Thyroid cancers (TCs) are the most prevalent malignancy of the endocrine system and the seventh most common cancer in women. According to estimates from the Global Cancer Observatory (GCO) in 2020, the incidence of thyroid cancer globally was 586,000 cases. As thyroid cancer incidences have dramatically increased, identifying the most important metabolic pathways and biochemical markers involved in thyroid tumorigenesis can be critical strategies for controlling the prevalence and ultimately treatment of this disease. Cancer cells undergo cellular metabolism and energy alteration in order to promote cell proliferation and invasion. Glutamine is one of the most abundant free amino acids in the human body that contributes to cancer metabolic remodeling as a carbon and nitrogen source to sustain cell growth and proliferation. In the present review, glutamine metabolism and its regulation in cancer cells are highlighted. Thereafter, emphasis is given to the perturbation of glutamine metabolism in thyroid cancer, focusing on metabolomics studies.  KG α-ketoglutarateTCA tricarboxylic acidOAA oxaloacetateGSH GlutathioneGLUD glutamate dehydrogenaseGOT glutamate oxaloacetate transaminaseGPT glutamate pyruvate transaminaseATC anaplastic thyroid cancerFNAB fine-needle aspiration biopsyCITED1 Cbp/p300-interacting transactivator1TTF-1 thyroid transcription factor 1CEA carcinoembryonic antigenHBME-1 hector battifora mesothelial-1ATP adenosine triphosphateGln glutamineNEAA non-essential amino acidASCT2 amino acid transporter-2GLS glutaminasemTORC1 mammalian targets rapamycin complex 13 TriiodothyronineTGSSG oxidized glutathione Globally, thyroid cancers (TCs) are the most common head and neck malignancy and the seventh most prevalent cancer in women . HistolThe complexity of cancer in terms of diverse processes that drive the formation, growth, development, and progression of tumor cells continues to present a great challenge to the medical field. Over the past decade, many theories of the molecular mechanisms involved in cancer with a focus on individual factors and processes have emerged. Presently, several defined hallmarks for the cancer process are co-opted together to provide a conceptual framework for the complexity inherent in cancer . MetaboGlutaminolysis is another considerable metabolic reprogramming of cancer cells that mediates anaplerotic reactions to supply tricarboxylic acid (TCA) cycle intermediates . GlutamThis paper will review the experiments conducted on the role of Gln metabolism in TCs with additional consideration on possible mechanisms linking perturbation of Gln metabolism to pathological conditions.4+ and can occur in several tissues such as the brain, liver, lungs, adipose and skeletal muscles . Furtheal., 2007; Roth, 2al., 2007). This ral., 2007). 4+ into Gln and ATP products  and glutaminase. GS in the cytosol is subject to transform glutamate plus NHal., 2017; Krebs, al., 2017). In facal., 2017; Neu et al., 2017). It is al., 2017). GLS inal., 2016; Curthoyal., 2016).via SLC7A5/ SLC3A2, and leucine enters the cell; thereby, adapting a rate-limiting step for mTORC1 ac-tivation . Among  Figure 1 . Moreoval., 2017). Furtheal., 2017; Yang etal., 2017). It shoal., 2017). In thial., 2009). Besideal., 2009). Additial., 2009), c-Jun al., 2009), p53 , K-Ras al., 2009), Rb , and Rhal., 2009) have be3) hormone produced by the thyroid gland is essential for numerous functions in the body. T3 can modulate Gln release rate from several tissues, including the liver, kidney, intestine, and immune system cells . Althoual., 1990). Nevertin vivo/in vitro metabolites . Over t1H HRMAS NMR spectroscopy to find metabolic changes in benign (nodular goiter (NG)), malignant , and normal thyroid tissue lesions , no neoplastic nodules (NN), follicular adenomas (FA), and malignant thyroid cancer [65]. In that study, glutamate was one of the remarkable elevated metabolites in all samples . The real., 2013). Metaboal., 2013). D‐glutal., 2013, Seo et al., 2013, Tian etal., 2013). Table al., 2013; Gu et aal., 2013; Lu et aal., 2013; Ryoo etd cancer . In thatal., 2013; Skorupaal., 2013; Tian etal., 2013; Wang etal., 2013; Wojtowial., 2013; Xu et aal., 2013; Zhou etal., 2013) shows a1H-NMR spectroscopy combined with GC/flame ionization detector (FID)/MS techniques  in comparison with healthy thyroid tissues (n = 10). Their work led to the observation that the total GSH was increased in cancer lesions compared to the healthy control group , MNG (n = 16), and healthy volunteers (n = 20), in a GC-MS-based metabolomics approach. It was observed that glutamic acid level was substantially increased in the PTC group compared to healthy subjects. Moreover, pathway analysis showed perturbations in D-Gln and D-glutamate and GSH metabolism with common impacts in both PTC and MNG tumorigenesis . While,al., 2020). Our teBRAF V600E mutation, and the expression of ASCT2 expression was raised in MTC , FTC: 112), MTC: (70), poorly differentiated carcinoma PDC: (23), and ATC: (8), and follicular adenomas, FA (152), a distinct expression pattern in Gln metabolism-related protein among the histopathological subtypes of thyroid cancer was identified . In thaal., 2016). Microa2, MTC:  and tissue samples using several molecular and biochemical approaches revealing that the GLS, a key enzyme in glutaminolysis, was overexpressed in cancer specimens and played a prominent role in the development and progression of PTC . In 201At a glance, increasing evidence suggests that Gln, as a NEAA, plays an important role directly or indirectly in tumorigenesis and cancer cell survival. However, despite the emerging understanding of the biological relevance of Gln in cancer, the research underlying perturbation of Gln metabolism on TCs is restricted. From the studies mentioned above, it is evident that most of the metabolomics studies that reported changes of Gln/glutamate and related metabolic pathways were those that performed NMR approaches with untargeted strategies. Hence, it will be essential to perform quantitative and targeted assays in cohort projects to unravel the biological mechanism underlying Gln metabolism and then find the effect of other factors on it in TCs. Thyroid gland plays pivotal roles in the growth and development of the human body and keeps metabolism under control, and by releasing certain hormones, regulates Gln metabolism. Therefore, significant efforts must be made to untangle the role of Gln metabolism in thyroid tumorigenesis, which can result in a comprehensive understanding of disease progression and ultimately lead to the discovery of novel therapeutic strategies. Crispin R. Dass and Mehdi Hedayati  22432500, Fax: +98(21) 22416264, E-mail: hedayati47@gmail.com, hedayati@endocrine.ac.ir) contributed equally as corresponding author.The authors declare that they have no conflict of interest.All authors contributed to the study conception and design. The first draft of the manuscript was written by Raziyeh Abooshahab. Kourosh Hooshmand and Fatemeh Razavi edited the manuscript. Mehdi Hedayati and Crispin R. Dass approved the final version. All authors participated in the critical revision of the manuscript for important intellectual content.


Culinary skills are important objects of study in the field of Public Health. Studies that propose to develop instruments for assessing such construct show lack of methodological uniformity to report validity and reliability of their instruments.To identify studies that have developed instruments to measure culinary skills in adult population, and critically assess their psychometric properties.We conducted a systematic review according to the PRISMA statement. We searched literature PubMed/Medline, Scopus, LILACS, and Web of Science databases until January 2021, and consulted Google Scholar for relevant grey literature. Two reviewers independently selected the studies, conducted data extraction, and assessed the psychometric quality of the instruments. A third reviewer resolved any doubts or disagreements in all steps of the systematic review.The search identified 1148 potentially relevant studies, out of which 9 met the inclusion criteria. In addition, we included 3 studies by searching the related articles and the reference lists of these studies, totaling 12 included studies in this review. Ten studies reported the development of tools measuring culinary skills in adults and 2 studies performed cross-cultural adaptations of original instruments. We considered adequate quality of internal consistency reliability in four studies. One study received adequate rating for test-retest reliability. No studies presented adequate rating for content validity and four studies showed satisfactory results for at least one type of construct validity. One study reported criterion validity and the quality of this psychometric property was inadequate.We identified many studies that surveyed culinary skills. Although the isolated measures appraised in this review show good promise in terms of quality of psychometric properties, no studies presented adequate measures for each aspect of reliability and validity. A more consistent and consensual definition of culinary skills is recommended. The flaws observed in these studies show that there is a need for ongoing research in the area of the psychometric properties of instruments assessing culinary skills. The discussion about the improvement of culinary skills and food practices has proven to be an important object of study in the field of Public Health; these skills are key factors associated with eating behaviors and with several complexities that represent social determinants of health .Several authors define the term culinary skills in their publications –6, howevCulinary skills are associated with other concepts that involve the practice of proper and healthy eating, such as food literacy, which takes into account the broader social and environmental dimensions of eating together, associated with an individual’s abilities . Those cTime devoted to cooking has decreased and has been viewed as a global trend: food industry investments in advertising and marketing to “solve the everyday food problem” devalue cooking as an emancipatory competence associated with a healthy food routine . Such deet al. (2001) [The main source of cooking knowledge and skills is through parents –17. This. (2001)  found frIn this scenario, culinary skills among adults, especially those responsible for preparing household meals, have been an important focus of research , 17, 19.Before being considered suitable, the instruments must offer accurate, valid, and interpretable data for the population’s assessment. Moreover, the measures are supposed to provide scientifically robust results. These results are established based on measures of reliability and validity of the instruments –22. ReliThere are public health policies focused on cooking in several parts of the world . Despiteet al. (2014) [McGowan . (2014)  conducteAdditionally, previous reviews have not proposed to appraise the quality of psychometric properties of instruments measuring culinary skills, which justifies the importance of this study, given the fact that the diagnosis of one’s skills entrusted to the application of these instruments may be flawed. This could result in planning inappropriate food and nutrition educational actions for providing emancipatory and self-care practices.Therefore, this systematic review aimed to identify studies that have developed instruments to measure culinary skills in adult population, and critically appraise the quality of their psychometric properties.We hope that this study can provide evidence-based guidance on the psychometric properties of instruments measuring culinary skills, to subsidize the selection of valid and reliable instruments by healthcare professionals to assess these subjects in clinical and public health settings and avoid unrealistic expectations about the information that such measures may provide.http://www.crd.york.ac.uk/PROSPERO/; registration number CRD42019130836). The protocol is available in the We registered the protocol of this systematic review on the International Prospective Register of Systematic Reviews . A third reviewer (T.M.L.) resolved any doubts or disagreements between the reviewers regarding the inclusion or exclusion of articles. The third reviewer compared the results of the independent selection of articles carried out by the two reviewers. If the third reviewer identified any differences, he would ask the two authors to discuss their opinions. If the two reviewers did not reach an agreement, the third reviewer would present his opinion.This review, included articles meeting the following criteria: 1) address culinary skills in adults; 2) describe the instrument’s validation and reliability process, which can be original or adapted instruments. No filters for year of publication, country or language were employed. Articles that developed original instruments or reporting cross cultural adaptation of instruments addressed to measure culinary skills in children and adolescents or those whose instruments were not available (in the article or upon request to the authors) were excluded. For initial screening of abstracts and titles, we used the  Reviews . Two autTwo authors (A.R.T. and D.B.) independently performed data extraction using a preformatted spreadsheet in Microsoft Excel. A third reviewer (T.M.L.) resolved any disagreements or doubts resolved any disagreements or doubts occurred in this step, by comparing the data extraction carried out by the two reviewers. If the third reviewer identified any differences, he would ask the two authors to discuss their interpretations. If the two reviewers did not reach an agreement, the third reviewer would present his opinion. We also consulted the third reviewer in case of any doubts regarding the inclusion of potentially relevant articles identified during this step of the systematic review.The information extracted consisted of descriptive data of the study .et al. [et al. (2007) [We determined the psychometric quality according to the rating system adapted from Hair Jr, Black, Babin et al. ; Pedrosaet al. ; and Ter. (2007) . The criet al., 2011 [et al, 2017 [et al, 2011 [et al, 2018 [et al, 2017 [et al, 2019 [et al, 2019 [et al, 2013 [et al, 2013 [The electronic search (including gray literature databases) identified 1148 potentially relevant studies. After reviewing the titles and abstracts, we selected 16 articles for full-text examination. Of these, nine studies  met theal, 2013 ). We ideal, 2013 ; Condraset al, 2011 [et al, 2013 [et al, 2017 [et al, 2019 [et al, 2019 [et al, 2013 [et al, 2018 [et al, 2011 [et al, 2017 [et al, 2011 [Studies were carried out in the United States of America , Brazilal, 2017 ; Martinsal, 2019 ), Canadaal, 2019 ; Kennedyal, 2019 ), Switzeal, 2013 ), Portugal, 2018 ), Scotlaal, 2011 ) and Noral, 2017 ). All ofal, 2011 ).et al, 2013 [et al, 2017 [et al l, 2019 [et al, 2019 [et al, 2017 [et al, 2018 [et al, 2011 [et al, 2013 [et al, 2011 [et al, 2011 [et al, 2011 [et al, 2019 [et al, 2019 [et al, 2018 [Included papers had distinct purposes: those reporting the development of an original instrument, or cross-cultural adaptation of a tool to explicitly measure cooking/food skills or a part thereof (n = 7) and original tools developed to evaluate a cooking and food skills intervention (n = 5). Most tools assessed cooking skills in adults from a particular country , parental, 2019 ), univeral, 2019 ; Jomori al, 2017 ; Kowalkoal, 2018 ) and adual, 2018 ; Condrasal, 2011 ; Condrasal, 2013 ; Barton al, 2011 ). Study al, 2011 , Condrasal, 2011 ; Martinsal, 2019 ; Kennedyal, 2019 ; Kowalkoal, 2018 ; Michaudal, 2018 ; Warmin,al, 2018 ; Vrhovnial, 2018 ). The paAll studies provided description of the construct, with conceptual framework or clear rationale to define their instruments’ construct.et al, 2011 [et al, 2013 [et al, 2011 [et al., 2017 [Six studies reported the development  or crosl., 2017 ) aiming et al. (2011) [et al. (2013) [et al. (2017) [Michaud (2007) , develop. (2011)  reported. (2013)  then ada. (2017)  describeet al. (2011) [et al., 2011 [et al., 2013 [et al., 2017 [Barton . (2011)  also des. (2011) ; Warmin,. (2011) ; Condrasl., 2011 ; Condrasl., 2013 ; Jomori l., 2017 ).et al., 2013 [et al., 2018 [et al., 2017 [et al., 2019 [et al., 2019 [The remaining studies  describet al., 2013 [et al., 2018 [The Cooking Skills Scale  focusedet al. (2017) [rate how good they are at: Microwave food, including heating ready-meals).Lavelle . (2017)  developeet al.’s cooking scale (2013) [et al.’s cooking confidence measure (2017) [et al., (2019) [Unlike the items shown in Hartmann e (2013)  and Lavee (2017) , the Coo, (2019)  focused et al.’s food skills confidence measure (2017) [et al.’s food skills questionnaire (2019) [et al.’s [rate your confidence in boiling, steaming or stewing) and using basic ingredients and seasoning . Vrhovnik’s Food skills survey tool (2012) [Lavelle e (2017)  consistee (2019)  focused et al.’s  instrumel (2012)  also conet al., 2019 [et al., 2013 [et al., 2013 [et al., 2011 [et al., 2019 [et al., 2019 [et al., 2018 [et al., 2017 [et al., 2011 [et al., 2017 [et al., 2018 [et al., 2011 [et al., 2017 [et al., 2019 [et al., 2019 [et al., 2011 [et al., 2011 [et al., 2018 [et al., 2017 [et al., 2019 [et al., 2019 [et al., 2013 [The studies reported analysis of the psychometric properties of their instruments: Only two studies presented statistical methods derived from the experts’ judgment for content validity . Six oul., 2019 ; Condrasl., 2013 , Hartmanl., 2013 ; Barton l., 2011 ; Kennedyl., 2019 ; Martinsl., 2019 ). Two stl., 2018 , Jomori l., 2017 ). Only ol., 2017 ) reportel., 2017 ; Condrasl., 2011 ; Jomori l., 2017 ; Kowalkol., 2018 ; Barton l., 2011 ; Vrhovnil., 2011 ; Lavellel., 2017 , Kennedyl., 2019 ; Martinsl., 2019 ) and/or l., 2019 ; Warmin,l., 2019 ; Condrasl., 2011 ; Barton l., 2011 ; Kowalkol., 2018 ; Lavellel., 2017 , Kennedyl., 2019 ; Martinsl., 2019 ; Hartmanl., 2013 ). Table We describe the quality of the psychometric properties of the instruments in et al., 2011 [et al., 2018 [et al., 2017 [et al., 2019 [et al., 2017 [et al., 2019 [et al., 2011 [et al., 2013 [et al., 2013 [We considered adequate quality of internal consistency reliability in four studies  Three sl., 2019 ; Jomori l., 2017 ; Kennedyl., 2019 ) showed l., 2011  did not l., 2011  did not l., 2011 ; Condrasl., 2013 ; and Harl., 2013 ) did notet al., 2011 [et al., 2013 [et al., 2018 [et al., 2011 [et al., 2017 [et al., 2019 [et al., 2019 [et al., 2018 [et al., 2019 [Kappa, despite adequate design and method. Five studies showed inadequate time interval . Howevel., 2018 ; Martinsl., 2019 ), since l., 2011 ; Hartmanl., 2013 ) or inadl., 2013 ; Warmin,l., 2013 ; Condrasl., 2011 ; Lavellel., 2017 ); therefet al., 2019 [et al., 2017 [et al., 2011 [et al., 2011 [et al., 2013 [et al., 2019 [et al., 2013 [No studies reporting the development or small changes of an original instrument provided adequate measures to show content validity. The authors did not calculate any index of agreement for content validity , or stal., 2013 ; Kennedyl., 2019 ). Moreovl., 2013 ).Regarding construct validity, six studies reported at least one kind of analysis .et al., 2011 [et al., 2018 [et al., 2017 [et al., 2017 [et al., 2017 [et al., 2017 [Self-Efficacy for Using Basic Cooking Techniques (SECT)). Two studies performed cross-cultural adaptations of original instruments . We clal., 2017 ) and retl., 2017 ). In addl., 2017 ), hence,l., 2017 ). Jomoril., 2017  performel., 2017  and Kowal., 2018 ). One ofl., 2018 ). Six stl., 2018 ; Condrasl., 2013 ; Hartmanl., 2013 ; Barton l., 2011 ; Kennedyl., 2019 ; Martinsl., 2019 ).Most studies did not provide information on criterion validity. Only one study  performTo our knowledge, this is the first systematic review to identify and appraise quality of psychometric properties of instruments for assessing culinary skills in adults. This article has provided a comprehensive critical analysis of the studies’ characteristics and their psychometric properties. We found twelve studies developing original instruments to measure culinary skills in adults, or performing cross-cultural adaptations.This systematic review has highlighted gaps in these instruments, suggesting the need to develop new studies with robust and standardized psychometric methodology that shows validity and reliability of culinary skills measurements. Although we considered adequate quality of internal consistency reliability in four studies, only one study received adequate rating for stability (test-retest reliability). No studies developing original instruments presented satisfactory measurement for content validity since the authors did not calculate any index of agreement. Only four studies showed satisfactory results for at least one type of construct validity  and only one study reported criterion validity, however, we considered inadequate quality of this measurement property. These results indicate that although there are isolated measures appraised in this review that show good promise in terms of quality of psychometric properties, no studies presented satisfactory results for each aspects of reliability and validity.et al., 2019 [Most studies are originally from countries whose native language is English. One Brazilian study  original., 2019 .et al., 2011 [Regarding submission of psychometric studies for ethical approval, one study  justifil., 2011 , 50.et al., 2019 [Most studies reported the development of scales, indexes, and questionnaires. One study classified their instrument as an index ; howevel., 2019 .A scale, on the other hand, measures levels of intensity at the variable level, like to what extent a person agrees or disagrees with a particular statement. A scale is a type of measure composed of several items that have a logical or empirical structure among them. The most commonly used scale is the Likert scale. The sum of scores for each of the statements creates an overall score of the intensity related to the assessed latent phenomenon .et al., 2013 [et al., 2018 [et al., 2019 [The majority of the included studies presented instruments with items assessing cooking self-efficacy (regarding food preparation techniques), meal planning and food selection and purchase. The main difference between the instruments referred to the conceptualization of culinary skills: some authors comprehend that such skills comprise the ability to prepare certain dishes, including those based on pre-prepared products and convenience foods . Howevel., 2019 . Thus, ul., 2019 . Hence, et al. (2017) [et al. (2019) [Some authors identify cooking skills as a distinct construct from food skills. Lavelle . 2017)  define c. (2017)  however,. (2019)  seem to . (2019)  conceptu  define . (2019) .Although all instruments reported some psychometric information, the evaluation of the psychometric quality using the criteria adopted in this systematic review exhibited some missing data.et al., 2011 [et al., 2017 [et al., 2018 [et al., 2011 [et al., 2017 [et al., 2019 [et al., 2019 [Regarding the reliability of the instruments, most studies reported internal consistency reliability . Internl., 2019 .et al., 2019 [et al., 2017 [Cooking Behavior scale . Similar results were observed in Jomori et al.’s (2017) [Cooking Behavior (CB) and Cooking Attitude (CA) scales showed low internal consistency reliability. The later authors argued that problems in the process of cross-cultural adaptations concerning translation of the original instrument into Brazilian Portuguese might have occurred. The items corresponding to these scales might not represent the constructs the authors intended to measure [Three studies showed insufficient results for Cronbach’s alpha . Two ofl., 2017  showed is (2017)  study: T measure . Thus, i measure .et al. (2011) [Barton . (2011)  did not . (2011)  tested oet al., 2011 [et al., 2011 [et al., 2013 [et al., 2017 [et al. (2013) [Kappa values (<0.7) in two studies that reported test-retest reliability. Therefore, we rated inadequate quality of this attribute.We considered indeterminate quality of stability reported in six studies, due to insufficient sample size or inadequate time interval to perform test- retest reliability . Hartma. (2013)  performe. (2013) . Particiet al., 2013 [et al., 2013 [et al., 2011 [et al., 2019 [et al., 2019 [Studies that relied exclusively on internal consistency reliability and stability analysis, without performing other psychometric measurements to validate their instruments, may not provide trustworthy results because these instruments reproduce only a consistent result in time and space from different observer (reliability), without measuring exactly what they propose  , 53. Sixl., 2013 ; Hartmanl., 2013 ; Barton l., 2011 ; Kennedyl., 2019 ; Martinsl., 2019 ). The auAll studies aiming to develop and validate an original instrument failed to show proper content validity: most studies relied on face validity, literature research, and experts’ judgment; however, the authors did not calculate any index to confirm experts’ agreement. Content validity based on the use of statistical methods derived from the experts’ judgment, proves itself to be essential. Otherwise, the mere fact that the experts report on the lack or excess of items representative of the construct, or that they simply determine to what extent each element corresponds to the latent phenomena, does not itself provide relevant information for the validation process , 39, 54.et al., 2011 [et al., 2017 [et al., 2018 [et al., 2017 [et al., 2017 [et al., 2017 [et al., 2018 [We evaluated the quality of construct validity measures of studies reporting structural validity , hypothl., 2017 ; Jomori l., 2017 ) or crosl., 2017 ; Kowalkol., 2018 ). We obsa priori ideas about the latent variables researchers intend to measure [Regarding structural validity, two studies performed principal component analysis and three studies performed exploratory factor analysis. No studies performed Confirmatory Factor Analysis (CFA). According to Gruijters, 2019 , explora measure , 31.et al., 2017 [et al., 2018 [Only two out of five studies reporting structural validity  describl., 2018 .EFA is a “large-sample” procedure and that generalizable or replicable results are unlikely if the sample is too small.Michaud (2007)  performeet al. (2017) [Self-Efficacy for Using Basic Cooking Techniques (SECT)). This type of validity evaluates the presence of differences in the measurements obtained between the groups, not whether the measure actually measures the intended construct [The cross-cultural adaptation of Michaud’s (2007)  instrume. (2017)  was adeqonstruct , hence, Vrhovnik (2012) did not provide statistical results for items factor loadings, which may imply inadequate decisions regarding retention or exclusion of an item .et al.’s study (2017) [Buying in Season; Using leftovers to create another meal; Keeping Basics in the cupboard and Reading the best before date), however they were retained in the ‘Food Skills’ factor. When a variable is found to have more than one significant loading, it is hard to make those factors be distinct and represent separate concepts [a priori factor structure could be flawed [Microwave food (not drinks/liquid) including heating ready-meals’. The Brazilian Food Guide (2014) states that although microwaving may be used in meal preparation  it is not seen as a cooking skill.Despite satisfactory results for convergent validity in Lavelle y (2017) , the expconcepts . If an ie flawed . Moreoveet al., 2018 [et al.’s cooking skills instrument (2013) [Kowalkowska l., 2018  performet (2013) . Howevert (2013)  recommenRegarding criterion validity, little information was available in the included studies. Only one study  presented criterion validity . However, we considered inadequate quality of this attribute. These findings were expected since most of the time, the criterion validity is a challenge for the researcher, because it demands a “gold standard” measure to be compared with the chosen instrument, which cannot be easily found in all knowledge areas , 59.This review has some limitations. It is possible that some studies were missed out because they were not indexed in the databases searched, or were published for institutions, foundations, or societies. In addition, although the criteria were adapted from previous studies, the difficulty of interpreting the studies may have under- or overestimated the quality of the instruments’ psychometric properties.This review identified many studies surveying culinary skills; we considered most instruments insufficient, according to the quality of their psychometric properties. Thus, the flaws observed in these studies show that there is a need for ongoing research in the area of the psychometric properties of instruments assessing culinary skills. Moreover, our findings contribute to supporting the selection of valid and reliable instruments by healthcare professionals in clinical and Public Health settings.Measuring culinary skills involves several separate but related domains, which integrate other constructs related to the culinary practices. Therefore, it is recommended that a more consistent and consensual definition of culinary skills as a construct be generated. Instruments should cover items and domains without overestimating one’s skills, based on his/hers ability of heating convenience food. Considering items measuring culinary skills related to the use of using basic ingredients and seasoning proves itself essential for greater understanding of barriers and facilitators related to healthy culinary practices.S1 Appendixhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42019130836.From: Aline Rissatto Teixeira, Daniela Bicalho, Tacio de Mendonça Lima. Evidence for the validation quality of culinary skills instruments: a systematic review. PROSPERO 2019 CRD42019130836. Available from: (PDF)Click here for additional data file.S2 Appendix(PDF)Click here for additional data file.S1 Table10.1371/journal.pmed1000097.From: Moher D, Liberati A, Tetzlaff J, Altman DG. The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.


The importance of prenatal maternal somatic diseases for offspring mood and anxiety disorders may be overlooked or undervalued. We conducted the first systematic review and meta-analysis assessing the risk of offspring mood and anxiety disorders in the context of prenatal maternal somatic diseases.We screened articles indexed in Embase , PsycARTICLES and PsycINFO databases up to August 2021. 21 studies were included. We examined the overall associations between prenatal maternal somatic diseases and offspring mood/anxiety disorders. Analyses were stratified according to maternal somatic diseases and follow-up duration.We observed an increased risk of mood and anxiety disorders in the context of prenatal maternal somatic diseases ; maternal obesity, hypertensive disorders  and infertility  were risk factors for mood disorders; maternal polycystic ovary syndrome , severe obesity  and moderate obesity  were risk factors for anxiety disorders. Prenatal maternal somatic diseases increased the risk of mood disorders in childhood and adulthood , as well as the risk of anxiety disorders in adulthood .The results indicate that prenatal maternal somatic diseases are associated with offspring mood and anxiety disorders, and that the associations may be long-lasting. Mood disorders (bipolar and depressive disorders) and anxiety disorders  are complex mental disorders resulting from multiple factors such as genetic predisposition, parenting style, family environment, socioeconomic status. Fetal origins of mental disorders have been attracting increasing attention. Awareness of prenatal risk factors is crucial for prevention strategies.et al., et al., et al., et al., et al., et al., Prenatal maternal health plays an important role in the subsequent mental health of offspring  , PsycARTICLES (via EBSCO) and PsycINFO (via EBSCO). The search strategy consisted of relevant Medical Subject Heading (MeSH) terms, Emtree term-exploded, keywords and word variants. The detailed search strategies for each database were fully described in online Supplementary Table S1. In addition, we searched the reference lists of all included studies, related reviews for further potential studies.in utero , (2) control group(s): had a comparison group(s) without the exposure(s), (3) outcomes: included mood or anxiety disorders diagnosed according to any recognised diagnostic criteria or self-report , (4) statistical indicators were provided to examine the effect of prenatal maternal somatic diseases on mood or anxiety disorders in offspring, (5) study design: cohort studies, including population-based cohort studies and registry-based studies.Articles were eligible if they met the following criteria: (1) exposures: offspring were exposed to maternal somatic diseases Articles were excluded if they met the following criteria: (1) exposed group was mixed with maternal somatic diseases diagnosed postpartum; (2) reviews, meta-analyses, abstracts or conference proceedings.When there were multiple groups of useful data in one article, only the data derived from the group with the largest sample size or the most severe exposure  were selected for the meta-analysis. In addition, we did not delete articles that presented overlapping samples as they included different maternal somatic diseases or outcomes, but only the data from the largest sample size was used in the meta-analysis.After removing duplications, titles and abstracts were reviewed independently by two researchers for initial screening, and then full text. Any disagreement was resolved through group discussions. Endnote was used as the bibliographic software.Two researchers independently extracted data. Any disagreement was resolved through group discussions. The following data were extracted: author, year of publication, the country where the study was conducted, sample and source, exposure and measure, outcome and measure, adjusted confounders, and measure of association. All included articles were assessed in terms of methodological quality according to the Newcastle–Ottawa Quality Assessment Scale (NOS) for cohort studies. NOS consists of eight items across three domains: selection , comparability  and outcome . Studies were graded as good quality (7–9 stars), fair (4–6 stars) and poor (0–4 stars).Q test and I2 statistics were used to evaluate the heterogeneity. A fixed-effects model was adopted when I2 < 50%, otherwise, a random-effects model was used. Funnel plot, trim and fill method and Egger test were used to detect potential publication bias. To assess the stability of the meta-analysis, sensitivity analysis was performed. Sensitivity analysis was performed by excluding studies one by one to explore the impact of each study on the overall results. Furthermore, analyses were stratified according to maternal somatic diseases and follow-up duration (or offspring's age at diagnosis). Quantitative meta-analysis was conducted for an outcome when more than one study presented relevant data. The reason why we adopted stratified analysis rather than traditional subgroup analysis was that the former can make better use of the data in our study. Analyses were performed with Stata 16.0.The method was based on the relative risk (RR) with 95% confidence intervals (CIs) obtained in each study. If the RR was not reported, the hazard ratio (HR)/odds ratio (OR) is considered to be approximately equal to RR. RRs fully adjusted were preferentially pooled in our analyses. Cochrane 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., In total, 21 articles were eligible for inclusion   .Fig. 2.Analyses were stratified according to maternal somatic diseases. Pooled effect of two studies showed that maternal obesity was significantly associated with offspring mood disorders  . In the et al., et al., et al., et al., et al., et al., et al., In the stratified analyses, we did not perform meta-analyses for maternal PCOS, cancer, asthma, diabetes, thyroid diseases and rheumatoid arthritis due to the limited number of eligible studies. These studies reported that prenatal exposure to maternal PCOS , including childhood (aged < 18 years) and adulthood (aged ⩾ 18 years). In the meta-analysis of five studies, prenatal maternal somatic diseases were associated with the increased risk for mood disorders in childhood  . The metet al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., I2 = 33%, p > 0.05)  .Analyses were stratified according to maternal somatic diseases. Pooled effect of two studies showed that the risk of offspring anxiety disorders significantly increased in the context of maternal PCOS  . In the et al., et al., In the stratified analyses, we did not perform a meta-analysis for maternal infertility and hyperemesis gravidarum due to the limited number of eligible studies. One study reported a significant association between maternal infertility and anxiety disorders of offspring . In the meta-analysis of five studies, prenatal maternal somatic diseases were not associated with offspring anxiety disorders in childhood  . The metp > 0.05), the asymmetric funnel plot suggested the possibility of publication bias . The ‘trim and fill’ method was then used to recalculate the pooled results. The adjusted pooled effect of mood disorders exhibited a similar trend with two potential studies filled  . The result for anxiety disorders was not altered with two potential studies filled   .Fig. 4.Sensitivity analysis did not significantly alter these findings, indicating that our results were relatively stable .To our knowledge, this is the first systematic review and meta-analysis assessing the risk of offspring mood and anxiety disorders in the context of prenatal maternal somatic diseases. The overall meta-analyses confirmed that prenatal maternal somatic diseases were associated with an increased risk of mood and anxiety disorders in offspring. For mood disorders, we identified that maternal obesity, hypertensive disorders, and infertility were risk factors. For anxiety disorders, risk factors were maternal PCOS and obesity. Furthermore, our study emphasised the impact of prenatal maternal somatic diseases on mood and anxiety disorders may be long-lasting.et al., et al., The overarching finding of the meta-analysis showed that prenatal maternal somatic diseases were related to offspring mood/anxiety disorders. Mood and anxiety disorders are complex mental disorders, the RRs generally <2 indicated that they each modulated risk by a relatively small. Prenatal exposure to both maternal somatic diseases and psychiatric factors implicates an adverse intrauterine environment, but they might point toward differing underlying mechanisms of an increased risk of mood/anxiety disorders. Although most of the included studies (16 of 21) adjusted maternal psychiatric disorders or distress, the effect of maternal psychosocial factors cannot be excluded, as a relationship has been reported early between somatic diseases and mental health  were associated with an increased risk of mood disorders in offspring, but the association with anxiety disorders was not statistically significant. Although a previous meta-analysis found that preeclampsia was associated with an elevated risk of offspring schizophrenia, the association with other psychiatric disorders was inconclusive  was significantly stronger than those postnatally diagnosed  in one of our included studies (Momen In the context of maternal somatic diseases, the risk of mood disorders was increased in both childhood and adulthood, as was the risk of anxiety disorders in adulthood. The findings suggested that the effects of prenatal maternal somatic diseases were long-lasting and even persist into old age. However, the results should be interpreted with caution because the two ages were not evaluated in the same study.There are some limitations as well. First, although a total of 21 studies were included, the majority of the studies were from northern European populations, and there was a lack of data from Asian populations. Second, when it came to specific exposures, the number of studies was small, and for some exposures, there were not enough studies to allow quantitative analysis. Third, a pooled risk consistently adjusted for the same variables could not be reached because different variables are adjusted in each study. Forth, different diagnostic criteria and follow-up periods were adopted for the same outcome, which may be the reason for the significant heterogeneity of some results. Fifth, in the context of maternal somatic disease, the effects of the disease itself and treatment measures are included, yet we cannot distinguish their effects in the associations. Sixth, it may be difficult to diagnose children, though mood and anxiety disorders occur at any time throughout the lifespan. And both mood and anxiety disorders may not be diagnosed for a long time after the onset. Therefore, the real risk may be underestimated.In conclusion, the results of our study indicate that prenatal maternal somatic diseases can be associated with offspring mood and anxiety disorders, and that the associations may be long-lasting. These findings advance the understanding of the prenatal origins of risk for mood and anxiety disorders. More high-quality prospective studies are needed to resolve the limitations mentioned above.


The ancient membrane protein TSPO is phylogenetically widespread from archaea and bacteria to insects, vertebrates, plants, and fungi. TSPO’s primary amino acid sequence is only modestly conserved between diverse species, although its five transmembrane helical structure appears mainly conserved. Its cellular location and orientation in membranes have been reported to vary between species and tissues, with implications for potential diverse binding partners and function. Most TSPO functions relate to stress-induced changes in metabolism, but in many cases it is unclear how TSPO itself functions—whether as a receptor, a sensor, a transporter, or a translocator. Much evidence suggests that TSPO acts indirectly by association with various protein binding partners or with endogenous or exogenous ligands. In this review, we focus on proteins that have most commonly been invoked as TSPO binding partners. We suggest that TSPO was originally a bacterial receptor/stress sensor associated with porphyrin binding as its most ancestral function and that it later developed additional stress-related roles in eukaryotes as its ability to bind new partners evolved. E. coli and Saccharomyces cerevisiae  was found to be a monomer   was conclusively shown to be located in the ER/Golgi by fluorescent tagging of N-terminal 6-histidine-tagged AtTSPO  in organisms of all kingdoms, questions that may only be answered by identifying specifically associated proteins.On the surface this ancient protein appears to have very different functions in different organisms, yet most of these functions relate to stress-induced changes in metabolism.2+ signaling  may alter TSPO’s binding to its partners, thereby affecting its role in various metabolic processes.It has been suggested that TSPO was originally a bacterial receptor/stress sensor that developed additional roles in eukaryotes  (Gatliff and Campanella Perhaps the most widely researched interaction of TSPO is that with the voltage-dependent anion channel (VDAC), a channel in the mammalian OMM that controls a wide range of processes involving transport of molecules into and out of mitochondria . This finding led the authors to suggest that TSPO could be directly or indirectly involved in regulation of the UPR (Rolland et al. Another potential TSPO interacting partner was proposed by Jurkiewicz et al. : the NACPseudomonas strains suggested several proteins for further study (Leneveu-Jenvrin et al. Pseudomonas homolog of VDAC, was predicted to functionally interact with TSPO (Leneveu-Jenvrin et al. RsTSPO and Sinorhizobium meliloti TSPO (Leneveu-Jenvrin et al. RsTSPO; the Kat B catalase, also predicted to interact with S. meliloti TSPO; hemolysin II/III, virulence factors that remove iron from heme; the adenine phosphoribosyltransferase Apt; a putative nucleoside-diphosphate-sugar epimerase Pfl01_0720 and the UDP-N-acetylmuramate-alanine ligase MurC, both involved in cell wall synthesis; orthologs of the thiol oxidoreductase PSPTO4367, involved in oxidative stress protection; and finally a putative hybrid histidine kinase Pfl01_2810, the interaction with which was suggested to be specific to P. fluorescens Pf0-1 (Leneveu-Jenvrin et al. RsTSPO (Li et al. A STRING database search for functionally-interacting partners for TSPO from RsTSPO (Yeliseev et al. AtTSPO (Jurkiewicz et al. Amid its many proposed binding partners and functions, can an ancestral function and partner for TSPO be discerned? It seems reasonable to conclude that some part of TSPO function, along with aspects of its structure, must be conserved throughout evolution, as mammalian TSPO has been shown to functionally substitute for the bacterial F. diplosiphon (Busch et al. Drosophila had reduced mitochondrial respiration and increased mitochondrial oxidative stress (Lin et al. The most widely observed function in all organisms is the binding of porphyrins, with affinities ranging from low micromolar in bacteria (e.g., 5 µM in the cyanobacterium In higher plants, the role of porphyrins and oxidative stress are strongly connected (Frank et al. R. sphaeroides (Yeliseev and Kaplan The handing of porphyrins to porin for export in bacteria, similar to what has been suggested for TSPO is an ancient protein whose varied and complex functions appear to be dictated by its location and its orientation in the membrane, as well as its binding partners. In many aspects of its behavior TSPO resembles a receptor or sensor; indeed, it shows some structural similarity to GPCRs (Li et al.


Mining genetic variation including structural variation from mammalian genomes is a crucial step towards investigating the relationship between genotype and phenotype. However, compared to the detection of single nucleotide variants and small indels, characterizing large and particularly complex structural variation is much more difficult and less intuitive . In the et al. presented high-quality draft genomes of the grey wolf (Canis lupus) and dhole , and then identified a large number of dog-specific structural variants [In the paper, Wang variants . Functio


Among the multiple reasons why plasticity rules in vivo might differ significantly from in vitro studies is that extracellular calcium concentration use in most studies is higher than concentrations estimated in vivo. STDP, like many forms of long-term synaptic plasticity, strongly depends on intracellular calcium influx for its induction. Here, we discuss the importance of considering physiological levels of extracellular calcium concentration to study functional plasticity.Since its discovery, spike timing-dependent synaptic plasticity (STDP) has been thought to be a primary mechanism underlying the brain’s ability to learn and to form new memories. However, despite the enormous interest in both the experimental and theoretical neuroscience communities in activity-dependent plasticity, it is still unclear whether plasticity rules inferred from  Spike timing-dependent plasticity (STDP) is a form of long-term synaptic modification thought to constitute a mechanism underlying formation of new memories. The polarity of synaptic modifications is controlled by the relative timing between pre- and post-synaptic action potentials , commonly between 2 and 3 mM  and [Ca2+]e (Südhof, 2+]e is associated with decreased synaptic transmission (Borst and Sakmann, 2+]e and is not triggered by Ca2+ entry via VDCC (Scanziani et al., Neocortical STDP relies heavily on presynaptic glutamate release and presynaptic firing rate (Markram et al.,  Südhof, . Reducedin vitro under physiological conditions will allow a more robust application in vivo.All studies use different protocols . The numin vitro studies, and by definition, in vivo studies are inherently in a physiological calcium concentration. First demonstration of STDP in vivo was performed in the retinotectal pathway of Xenopus (Zhang et al., in vitro studies are performed in juvenile rodent while in vivo studies are performed in older animals. This may constitute an additional limitation to the transposition of the results observed in vitro. Several studies suggest that the capacity to induce t-LTD decreases with age (Banerjee et al., in vivo are obtained in the anesthetized animal. Although there are variations in extracellular calcium concentration of about 0.2 mM between awake and anesthetized animals (Ding et al., In opposition to As demonstrated by Inglebert et al. fine tuning of pre- and postsynaptic activity can restore t-LTD and t-LTP in physiological extracellular calcium condition. But would it be possible to restore classic plasticity rules under regular patterns of activity? The key component could be neuromodulation. Interestingly, replay of activity from place-cells with overlapping firing field in hippocampal slices induced t-LTP only in the presence of Carbachol, a cholinergic agonist (Isaac et al., The use of physiological external calcium concentration not only modulates the learning rules for long-term synaptic plasticity but it also enhances context-dependent synaptic plasticity. Analog-digital modulation of action potential-evoked synaptic transmission lies on modification of spike shape, by either broadening the axonal spike (Shu et al., H or IA (Daoudal and Debanne, Hebbian plasticity and Intrinsic plasticity are closely linked and are synergistically modified (Debanne et al., YI and DD wrote the article and YI built the figures. 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.


Dear Editor,Rosmarinus officinalis) extracts have been extensively studied for their ability to ameliorate traits of metabolic dyshomeostasis . Carnosal., 2015). Carnosal., 2015; Lee et al., 2015; Lipina al., 2015; Naimi eal., 2015; Ou et aal., 2015, 2018[13al., 2015; Park anal., 2015; Song etal., 2015; Tsai etal., 2015; Wang etal., 2015, 2019[24al., 2015; Xie et al., 2015, 2018[29al., 2015), antiobal., 2015), and neal., 2015) propertal., 2015).Rosemary or rosemary-derived preparations have been demonstrated to modulate glycemic parameters in human subjects. Consumption of rosemary tea for 90 days has been reported to reduce glycated hemoglobin levels in addition to alleviating insulin resistance in type 2 diabetes subjects . ReductAuthors are thankful to Jain (Deemed to be University), Bangalore for the support.None.


Micronutrient deficiencies are known to affect more than two billion people globally . The magn = 32) of the studies in this systemic review measured child health outcomes in early infancy while the remainder measured outcomes in children whose ages ranged from 24 h after birth until school age. Quezada-Pinedo et al. concluded that there was a need for more high-quality studies examining the long-term effects of maternal iron status during pregnancy on child health outcomes.Several articles in this issue focus on anaemia and iron deficiency. In a systematic review including 44 studies published from 1975 to January 2021, Quezada-Pinedo et al. [In a narrative review including 14 articles published in the 10 years up until 2021, Wawer et al.  reportedThe World Health Organization recommends iron and folic acid (IFA) supplementation for all pregnant women to prevent anaemia and adverse foetal outcomes . In a stThe original research by Ahmed et al.  found a n = 71,728), Solé-Navais et al. [n = 2628), the authors failed to observe any association between whole blood selenium concentration and birth weight or SGA. Solé-Navais et al. pointed out that this lack of association could be due to the homogenous group of subsamples with fairly good selenium status. The authors concluded that, while a maternal diet rich in selenium during pregnancy may be beneficial for foetal growth, further interventional studies were needed to confirm the causal relationship.Using data from a large Norwegian pregnancy cohort  published prior to October 2020, Zgliczynska and Kosinska-Kaczynska [In another review including 85 studies published between 1981 and 2020, Jouanne et al.  reportedThe collection of articles in this issue brings together the latest research on a broad range of topics on micronutrients and pregnancy, including the prevalence of various micronutrient deficiencies and their risk factors, as well as highlights the potential benefits of adequate micronutrient and/or risk of deficiencies on children’s birth outcomes. I am sure that the findings of these studies will contribute to enhancing our current knowledge of the importance of micronutrients during pregnancy and will encourage readers to conduct further studies in this important area of research.


Clostridium clariflavum for utilization in biofuel industry’ by Asma Zafar et al., RSC Adv., 2021, 11, 9246–9261, DOI: 10.1039/D1RA00545F.Correction for ‘Efficient biomass saccharification using a novel cellobiohydrolase from  The authors regret that in the original article, the name and affiliation for one of the co-authors (Hasan Ufak Celebioglu) were incorrectly given. The correct name and affiliation are shown here.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.


Retirement is a major life transition that may improve or worsen mental health, including depression. Existing studies provide contradictory results. We conducted a systematic review with meta-analysis to quantitatively pool available evidence on the association of retirement and depressive symptoms.v. cross-sectional studies), study quality score (QS) and considering studies using validated scales to diagnose depression. Heterogeneity between studies was evaluated with I2 statistics.We applied PRISMA guidelines to conduct a systematic review and meta-analysis to retrieve, quantitatively pool and critically evaluate the association between retirement and both incident and prevalent depression and to understand better the potential role of individual and contextual-level determinants. Relevant original studies were identified by searching PubMed, Embase, PsycINFO and the Cochrane Library, through 4 March 2021. Subgroup and sensitivity meta-analyses were conducted by gender, study design  from 60 datasets suggested a protective effect of retirement on the risk of depression , although with high statistical heterogeneity between risk estimates . Funnel plot asymmetry and trim and fill method suggested a minor potential publication bias. Results were consistent, confirm their robustness and suggest stronger protective effects when progressively restricting the included studies based on quality criteria: (i) studies with the highest QS , (ii) studies with a high QS and using validated assessment tools to diagnose depression  and (iii) studies of high quality, using a validated tool and with a longitudinal design . We observed a progressive reduction in funnel plot asymmetry. About gender, no statistically significant difference was found .Forty-one original studies met our a priori defined inclusion criteria. Meta-analysis on more than half a million subjects (Pooled data suggested that retirement reduces by nearly 20% the risk of depression; such estimates got stronger when limiting the analysis to longitudinal and high-quality studies, even if results are affected by high heterogeneity.As retirement seems to have an independent and protective effect on mental health and depressive symptoms, greater flexibility in retirement timing should be granted to older workers to reduce their mental burden and avoid the development of severe depression. Retirement may also be identified as a target moment for preventive interventions, particularly primary and secondary prevention, to promote health and wellbeing in older ages, boosting the observed impact. Briefly, we used a combination of free text and exploded MeSH headings, identifying: (i) the concept of ‘retirement/transition to retirement’ and (ii) ‘depression/depressive symptoms’. Further studies were retrieved from manual reference listing of relevant articles and consultation with experts in the field. Details on inclusion and exclusion criteria are reported in ad-hoc developed data extraction spreadsheet. The data extraction spreadsheet was piloted on ten randomly selected papers and modified accordingly. Data extraction included: full reference details, country of study conduction, study design, study setting, study population details, sample size, exposure details, outcomes of interest, including validated assessment tools for depression, and quantitative results, including ESs and corresponding confidence intervals (CIs). Corresponding authors were contacted by e-mail in case of incomplete data. Quality appraisal of included studies was carried out applying the 14-item scoring system developed by Shim et al. for population-based studies on retirement as a risk factor  in a two-step process; a first screening was performed based on title and abstract. Then, full texts were retrieved for a second screening. At both stages, disagreements among reviewers were resolved by consensus and by consulting a third senior author (A.O.) when disagreement persisted. Data were independently extracted by two authors (V.G. and G.P.V.), supervised by a third author (A.O.), using an et al., s.e.s), we mathematically converted them into ORs with corresponding CIs  and visual inspection of funnel plots. We performed sensitivity analyses progressively limiting meta-analysis to: (i) high-quality studies; (ii) high-quality studies using validated scales to diagnose depression; (iii) high-quality longitudinal studies using validated scales to diagnose depression. Moreover, we conducted a subgroup meta-analysis by gender strata and study design.We performed descriptive analysis to report and pool the characteristics of included studies using ranges and average values. With regard to the pre-specified outcomes of interest, we would expect variability between studies, e.g. by study design and population. We, therefore, applied random-effects meta-analyses to acquire estimates of the association between retiring and risk of depression/depressive symptoms, rather than to assume a single true value in a fixed-effects approach  software.We assessed publication bias with funnel plot visual inspection  published in the last 5 years. The majority of the studies  were conducted in Europe  and in the USA . Four studies were conducted in Asia, one in Brazil, one in Australia; four were multi-centre studies conducted at the global and European level.We identified 2470 studies by searching the selected databases and listing references of relevant articles. After removing duplicates, 1619 records were retrieved. Papers were screened and selected, as illustrated in n = 12, 60.0%) having less than 10 years of follow-up. Most of the longitudinal analyses were derived from the Survey on Health and Ageing and Retirement in Europe , followed by the Health and Retirement Study  and the Gaz et Electricité cohort study . Twenty-one studies (51.2%) had a cross-sectional study design, while only one study reported both cross-sectional and longitudinal data . One study included only males  studies were longitudinal studies; their follow-up time ranged from 2 to 25 years, with most of them  and Question 13 [Was the loss to follow-up appropriately addressed and/or adequately described in the study?] (n = 11) reported the lowest scores .More than ninety per cent of included studies used validated tools to diagnose depression-related outcomes, including the Center for Epidemiologic Studies Depression scale (CES-D) in 17 studies (41.5%), the Euro Depression-scale (EURO-D) in eight studies (19.5%), the Geriatric Depression Scale (GDS) in three studies (7.1%) and the Zung Self-rating Depression Scale (ZSDS) in two studies (4.9%). The International Classification of Diseases-10 (ICD-10) was used to identify depression-related conditions in three studies (7.1%). The Patient Health Questionnaire-8 (PHQ-8), the Hospital Anxiety and Depression Scale (HADS), the Composite International Diagnostic Interview (CIDI), the Depression Adjective Check List (DACL) and the Clinical Interview Schedule-Revised (CIS-R) were used in only one study each . Three sn = 15, 36.6%) of included studies reported a statistically significant negative association between retirement and depression (i.e. retirement decreased the risk of depression)  reported a positive association  did not report statistically significant associations between retirement and depression  (n = 19), ORs (n = 11), χ2 (n = 3), relative risks (RRs) (n = 1), hazard ratios (HRs) (n = 1) and mean differences (n = 2). Almost all included studies reported adjusted effect estimates . The funnel plot resulted slightly asymmetrical at visual inspection, showing a low potential for publication bias, not confirmed by Egger's linear regression test . Moreover, the ES change after the trim and fill method was minor [0.84 (95% CI = 0.75–0.94)], and two studies were trimmed in the lower right quarter of the funnel plot . Then, we limited the analysis to studies with high QS and using validated assessment tools to diagnose depression. In this analysis, 44 datasets were included, for a total of 239 453 subjects, strengthening the significant association between retirement and decreased risk of depression . Finally, only studies (i) with a QS equal or higher than 15, (ii) using validated assessment tools to diagnose depression and (iii) with a longitudinal study design were included. We report a statistically significant association between retirement and depression , with high statistical heterogeneity , but no publication bias, as confirmed by funnel visual inspection and Egger's test , a statistically significant association between retirement and depression was equally found  and high heterogeneity  and high heterogeneity between studies (Gender-strata meta-analyses are reported in online Supplementary Fig. 2b and 2c. When only considering women, the analysis included 21 datasets and a total of 219 655 subjects, reporting no statistically significant association between retirement and depression (pooled ES = 0.79, 95% CI = 0.61–1.02, ogeneity . About m studies . In bothPooled data from 41 original studies and more than half a million subjects suggested that retirement or transition to retirement reduce by nearly 20% the risk of depression or depressive symptoms; such estimates remain consistent when limiting the analysis to longitudinal and high-quality studies.et al., Before interpreting our findings further, we must account for the considerable heterogeneity among the included studies, which might limit the generalisability of pooled effect estimates. To overcome this and test the results level of strength, we first applied a random-effect model. Secondly, we conducted sensitivity and stratified meta-analyses by study design and QS. The reasons behind the high level of heterogeneity among the included studies are to be explored in light of, on one side, the wide variety of studies’ designs, settings and populations, definitions and methodological quality and, on the other side, of the complex, multi-determinant and multi-mediator relationship between the process of retirement and mental health and wellbeing (Pesaran et al., Despite half of the retrieved studies being cross-sectional, which did not allow us to explore causality, they accounted for less than one-third of included subjects. Another limitation to consider is that duration of retirement was not reported in most studies, so we could not differentiate among the potential risk of depression for short- or long-term exposure to retirement. A subgroup analysis considering the work before retiring was not possible since only two included studies stratified results for this variable (Belloni To the best of our knowledge, this is the first systematic review and meta-analysis pooling all original studies investigating the association of retirement with prevalent and incident depression. We used a comprehensive range of databases and search terms to maximise the number of studies retrieved and minimise the chance of publication bias. Besides, further studies were retrieved from the reference listing of relevant articles. Such a comprehensive and rigorous summary of the available evidence offers several meaningful insights, valuable to plan, implement and evaluate public health and preventive strategies, public policies, as well as future avenues of research.Despite the well-known assumption that considers retirement as a potentially stressful life event Kremer, , one of Characteristics of the transition refer to the type and conditions of retirement, which were available in 76% of included studies. For instance, we report different impacts on depression between voluntary and involuntary retirement, with the more considerable impact of the latter (Mosca and Barrett, et al., et al., et al., et al., et al., There is extensive literature on how employment characteristics influence health after retirement (Hernberg, et al., et al., et al., With reference to resources, access to social and financial resources around retirement might compensate and mitigate the impact of lifestyle changes and the psychological consequences of retiring. We reviewed data where the risk of depression at retirement is differentially distributed by household socioeconomic status (Arias-De La Torre Concerning individual appraisal, personality characteristics influence the meaning assigned to retirement and the ability to cope with this change. Negative expectations and fears about retirement are more likely related to adverse repercussions on individuals’ wellbeing (Barnes-Farrell, Regarding gender, differences in primary role between women and men, at home and work, respectively, could explain differences in adapting to the event and in health outcomes by gender Moen, , but neeet al. (et al. (et al. (Overall and sensitivity analyses results are consistent with other reviews on the topic. Van Der Heide et al.  focused  (et al.  analysed (et al. ; they suet al., et al., et al., et al., et al., et al., et al., Regarding public health and preventive strategies, we demonstrated that, besides other factors influencing the risk of late-life depression, transition to retirement, as a life event that almost the entire population experience at some point (Clark and Oswald, et al., et al., et al., et al., About public policies, our data complement the accumulating evidence on the impact of pension reforms on health and mental health (Eibich, et al., et al., Concerning research, it clearly emerges from our analysis that, in order to reduce heterogeneity and accumulate solid evidence, shared methodological standards and definitions should be followed in the future. More extended longitudinal studies should be preferred so as to reduce inverse causality issues and might help disentangle and quantify the different components that mediate the effects of retirement on the risk of depression and its determinants and monitor such association's temporal evolution. It would also be necessary to further differentiate between contextual and individual characteristics to adapt coping strategies at the public health and clinical levels. Special attention should be paid to health inequalities to investigate better socioeconomic status indicators role in the relationship between retirement and health (Adler As a matter of fact, despite current trends in extending working lives, life expectancy after regular retirement is projected to grow faster than increases in the pension age, reaching 20.3 years for men and 24.6 years for women in 2050 OECD, . Therefo


This review outlines how CRISPR/Cas9 has transformed T cell research allowing immunologists to rapidly probe the roles of genes in T cells thus paving the way for novel therapeutics. Furthermore, this review describes how these tools reduce the requirement for genetic mouse models, while increasing the translational potential of T cell research.Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 allows for precise gene targeting in mammalian cells, including T cells, allowing scientists to disrupt or edit specific genes of interest. This has enabled immunologists to investigate T cell functions as well as opened the path for novel therapeutics involving gene editing of T cells  By enabling easy, swift, and precise manipulation of the genetic code, scientists can probe the roles of novel genes with an unprecedented speed and precision. The Nobel prize awarded to Jennifer Doudna and Emmanuelle Charpentier in 2020 for their discoveries of CRISPR/Cas9 celebrates the beginning of a biological revolution. CRISPR was discovered in bacteria as a defense mechanism used to disrupt invading foreign DNA from invading bacterial viruses (i.e. bacteriophages) by guiding a DNA cleaving nuclease to the foreign genomic DNA  composed of a trans-activating CRISPR RNA (tracrRNA), which facilitates binding of the Cas9 enzyme, and a CRISPR RNA (crRNA), which engages the target DNA and the tracrRNA bound in the Cas9 enzyme, thus guiding the enzyme specifically to its target site. The gRNA-bound Cas9 enzyme binds gRNA-complementary genomic DNA sequences upstream of protospacer adjacent motifs (PAM)  with high specificity and efficacy  . These et al., et al., in vivo after Cas9-mediated editing. To overcome this challenge, scientists could combine Cas9-modified human T cells with organoid systems, where organized three-dimensional tissue cultures are grown in culture , and are limited to studying certain tissue types. Cas9-edited human T cells can also be studied in vivo in so-called humanized mice, which are immunodeficient mice that are reconstituted with human immune cells. These have shown some potential in increasing translational potential of therapies from preclinical models (Tao and Reese, et al., in vivo setting. Unfortunately, these models are not trivial to set up and are generally not broadly available to the research community (et al., CRISPR/Cas9 has already aided in discovery of multiple gene programs critical for human T cell activation, proliferation, and signaling (Shifrut ommunity  (Allen e et al., . NonetheIn summary, these described model systems have the advantage of being high throughput compared with conventional genetically modified mouse models. Furthermore, as Cas9-edited human T cells are somewhat easier to generate, it is now possible to conduct studies in a model with greater translational potential, while accommodating the principles of the 3Rs. These benefits of using CRISPR/Cas9 in T cell research are also applicable to many other cell types. Although it is still a challenge to effectively implement these tools with many other primary human cell types, future innovation will likely enable this.et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., et al., CRISPR/Cas9 has further allowed for generation of genetically modified T cells that can be used in patients for therapies. CRISPR/Cas9 has been adapted for generating efficacious CAR-T cells for therapy, which have an artificially introduced antigen receptor (Eyquem CRISPR/Cas9 has changed the way scientists conduct research in multiple fields, including the field of immunology. In T cell research CRISPR/Cas9 mutagenesis has already been used for multiple important discoveries, and has paved the way for novel, faster, and more translational techniques that in coming years have the potential to disrupt the way T cell studies are performed. Future developments will likely further enable CRISPR/Cas9-mediated development of highly efficacious T cells for cancer therapies, including CAR-T cells and adoptive T cell transfer.


Prevalence of SARS-CoV-2 specific neutralising antibodies in blood donors from the Lodi Red Zone in Lombardy, Italy, as at 06 April 2020’ by Percivalle et al., published on 18 June 2020, incorrect protocol numbers were mistakenly quoted in the Ethical statement. The text was corrected on 20 January 2022 at the request of the authors. In the article ‘


More than 85% of pre-clinically tested drugs fail during clinical trials, which results in a long, inefficient and costly process, suggesting that animal models are often poor predictors of human biology . The abiThe research topic of this issue is aimed at providing further context to the use of iPSC-derived cells  as disease models (“disease in a dish” models) for screening leads for drugs.In this context, Trudler et al. , Lu QianWang et al.  describeAccording to Vokner et al.’s  review, Interestingly, iPSC-based models can also serve for screening potential drugs against complex diseases such as Parkinson’s disease , AlzheimThe model of iPSC-derived cardiomyocytes with very long-chain acyl-CoA dehydrogenase deficiency (VLCADD), studied by Knottnerus et al. , impliesiPSC-derived cardiomyocytes also serve as attractive models for dilated cardiomyopathy, such as propionic acidemia (PA), caused by mutations in either the PCCA or PCCB genes encoding both subunits of the mitochondrial propionyl-CoA carboxylase (PCC) enzyme  and in CUrea cycle disorders are enzymopathies resulting from inherited deficiencies in any genes of the cycle. Zabulica et al.  demonstrTo study the rare disease riboflavin transporter deficiency (RTD), Marioli et al.  used iPSAmong the applicative future goals in studying iPSCs is the potential to generate patient specific organs such as liver, hearth patch, etc. Olgasi et al.  describePregnancy miscarriages have many unknown causes and are complex processes that require solution. Bohnke et al.  were abl


Homocysteine levels can be increased by different conditions including genetic factors, diet, life style, several medications, etc. Elevated levels of homocysteine, called hyperhomocysteinemia (hHcy), are associated with a higher risk of neurovascular diseases, dementia, migraine, developmental impairments or epilepsy. The mechanisms underlying the neurotoxicity of homocysteine include oxidative stress, DNA damage, protein thiolation or protein homocysteinylation, triggering apoptosis and excitotoxicity. Recent data indicate that inflammation during hHcy comes along with increased levels of several cytokines and changes in DNA methylation.Homocysteine is a non-proteinogenic sulfhydryl-containing amino acid derived from methionine and is a homologue of cysteine. The concentration of homocysteine is regulated by two key pathways: remethylation back to methionine or transsulfuration to cysteine with the simultaneous production of hydrogen sulfide , which is a major regulator of cellular methylation reactions that occur in eukaryotic and prokaryotic organisms. SAHase activity is a significant source of homocysteine and adenosine. The author presents structural characteristics of the two principal domains of the SAHase subunit, which are based on the Rossmann fold. The study highlights similarities and differences in the spatial arrangements of both major domains. In his review, Brzezinski  summarizIn their review Rizzo and Lagane  summarizhHcy which has been linked to different systemic and neurological diseases, is well known as a risk factor for systemic atherosclerosis and cardiovascular disease (CVD), and has been identified as a risk factor for several ocular disorders, such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). Oxidative stress, endoplasmatic reticulum (ER) stress, inflammation, and epigenetic modifications have been suggested as possible mechanisms of hHcy-induced blood retinal barrier (BRB) dysfunction. More recently hHcy-induced brain inflammation was reported as a mechanism of blood-brain barrier (BBB) dysfunction and pathogenesis of Alzheimer’s disease (AD). The contribution by Tawfik et al.  focuses The original study by Elsherbiny et al.  demonstrIn the paper by Kovalska et al. , a methiN-methyl-d-aspartate receptors (NMDARs) and a reducing agent. In the paper by Sibarov et al. [Homocysteine (HCY) combines distinct pharmacological properties as an agonist of v et al. , the rolIvanova et al.  provide 2S in kidney ischemia-reperfusion injury and oxidative stress in the heart.Hydrogen sulfide has been implicated in cardiovascular protection through redox balance and vessel relaxation. The paper by Wijerathne et al.  emphasiz2S. Prenatal hyperhomocysteinemia (hHCy) was found to induce behavioral impairments and oxidative stress in brain tissue of rats, with a decreased expression of the H2S generating enzyme-cystathionine-beta synthase and concentrations of H2S in the brain. The administration of the H2S donor to females with hHcy during pregnancy prevented behavioral alterations and oxidative stress of their offspring. The acquisition of behavioral studies together with biochemical studies will improve our knowledge about homocysteine neurotoxicity and proposes H2S as a potential agent for the therapy of hHcy-associated disorders.Finally, Yakovleva et al.  accentuaThis Special Issue describes several pathological conditions associated with elevated levels of homocysteine, some further mechanisms of homocysteine action, and opens new possibilities for treatments.


Cell membranes develop extraordinarily complex lipids and proteins geared to perform functions required by cells. The collective processes occurring within membranes strongly impact their cellular behavior and biochemistry; thus, understanding these processes poses unique challenges due to the often complex and multiple interactions among membrane components. The plasma membrane surface accommodates different types of lipid and protein clusters; however, the functional role of membrane surface clustering has not been fully understood yet. Super-resolution microscopy (SRM) has been extremely helpful in expanding our knowledge and changing the paradigm on both the structure and function of these clusters. These SRM techniques have been used to examine the organization and dynamics of plasma membrane components, thus giving insight into the fundamental interactions determining membrane functions.Membranes Special Issue, entitled “Dynamics and Nano-Organization in Plasma Membranes”, presents both an update and a comprehensive overview of recent developments in plasma membrane nano-organization. It features eight contributions, namely six research papers and two reviews. A brief descriptive summary of the scientific contributions is reported here. This Kure et al.’s  review p2/s, which is comparable to similar studies of other aquaporins. From the kICS analysis, it can be concluded that the addition of actin polymerization-inhibiting compounds, cytochalasin D and latrunculin, did not significantly affect the diffusion coefficient of AQP9 in these cells, indicating that there was no correlation between the actin cytoskeleton network and AQP9; in addition, decreases in the diffusion coefficients were observed when adding Methyl-β-Cyclodextrin (MβCD). These observations, when combined, suggest that, unlike other AQPs , AQP9 is not a nano-domain membrane protein.Kure et al.  also repIn the paper by Jaszul et al. , the molSezgin et al.  reportedYang et al.  reviewedIn their paper, Allender et al.  discusseLast, Tintino et al.  studied In conclusion, the papers in this Special Issue provide a significant contribution to increasing our understanding of the complexity in cell membrane organization. Super-resolution microscopy techniques are highlighted as powerful tools for obtaining new information about plasma membrane nano-organization, nanodomains, lipid as well as protein diffusion, along with membrane proteins and their interaction with plasma membranes. Moreover, important contributions related to the development of new methodologies to generate model lipid membranes as well as an alternative theory were described in order to explain the physical origin of membrane domains.


Dvorak describes that VEGF is widely believed to induce angiogenesis by its direct mitogenic and motogenic actions on vascular ECs. However, he emphasizes the role of VEGF in vascular permeability, the role of delayed hypersensitivity in pathological stroma generation, particularly extravascular fibrin deposition and clotting within the tumor microenvironment (TME). Based upon his prior work where he concludes that tumors are “wounds that do not heal,” he now proposes that tumors are wounds that continually exhibit elements of local healing but do damage the host (patients) whereas the healing process actually facilitates tumor survival and growth. Moreover, solid tumors, and healing wounds feature enlarged feeder arteries, draining veins, and several other abnormal vessel types in addition to new angiogenic blood vessels. He also proposes that that VPF/VEGF induces stroma formation primarily by way of its potent “VPF” function. Much remains to be explored about the signaling and functions of VEGF in wound healing, tumor progression and chronic inflammatory diseases.We begin with vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), one of the most important growth factor in EC and vascular biology. This important proangiogenic molecule was discovered over 3 decades ago by the Dvorak Laboratory at Harvard Medical School  and was Wang et al. describe the basics of VEGF/VEGFR-2 signaling and provide an update on VEGFR-2 signaling-mediated physiological and pathological functions as well as potential treatment strategies. Potent VEGF signaling also promotes angiogenesis and dictates arterial fate but inhibits venous specification, and this may depend on Notch signaling status  and thus conferring therapeutic resistance. They also discuss the Notch signaling crosstalk between CSCs and vascular ECs within the TME. They believe that therapeutic approaches could be developed by targeting the essential role of Notch pathway in CSCs and development of the arteriolar niche that promotes the self-renewal of CSCs  , a predog status . Akil et of CSCs .Alfaidi et al. emphasize the role of Nck1/2 adaptor proteins in vascular biology, vascular permeability and angiogenesis, and discuss their therapeutic potential. A study on an adaptor protein widely expressed in vascular ECs by Liu et al. demonstrates that the mitogen-inducible gene 6 acts as a potent anti-angiogenic factor in the regulation of physiological and pathological angiogenesis. In terms of anti-angiogenesis, thrombospondin-1 (TSP-1) is one of the first discovered endogenous angiogenesis inhibitor, and negatively regulates EC functions . Although VEGF-activation of Notch signaling is known as the key to arterial specification, they have performed carefully analysis in the settings of de novo vasculogenesis of the dorsal aorta during early embryogenesis and vasculature development in the neonatal mouse retina and described novel signaling mechanisms and a new understanding of this subject. They also emphasize the role of shear stress in the maintenance of arterial identity after blood circulation is established, as shear-induced Notch signaling activation and cell cycle arrest may contribute to A/V specification process  mainly originates from the mitochondria in diabetes, a study from Zhao et al. describe the paradox of adenosine monophosphate-activated protein kinase (AMPK), a heterotrimeric serine-threonine kinase, in the involvement of vascular remodeling and the development of pulmonary hypertension. They emphasize the differential effects of AMPK on pulmonary vasoconstriction and pulmonary vascular remodeling, which may also be involved in the regulation of pathological microvascular remodeling and angiogenesis under obese conditions . They functionally classify ECs as quiescent ECs involved in maintaining homeostasis, proliferative ECs, inflammatory ECs, remodeling ECs, ECs involved in EndMT, and ECs involved in angiogenesis. This classification may well explain two new connected processes such as inflammatory angiogenesis and non-inflammatory regenerative angiogenesis dissected in hind-limb ischemia-triggered angiogenesis  shows that lipopolysaccharide induces transcriptional activation of forkhead box protein C2 and promotes itself expression in a histone acetylation manner using lung ECs and a sterile sepsis model in neonatal mice.EC heterogeneity is emerging as an important area in vascular biology. It is well known that ECs show tissue- and organ-specificity, and significantly contribute to the formation of different types of blood and lymphatic vessels. They serve as an important cell type in the development of vasculogenesis, angiogenesis, venogenesis and arteriogenesis under physiological and pathological conditions. As newly classified innate immune cells , ECs areogenesis . Dawson Fang et al. propose that an EndoMT program is partially and reversibly activated event in angiogenic ECs to support acquisition of the subset of mesenchymal characteristics, which is necessary to develop sprouting angiogenesis. They also discuss the potential signaling and regulatory mechanisms that may control the EndoMT program as well as potential therapeutic approaches in cancers. EndoMT is known to be regulated by transforming growth factor-β (TGF-β) family. Ma et al. report that TGF-β2 may be essential for this process by regulation of the balance between transcription factor SNAIL and ID factors  and this may also regulate angiogenesis . Additionally, a study by Hunyenyiwa et al. shows that obesity inhibits angiogenesis via TWIST1-SLIT2 signaling, similar to an angiogenic phenotype occurred in tumor angiogenesis under diet-induced obesity conditions  and partial epithelial-to-mesenchymal transition (EMT)/EndoMT have been extensively reported. EndoMT is a process whereby an EC undergoes a series of molecular events that lead to a change in phenotype toward a mesenchymal cell. In a hypothesis and theory article, nditions . It shouPaulson et al. show that primary cilia exists in lymphatic vasculature, and surprisingly is expressed on the abluminal surface of the lymphatic vessel. They also present evidence that lymphatic vessel patterning is regulated by a primary cilium protein IFT20 in lymphatic ECs during development and inflammation, which could lead to a new paradigm in the field of lymphangiogenesis. Last but not the least, Norden and Kume provide an elegant review about current status and the mechanisms by which lymphatic permeability and function are regulated in a tissue- and organ-specific manner, including lacteals of the small intestine. Disrupted lymphatic EC junctions are associated with various diseases, including lymphatic leakage present in chylothorax and lymphedema, metabolic syndrome, and impaired immune surveillance. They also describe key signaling pathways and factors that control lymphatic EC junctional integrity including VEGF, S1P, LPA signaling molecules and FOXC1 and FOXC2 transcription factors as well as RhoA/ROCK and Ephrinb2-Ephb4 pathways.In addition to new sprouting from blood vessels, the sprouting of lymphatic vessels, lymphangiogenesis, is actively involved in many pathological processes including tissue inflammation and tumor dissemination but is insufficient in patients suffering from lymphedema. Cilia, a microtubule-based organelle expressed on the apical surface of blood ECs is thought to function as a blood flow sensor. via toll-like receptor 2 signaling (de novo arteriogenesis, particularly under pathological conditions (Ren et al.; Heterogeneous endothelium and vasculature play a pivotal role in the regulation of tissue and organ homeostasis in human health and disease progression. This topic only covers the tip of iceberg in the field of EC and vascular biology, and significant studies are urgently needed to move the field forward. One emerging area is the immunological properties of ECs and their role in angiogenesis and lymphangiogenesis. ECs show distinguished immunological functions and have innate and trained immunity . McCoy eignaling . Secondlignaling . The resignaling . Thirdly