In the Indeed, the field is already successfully moving in the direction of examining oxytocin function under more naturalistic contexts and more holistically, aided by advancements in technology ,47 and d. 2Oxytocin, and the closely related arginine-vasopressin, are the result of ancient gene duplication in vertebral evolution –55. Whilet al. [et al. [Macaca mulatta) display sexual skin. This modulation of stimulus preference indicates that both oxytocin and testosterone influence reproductive behaviours by possibly increasing the visual salience of sexual features. Similarly, Paletta et al. [In this theme issue, Bakermans-Kranenburg et al.  asks how [et al.  examineda et al.  review h. 3Microtus ochrogaster) model of pair-bonding has been demonstrated to be mediated not just by oxytocin receptors in the nucleus accumbens [et al. [In situ hybridization to visualize and quantify oxytocin receptor mRNA found no differences between groups, suggesting that the difference in receptor expression was possibly the result of local dysregulation in oxytocin receptor protein translation or changes in the endocytosis and recycling rates.Interactions between oxytocin and other neuromodulator or neurotransmitter systems remain broadly underappreciated in the literature. However, links between oxytocin and the dopaminergic system are arguably the most well understood . The claccumbens –39,41, bccumbens . Explori [et al.  in this The nucleus accumbens is a key site of oxytocin–dopamine interactions, as detailed thoughtfully in a review by Borie and colleagues  that expExamining the relationship that oxytocin has with the dopamine and serotonin systems in maternal behaviours, Grieb & Lonstein  in this in vitro [Beyond the classical neurotransmitters, oxytocin also interacts with other neuromodulatory systems. One notable example is interactions between oxytocin and the opioid receptor system, observed both in vitro –73 and iin vitro . Putnam in vitro  detail i. 4et al. [The promise of using oxytocin as a therapeutic intervention remains a tantalizing goal for the field of social neuroscience ,75. Howeet al.  in this et al. [In an intervention-focused research article, Daughters et al.  compare . 5A holistic understanding of oxytocin extends beyond specific neurotransmitters or brain regions but encompasses underappreciated aspects of neurobiology. A prime example of this is reviewed by Gonzalez and Hammock , who exaSimilarly, a review piece by Carter & Kingsbury  offers aAt the neurobiological level, ageing also drastically impacts cognitive capacities. However, the link with neuropeptides is understudied. Polk and colleagues  examine Oxytocin interactions also encompass broad life events, as expounded by Bales and Rodgers  in a rev. 6et al. [The final paper of our theme issue by Leng et al.  takes a


Breast cancer (BC) ranks as the first malignant disease and the second leading cause of death by cancer in women . DespiteLiterature reported that the tumor progression, treatment response, and clinical outcome would be affected by host metabolic abnormalities, including diabetes, obesity, and metabolic syndrome . MeanwhiDong et al., metabolic syndrome could affect prevalence, treatment response, progression and survival of breast cancer. As for the initiation of breast cancer, Yan et al. studied the association between mammary tumorigenesis and metabolome in a novel mouse model and showed that MCP-1 derived from adipose could contribute to breast tumorigenesis. By performing a nationwide population-based cohort study, Seol et al. found that elevated GGT level could be a risk factor for breast cancer, especially in the obese post-menopausal group.In the review by Wang et al. illustrated that Lactate Dehydrogenase-A (LDHA) mediated a loop between breast cancer stem cell plasticity and tumor-associated macrophage infiltration, which would a potential target for combating metastasis. Since both intrinsic and extrinsic factors contributed to metabolic reprogramming phenotypes, Wang et al. comprehensively reviewed the metabolic mechanisms underlying BC metastasis.In terms of progression and metastasis, Lu et al. found that the UCHL1, a deubiquitinating enzyme, could lead to chemoresistance by modulating free fatty acid synthesis. Wang et al. found that pyrotinib and adriamycin had synergistic effects on HER2-positive BC. Qiu et al. reviewed the newly published studies in the correlation between hyperglycemia and chemoresistance, as well as the hyperglycemic microenvironment and glucose metabolism. Li and Li. further summarized the recent studies about mitochondrial metabolism and therapeutic resistance in breast cancer. And Wang et al. made a review of the mechanisms by which salinomycin protected against breast cancer and discussed its future clinical applications. In additional, He et al. studied the lipid changes during endocrine therapy and found that tamoxifen would improve total cholesterol and low-density lipoprotein levels in premenopausal patients, and that aromatase inhibitors had no adverse effects on lipid profiles.Several authors focused on the therapeutic response and resistance. Qin et al. studied the relationship between hormone receptor status and prognosis between medullary breast carcinoma and atypical medullary carcinoma of the breast. And Tong et al. analyzed the correlation between 21-gene recurrence score (RS) and obesity, indicating RS varied among different obesity status.Furthermore, Du et al. and Ni et al. indicated that long non-coding RNAs MIR210HG and ADAMTS9-AS2 could modulate the metabolic reprogramming and progression of triple-negative breast cancer (TNBC). Sheng et al. further illustrated the latest progress in DNA N6-Methyladenine modification and drug resistance in TNBC. And Zhang et al. reviewed the role of hypoxia in breast cancer, and discussed the relationship between hypoxia and therapeutic response, as well as the clinical values of hypoxia biomarkers.Several articles studied the molecular mechanism beyond metabolic changes in breast cancer, including non-coding RNAs, RNA modification, and hypoxia. In conclusion, all these publications in the present Research Topic provide new insights into the role of metabolic abnormalities in the disease development, treatment response, and prognosis of breast cancer. We hope that the finding of the articles in this Research Topic would provide novel treatment strategies to improve survival of BC patients.All authors contributed equally to this Editorial. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The cell division cycle in eukaryotic cells is a series of highly coordinated molecular interactions that ensure that cell growth, duplication of genetic material, and actual cell division are precisely orchestrated to give rise to two viable progeny cells. Moreover, the cell cycle machinery is responsible for incorporating information about external cues or internal processes that the cell must keep track of to ensure a coordinated, timely progression of all related processes. This is most pronounced in multicellular organisms, but also a cardinal feature in model organisms such as baker's yeast. The complex and integrative behavior is difficult to grasp and requires mathematical modeling to fully understand the quantitative interplay of the single components within the entire system. Here, we present a self-oscillating mathematical model of the yeast cell cycle that comprises all major cyclins and their main regulators. Furthermore, it accounts for the regulation of the cell cycle machinery by a series of external stimuli such as mating pheromones and changes in osmotic pressure or nutrient quality. We demonstrate how the external perturbations modify the dynamics of cell cycle components and how the cell cycle resumes after adaptation to or relief from stress. The yeast cell cycle has a tight control system and responds to external perturbations, which are considered here in a quantitative model. The cell cycle machinery coordinates all processes that are required for a cell to duplicate and ensure faithful inheritance of all its critical components. Therefore, it is per definition deeply entangled with nearly all physiological processes that happen within and around a cell. Yet, the cell cycle machinery itself is already a large and complex network of many interacting partners with regulation spanning many levels, including transcriptional and posttranslational control as well as stoichiometric inhibition or activation of protein function (Enserink and Kolodner 1 and G2) in which the cell primarily grows. Various checkpoints monitor transitions between the phases controlling that the processes of the previous phase have been completed and, otherwise, arrest cell cycle until the requirements are met  phase, in which DNA is replicated, and mitosis (M), in which the chromosomes are separated between the progeny cells. The S and M phases are interspaced by two gap phases  to inhibit its activity  Sic1 during Get al. et al. et al. et al. The final B-type cyclins, Clb1/2, are required for mitotic entry and the isotropic switch. Cdc28-Clb1/2 regulates mitotic spindle elongation  cascades are employed for this task. Many interactions between components of signaling pathways and the cell cycle machinery have been described, e.g. the cell wall integrity pathway (CWI) Levin ; the higet al. et al. Growth is the most important determinant of cell cycle progression. The growth rate of unicellular organisms is determined by nutrient availability and influences cell size, ribosome content and metabolic efficiency , the well-studied High Osmolarity Glycerol (HOG) pathway mainly coordinates the adaptation to increased osmolarity  activity as a mark for the G1/S transition   with 111 parameters (Tables S1 and S2). It is implemented in the Systems Biology Markup Language (SBML) and is available in the supplementary data (File S1). The cell cycle part of the model is implemented without events. However, we use events to turn pheromone signaling or osmotic stress on and off. The cell cycle duration of our reference condition, i.e. the standard parameter set (Table S2) without any stress, is ∼122 minutes. Our implementation results in limit cycle oscillations, as shown in Fig.et al. et al. et al. S.cerevisiae—Whole organism (integrated)’ data set from the Protein Abundances Across Organisms database (PaxDB) (Wang et al. All parameters were adjusted with respect to cell cycle phase duration (Skotheim In the following, we describe how the model behaves when exposed to alpha factor treatment, high osmotic stress, and how the cell cycle duration is affected by the availability of nutrients.1/S transition. The arrest caused by the sensing of pheromone in the environment is mediated by the CKI Far1 (‘Factor ARrest’, (Chang and Herskowitz et al. 1 is a stabilizing phosphorylation of Far1 at Thr306 by Fus3 (Gartner et al. et al. 1 phase (Fig. Pheromone treatment leads to arrest before the Gase Fig. –D. This et al. Both Far1 as well as its stabilized form are subject to phosphorylation at the S87 residue by Cdc28-Cln1/2, triggering ubiquitination and proteasomal degradation (Henchoz Cells released from alpha-factor are synchronized in their cell cycle, independent of the time point when the cell was treated with the pheromone (compare Fig.1 to S phase (Iyer et al. CLN1/2 and CLB5/6 is downregulated (Adroveret al. et al. 1, where Cln1/2 and Clb5/6 are the prevalent drivers of cell cycle progression (Figs et al. et al. et al. et al. Budding yeast has developed adaptation programs to certain stresses in order to arrest the cell cycle, react to the stress appropriately and, upon successful adaptation, resume cell cycle progression. Osmotic stress induces activation of the HOG MAP kinase cascade, which ultimately leads to the activation of Hog1. The response on the level of cell cycle regulation is depicted in Fig.2 to M transition requires degradation of the Cdc28 kinase inhibitor Swe1. In the unperturbed cell cycle, Swe1 degradation requires its localization to the bud neck. This recruitment is mediated by Hsl7. Hsl7 forms a complex with Hsl1, which, in turn, is attached to septin. Export from the nucleus and tethering to the Hsl1/Hsl7 complex in the budneck primes Swe1 for phosphorylation by Clb2-Cdc28 and Cdc5 (Howell and Lew 2/M transition is implemented in a simplified manner: In the model, Swe1 phosphorylation is only mediated by Clb2. The stress induced Hog1 activity results in sustained Swe1 levels (Fig. The Gels Fig. –D and stels Fig.  and D orels Fig.  and B.Additionally, Hog1 directly inhibits phosphorylation of Swe1 Fig. , thus, tS. cerevisiae changes with the nutritional condition the cells live in (Barford and Hall et al. et al. et al. et al. et al. It is well known that the cell cycle duration of et al. et al. et al. et al. We present a model of the yeast cell division cycle that incorporates dynamics of the major cyclins, cyclin dependent kinase inhibitors, transcription factors, and other key players. The model structure is largely based on well-studied concepts of the cell cycle network (Barberis We used the model to specifically analyze the response to pheromone treatment. In accordance with experimental findings, the interaction of the pheromone pathway with the cell cycle was implemented via the modification of Far1 activity Fig. . This imet al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. et al. 1, cells arrest prior to Start, when the stress occurs later, however, cells pass into S phase and continue the cell cycle until reaching the next checkpoint. Interestingly, the model predicts that osmotic stress applied in M phase can lead to early mitotic exit (Radmaneshfar et al. et al. The osmotic shock response is the prime example used to study how single cells and cell populations cope with stress and recover from changes in their environment (Hohmann et al. et al. et al. et al. pk of protein production, should be linked to or completely substituted by the output of the metabolic network extension. This would, however, not cover direct effects from signaling pathways that communicate nutritional information such as PKA. Such signaling must be integrated in appropriate fashion.Growth is a fundamental property of life, which critically depends on the available nutrients. Therefore, we also analyzed the impact of change in the nutritional conditions on cell cycle progression. While the interfaces between the cell cycle and signaling pathways described above are well defined, the implementation of the cell cycle response to nutrient changes was more challenging due to the complexity of interaction. In the end, we settled for the simplest, most straightforward implementation we could think of. We incorporated nutrient quality as a global parameter that modifies the rate of all protein production reactions equally. The model dynamics scaled appropriately with nutrient quality, i.e. poorer nutritional conditions caused slower accumulation of regulatory proteins leading to slower proliferation, while richer nutrition enhanced cell cycle progression Fig. . This beThe presented model also has a number of other properties that will make it useful above the case scenarios for which we have analyzed it here. First, the model comprises a system of only ODEs without any additional algebraic, stochastic or Boolean-like equations, thus remains quite manageable and comprehensible. It is formulated in SBML and it complies with current modeling standards. This is an important aspect to mention for it ensures model reusability. Our model can easily be integrated with any SBML-compliant ODE integrator offering ease of use without risking critical behavior. The model represents realistic orders of magnitude for protein amounts instead of frequently used arbitrary values, thus it can be compared to experimental data and can be integrated with other models employing realistic molecule numbers or concentrations.et al. et al. et al. Driving the concept of integrating different cellular networks forward, cellular dynamics upon cell cycle progression, development, external stimulation, feeding or other causes of change are extremely complex since, loosely spoken, everything is connected to everything. Given a eukaryotic organism such as yeast with about 6000 genes (Goffeau foac026_Supplemental_FilesClick here for additional data file.


Ross et al., Chem. Sci., 2022, https://doi.org/10.1039/d2sc02402k.Correction for ‘Jahn-Teller distortion and dissociation of CCl The correct email address is The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.


We thank Campbell et al. for their comment  on our mJournal of Human Hypertension [We strongly agree with Campbell et al.  that redrtension . Howeverrtension . Still, rtension . The metrtension  cited byrtension  reportedrtension  . As Camrtension , there irtension ,9,10). Irtension , that arAlthough controversial or “unexpected” data regarding non-classic findings of diet sodium restriction, such as the absence of a relevant curvilinear association between salt consumption and reduction in CVD-associated mortality in some papers , cannot In their recent paper, Cappuccio et al.  raise awThe paper of Hogas et al.  totally Campbell et al. further state in their comment  that theFinally, reducing dietary sodium—even slightly—is beneficial beyond doubt in the general population, while some reverse causality reports are still to be investigated and confirmed in specific populations. We agree with Campbell et al. that a population-wide approach would be beneficial, with salt-reduction strategies resulting in less people suffering from arterial hypertension and its consequences . Reducin


They cause hyperkeratinization of the pilosebaceous follicles and seborrhea. Endocrine diseases characterized by increased levels of androgens often present with acne vulgaris. A correlation between serum androgen levels and acne severity exists, and the assessment of serum androgen levels is therefore essential in women with severe acne vulgaris and treatment resistant acne.the study was conducted in the Dermatology Clinic of the University of Nigeria Teaching Hospital, Ituku Ozalla. Seventy females with acne vulgaris and seventy females without acne vulgaris were recruited as subjects and controls respectively. Blood samples were taken from subjects and controls to measure levels of serum testosterone, dehydroepiandrosterone sulfate (DHEAS) and androstenedione. Acne severity was measured using global acne grading system (GAGS).the median levels of DHEAS and androstenedione (1.20µg/ml and 1.80ng/ml respectively) were higher in subjects than 1.00µg/ml and 1.70ng/ml in controls respectively, although these findings were not statistically significant. There was also no significant difference between the levels of serum testosterone in both the subjects and the controls. No correlation existed between levels of serum androgens and acne severity.there was no statistically significant difference in the serum androgen levels between the subjects and the control population, and no relationship between androgen levels and severity of acne vulgaris was demonstrated. Propionibacterium acnes (P. acnes) [Propionibacterium acnes in individuals who have a genetic predisposition to acne [Acne vulgaris (AV) is an inflammatory disorder of the pilosebaceous glands of the skin that is characterized by comedones, papules, pustules, nodules and cysts . It is a. acnes) . Serum a. acnes) . They ca to acne .Endocrine diseases such as acromegaly, cushing´s syndrome and adrenal androgen secreting tumors in which increased levels of androgens occur, are characterized by acne vulgaris. Polycystic ovarian syndrome (PCOS) and congenital adrenal hyperplasia (CAH) also present with acne vulgaris . Acne vuObjective: this study was conducted to investigate the serum androgen levels in females with acne vulgaris and correlate it with its severity.Study design: this study was a prospective, cross-sectional study conducted at the Dermatology Clinic of the University of Nigeria Teaching Hospital (UNTH) in Southeastern Nigeria. It was done between April and October 2016.Sample size: the sample size was calculated using the Kish and Leslie formula [ formula .Where n= minimum sample sizeZ= constant at 95% confidence interval from Z table, p = prevalence of acne vulgaris in Enugu (4.3%) , q = 1 -s= sample size to be selected, n = original calculated sample size, a = anticipated response = 90%. Calculation:Where n=70 (to the nearest whole number). For the purpose of this study, 140 patients (70 cases and 70 controls) were recruited using a consecutive sampling method. Inclusion criteria for the cases were consenting patients with clinically diagnosed active acne vulgaris .Patients with any of the following criteria were excluded: A) Pregnant women and lactating mothers ,17; B) pEthical consideration: ethical clearance was sought and obtained from the Ethics Review Board of UNTH, Ituku Ozalla (NHREC/05/01/2008B-FWA 002458-IRB 00002323). Informed written consent was obtained from all participants recruited into the study or their parents/guardian if the patient was between 16 and 18 years of age before enrollment. For the unlettered participants, the informed consent form was read to them in the local language and their thumb prints were obtained in the presence of a witness.Statistical analysis: data analysis was carried out using the Statistical Package for Social Sciences (SPSS™) version 21.0 . The socio-demographic and clinical characteristics of the participants were presented as frequency distribution tables. Mean and standard deviation were computed for normally distributed continuous variable while median and interquartile ranges were computed for skewed continuous variables. Categorical variables were presented as frequencies and percentages. Continuous variables were compared using student´s t-test for normally distributed data while Mann-Whitney U test and Kruskal-Wallis test were performed for skewed data. Association between categorical variables was evaluated using Chi-square and Fisher´s exact test, while the correlation between continuous variables was done using Spearman correlation analysis. A p-value of ≤0.05 was deemed statistically significant.2and 24.55 kg/m2, and there was no statistically significant difference between the two groups (p = 0.844). On grading the severity of the acne vulgaris with the global acne grading scale, we observed that forty-six subjects (65.7%) had moderate acne while thirteen subjects (18.6%) had mild acne. Eleven subjects (15.7%) had severe acne. We looked at the symptoms of hyperandrogenemia, the commonest symptoms of hyperandrogenemia were hirsutism and alopecia, seen in twenty-five subjects and fourteen subjects (35.7% and 20%) respectively. The two groups of participants had similar age distributions, the mean ages being 27 ± 7.28 years and 30.4 ± 9.59 years for the females with acne vulgaris and the controls respectively. There was a statistical significance between the educational levels of the subjects and controls. Also, the mean BMI of the subjects and controls was 24.71 kg/met al. [et al. [This present study aimed to determine the serum androgen levels of females with acne vulgaris and to correlate it with the severity of acne vulgaris. The age range of the study participants was 16 to 50 years. The subjects aged 20-24 years were about a third and this was followed closely by those aged 30-34. This is similar to findings in previous studies ,17,26 anet al.  where itet al. . Althoug [et al.  in Southet al. [et al. [et al. [et al. [et al. [et al. [This may be explained by the fact their study population were recently admitted undergraduates. Other hospital-based studies in Africa reported their mean ages: 23 years in Togo  and 25 y [et al.  and Khon [et al. . This ag [et al.  reported [et al.  found th [et al.  reportedet al. [et al. [et al. [et al. [Hirsutism, which usually causes cosmetic concerns and embarrassment for affected females, was the commonest symptom of excessive serum androgens in this study. This is consistent with the findings by Karrer-Voegeli et al. . A possi [et al.  alopecia [et al. ,37. Some [et al. ,35,38. I [et al. . Further [et al.  found no [et al. . Howeveret al. [et al. [et al. [et al. [et al. [This study did not demonstrate an overall correlation between serum androgen levels and acne severity. Some researchers ,35,42 reet al. , in thei [et al. , titled  [et al. . The fac [et al.  found th [et al.  who also [et al. , concludLimitations: this was a clinic-based study. A population study may have more robust outcome and the findings more generalizable. The assay of other serum androgenic parameters like free testosterone, dihydrotestosterone and sex hormone binding globulin (SHBG) might have given a wider androgenic profile.Recommendations: this study has raised questions that would need further research; larger scale studies will further elucidate the role of androgens among women with acne who have normal androgenic values. Further work comparing the degree of response of anti-androgen treatment between women with abnormal androgenic and normal androgenic parameters may give more and better insight the role of androgens among women with acne. Population based research is desirable as it may give a better representation of the serum androgen levels and the effect of acne on the quality of life of women.Although this study did not show a difference between serum androgen levels in subjects and controls, it does not undermine the importance of hormonal assay, especially in patients with treatment resistant acne, persistent acne and with other clinical signs of hyperandrogenemia. There was no correlation between the androgen levels with the degree of severity of acne in our subjects. However, the small sample size may make it difficult to generalize this finding. Large-scale studies in this area may shed more light on the role of androgens in the severity of acne vulgaris.Serum androgens play an important role in the pathogenesis of acne vulgaris;It is essential to assess serum androgen levels in women with severe acne, persistent acne or PCOS.The difference in serum androgen levels were not statistically significant between women with acne vulgaris and women without acne;Acne vulgaris may be dependent on the degree of sensitivity of the sebaceous glands to serum androgens and not the levels of serum androgens.


Cancer is a major public health problem worldwide. Studies on oncogenes and tumor-targeted therapies have become an important part of cancer treatment development. In this review, we summarize and systematically introduce the gene enhancer of rudimentary homolog (ERH), which encodes a highly conserved small molecule protein. ERH mainly exists as a protein partner in human cells. It is involved in pyrimidine metabolism and protein complexes, acts as a transcriptional repressor, and participates in cell cycle regulation. Moreover, it is involved in DNA damage repair, mRNA splicing, the process of microRNA hairpins as well as erythroid differentiation. There are many related studies on the role of ERH in cancer cells; however, there are none on tumor-targeted therapeutic drugs or related therapies based on the expression of ERH. This study will provide possible directions for oncologists to further their research studies in this field. Cancer is a major public health problem worldwide and is the second leading cause of death in the United States: 1,918,030 new cancer cases and 609,360 cancer deaths are projected to occur in the United States in 2022 , 5. In tet al. first started to suspect and discover the relationship between ERH and malignant tumors , nematodes (Caenorhabditis elegans), and insects (Aedes aegypti). Lower vertebrates (Zebrafish), mammals (Mus musculus), and humans (Homo sapiens) also have a high degree of sequence conservation. ERH is not found in the fungi, except for the fission yeasts Schizosaccharomyces, S. pombe, S. octosporus, S. cryophilus, and S. japonicus  Assay, Pogge et al.  demonstrn factor . But theAnalyzed by Co-Immunoprecipitation (Co-IP) and mass spectroscopy (MS), Kwak et al. found that ERH is associated with SPT5 elongation factor Figure 2Analyzed by YTH screening, Smyk et al.  demonstret al.  was shown to interact with ERH using YTH screening. They demonstrated by fluorescence co-localization assay that when Ciz1 and ERH are co-expressed in HeLa cells, Ciz1 could recruit ERH to the region of DNA replication. They indicated that ERH can block the action of Ciz1, and then reduce the expression of ERH inducted by DNA damage, which facilitates CDK-cyclinE-p21Cip1/Waf1 complex formation and enables the repair of DNA damage.It is inferred that phosphorylation of CKII sites (Thr18 and Ser24) would disrupt the dimerization of ERH and then disrupt its interaction with other proteins . In 2008et al.  found anet al. Figure 2Analyzed by co-IP and MS in 2011, ERH was shown to interact with HOTS, a tumor growth inhibitor encoded by H19 antisense transcript Figure 2ERH was shown using stable isotope labeling by amino acids in cell culture MS that it can interact with Sm protein SNRPD-3 Figure 2et al.  family member, to have an effect on serine-phosphorylated STAT3, regulating canonical tyrosine phosphorylation and enhancing transcriptional activity in gastric cancers . ERH canet al.  cells . Ishikawet al.  discoveret al.  ; Jiangsu Maternal and Child Health Association Project (FYX202026); Jiangsu Province key research and development program ; Xuzhou Medical University Excellent Talent Fund Project ; Jiangsu Province, the medical innovation team (CXTDA2017048).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Also questionable and not justified by the authors is the inclusion of only RCTs comparing lithium against placebo or treatment as usual, but not against an active comparator. At least three studies were excluded on this basis: (1) the randomised comparison of lithium v. lamotrigine in bipolar II disorder .In addition, the authors' assumption that no suicides took place in studies with no information on suicide events is flawed; this compromises the validity of included data. It also leads to an inflation of zero studies, i.e. studies with no events in either treatment arm, potentially biasing the results towards false negative. Furthermore, the largest RCT included by the authors . For the analysis of rare events, it is also useful to use large open studies. In fact, in a meta-analysis of 31 studies with a total of over 85 000 person-years of risk exposure, Baldessarini et al. (p < 0.0001).The analysis of rare events leads to statistical difficulties Liu, , as disci et al.  showed ap = 0.002). The meta-analysis by Cipriani et al. (p = 0.01). Remarkably, in this meta-analysis, Cipriani et al. also demonstrated a statistically significant reduction in all-cause mortality in the lithium groups , thereby confirming older studies (Ahrens et al., The adequate evaluation of RCTs also provides statistically reliable evidence of the preventive effect of lithium on suicidal acts: In an overview of RCTs, Baldessarini and Tondo  recentlyi et al.  found siet al.'s findings that are probably flawed and a misleading representation of the evidence base. Looking at the whole picture of all studies available demonstrates the well-established effect of lithium to prevent suicidal acts.For these reasons, we question the validity of Nabi


Lentini et al. present the potential of in situ brain regeneration to address neurodegeneration in the epileptic brain.Drug-refractory forms of neurological diseases could find their next breakthrough therapy in non-pharmacological approaches to brain repair.  Lentini et al. [When millions of patients suffering from drug-refractory forms of neurological diseases face a therapeutic void, can we push the limits of current medicine to heal the brain from within? An elegant study by i et al. . providei et al. . This faLentini et al. [Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) is a dreadful epileptic syndrome which usually manifests several years following an early childhood triggering event such as brain injury or febrile seizure . The pati et al. . first pLentini et al. [Lentini et al. [The study by i et al. . providei et al. . relies i et al. . SupplemSMN1, Zolgensma®, Novartis) and biallelic RPE65 mutation-associated retinal dystrophy  have been at the forefront of medical advances and their recent approval by regulatory institutions paves the way for the use of gene delivery-based regenerative methodologies in other settings. The targeting of reactive glia for lineage conversion is an attractive strategy because of their potentially harmful role in neurodegeneration. Their elimination by conversion into functional neurons could therefore play a dual role of removing detrimental cells while effectively correcting the loss of neurons. On a larger scale, by combining two promising technologies, in situ cellular regeneration opens new spheres of possibilities for other untreatable disorders such as Parkinson’s, Huntington’s or retinal diseases, which could very well benefit their next breakthrough therapy in lineage conversion strategies [Gene therapies to halt the manifestation and/or progression of devastating diseases such as spinal muscular atrophy (AAV9-rategies –6.


It is aetiology .Further research into the identification of candidate causal genes will create opportunities to study the molecular mechanisms underlying the disease phenotype and will enable clinicians to make timely and accurate clinical diagnoses . This wide novo mutations have a prevalence rate of 1 in 213 to 1 in 448 live-births  and adaptive function  among children aged 5 years or younger. The global prevalence of DD is 1–3% among children aged 5 years or younger . The pree-births .Advances in variant detection technology have evolved in recent years, leading to accelerated causal gene discovery and understanding of genomic lesions in ID/DD cohorts. After preliminary confirmation of the disease through clinical, laboratory and radiological examination, clinicians can order further diagnostic testing, which is influenced by initial findings and availability and access to resources. The range of potential lines of inquiry include but are not limited to: karyotyping to identify gross chromosomal abnormalities; chromosome microarray (CMA) to identify deletions, duplications, loss of heterozygosity, and aneuploidy; and genomic sequencing  to identify disease-causing variants .Cerminara et al.; Chen et al.; Deng et al.; Fan et al.; García-Ortiz et al.; Li et al.; Servetti et al.; Smetana et al.; Tao et al.; Wan et al.; Wang et al.; Xiang et al.; Zarate et al.; Zhang et al.; Ali Alghamdi et al.; Binquet et al.; Ha et al.; Li et al.; Rong et al.; Yue et al.; Zhao et al.).This Research Topic features new causal genes for DD and ID, advances in the mechanistic understanding of previously reported DD and ID genes, and potential therapeutic applications. We received 40 submissions and accepted 21 papers after rigorous peer review . The authors delineate the genotype-phenotype correlation for 12q interstitial deletions and discuss likely causative genes. Wang et al. reported familial translocation t   . They describe a range of complex phenotypes associated with these chromosomal abnormalities. This paper highlights the value of studying extended families for intrafamilial variation in genotypes and associated phenotypes. Smetana et al. reported a case of Xq22.3 deletion associated with Alport syndrome with intellectual disability  with genotype phenotype correlation . The deletion is larger in size compared with previously reported cases and includes two additional genes. This may explain a broader phenotype with additional features in the proband. Fan et al. reported a case with deletion of chromosome 7q35-7q36.3, which causes congenital brain dysplasia, DD and ID . Servetti et al. used an integrated framework to analyse 12 cases of neurodevelopmental disorders with complex phenotypes and suggested that those cases can be explained by multiple mechanisms, including additive effects of multiple CNVs, involving known neurodevelopmental disorder genes and novel candidate genes . One study leveraged a consanguineous family with four affected individuals to identify a likely pathogenic homozygous variant in OSGEP . Detailed phenotyping and proteomic analysis are a valuable part of this study .Four publications are based on chromosomal aberrations associated with DD and ID. Deng et al. reported two new cases of chromosome 12q14 deletions and reviewed the published literature . Xiang et al. used whole exome sequencing to investigate 17 patients with unexplained DD and/or ID . They used the whole exome data for analysis of CNV, SNV and indels. Seven affected individuals carried a single nucleotide variant or an indel that explained the disease, and three cases carried a disease-associated CNV. Zarate et al. reported two cases of SATB2-Associated Syndrome . The clinical symptoms overlapped with mitochondrial disease presentation. The authors recommended considering exome sequencing in suspected cases of mitochondrial disease.Three studies are based on the evaluation of multiple cases. Wan et al. reported six new variants in seven cases and provided phenotype descriptions for MEF2C haploinsufficiency syndrome (MCHS) . This is an indication of new avenues in the field that are moving toward reduced costs of sequencing. Garcia-Ortiz et al. examined methylation in blood samples of patients with autism spectrum disorder (ASD) . In a case report, Cerminara et al. reported an affected individual with a complex phenotype including ASD and its association with a maternally inherited X-linked missense variant in HUWE1 and a de novo stop variant in TPH2 .Binquet et al. reported a study that compares the diagnostic yield of trio sequencing in 1,275 cases with the current strategy for fragile X diagnostics, which involves microarray and panel sequencing for 44 genes . The predominant phenotype was a focal epilepsy. This gene has been implicated previously in autosomal recessive focal seizures. Tao et al. reported a case of complete maternal uniparental disomy of chromosome 2 with a rare UNC80 c.5609-4G>A intronic variant in a Chinese patient with infantile hypotonia, psychomotor retardation and facial dysmorphology . Disomy resulted in a homozygous mutation. These two reports reinforce the paradigm of parental disomy causing homozygous disease in outbred populations . Two additional papers reported compound heterozygous mutations causing recessive disorders  in outbred populations .In a study by Chen et al., maternal uniparental disomy resulted in a homozygous variant in Li et al.). They used different techniques including FISH and low pass whole genome sequencing to identify the genetic changes. Zhang et al. identified a pathogenic variant in GRIN1 in a single case and performed further experiments to study the pharmacological impact of the DNA change and rescue mechanisms . Zhao et al. described a nonsense variant in ZNF462 associated with Weiss-Kruszka syndrome-like manifestations . Li et al. identified a novel homozygous splice-site variant in a female child with Cohen syndrome . Rong et al. reported a milder phenotype produced by a novel mutation in SEPSECS .Li et al. described a case of mosaic Turner syndrome 45, X [56.5%]/46, X, del(Y) (q12) [43.5%] (In conclusion, this special issue reports on both CNVs and SNVs associated with DD and ID. In the future, more refined cellular and molecular studies are required to understand the disease mechanisms . This co


White matter lesions (WMLs), often due to cerebral small vessel ischemia and several inflammatory demyelinated diseases such as multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), are characterized as focal demyelination with a certain degree of inflammation. Brain-resident microglia and macrophages are highly dynamic cells that rapidly respond to cues in the injury sites and provide a neuroprotective or detrimental microenvironment for myelin maintenance by changing their activation state. Microglia/Macrophage phenotypic heterogeneity and their diverse responses are likely related to the differences in demyelinated pathology in WMLs. The peripheral immune cells, including attracted monocytes and T lymphocytes to the CNS, can also modulate microglia responses. The goal of this Research Topic is to gather contributions to advance research on immune mechanisms in white matter lesions as well as to explore potential interventions for ischemic white matter lesions or inflammatory demyelinated diseases.Guerrero and Sicotte). Based on the recent understanding of microglial function, microglia-targeting therapeutic may represent a potential treatment for WMLs .Microglia are the major immune cells of the central nervous system (CNS). The conventional view holds that the activation of microglia is deleterious in the pathological process, but accumulating evidence indicates that microglial activation may also have neuroprotective effects. The dual role of microglia suggests a diversity of potential functions of microglia . SpecifiIschemic white matter lesions, the main pathological feature of cerebral small vessel disease (CSVD), is a disorder of cerebral microvessels that causes white matter injury, accompanied by inflammatory activation of microglia . Qin et Wang et al. assessed possible factors associated with WMLs heterogeneity in patients with cognitive impairment in CVSD. Wang et al. graded WMLs, enlarged perivascular spaces (ePVS), microbleeds, and lacunes on brain MRI. Cognitive impairment was assessed with Montreal Cognitive Assessment (MoCA) scores. Wang et al. defined mismatch as the severity of WMLs do not match the severity of cognitive impairment. Further, they used penetrating artery imaging to clarify this mismatch’s underlying mechanism. Eventually, Wang et al. suggested that conventional imaging features and penetrating artery damage may be responsible for the heterogeneity of WMLs in cognitively impaired patients with CSVD, which may be therapeutic targets for early identification and prevention of cognitive impairment Wang et al.In this topic, Seals et al. reviewed B cell biology and the role of B cells in autoimmune inflammatory demyelinating diseases and provided a novel review about the possible regulation of microglial activation by IgE in MS/EAE Seals et al.MS is the most common chronic inflammatory demyelinating disease of the CNS, which lead to immune-mediated inflammation, demyelination, and subsequent axonal damage in white matter . TraditiZhang et al. delineated the repulsion guide molecule-a (RGMa) is involved in the pathogenesis of MS/EAE by affecting BBB permeability. Next, Zhang et al. demonstrated that RGMa causes dysfunction of endothelial cells through BMP2/BMPR II/YAP, leading to disruption of BBB integrity in MS. This provides new insights for MS clinical treatment focusing on maintaining the BBB Zhang et al.In the early stages of MS, inflammatory cells infiltrate into the CNS through a compromised blood-brain barrier (BBB). Chen et al. Meanwhile, CD4+CD25+forkhead box P3+ (Foxp3) regulatory T cells (Tregs) play a central role in the immune regulation of NMOSD. Ma et al. discovered that Tregs attenuated immune cell infiltration in NMOSD mice, and polarized macrophages/microglia to an anti-inflammatory phenotype, thus mitigating white matter inflammation  and involves the optic nerve and spinal cord. Previous studies have proved that microglial and macrophage activation are required for NMOSD pathogenesis ammation .Wang et al. detected lymphocyte subsets in whole blood by flow cytometry and explored the changes in circulating lymphocyte subsets before and after immunotherapy for NMOSD and their correlation with clinical outcomes. Tacrolimus (TAC) inhibits the immune inflammatory response by interfering with the differentiation and proliferation of T cells and was used for the maintenance treatment of NMOSD in some studies. Wang et al. found that the proportions of some lymphocyte subsets changed obviously before and after TAC treatment. EDSS score may be associated with certain lymphocyte subsets after TAC therapy Wang et al..Besides, numerous B cell subsets also play significant roles in the pathogenesis of NMOSD. Wang et al. developed an outcome prediction model and validated it in a multicenter validation cohort. Wang et al. reported a variety of factors, including demographics, clinical and therapeutic predictors of relapse, etc. to identify factors that predict relapse in AQP4-ab-positive NMOSD patients. These results suggest that early identification of patients at risk of adverse outcomes has significant implications for clinical treatment decisions Wang et al.In addition, predictors of disease relapses in AQP4-ab-positive NMOSD patients are critical for individualized therapy. Immune Mechanism in White Matter Lesions: Clinical and Pathophysiological Implications” has collected a variety of valuable research and contributions on WMLs. The articles on this topic highlight the molecular mechanism involved in the pathology of demyelination and the innovative therapeutic approaches for white matter lesions, both of these are of clinical and pathophysiological importance.In summary, the Research Topic of “X-WP drafted the manuscript, CM, WQ, L-JWand D-ST collaborated the topics. All authors contributed to the article and approved the submitted version


Histories of large-scale horizontal and vertical lithosphere motion hold important information on mantle convection. Here, we compare continent-scale hiatus maps as a proxy for mantle flow induced dynamic topography and plate motion variations in the Atlantic and Indo-Australian realms since the Upper Jurassic, finding they frequently correlate, except when plate boundary forces may play a significant role. This correlation agrees with descriptions of asthenosphere flow beneath tectonic plates in terms of Poiseuille/Couette flow, as it explicitly relates plate motion changes, induced by evolving basal shear forces, to non-isostatic vertical motion of the lithosphere. Our analysis reveals a timescale, on the order of a geological series, between the occurrence of continent-scale hiatus and plate motion changes. This is consistent with the presence of a weak upper mantle. It also shows a spatial scale for interregional hiatus, on the order of 2000–3000 km in diameter, which can be linked by fluid dynamic analysis to active upper mantle flow regions. Our results suggest future studies should pursue large-scale horizontal and vertical lithosphere motion in combination, to track the expressions of past mantle flow. Such studies would provide powerful constraints for adjoint-based geodynamic inverse models of past mantle convection. Figure et al. . Couette [et al.  tied to  [et al.  from pre [et al.  for timen et al. . This flnd (e.g. ). We cho m (e.g. ). Δx is c models ,138. The [et al. . It varic models –143. The2 N m−1 ,150137,1Base of Lower Cretaceous, figure 3a, for Africa and South America. This result is a consequence of the large Couette flow inferred at that time for the upper mantle beneath Africa and South America from the assumed plate motion model [et al. [et al. [We close with some implications, starting with the Poiseuille flow dominated area on model . The laton model  from preon model  for timen et al. . O’Neil  [et al.  drew atton (e.g. ), which on e.g. ,154). Bu. BuAf coon e.g. ,143) see seeAf coet al. [Next, we recall that Hayek et al. ,46 interet al.  for a reet al. ,157), thet al. ). Our re cm yr−1  as repreFinally, we turn to plate boundary forces. Several studies emphasized their role in the Indian Ocean realm –118 owin. 6We have used continent-scale hiatus maps as a proxy for mantle flow induced dynamic topography and compared them with plate motion variations in the Atlantic and Indo-Australian realms since the Jurassic, building upon earlier work and exploiting growing observational constraints on both. We find that oceanic spreading rate changes and hiatus surfaces frequently correlate, except when plate boundary forces may play a significant role. Our work is geodynamically motivated from the description of asthenosphere flow beneath tectonic plates in terms of Poiseuille/Couette flow. This description explicitly relates plate motion changes, induced by evolving basal shear forces (Poiseuille flow), to non-isostatic vertical motion of the lithosphere. Our analysis reveals a timescale on the order of a geologic series between the occurrence of continent-scale hiatus and plate motion changes. It is best interpreted through dynamic topography response functions of dynamic Earth models, because a weak asthenosphere delays significant surface deflections into the final phase of material upwellings, when buoyant flow enters from the lower into the upper mantle. Our analysis suggests that the spatial scale of interregional hiatus, which is on the order of 2000–3000 km in diameter, should be interpreted through Poiseuille flow, where it corresponds to regions of active plume-driven upper mantle flow. We use fluid dynamic arguments to show that such active upper mantle flow can induce plate motion changes of


With the increased use of extended-criteria donors, machine perfusion became a beneficial alternative to cold storage in preservation strategy for donor livers with the intent to expand donor pool. Both normothermic and hypothermic approach achieved good results in terms of mid- and long-term outcome in liver transplantation. Many markers and molecules have been proposed for the assessment of liver, but no definitive criteria for graft viability have been validated in large clinical trials and key parameters during perfusion still require optimization.In this review, we address the current literature of viability criteria during normothermic and hypothermic machine perfusion and discuss about future steps and evolution of these technologies. The ongoing discrepancy between organ demand and supply has moved the spotlight toward implementing rescue strategies for extending the pool to deceased donors that were previously considered marginal or even unsuitable for transplantation ,2,3. In In this review, we evaluate the current literature on MP with the aim to provide a concise overview on the adopted viability criteria during NMP and HMP and discuss about the future steps and the evolution of these technologies.A systematic of the published literature, with the goal to investigate viability criteria in machine perfusion for LT was carried out on the 1 August 2022. Inclusion criteria for this review were as follows: A search of the MEDLINE, Scopus and Cochrane Database was conducted using the following terms: for NMP section: (“normothermic” AND/OR “machine perfusion”) AND liver transplantation” AND ((“2005/01/01”[Date—Publication]: “2022/08/01”[Date—Publication])), for HMP section: ((hypothermic) AND (machine perfusion)) AND ((“2005/01/01”[Date—Publication]: “2022/08/01”[Date—Publication])). The references of each of the selected articles were also evaluated in order to locate additional studies that were not included in the initial search. Only clinical studies on human graft were considered.The search streategy was performed by the Preferred Reporting Items for Systemic Reviews and Meta-Analysis (PRISMA) guidelines  Figure . Relevant articles were extracted independently by four authors  who evaluated and excluded duplicates. No specific search dates were used. Consensus for the relevance of an included study were carried out by four senior authors . Given the heterogeneity of the selected studies and paucity of patients identified within the selection criteria, the results are reported as a narrative review.NMP provides a near-physiological environment to the liver, has the potential to evaluate high-risk grafts viability, allow organ therapeutics and improve transplant logistic by prolonging the preservation time up to 24 h .® device for a median of 9.3 h (3.5–18.5h). The study demonstrated that NMP was safe and feasible reporting 100% graft survival at 1 and 6 months in the NMP groups versus 97.5% at the same time points in the static cold storage (SCS) group, respectively. Selzner et al. [TM as an alternative to a red blood cell-based perfusate. They reported a 100% 3-months graft survival in the study group and demonstrated the safety of the Steen SolutionTM for ex-situ NMP. Bral et al. [® device was initiated at the donor center. Nasralla et al. [p = 0.01), evidence of IRI at histology , incidence of IC at 6  and 12 months after LT , larger use of DCD livers . Reiling et al. [The first phase-1 non-randomized prospective clinical trial evaluating NMP in LT was performed in 2016 by Ravikumar et al.  in which3 h 3.5–1.5h. The a et al.  analyseda et al.  investiga et al.  performea et al.  showed bg et al.  describeg et al.  presente.3 h 3.5–.5h. The g et al.  tested tMany metabolic and dynamic parameters are used during ex-situ NMP to evaluate graft quality and viability, but the predictive value of perfusate biomarkers on post-LT outcomes remains to be established. The studies that focused on the liver viability parameters during NMP are summarized in p = 0.02), IC , biliary complications , and 1-year graft survival . Re-transplantation rate was higher in SCS group (18% vs. 0%). Similarly, Guarrera et al. [HMP is gaining increasing widespread acceptance in the preservation of marginal liver grafts ,22,23,24a et al.  perfuseda et al.  compareda et al. . In anota et al. . Moreovea et al. .NMP is an ex-situ technology that maintains the liver at 37 °C in a physiological state through the delivery of oxygen and nutrition. Throughout perfusion, hepatic artery (HA) pressure is set to 70 mm Hg and portal pressure to 6–8 mm Hg. The flow rates targets are >150 mL/minute in the HA and 600–1200 mL/minute in the portal vein (PV). During perfusion, serial arterial perfusate and bile samples are collected and biopsies for serial histological analysis can be obtained. Many metabolic and dynamic parameters are used during ex-situ NMP to evaluate graft quality and viability, but the predictive value of perfusate biomarkers on post-LT outcomes remains to be established. LactatesLactate clearance is the most used viability criteria during NMP evaluation. Lactate is a product of anaerobic glycolysis. The anoxia in the donor is the common cause of lactate elevation. The liver is the major organ responsible for lactate clearance, thus lactate represents a dynamic biomarker to monitor the function of the liver grafts . In the In the first experience of Mergental et al.  lactate Ghinolfi et al. ,33 propoQuintini et al.  argued tTo date, not only lactate clearance but a combination with other parameters and the normalization of the lactate values per liver size and amount of perfusate are key factors for the decision to transplant a graft. TransaminasesAlthough transaminases value is one of the most used markers of injury during perfusion, its correlation with post-operative outcome is poor and the level during perfusion could be influenced by the “wash-out” phenomenon and the size of the liver . Wash-ouIn the clinical setting, no defined cut-off values were adopted. Only grafts with very high levels of perfusate transaminases are discarded (ranging from >5000 up to 9000 IU/L based on center experience and preferences). Watson et al.  reportedp = 0.092; r = 0.560).Nasralla et al.  showed tGlucose MetabolismGlucose is also an easy and rapid marker of viability. Initially, glucose in the perfusate is high due to the glycogenolysis activated during SCS. One hour after commencing NMP, functioning livers determine the glucose concentration fall due a block of glycogenolysis and trigger of glycogenesis. Low levels of glucose at NMP start are related to PNF. The stimulation test with exogenous glucose was suggested by Watson . In caseSeveral authors considered glucose metabolism as an important viability marker in multiparametric assessment ,19,34. NPhPerfusate pH is usually low at the beginning of NMP due to hypoxia and anaerobic metabolism. During perfusion, pH must maintain within a physiological range. Bicarbonate may be administered at the beginning to correct pH, but several authors  reportedPlatelet and Coagulation FactorsProduction of coagulation factors could show the efficient synthetic function of the liver. Eshmuminov et al.  in theirMore recently, Weissenbacher et al.  tested tBile EvaluationBile storage and analysis are routinely performed during NMP with the aim to find markers predictive of IC or biliary complications, which remain the Achille’s heel of LT ,41,42,43Watson et al.  were theSeveral groups proposed to evaluate the bile in relation to other perfusate parameters. Matton et al.  showed tNovel biliary biomarkers have been recently reported in literature. Matton et al.  investigCold preservation relies on the suppression of the metabolic rate, as most enzymatic reactions slow down with temperature reduction. Therefore, hypothermic technologies are traditionally considered less useful in assessing graft viability. Moreover, in the cold, there is a lack of active secretion of bile, which is used as viability parameter during NMP. Even when the perfusion is through the portal vein only, a certain fluid secretion through the biliary tree has been observed during HOPE, corresponding to perfusate mixed with molecules released from the hepatocytes . HoweverAccording to recent research, the key mechanism of (D-)HOPE seems to be the modification of the mitochondrial metabolism, as reported in mammalian hibernation and suspended animation . The delPressure, Flow, and ResistanceVascular resistance during HMP is an independent predictor of functional recovery and graft survival in the context of kidney transplantation, nevertheless, the predictive accuracy is modest and vascular resistance is discouraged to be used as the sole basis for organ acceptance ,51. A siTransaminase, Lactate Dehydrogenase, Glucose, and LactateIn the first clinical series published by Guarrera et al.  transamiFlavin MononucleotideAmong the many functions of the liver and the consequent many confounders, Panconesi et al.  have poiThe Zurich group has recently found that FMN, determined by fluorescence spectroscopy in HOPE perfusate, correlated with early graft loss, cumulative complications, and hospital stay after liver transplant ,60. BaseDespite the validation in several cohorts, the establishment of reliable markers during NMP and HMP requires higher caseloads and RCT. Nevertheless, these trials can be hardly planned for many reasons: (1) no clear endpoints and graft risk scores are defined in the field of LT and machine perfusion, (2) the presence of several perfusion devices and protocols make multicentric study difficult to be planned, (3) the prohibitive costs discourage the broad utilization of machines .In this scenario, it is very difficult to validate viability parameters during NMP, and lactates and transaminases, the most used markers, have been recently downgraded in several experiences on liver perfusion due to the poor predictive value. Graft viability testing and selection can also be performed during (D-)HOPE. Different parameters have been explored, but only FMN correlated with graft failure. Besides graft selection, the addition of specific molecules to limit IRI may be considered in future research .The challenge for the future is to find dynamic, very specific, rapidly measurable markers able to predict postoperative complications and long-term outcome. Technical advance in laboratory technique , genomic


The physical situation was modelled using boundary layer analysis, which generates partial differential equations for a variety of essential physical factors (PDEs). Assuming that a spinning disk is what causes the flow; the rheology of the flow is enlarged and calculated in a rotating frame. Before determining the solution, the produced PDEs were transformed into matching ODEs using the second order convergent technique (SOCT) also known as Keller Box method. Due to an increase in the implicated influencing elements, several significant physical effects have been observed and documented. For resembling the resolution of nonlinear system issues come across in rolling fluid and other computational physics fields.The purpose of this research was to estimate the thermal characteristics of tri-HNFs by investigating the impacts of ternary nanoparticles on heat transfer (HT) and fluid flow. The employment of flow-describing equations in the presence of thermal radiation, heat dissipation, and Hall current has been examined. Aluminum oxide (Al An artificial neural network was used by Mandal et al.2 to provide investigative statistics. A study of the HT and rheological properties of HNFs for refrigeration presentations was described by Saha et al.3. In this direction different investigations are serviced and documented by Al-Chlaihawi et al.4, Kursus et al.5, Xiong et al.6, and Muneeshwaran et al.7, while Dubey et al.8 provided a brief study in HNF on mechanical revisions. Syed and Jamshed9 looked at how an MHD tangent HNF might migrate across the boundary layer of a stretched slide. In addition, Qureshi10, Jamshed et al.11 and Parvin et al.12 tested the proof of the extended HT of tangent hyperbolic liquids crossways a nonlinearly wavering transparency containing HNFs. References14 list literature related to recent advancements in fluid flow in light of various fluid models.Hybrid nanofluids (HNFs) have distinctive qualities that make them effective in numerous heat transfer applications (HT). When used in conjunction with the wrong fluid, these resources improved heat behavior and convective heat operator measurement. Years ago, the concept of boundary level flow of HNFs over an expanding surface became more astounding due to its generous requests in engineering and industrial research. The investigators have shown a great deal of attention to rehabilitate HNFs that shatter heat transfer due to their affability to the many uses of HNFs. Truncated transfer charges are present in steady liquids such as ethylene, water, glycol combinations, and some types of oils. A 3D-class of HNF was planned by Said et al.16 investigated the stability of tri- HNFs in water-ethylene glycol combination. Sahu et al.17 presented a steady‐state and fleeting hydrothermal examines of single‐phase ordinary movement loop utilizing water‐based tri‐HNFs. Muzaidi et al.18 studied the heat preoccupation possessions of tri-HNFs and its possible upcoming path towards solar thermal applications. Safiei et al.19 patterned the effects of tri-HNFs on surface coarseness and wounding heat in end crushing process. Adun et al.20 introduced a review of tri-HNFs studying the synthesis, stability, thermo physical possessions, HT applications, and ecological properties. Gul and Saeed21 presented a nonlinear assorted convection couple pressure tri-HNFs movement in a Darcy-Forchheimer porous intermediate over a nonlinear widening superficial. Zahan et al.22 used the current presentation of tri-HNFs in water-ethylene glycol mixtures. Hou et al.23 studied the dynamics of tri-HNFs in the rheology of pseudo-plastic fluid with thermal-diffusion and diffusion-thermo properties.Three different kinds of single nanofluids were combined and disseminated in the base fluid to create tri-HNFs. Ramadhan et al.24 improved the effectiveness and PEC of geometric solar gatherer having tri-HNFs utilizing interior helical flippers on rotating discs. Hafeez et al.25 employed the finite element analysis of current energy predisposition founded by tri-HNFs, which influenced by persuaded magnetic field over the rotating discs. Haneef et al.26 presented a arithmetical training on temperature and mass transfer in Maxwell liquid with tri-HNFs using rotating discs. Nazir et al.28 investigated the thermal and mass classes’ conveyance in tri-HNFs with temperature foundation over perpendicular heated cylinder (rotating discs). Alharbi et al.29 gave a computational valuation of Darcy tri-HNFs movement transversely a spreading cylinder with initiation effects.Numerous mechanical devices such as flywheels, gears, brakes, and gas turbine engines, utilize rotating discs. The power needed to effort the circle to overwhelmed frictional drag is determined by shear stresses between the disc and the liquid in which it is rotating, and the local flow field will have an impact on heat transfer. Inappropriately, a lot of variables conspire to thwart any universal analysis; therefore, it is important to consider the flow characteristics as well as the proximity of local geometry. Suliman et al.30. Finite element analysis was used by Mourad et al.31 to study the HT of tri-HNFs engaged in curved addition with uniform MHD. A unique multi-banding application of MHD to a convective transport arrangement using a porous medium and tri-HNF was demonstrated by Manna et al.32. Unsteady hugging movement of tri-HNF in a straight channel with MHD was studied by Khashi'ie et al.33. Using an arcade current and MHD, Lv et al.34, Khan et al.35, and Alkasasbeh et al.36 distributed a numerical technique near microorganisms tri-HNF movement over a rotating flappy. The HT of MHD dusty HNFs along a decreasing slide was examined by Roy et al.37. The fractional calculus was reused by Khazayinejad and Nourazar38 to describe a 2D-fractional HT analysis of HNF in conjunction with a leaky plate and MHD. The tri-HNF curved in a depressed tube endangering the MHD was compressed by Gürdal et al.39. A study on a quick and sensitive MHD device based on a photonic quartz grit with magnetic liquid penetrated nanoholes was reported by Azad et al.40. The impact of the MHD on the thermal effect in magnetic fluid was taken into consideration by Skumiel et al.41. The effect of adjustable MHD on the viscous fluid between 3-D rotatory perpendicular hugging platters was investigated by Alam et al.42.The magnetic effect on stirring rechargeable jobs, power-driven flows, and magnetic resources is controlled by a Magnetohydrodynamics (MHD), which can be conceptualized as a vector field. A force perpendicular to the control's own velocity and the MHD is used as an influencing control in an MHD. The MHD of nanoscale HT of magnetized 3-D chemically radiative HNFs was discussed by Ayub et al.43 considered an examination of the moderately ionized kerosene oil-based tri-HNFs movement over a convectively animated revolving shallow. Wang et al.44 presented a strategy for tri-HNFs combination in ethylene glycol encompassing movable diffusion and current conductivity using non-Fourier’s scheme. Sohail et al.46 suggested a study of tri-HNFs diffusion species and energy transfer in material prejudiced by instigation energy and heat source. Nazir et al.47 presented a significant manufacture of current dynamism in incompletely ionized hyperbolic tangent substantial created by ternary tri-HNFs50. Include recent updates that explore nanofluids with heat and mass transmission in diverse physical circumstances.While an electric field is supplied to an electrode that also contains a MHD, the current continuously exists and is known as a Hall current . Ramzan et al.54 utilized the KBM in different types of tri-HNFs to improve the thermal efficiency, comparative examination, single phase based study, thermal expansion optimization and a numerical frame effort respectively. Shahzad et al.55 studied the movement and HT occurrence for dynamics of tri-HNFs in sheet subject to Lorentz force and debauchery possessions. Alwawi et al.56 used the KBM to optimize the HT by MHD tri-HNFs over a cylinder. Alazwari et al.57 considered the KBM to discuss the entropy optimization of first-grade viscoelastic tri-HNFs movement over a widening slip by consuming classical KBM. Kumaran et al.59 presented numerical studies based on KBM.The Keller-Box method (KBM) is an implicit approach for reducing a set of ODEs to a system of first-order DEs, which is one of the numerical strategies for solving problems. The KBM is used widely by many researchers in HNF generally and tri-HNFs particularly. Jamshed et al.2O3), copper oxide (CuO), silver (Ag), and water (H2O) nanomolecules make up the ternary HNFs under study. The resilient SOCT is used to find numerical solutions once the controlling PDEs system is converted into linear ODEs using the correspondence approach. Numerical results are shown graphically, and comments are built upon. The effects on particle morphologies, the convective slip boundary condition, the thermal radiative flow, and the slippery velocity have all been well addressed.Nobody has looked into the HT of tri-HNFs in excess of a revolving disk using linear energy, Hall current, and heat degeneracies, or the mixing of ternary HNFs in MHD flow. Aluminum oxide  electrically steering movement of HNFs across a stretchable spinning disk with current energies and Hall movement in the cylindrical coordinate system mentclass2pt{minim60 were made in order to simplify the issue:The succeeding presumptions2O3, Ag and CuO.There are three different types of nanoparticles in the flow, including AlIt is expected that a adequately enough magnetic field persuades the Hall current. When an electric field is present, the comprehensive Ohm's law has the subsequent arrangement:2, Al2O3, and Ag with the consideration of water (H2O) as an improper fluid in the current problem.Figure s) at z = 0 may be stretched uniformly in the radial direction at a stretching rate of (c). Hence, the governing equations60 of continuity, momentum and energy areThe schematic diagram in cylindrical coordinates  and  and 6) aWith boundary conditionsAt the nanoscale, skin friction and the Nusselt quantity are very useful for manufacturing purposes. Skin frictions, a modern physical issue, are described as:64). In the dimensionles governing Eqs.  known as Keller box method (KBM) (seeing Eqs. –15) wit wit64). ing Eqs. . The doming Eqs. a.Figure We start with introducing new independent variables on, Eqs. –15) red red\docuFurthermore, domain discretization in entclass1pt{minimaApplying central difference preparation at midpoint Equations –35) are are35) aSubstituting the terminologies gotten in –35) and and35) aThe linearized scheme then takes the chunk tridiagonal assembly shown below.Now we factorize A as66. In addition, Table Table (M) are displayed in Fig. 2O3, CuO and Ag nano-molecule. In the profiles, the Al2O3 + CuO + Ag/water tri-hybrid nanofluids demonstrated stronger impact on the flow dimensions than the Al2O3 + CuO/water hybrid nanofluid and unitary Ag/water nanofluid. The gyration and random motion of the nanoparticles encouraged the fluid thermodynamic mechanism, which leads to an enhanced flow characteristic. The metal oxide and metallic nanoparticles carry current and heat energy about the stretching boundary plate to influence the fluid thermal dispersion.The sensitivity of the movement appearances to the rising magnetic term 2O3 + CuO + Ag/water tri-HNFs. The rising effect is significant because of the generated electric potential that is normal to the applied right angle magnetic field and the flowing electric current past a conducting nanomaterial. Therefore, the current carrying nanoparticles stimulate viscous heating that discourages molecular bonding, which leads to the overall rise in the flow characteristics. The effect of nanoparticle fractional volume 2O3 + CuO + Ag/water tri-HNFs, the more the thermal conductivity of the nanoparticles. The particle volume fraction increased the thermal coefficient and the density of the nanoparticles, which correspondingly raised the heat transfer as presented in the plot.In Fig. 2O3 + CuO + Ag/water tri-hybrid nanomaterial to break nanoparticles chemical and molecular bonds. This propels nanoparticle interaction, and boosted the heat conduction and transfer rate. Thus, temperature distribution is raised. Likewise, in Fig. 2O3 + CuO + Ag/water tri-hybrid nanomaterials, which encouraged thermal conductivity.Figure The comparison of the numerical outcomes for various fluid dynamical parameters is presented in Tables 2O3 + CuO + Ag/water tri-hybrid nanomaterial is investigated in a base fluid. To investigate the sensitivity of thermodynamic fluid parameters under considered boundary conditions, quantitative numerical results and qualitative graphical results are presented. The following are the study's findings, as summarized below: The base fluid thermal conductivity is strengthened with the combined Al2O3 + CuO + Ag/water tri-HNFs.The volume fraction of nanoparticles had a significant impact on flow characteristics and heat distribution.A rising value of the Hall current term momentously encouraged the flow velocity field and thermal distribution all over the flow regime.The increasing values of the radiation, heat dissipation, and unsteadiness factors increase the HT rate.To investigate the impact of Hall current on the radiative ternary HNF flow over a rotating disc influenced by magnetic field, a second order convergent analysis was performed. The thermal conductivity strength of the flowing AlHence, tri-HNFs will assist in obtaining the desired thermal conductivity strength of an industrial working fluid and improved nanotechnology advancement.To contribute to the increasing demand of nanofluids for industrial and domestic usages, further study is encouraged. As such, this investigation can be extended to various combination of nanofluids under diverse boundary constraints. Also, different base fluids such as engine oil, glycol and others can be considered to appropriately determine the best nanomaterial for the augmentation heat propagation and conduction.73.The SOCT could be applied to a variety of physical and technical challenges in the future


Key messageFasciitis might be a cause contributing to myalgia in patients with MCTD.Dear Editor, MCTD, a concept proposed by Sharp et al. . ANAs were present at a titre of 1:5120 in a speckled pattern. Anti-Sm and anti-dsDNA antibodies were negative. Anti-U1-RNP antibody was positive at 550 U/ml. A CT scan of the lung revealed a small amount of pleural effusion and very mild reticular opacities. Ultrasonic cardiography showed no evidence of pulmonary hypertension and preserved left ventricular function. A diagnosis of MCTD was made according to criteria proposed by the Ministry of Health and Welfare of Japan [e fibres  and milde fibres . No eosiThe most remarkable characteristic in this case is that fasciitis was detected histopathologically instead of myositis, although the patient showed severe myalgia. We reported that myalgia in patients with DM and PM was attributable to fasciitis rather than myositis . Clinicaet al. [Matsuda et al.  reportedet al. . Taken tWe report a unique case of MCTD with severe myalgia and fasciitis. Fasciitis can lead to severe myalgia. When patients with MCTD show severe myalgia, we should suspect the presence of myositis and fasciitis.Funding: This work was supported by JSPS KAKENHI grant number 22K08551 and Japanese Non-surgical Orthopedics Society （JNOS） grant number JNOS202101.Disclosure statement: The authors have declared no conflicts of interest.


Interface Focus (in two parts) brings together articles on time-keeping and decision-making in living cells—work that uses precise mathematical modelling of underlying molecular regulatory networks to understand important features of cell physiology. Part I focuses on time-keeping: mechanisms and dynamics of biological oscillators and modes of synchronization and entrainment of oscillators, with special attention to circadian clocks.To survive and reproduce, a cell must process information from its environment and its own internal state and respond accordingly, in terms of metabolic activity, gene expression, movement, growth, division and differentiation. These signal–response decisions are made by complex networks of interacting genes and proteins, which function as biochemical switches and clocks, and other recognizable information-processing circuitry. This theme issue of  As in aytoplasm . Cellulaet al. [Journal of the Royal Society Interface on ‘biological switches and clocks'. As a follow-up to that issue, Interface Focus is presenting a two-part collection of articles on the theme of ‘time-keeping and decision-making in living cells'.The theoretical foundation for understanding time-keeping and decision-making in molecular regulatory networks was crafted in the 1960s and early 1970s by the pioneering work of Goodwin ,9, Roesset al.  in a supet al. [2+/cyclic AMP (cAMP) oscillations), glycolytic oscillations and inflammatory responses (nuclear factor-κB (NFκB) oscillations). Next, Goldbeter & Yan [et al. [et al. [block transcription , R binding to A may displace A from the promoter (R + A:P → R:A:P → R:A + P) and R binding to A may sequester A from P (R:A prevents A from binding to P)—they show that synergistic interactions of the three modes generate ultrasensitive transcriptional responses and robust oscillations.Part I focuses on time-keeping, in particular on mechanisms of biological oscillators, on synchronization of intercommunicating oscillators and on entrainment to external driving rhythms, with particular emphasis on circadian rhythms. Jiménez et al.  lead offer & Yan  present  [et al.  provide  [et al.  investigPart II will focus on decision-making in cell differentiation, development and cell cycle progression.. 2Because this theme issue presents only a few snapshots of the immense progress that has been made on biological clocks since the 2008 collection, we review here some other recent developments.Per1, Per2, Cry1, Cry2, Clock, Bmal1, Rev-erbα and Rorα), have been remarkably successful in accounting for the physiological properties of circadian rhythms in wild-type and mutant cell lines [et al. [et al. [et al. [et al. [Cry1 −| Per2 −| Rev-erbα −| Cry1) as a dominant source of oscillations in their models [et al. [As might be expected, considerable progress has been made in understanding the molecular mechanisms underlying circadian rhythms. Firstly, some new models of mammalian clock, taking into account interactions among the principal clock genes . By fit [et al. ,41 identr models . Ko et a [et al.  have hig [et al. –46.et al. [et al. [et al. [et al. [et al. [Intercellular coupling and synchronization of circadian clocks have also been the subject of many publications. Bernard et al.  showed t [et al.  suggeste [et al. . Studies [et al. ,50 and b [et al.  have foc [et al.  further Neurospora crassa, Dovzhenok et al. [et al. [et al. [The interplay of circadian clocks and metabolism has received much attention. Using a combination of mathematical modelling and experiments in k et al.  found an [et al.  introduc [et al.  used a c [et al. ,57 devel [et al.  used a met al. [Wee1 is upregulated by an E-box, which binds to the master transcription factor BMAL1 : CLOCK. Zamborszky et al. [Wee1 expression, would generate quantized cell cycle times and cell division sizes. Later, Gerard & Goldbeter [et al. [et al. [et al. [We also draw your attention to some additional studies of interactions between the circadian clock and the cell division cycle, based on the unexpected discovery by Matsuo et al.  that tray et al.  used matoldbeter  found en [et al.  found mu [et al. . And, Ma [et al. , using d [et al.  used matFinally, we review recent proposals that the cell division cycle is a ‘clock-shop' of autonomous (independent) oscillators entrained to one another. It is commonly thought that cell cycle events  are controlled by a ‘master programme' based on fluctuations of cyclin-dependent kinases (Cdks) and their immediate regulators ,67. HoweAltogether, these recent studies and many others have contributed greatly to our understanding of the molecular regulatory mechanisms underlying biological oscillations and of their advantageous properties, such as robustness, tunability, entrainment and temperature compensation. Also, we now have a better appreciation of the—often non-intuitive—dynamics resulting from the interplay between clocks and clock-controlled processes. This progress has revolutionized our interpretation of experimental observations and our vision of future progress in health science and biotechnology.. 32+ waves in fertilized eggs [Joel E. Keizer (1942–1999). As a physical chemist, Joel Keizer made fundamental contributions to the theory of non-equilibrium thermodynamics before turning his attention to the application of dynamical systems theory to problems in cell physiology, most notably complex bursting oscillations in pancreatic β-cells and Cazed eggs ,82.Benno Hess (1922–2002). As director of a Max-Planck-Institute in Dortmund, Germany, Benno Hess directed a large group of biochemists and mathematical modellers exploring the molecular mechanisms of glycolytic oscillations in yeast cells .Arthur T. Winfree (1942–2002). An engineer by training, Art Winfree turned his creative mind to the dynamics of oscillations and wave propagation in living organisms. His predictions of ‘phase singularities' in circadian rhythms and cardiac physiology revolutionized our understanding of these fields ,85.Rene Thom (1923–2002). The purest of pure mathematicians, Rene Thom was among the first persons to recognize the relevance of bifurcations of vector fields to temporal and spatial organization in living organisms ,87.Ilya Prigogine (1917–2003). The 1977 Nobel Prize in Chemistry was awarded to Ilya Prigogine for his fundamental insights on far-from-equilibrium thermodynamics, most notably on ‘dissipative structures'  in living organisms .Lee A. Segel (1932–2005). A world-renowned applied mathematician, Lee Segel made major contributions to the theory oscillations, pattern formation and wave propagation in living cells ,90.Reinhart Heinrich (1946–2006). A physicist who moved into biochemistry, Reinhart Heinrich combined modelling of specific cellular systems with a search for general principles. As one of the founding intellects behind metabolic control theory, he upset the paradigm of ‘rate-limiting' steps in biochemistry by showing, in quantitative detail, how flux control is distributed across all enzymes in a metabolic network .Brian Goodwin (1931–2009). A Canadian émigré who got his PhD at the University of Edinburgh under Conrad Waddington, Brian Goodwin had a lifelong interest in development and evolution and was a leading figure in the renaissance of mathematical biology in the 1960s. His pioneering work on biochemical oscillators is reverberating to this day .Christopher Zeeman (1925–2016). A leading English mathematician and early convert to Thom's theory of singularities of vector fields, Christopher Zeeman applied ‘catastrophe theory’ in creative ways to a wide variety of phenomena in biology, as well as other fields ,94.Rene Thomas (1928–2017). The Belgian biochemist Rene Thomas was an early proponent of ‘logical modelling' of biochemical reaction networks (i.e. modelling by Boolean functions). Early on he recognized the importance of negative feedback in generating biochemical oscillations and positive feedback in creating biological switches .Gregoire Nicolis (1939–2018). A chemical physicist at the Free University of Brussels, Gregoire Nicolis led a team of talented and creative younger scientists in the application of Prigogine's abstract ideas about non-equilibrium thermodynamics and ‘dissipative structures' to real-world problems in chemistry, physics and biology ,97.George F. Oster (1940–2018). After an unusual start in the merchant marines and nuclear physics, George Oster studied biophysics and applied his massive intellect to a theoretical understanding of some of the toughest problems in molecular cell biology, including morphogenesis, pattern formation and molecular motors ,99.Garrett M. Odell (1943–2018). Trained in applied mathematics and theoretical mechanics, Garry Odell took an abrupt turn to mathematical biology, where he made many remarkable contributions to our understanding of chemotaxis, embryogenesis, molecular motors, gene regulatory networks and cytoskeletal mechanics .The theoretical foundations of time-keeping and decision-making by the molecular regulatory networks in living cells were laid out in the 1970s and 1980s by a small band of physical chemists, biochemists, chemical engineers and mathematical biologists. Unfortunately, many of these pioneering scientists have passed away and are sorely missed. In conclusion, we would like to recognize their contributions to the field.