et alt al. [ϕ b. ResultEach of the works indicate that improvements in SINR can be achieved at a receiver by employing more PDs. However, they do not account for the variations in receiver orientation, which is critical to link performance ,71,72.(iv)et al. [Less stringent in its requirements, blind interference alignment (BIA)  is a varet al.  analyse (v)et al. [−3.Ryoo et al.  propose Limitations of this approach exist when scaling to many UDs or in the presence of occlusions or variations in device orientation which may mask only a single channel. The use of a polarizer inherently limits incident signal strength as well.(vi)et al. [c). This method has been successfully demonstrated. It shows promise in being able to isolate the channels at the receiver, support diversity combining, and is relatively integratable into a working system.Spatial light modulators (SLMs) can be used reflectively or transmissively to manipulate or modulate optical signals. One approach leverages an array of mirrors to focus and enhance signal strength directed towards one or more PDs. The array of mirrors can be individually steered to reflect light from the target. All or a subset of the mirrors. By pointing the mirrors the signal strength of the target is increased (maximized) and the noise from other sources is minimized. Bare PDs do not have this feature. Chau et al.  propose 4.The techniques discussed up to this point represent the building blocks for the construction of high-performance OWC systems. The introduction of device mobility, orientation, density and traffic use priorities each introduce new complexities for maintaining consistent performance. These factors motivate addressing the development of adaptive approaches that can react to changes in system state. The main topics considered here are (a) resource allocation and load balancing, (b) coordinated transmission, (c) combined beamforming, and (d) beam and FOV control.(a)Many works in the literature aim to optimize resource allocation and load balancing with different end goals in mind. We focus on the works that target interference mitigation.et al. [Mondal et al.  propose et al. [et al. [Li et al.  investig [et al.  build a et al. [To improve load balancing results, Soltani et al.  consideret al. [et al. [et al. [a priori knowledge of the users’ wireless traffic distribution and then form an optimization problem that maximizes the sum rate for the duration of several future time slots weighted by the evolving queue backlog of each user over many future time slots. They compare their anticipatory association (AA) with responsive association (RA), which maximizes the sum rate at a current time slot weighted by the current queue backlog of the user. They report that their system outperforms RA achieving better trade-off between the average system queue backlog and the average per user throughput. They also note that their study indicates that the overall system average delay can be reduced when AA is employed. However, their choice of mobility model was the random waypoint model which is not practical and the assumption of perfect receiver location is not quite robust. Designing a predictive system is a step in the right direction but much more analysis and study is needed to delve deeper in the variations of this dynamic system and its reliability. There is definitely room for innovation in this area.Wang et al.  study lo [et al.  perform  [et al. . However [et al.  propose (b)Coordinated transmission involves multiple transmitters working together to produce signals decoded by one or more receivers. This includes (i) coordinated and non-cooperative cases and (ii) coordinated and cooperative cases.(i)et al. [Self-organizing interference coordination in optical wireless networks is the topic of the work of Ghimire et al. . The autet al. [b). Owing to this partitioning they provide a power control factor β to help edge users get higher power than centre ones. This method improves the cell-edge user and overall system throughput.Chen et al.  study fret al. [a). While accommodating illumination requirements, they propose a static scheduler that adjusts power control to give centre cell users the minimum required communication performance to mitigate interference for cell edge users, as well as a dynamic scheduler for dense scenarios when the static scheduler is not sufficient to combat interference for the cell edge users. The dynamic scheduler limits colour usage in some attocells according to interference intensity and under SINR demands of all the UDs. It is intended to function in one of two modes: (1) a distributed stage followed by a centralized stage jointly to adjust colour usage, or (2) a greedy approach based on dividing the hexagon cell into rings which would then get colours according to their location. They compare their results with CD which is the one colour per cell plan and NoICIC which is the plan where a cell is allowed to use all colours. They show results based on inter-LED distances but the system has a very high overhead, requires two scheduling phases which can provide delays for highly mobile users, and also depends on reliable feedback channels which may not be practical.Zhou et al.  analyse et al. [et al. [Of the works that study interference coordination employing NOMA (§3a(iii)), Kashef et al.  study an [et al. , who exp(ii)et al. [Bai et al.  propose These areas are very interesting; there is a need to identify ways to realize maximum performance obtainable from the diverse set of physical layer techniques under dynamic conditions. We would hope that future work would define upper bounds on number of supported users on repeatable benchmark traffic and mobility configurations. We note that some of the aforementioned techniques will be challenging to scale to many APs (e.g. the use of synchronized transmitters).(c)Combined beamforming  employs et al. [Mostafa et al.  suggest (d)d) is more active in adapting the FOV and orientation to allow the user the best SNR quality and is able to change them dynamically with system changes. By contrast, work that proposes dynamic beam and steerability adapt the transmit side to change along with the user density, location and overall motion within the room to allow for better coverage and communication quality. Both areas are very interesting and have room for more analysis in the system scale.Beam and FOV control can also be used to address dynamic user behaviour. Examples include aforementioned work  and refefigure 9(e)et al. [Here, we discuss systems that generally combine some of the building blocks discussed in §et al.  propose et al. [Adnan-Qidan et al.  study us5.(i)VLC provides links that have unique properties of light leading to methods and performance unique to OWC.(ii)When we adopt and replicate VLC for APs, we need to address interference among UDs and among the multiple APs.(iii)Many interesting techniques exist  each with different considerations for interference.(iv)Techniques can be combined and optimized for static scenarios, but ultimately we need to study how they interact and can adapt to follow the dynamics introduced by device mobility, orientation and data traffic models.(v)Future work will address system dynamics including optimization and management in the context of overall network performance adaptation.OWC promises to provide a huge boost to the capacity of indoor AP networks including those coupled to the lighting function as VLC. However, the properties of the optical spectrum and the anticipated increase in density of mobile-UDs requires a revisit to interference management for this media type. In this paper, we explore the state of the art with respect to multiple user optical access and develop a classification of current technical approaches for exploiting this technology and managing interference. There are a few key takeaways from the survey which we summarize here:Finally, we emphasize the importance of being able to compare the strengths of future innovations by ensuring that a common set of operating conditions are adopted. With such a foundation we would expect the most critical performance metrics will be (1) system throughput, (2) sustained single-user link speed, and (3) system complexity. We hope to evaluate future work based on these primary metrics.


After 40 years of intense study on HIV/AIDS, scientists have identified, among other things, at risk populations, stages of disease progression and treatment strategies. What has received less attention is the possibility that infection might elicit an increase in sexual behavior in humans. In 2000, Starks and colleagues speculated that HIV infection could alter host behavior in a manner that facilitated the spread of the virus. Retrospective and self-report data from five studies now support this hypothesis. Individuals with acute—versus nonacute—stage infections report more sexual partners and more frequent risky sex. Additionally, male sexual behavior increases nonlinearly with HIV viral load, and data suggest a potential threshold viral level above which individuals are more likely to engage in risky sexual behavior. Taken together, these data suggest that HIV infection influences male sexual behavior in a manner beneficial to the virus. Here, we present these findings, highlight their limitations and discuss alternative perspectives. We argue for increased testing of this hypothesis and advocate for increased public health measures to mitigate the putative impact on male sexual behavior.Lay Summary In 2000, Starks and colleagues speculated that HIV infection could alter host behavior in a manner that facilitated the spread of the virus. Retrospective and self-report data from five studies now support this hypothesis. We argue for increased testing of this hypothesis and advocate for increased public health measures to mitigate the putative impact on male sexual behavior. As in the acute stage, viral load is often high during AIDS [The progression of HIV infection is divided into distinct stages marked by differences in serology, viral load, and CD4+ cell counts. Acute infections are active during the period ∼2–5 weeks after transmission, with the production of HIV-specific antibodies commencing around 3–4 weeks after transmission . Like thing AIDS . Our hypA 2016 review  notes thDirectly testing our hypothesis is challenging. Assessment of altered sexual behavior caused by HIV infection requires observation before and after infection. A randomized controlled trial would require an at-risk group to be monitored for an extended period. Given the potentially confounding impacts of both knowledge of infection and treatment with antiretrovirals, individuals would need to remain unaware of their infection and remain untreated. For obvious ethical reasons, such an experimental design cannot be implemented. It is possible, however, to examine sexual behavior of HIV+ individuals as related to stage of infection or viral loads. In particular, stage of infection studies can offer similar experimental benefits to the aforementioned morally problematic design. Here, we use retrospective and self-report data from five studies to examine our hypothesis.et al. [Joseph Davey et al.  found thet al. . Had sexet al. [et al. [et al. [n = 169) compared with nonacute (n = 5015) HIV infection in homosexual men was associated with 5-fold higher odds for future risky sexual behavior, which they defined as condomless sex with an occasional partner .Joseph Davey et al.  also fou [et al. , Braun e [et al.  report tet al. [2 to 104 copies/ml and then rises parabolically to around 80% at between 106 and 107 copies/ml . When subdivided, there is strong trend  toward increased unprotected sex with casual partners with a recent increase in serum viral load above 105 copies per ml. Continued elevated viral load was not significantly related to riskier sexual practices with casual partners, but the rate of unprotected sex was still elevated (OR=1.5). Consistent with the findings presented by Joseph Davey et al. [Huerga et al.  found thy et al. , this suy et al. . This acy et al. . This suet al. [5 viral copies/ml is a threshold level above which the number of insertive acts rapidly increases. Stratifying semen viral loads by less than or greater than 105 copies/ml shows a significantly greater frequency of insertive sexual acts in the group with higher viral loads . In sum, although supporting our hypothesis, all five referenced articles suffer from some limitations.Data presented by Huerga et al.  in Fig.  [et al.  was smalet al.’s data [It can be argued that Joseph Davey .’s data  listed iet al. [et al. [et al. [Dukers et al. , Huerga  [et al.  and Kali [et al.  did not  [et al. , 30. Pera priori and when assessed in light of the findings on sexual partner diversity and risk taking in uninfected, acute stage and nonacute stage individuals reported by Joseph Davey et al. [et al. [These are but two of several potential explanations for the observations raised by these studies. However, the suggested alternate explanations seem less plausible than our hypothesis both y et al.  and Brau [et al. .We believe that future research on HIV and its potential impact on sexual behavior should examine semen viral loads in addition to blood viral loads since these only weakly correlate . Blood vAdditionally, there are at least four broad groups of HIV-1  which are further distinguished into subtypes that can have different biological effects . We suggFinally, HIV-1 is a relatively new human pathogen that originates from African primates; it first infected humans about 100 years ago , 33. AccThe fact that pathogens can influence the behavior of hosts is well understood. It stands to reason that sexual behavior is the most likely trait for a sexually transmitted virus to manipulate, and data show that risky sexual behavior increases following infection during the acute stage and with increasing viral loads. The data upon which we have based our analysis are limited. Consequently, we hope to spur further research that would more definitively support or reject our hypothesis. Seeing as knowledge of infection seems able to curb risky sexual behavior, our hypothesis argues strongly in favor of frequent screening in order to catch infections early on when they are most infectious and manipulative . In addi


These results suggest that supplementary protein (plant-based) may improve strength in the absence of exercise, a finding that was independent of lean mass [p < 0.001), which may further indicate protein inadequacy in this population. We appreciate the critique of our paper  by Genoean mass . In thisGenoni et al.  stated tSecondly, Genoni et al. are critical of our use of the DIAAS in athletes stating that DIAAS analyses do not consider the metabolic demand for protein in the context of exercise. Citing Burd et al. , Genoni p = 0.074); furthermore, we reported that this statistic was further attenuated when gender was controlled. Had we controlled for gender, age, and energy intake, the resulting p value was similar to the unadjusted value (p = 0.078). We did not control for lean mass in this comparison between diet groups as our premise was that lean mass was a reflection of diet type. Indeed, peak torque per kilogram lean mass was virtually identical between diet groups. Tong et al. also reported a slight but significant reduction in strength for vegetarians versus omnivores from a large UK cohort  and concluded that the differences in height, lean mass, and physical activity likely contributed to the difference in strength in vegetarians versus omnivores [Finally, Genoni et al. suggest that our statistical analyses were “flawed” for comparing strength differences between diet groups since we did not control for age, gender, energy intake, and lean mass. The stated purpose of our study was to “analyze dietary protein availability using the DIAAS method and to relate available protein to muscle mass and strength.” We demonstrated significant relationships between available protein and muscle mass (r = 0.541) and available protein and peak torque (r = 0.315) in our participants. We also reported that peak torque between diet groups was not significant (mnivores . We wereWe hope that these comments adequately address the concerns of Genoni et al. We value the opportunity to discuss our results in further detail.


Gene editing and/or allele introgression with absolute precision and control appear to be the ultimate goals of genetic engineering. Precision genome editing in plants has been developed through various approaches, including oligonucleotide‐directed mutagenesis (ODM), base editing, prime editing and especially homologous recombination (HR)‐based gene targeting. With the advent of CRISPR/Cas for the targeted generation of DNA breaks (single‐stranded breaks (SSBs) or double‐stranded breaks (DSBs)), a substantial advancement in HR‐mediated precise editing frequencies has been achieved. Nonetheless, further research needs to be performed for commercially viable applications of precise genome editing; hence, an alternative innovative method for genome editing may be required. Within this scope, we summarize recent progress regarding precision genome editing mediated by microhomology‐mediated end joining (MMEJ) and discuss their potential applications in crop improvement. The broken genome should be repaired to maintain its stability; otherwise, it may lead to cellular malfunctioning. Even single double‐stranded break (DSB) damage in chromosomes could lead to cell death if it is not properly repaired , including rapidly emerging clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‐associated (Cas) protein complexes ‐dependent targeted integration (MITI) or Precise Integration into Target Chromosome (PITCh), an application of MH‐mediated end joining (MMEJ) repair of DNA DSBs , and HR  and frogs (Xenopus laevis) were much higher than they were in the HR pathway. Due to the dimeric active forms of FokI, a pair of TALENs must be designed for each of the dsDNA cut sites on the donors and targeted genomic sites. Moreover, to avoid recurrent cutting by the same TALENs after ligation, the junction sites have to be shortened from their original forms, thereby limiting the ability of TALEN‐based PITCh to perform a targeted insertion with unaltered sequences at the junctions. However, the CRISPR/Cas‐based PITCh does not have the latter limitation, as it could be designed to precisely edit genomic loci without resulting in any undesirable sequence modification  that used TALENs and CRISPR/Cas9 for targeted genome modifications via the MMEJ pathway (8‐nt MH) in various animals was successfully engineered  selection of CRISPR/Cas complexes for site‐specific DSB formation, (ii) delivery method for introducing the editing tools into plants, that is via Agrobacterium or particle bombardment‐mediated transformation, or PEG or electroporation‐mediated protoplast transformation, (iii) the type of CRISPR/Cas editing tools to the nucleus and the targeting sites , (iv) synchronization or spatial and temporal controls of the expression of Cas proteins, gRNAs and donors, (v) the DNA donor length and (vi) possible methods for quantification MMEJ frequency .et al., et al., It is worth understanding that the MMEJ‐mediated repair mechanism in plants may be different from that of animal systems, as some MMEJ repair components, such as DNA ligase III and SIRT6 proteins, have yet to be identified in plants. Another possibility following from MMEJ is the generation of chromosomal translocation or arrangement, probably due to kinetics of its repair process being slower than the SSA pathway , with Cas9 protein in et al., Drosophila and mammals was shown to preferentially adopt certain MH patterns  in mouse culture cells (Hogan and Faust, et al., et al., et al., et al., et al., et al., et al., et al., et al., Mapping of the MHs among DSB repair outcomes by deep sequencing techniques has been very powerful for understanding their distributions and selections for annealing during MMEJ. Analysis of CRISPR/Cas9‐based DSB repair outcomes by NGS revealed and validated the major involvement of MMEJ in the repair process and generated corresponding maps of MH usage in human cells (Bae et al., S. cerevisiae POL3/CDC2 (Galli et al., et al., et al., et al., Other MMEJ improvement approaches might be connected to early or late steps of the repair process. K48‐linked polyubiquitylation‐mediated removal of KU80 from DSB ends may promote alternative repair pathways (Postow et al., et al., et al., et al., et al., MMEJ‐based gene editing offers alternative tools for precision engineering of organisms of interest at a potentially higher frequency than what is achieved with HR‐based approaches. Substantial understanding of MMEJ activation and its mechanism in DSB repair Figure  has beenAgrobacterium‐mediated transformation or particle bombardment or protoplast transfection; Agrobacterium‐mediated transformation is the most widely used thanks to its ease and low cost. However, Agrobacterium‐mediated transformation usually delivers low copy numbers of the editing tools in its T‐DNA system, thereby limiting the competitiveness of exogenous donors to prevent re‐ligation of a broken end by cNHEJ. Recent advances in HR works have used DNA replicons as efficient donor DNA cargo for plant genome editing (Baltes et al., et al., et al., Since the advent of CRISPR/Cas technology, DSB formation has become much more precise, flexible and customizable. In general, both blunt‐end and cohesive‐end DSBs can be used in MMEJ‐mediated editing, but the former type might be easier to design and might produce more predictable repair outcomes. Moreover, due to the need for end resection to generate 3′ overhangs, Cas complexes that produce 5′ overhangs, such as Cas12a, may not be energetically preferred. The DSB inducers and donor DNAs are conventionally introduced into plants by et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., In this review, we summarize the MMEJ‐mediated DSB repair mechanism at each step that requires the involvement of a cascade of DNA damage repair proteins/enzymes Figure . MMEJ‐meNo conflicts of interest are declared.Conceptualization, T.V. V and J.Y.K.; Methodology, T.V. V and J.Y.K.; Writing—Original Draft, T.V. V., D.T.H. D., J.K., Y.W.S., M.T.T., Y.J.S. and S.D.; Writing—Review and Editing, T.V. V., D.T.H. D., J.K., S.D. and J.Y.K.; Funding Acquisition, J.Y.K.; and Supervision, T.V. V and J.Y.K.