bluuebunny/crossref_metadata_2025 huggingface dataset:
Maternal age at birth of last child and cardiovascular disease mortality later in life among a national cohort of postmenopausal women from the United States
Authors: Appiah Duke , Kim Catherine , Fuquay Taylor , de Riese Cornelia , Ebong Imo A. , Nwabuo Chike C.
Published: February 2023

Objective

Maternal age at last birth (ALB) of child is increasing in the United States, and it has been reported to influence future chronic diseases. However, the relationship of ALB and cardiovascular disease (CVD) events later in life has not been widely studied. We evaluated the association of ALB with CVD mortality.

Methods

Data were from 7,971 parous postmenopausal women older than 45 years who participated in the US National Health and Nutritional Examination Survey from 1999 to 2018 and had mortality follow-up data through to December 31, 2019. ALB was self-reported, whereas CVD mortality was assessed using International Classification of Diseases codes. Cox regression was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI).

Results

The mean age of participants was 63 ± 9.8 years, with 9.5% being non-Hispanic Black, 9.7% being Hispanic women, and 21% reporting ALB ≥35 years. During a median follow-up of 8.1 years, 443 participants died from CVD. In age-adjusted models, CVD mortality was elevated for women with ALB of <25 years (HR, 1.68; 95% CI, 1.23‐2.29) and ALB of ≥35 years (HR, 1.37; 95% CI, 1.00‐1.88). However, after additional adjustment for race and ethnicity, foreign born, education, marital status, poverty income ratio, parity, smoking status, age at menarche, oral contraceptive pills use and family history of myocardial infarction, these estimates were attenuated resulting in no association between ALB and CVD mortality.

Conclusions

In this study of nationally representative sample of postmenopausal women, there was no conclusive association between maternal ALB and CVD mortality later in life.
Potential Airborne Releases and Deposition of Radionuclides from the Santa Susana Field Laboratory during the Woolsey Fire
Authors: Rood Arthur S. , Mohler H. Justin , Grogan Helen A. , Mangini Colby , Caffrey Emily A. , Till John E.
Published: February 2023

The Santa Susana Field Laboratory (SSFL), located in southern California, is a former research facility, and past activities have resulted in residual radioactive contamination in Area IV of the Site. The Woolsey Fire burned across the site, including some of the contaminated areas, on 8–11 November 2018. Atmospheric transport modeling was performed to determine where the smoke plume went while the fire burned across the SSFL and the deposition footprint of particulates in downwind communities. Any radionuclides on vegetation and in surface soil released by the fire were assumed to follow particulate matter transport path and deposition. The predicted deposition footprint was used to guide confirmatory soil sampling at 16 locations including background. Highest offsite deposition was determined to be northeast of the Oak Park community, which is located about 6 km southwest of SSFL. Depth-profile sampling was used to evaluate whether radionuclides of SSFL origin were potentially emitted and deposited during the Woolsey Fire. If radionuclides had been deposited from the Woolsey Fire at sufficient concentrations, then they would be detected in the surface layer and would be expected to be higher within the plume footprint than outside it. An upper bound estimate of the hypothetical effective dose to a person in Oak Park based on measured radionuclide concentrations in soil and vegetation on the SSFL was less than 0.0002 mSv. The occurrence of naturally occurring radionuclides at concentrations above the established background for the SSFL was attributed to natural variability in geologic formations and not SSFL. No anthropogenic radionuclides were measured at levels above those expected from global fallout. The soil sampling confirmed that no detectable levels of SSFL-derived radionuclides migrated from SSFL at the locations sampled because of the Woolsey Fire or from past operations of the SSFL.
Aqueous extract from urucum (Bixa orellana L.): antimicrobial, antioxidant, and healing activity
Authors: Franklin Victor A. , Bach Hi Edgar M. , Wadt Nilsa S. Y. , Bach Erna E.
Published: February 2023

Background: Annatto was obtained from seed B orellana (urucum) and is commonly used in food and cosmetic industries. The objective of this study was to identify the antimicrobial and antioxidant activity of the aqueous extract from urucum seeds and its skin healing potential in exposed cutaneous lesions in rats treated with the gel containing the extract.

Methods: Three types of extracts from seeds were made using chloroform, sodium hydroxide, water, and estimated bixin and norbixin. In the presence of antioxidants, antibacterial was observed and then evaluated the skin healing in rats using aqueous extract.

Results: Annatto dyes have been evaluated in all three extracts. When the seeds were extracted with chloroform, bixin was detected. If extraction was performed by sodium hydroxide or water, norbixin was detected. For healing use, 10% of aqueous extract was mixed in a gel base. The finding obtained from the antioxidant assay revealed that the activities of the water extract could be used as a source of polyphenolic compounds. In chloroform extract, the antioxidant was not effective because it has weak radical scavengers. With respect to antimicrobial activity, it has been observed that aqueous extract has more effect. For skin healing assay, a total of 3 study groups were tested: negative control group (gel base), positive control group (fibrinase), and test group (gel with urucum aqueous extract). After 7 days of treatment, animals treated with fibrinase had an improvement of 4.7% in total wound area when compared with the negative control while those treated with urucum aqueous extract presented an improvement of 51.55% in comparison. After 14 days, the total wound area of animals within the test group had a decrease of 94.97% when compared with the negative control (gel base) results while the control group presented an improvement of 56.58% in total wound area. These results indicate that wounds treated with urucum aqueous extract were 38.39% more efficient than fibrinase, a cream used for skin healing.

Conclusions: It is possible to conclude that gel with aqueous extract is effective in skin healing in rats, being used as a phytotherapic, besides possessing antioxidant and antimicrobial activity.
The use of innovative targeted angiogenic therapies for ischemic diabetic foot ulcer repair: From nanomedicine and microRNAs toward hyperbaric oxygen therapy
Authors: Canha Fatigracy , Soares Raquel
Published: February 2023

Diabetes mellitus is a metabolic disease that has a high prevalence worldwide and is characterized by chronic hyperglycemia leading to the development of vascular or nonvascular complications. It is these complications that result in huge mortality rates in patients with diabetes, especially vascular ones. This work focuses on diabetic foot ulcers (DFUs), which are one of the most common complications of type 2 diabetes mellitus (T2DM) and cause significant morbidity, mortality, and healthcare costs. The healing of DFUs is hindered by deregulation of nearly all phases of this process because of the hyperglycemic environment. Although therapies currently exist to treat a patient with DFU, they are proving inadequate. In the present work, angiogenesis is highlighted as part of the proliferative phase, which, when diminished, plays an important role in the impaired healing of DFU and other chronic wounds. Therefore, the search for new therapeutic strategies targeting angiogenesis is of great interest. In this study, we provide an overview of molecular targets with therapeutic potential and therapies that act on angiogenesis. To this end, a search of articles in PubMed and Scopus databases from 2018 to 2021 was performed to review angiogenesis as a therapeutic target for DFU. Growth factors, microRNAs, and signaling pathways were investigated as molecular targets, and negative pressure, hyperbaric oxygen therapy, and the use of nanomedicine were explored as therapies.
Copy number variations on chromosome 2: impact on human phenotype, a cross-sectional study
Authors: Sousa Beatriz , Grangeia Ana , Pinto Joel , Santos Helena , Dória Sofia
Published: February 2023

Background:

Copy number variations (CNVs) on chromosome 2 are associated with a variety of human diseases particularly neurodevelopmental disorders. Array comparative genomic hybridization (aCGH) constitutes an added value for the diagnosis of neurodevelopmental or neuropsychiatric diseases. This study aims to establish a genotype–phenotype correlation, reporting CNVs on the chromosome 2, contributing for a better characterization of the molecular significance of rare CNVs in this chromosome.

Methods:

To accomplish this, a cross-sectional study was performed using genetic information included in a database of the Department of Genetics of the Faculty of Medicine and clinical data from Hospital database. CNVs were classified as pathogenic, benign, variants of unknown significance, and likely pathogenic or likely benign, in accordance with the ACMG Standards and Guidelines.

Results:

A total of 2897 patients were studied using aCGH, 32 with CNVs on chromosome 2, 24 classified as likely pathogenic, and 8 as pathogenic. Genomic intervals with a higher incidence were one 2p25.3 and 2q13 regions.

Conclusions:

This study will help to establish new genotype–phenotype correlations, allowing update of databases and literature and the improvement of diagnosis and genetic counseling which could be an added value for prenatal genetic counseling.
Risk factors for antibody-mediated rejection in ABO blood-type incompatible and donor-specific antibody-positive liver transplantation
Authors: Tajima Tetsuya , Hata Koichiro , Haga Hironori , Kusakabe Jiro , Kageyama Shoichi , Yurugi Kimiko , Hishida Rie , Zhao Xiangdong , Nishikori Momoko , Nagao Miki , Takaori-Kondo Akifumi , Uemoto Shinji , Hatano Etsuro
Published: February 2023

Antibody-mediated rejection (AMR) is a refractory rejection after ABO blood-type incompatible (ABOi) or donor-specific antibody (DSA)-positive liver transplantation (LT). Pretransplant rituximab desensitization dramatically reduced posttransplant AMR development; however, risk factors for AMR in the rituximab era remain unclear in both ABOi living-donor LT (ABOi-LDLT) and preformed DSA-positive LT (pDSA-LT). Of our 596 adult LDLTs (≥18 y) after rituximab introduction (2004–2019), 136 were ABOi-LDLT (22.8%). After excluding retransplants (9), acute liver failure (7), and protocol deviations (16), 104 ABOi-LDLTs were finally enrolled. Of these, 19 recipients developed AMR, 18 of which occurred within 2 weeks after transplantation (95%). ABOi-AMR significantly worsened graft and recipient survival than those without (p=0.02 and 0.04, respectively). Model for End-stage Liver Disease (MELD) ≤13 (OR: 5.15 [1.63–16.3], p=0.005) and pre-rituximab anti-ABO IgM-titer ≥128 (OR: 3.25 [1.05–10.0], p=0.03) were identified as independent risk factors for ABOi-AMR development. Recipients fulfilling both factors showed significantly worse survival rates than those who did not (p=0.003). Of 352 adult LTs, after introducing the LABScreen Single Ag method (2009–2019), pDSA with mean fluorescence intensity (MFI) ≥500 was detected in 50 cases (14.2%). After excluding 10 ABOi-LDLTs, 40 pDSA-LTs were finally analyzed, of which 5 developed AMR. The combination of high-titer (sum-MFI ≥10,000) and multi-loci pDSAs was a significant risk factor for pDSA-AMR development (p <0.001); however, it did not affect the 5-year recipient survival compared with those without (p=0.56). In conclusion, preoperative MELD ≤13 and pre-rituximab anti-ABO IgM-titer ≥128 for ABOi-LDLT, and the combination of sum-MFI ≥10,000 and multi-loci pDSAs for pDSA-LT, are risk factors for AMR in the era of rituximab desensitization. Characteristically, ABOi-AMR significantly deteriorated graft and recipient survival, whereas pDSA-AMR did not.
Palliative Care Education and Serious Illness Communication Training for Baccalaureate Nursing Students
Authors: Rauch Lisa , Dudley Nancy , Adelman Toby , Canham Daryl
Published: February 2023

Background:

Palliative care is an essential component of community health for a growing population of seriously ill older adults residing in the community. Yet, nursing students are often challenged in initiating and engaging in serious illness conversations.

Purpose:

This study implemented and evaluated an educational activity designed to increase nursing students' skills and self-efficacy to initiate and conduct conversations with patients/clients experiencing serious illness.

Methods:

A mixed-methods approach was used to study how statement cards and prompts facilitated students' readiness to engage in such conversations. A quantitative pre- and posttest survey was used to evaluate self-efficacy and students' perception of their ability to engage in challenging conversations.

Results:

The results indicated a significant increase in student confidence in conducting serious illness conversations.

Conclusion:

Students reported an improved perception of their ability to conduct serious illness conversations and emphasized the need to practice these conversations in clinical practice.
Treponema pallidum Strains Among Women and Men Who Have Sex With Women in Amsterdam, the Netherlands and Antwerp, Belgium Between 2014 and 2020
Authors: Zondag Hélène C.A. , Zwezerijnen-Jiwa Florine H. , de Vries Henry J.C. , De Baetselier Irith , Bruisten Sylvia M.
Published: February 2023

The Treponema pallidum strain distribution among men who have sex with women were similar to the strain distribution men who have sex with men. The most prevalent strains and percentage of strains belonging to the Nichols lineage are similar to previous studies in Amsterdam focusing on men who have sex with men.
Impact of a Community Empowerment Intervention on Sexually Transmitted Infections Among Female Sex Workers in Baltimore, Maryland
Authors: Sherman Susan G. , Tomko Catherine , Nestadt Danielle F. , Silberzahn Bradley E. , Clouse Emily , Haney Katherine , Allen Sean T. , Galai Noya
Published: February 2023

Background

Female sex workers (FSWs) are vulnerable to a number of health issues, but often delay seeking health care due to structural barriers. Multiservice drop-in centers have been shown to increase FSW access to health services globally, but their impact on FSW in the United States is lacking. This study seeks to evaluate the effect of a community-level empowerment intervention (the multiservice drop-in SPARC center) on cumulative sexually transmitted infections (STIs) among FSW in a city in the United States.

Methods

Between September 2017 and January 2019, 385 FSWs were recruited in Baltimore. Participants from areas served by SPARC were recruited to the intervention; other areas of Baltimore were the control. Follow-up occurred at 6, 12, and 18 months. The primary outcome is cumulative STI (ie, positive gonorrhea or chlamydia test at any follow-up). We tested effect modification by condomless sex with paying clients reported at baseline. Logistic regressions with propensity score weighting were used to estimate intervention effect, accounting for loss to follow-up, with bootstrap confidence intervals.

Results

Participants completed 713 follow-up study visits (73%, 70%, 64% retention at 6, 12, and 18 months, respectively). Baseline STI prevalence was 28% and cumulative STI prevalence across follow-ups was 26%; these both did not differ between control and intervention communities in bivariate analyses. After adjusting for covariates, FSW in the intervention had a borderline-significant decrease in odds of cumulative STI compared with control (odds ratio, 0.61, P = 0.09). There was evidence of effect modification by baseline condomless sex, such that FSW in the intervention who reported condomless sex had lower odds of cumulative STI compared with FSW in the control community who also reported baseline condomless sex (odds ratio, 0.29; P = 0.04).

Conclusions

Results demonstrate the value of a low-barrier, multiservice model on reducing STIs among the highest-risk FSW.

Clinical Trial Number: NCT04413591
Epidemiology and Burden of Astigmatism: A Systematic Literature Review
Authors: Zhang Jun , Wu Yifei , Sharma Bhavna , Gupta Ritu , Jawla Shantanu , Bullimore Mark A.
Published: February 2023

Significance

This is the first literature review to report the epidemiology, patient burden, and economic burden of astigmatism in the general adult population. The unmet needs of astigmatism patients with co-existing ocular conditions (cataract, glaucoma, dry eye, presbyopia, or macular degeneration) and risks associated with untreated astigmatism are also reviewed and reported.

Purpose

To identify, report and summarize the published literature on epidemiology, patient burden, and economic burden of astigmatism using a systematic literature review.

Methods

MEDLINE, EMBASE, and Cochrane Library databases were searched (January 1996-May 2021). Search results were limited to the English language. Proceedings (2018-2021) from ophthalmology congresses were searched along with gray literature using the Google Scholar platform.

Results

The literature search yielded 6,804 citations, of which 125 met the inclusion criteria (epidemiology: 68; patient burden: 60; economic burden: 6). Astigmatism prevalence in the general population varied from 8% to 62%, with higher rates in individuals ≥70 years. The prevalence of with-the-rule astigmatism was higher in individuals ≤40 years, while rates of against-the-rule and oblique astigmatism increased with age. Astigmatic patients experienced decreased vision quality, increased glare (53 to 77%), haloes (28 to 80%), night-time driving difficulties (66%), falls, and spectacle dependence (45 to 85%). Astigmatic patients performed vision-related tasks slower (1 D: 9% slower, 2 D: 29% slower) and made more errors (1 D: 38% more errors, 2 D: 370% more errors) compared to fully corrected individuals. In cataract patients with astigmatism, the annual mean per patient productivity loss costs ranged from €55 ($71) to 84 ($108) and mean informal care costs ranged from €30 ($39) to 55 ($71) with a mean of 2.3 to 4.1 hours spent on informal care.

Conclusions

Uncorrected astigmatism decreases patients' vision-related quality of life; decreases productivity among working-age adults and poses an economic burden on patients and their families.
On requests for validation of names published in electronic material that does not provide a permanent record
Authors: Oren Aharon , Göker Markus
Published: February 2023

The validation of the name of a prokaryotic taxon under the International Code of Nomenclature of Prokaryotes (ICNP) is occasionally attempted although the original proposal of the name does not meet all requirements. The publication of a corrigendum is necessary in such a case but authors must ensure that the corrigendum contains the full description of the respective taxon. The modification of the original article is not compatible with the ICNP. One requirement for valid publication is that the effective publication of a taxon name constitutes a permanent record. Journals which modify articles after publication are not acceptable as a source of effective publications.
A complex three-dimensional microfluidic model that mimics the early stage events in the human atherosclerotic artery
Authors: Maringanti Ranganath , van Dijk Christian G.M. , Meijer Elana M. , Brandt Maarten M. , Krebber Merle M. , Chrifi Ihsan , Duncker Dirk J. , Verhaar Marianne C. , Cheng Caroline
Published: February 2023

Background

Atherosclerosis is a complex inflammatory vascular disease characterized by lipid and immune cells accumulation in the vessel wall, leading to lumen narrowing. Although several 3Din vitromicrofluidic systems were previously described, a realistic reconstruction of thein vivohuman atherosclerotic environment requires co-culture of different cell types arranged in atherosclerotic vessel-like structures with exposure to flow and circulating cells, creating challenges for disease modelling.

In this study we developed a 3D tubular microfluidic model with quadruple coculture of human aortic smooth muscle cells (hAoSMCs), human umbilical cord vein endothelial cells (HUVECs) and foam cells to re-create a complex human atherosclerotic vesselin vitroto study the effect of flow and circulating immune cells.

Methods & Results

Our new co-culture protocol with BFP-labelled hAoSMCs, GFP-labelled HUVECs and THP-1 macrophages-derived, Dil-labelled Oxidized Low-Density Lipoprotein (Dil-Ox-LDL) foam cells in a fibrinogen-collagen-I based 3D extracellular matrix (ECM) resulted in vessels with an early lesion morphology, showing a layered vessel-like composition with an endothelium and media, with foam cells accumulating in the sub-endothelial space. Perfusion for 24 hours of atherosclerotic and “healthy” vessels (BFP hAoSMCs and GFP HUVECs without foam cells) showed that the layered wall composition remained stable. Perfusion with circulating THP-1 monocytes demonstrated cell extravasation into the atherosclerotic vessel wall and recruitment of THP-1 cells to the foam cell core. QPCR analysis revealed increased expression of atherosclerosis markers in the atherosclerotic vessels and adaptation in VSMCs migration to flow and the plaque microenvironment, compared to control vessels.

Conclusion

We present a 3D tubular microfluidic model of a complex early atherosclerotic human vessel that can be exposed to flow and circulating THP-1 monocytes to study hemodynamic changes and immune cell recruitment under live confocal imaging. This novel atherosclerosis-on-a-chip model offers a humanized platform for in-depth mechanisticin vitrostudies and drug testing.
GBAin Parkinson’s disease: variant detection and pathogenicity scoring matters
Authors: Gabbert Carolin , Schaake Susen , Lüth Theresa , Much Christoph , Klein Christine , Aasly Jan O. , Farrer Matthew J. , Trinh Joanne
Published: February 2023

Background

GBAvariants are the strongest genetic risk factor for Parkinson’s disease (PD). However, the pathogenicity ofGBAvariants concerning PD is still not fully understood. Additionally, the frequency ofGBAvariants varies widely across populations.

Objectives

To evaluate Oxford Nanopore sequencing as a strategy, to determine the frequency ofGBAvariants in Norwegian PD patients and controls, and to review the current literature on newly identified variants that add to pathogenicity determination.

Methods

We included 462 Norwegian PD patients and 367 healthy controls. We sequenced the full-lengthGBAgene on the Oxford Nanopore GridION as an 8.9 kb amplicon. Six analysis pipelines were compared using two aligners (NGMLR, Minimap2) and three variant callers (BCFtools, Clair3, Pepper-Margin-Deepvariant). Confirmation ofGBAvariants was performed by Sanger sequencing and the pathogenicity of variants was evaluated.

Results

We found 95.8% (115/120) true-positiveGBAvariant calls, while 4.2% (5/120) variant calls were false-positive, with the NGMLR/Minimap2-BCFtools pipeline performing best. In total, 13 rareGBAvariants were detected: two were predicted to be (likely) pathogenic and eleven were of uncertain significance. The odds of carrying one of the two most commonGBAvariants, p.L483P or p.N409S, in PD patients were estimated to be 4.11 times the odds of carrying one of these variants in controls (OR=4.11 [1.39, 12.12]).

Conclusions

In conclusion, we have demonstrated that Oxford long-read Nanopore sequencing, along with the NGMLR/Minimap2-BCFtools pipeline is an effective tool to investigateGBAvariants. Further studies on the pathogenicity ofGBAvariants are needed to assess their effect on PD.
Prevalence and correlates of anxiety and depression among female sex workers in Dire Dawa city Administration, Eastern Ethiopia
Authors: Yesuf Yassin Mohammed , Mekonnen Dawit , Teklu Hareg , Kebede Sebsibew Atikaw
Published: February 2023

Background

The mental health states of Female Sex Workers (FSWs) are least explored. The present study examined the levels of anxiety and depression as well as associated factors among FSWs in Dire Dawa city.

Methods

Cross-sectional explanatory sequential mixed-method research design was used. Snowball technique was used to recruit respondents. Beck Anxiety Inventory and Patient Health Questionnaire were used to measure anxiety and depression, respectively. Valid questionnaires were collected from 292 respondents (81% response rate) and interviews were made with six FSWs. Data collected through the questionnaire were analyzed using frequency, percentage, independent sample t-test, ANOVA, Pearson correlation and multiple linear regression while thematic analysis was used to analyze the qualitative data.

Results

The prevalence rates of anxiety and depression were 43.5% and 69.8%, respectively. Psychosocial and demographic variables were important correlates explaining 56% (F=43.324, p=<0.01, R2=.557) and 23% (F=10.319, p<0.01, R2=.228) of the variations in anxiety and depression, respectively. Specifically,Khatuse (β= .371, t=8.744, p<0.01), violence (β= .272, t= 6.521, p<0.01), stigma (β= .258, t= 5.427, p<0.01), tobacco use (β=.200, t= 3.837, p<0.01) and alcohol use (β= -.136, t= -3.327, p<0.01) were significantly correlated with anxiety. Besides, violence (β= .298, t= 5.439, p<0.01), alcohol use (β= -.162, t= 3.011, p<0.01), stigma (β= .160, t= 2.549, p<0.05), andKhatuse (β= .151, t= 2.915, p<0.01) were significantly associated with depression. The qualitative findings substantiated the survey results.

Conclusion

From the findings it is concluded that FSWs in Dire Dawa city were experiencing higher levels of anxiety and depression where psychosocial were important correlates of FSWs’ mental health. Therefore, organizations that are working with and/or concerned about FSWs need to provide evidence-based mental health and psychosocial interventions.
Genetic evidence that high BMI in childhood has a protective effect on intermediate diabetes traits, including measures of insulin sensitivity and secretion
Authors: Hawkes Gareth , Beaumont Robin N , Tyrrell Jessica , Power Grace M , Wood Andrew , Laakso Markku , Silva Lilian Fernandes , Boehnke Michael , Yin Xianyong , Richardson Tom G , Davey Smith George , Frayling Timothy M
Published: February 2023

Determining how high body-mass index (BMI) at different time points influences the risk of developing type two diabetes (T2D), and affects insulin secretion and insulin sensitivity, is critical. By estimating childhood BMI in 441,761 individuals in the UK Biobank, we identified which genetic variants had larger effects on adulthood BMI than on childhood BMI, and vice-versa. All genome-wide significant genetic variants were then used to separate the independent genetic effects of high childhood BMI from high adulthood BMI on the risk of T2D and insulin related phenotypes using Mendelian randomisation and studies of T2D, and oral and intravenous measures of insulin secretion and sensitivity. We found that a 1.s.d. (= 1.97kg/m2) higher childhood BMI, corrected for the independent genetic liability to adulthood BMI, was associated with a protective effect for seven measures of insulin sensitivity and secretion, including an increased insulin sensitivity index (β = 0.15 [0.067, 0.225], p = 2.79×10−4), and reduced fasting glucose (β = -0.053 [-0.089, -0.017], p = 4.31×10−3). There was however little to no evidence of a direct protective effect on T2D (OR = 0.94 [0.85 - 1.04], p = 0.228), independently of genetic liability to adulthood BMI. Our results thus cumulatively provide evidence of the protective effect of higher childhood BMI on insulin secretion and sensitivity, which are crucial intermediate diabetes traits. However, we stress that our results should not currently lead to any change in public health or clinical practice, given the uncertainty in biological pathway of these effects, and the limitations of this type of study.

Research in Context

High BMI in adulthood is associated with higher risk of type two diabetes, coupled with lower insulin sensitivity and secretion.

Richardson et al [2020] used genetics to show that high BMI in childhood does not appear to increase the risk of type diabetes independently from its effect on adult BMI.

We asked: does high childhood BMI affect insulin related traits such as fasting glucose and insulin sensitivity, independently of adulthood BMI?

We used genetics to show that high childhood BMI has a protective effect on seven insulin sensitivity and secretion traits, including fasting glucose and measures of insulin sensitivity and secretion, independently of adulthood BMI.

Our work has the potential to turn conventional understanding on its head – high BMI in childhood improves insulin sensitivity (when adjusting for knock on effects to high adult BMI) and opens up important questions about plasticity in childhood and compensatory mechanisms.
The seminal odorant binding protein Obp56g is required for mating plug formation and male fertility inDrosophila melanogaster
Authors: Brown Nora C. , Gordon Benjamin , McDonough-Goldstein Caitlin E. , Misra Snigdha , Findlay Geoffrey D. , Clark Andrew G. , Wolfner Mariana F.
Published: February 2023

InDrosophila melanogasterand other insects, the seminal fluid proteins (SFPs) and male sex pheromones that enter the female with sperm during mating are essential for fertility and induce profound post-mating effects on female physiology and behavior. The SFPs inD. melanogasterand other taxa include several members of the large gene family known as odorant binding proteins (Obps). Previous work inDrosophilahas shown that someObpgenes are highly expressed in the antennae and can mediate behavioral responses to odorants, potentially by binding and carrying these molecules to odorant receptors. These observations have led to the hypothesis that the seminal Obps might act as molecular carriers for pheromones or other compounds important for male fertility in the ejaculate, though functional evidence in any species is lacking. Here, we used RNAi and CRISPR/Cas9 generated mutants to test the role of the seven seminal Obps inD. melanogasterfertility and the post-mating response (PMR). We found thatObp56gis required for male fertility and the induction of the PMR, whereas the other six genes had no effect on fertility when mutated individually.Obp56gis expressed in the male’s ejaculatory bulb, an important tissue in the reproductive tract that synthesizes components of the mating plug. We found males lackingObp56gfail to form a mating plug in the mated female’s reproductive tract, leading to ejaculate loss and reduced sperm storage. We also examined the evolutionary history of these seminalObpgenes, as several studies have documented rapid evolution and turnover of SFP genes across taxa. We found extensive lability in gene copy number and evidence of positive selection acting on two genes,Obp22aandObp51a. Comparative RNAseq data from the male reproductive tract of multipleDrosophilaspecies revealed thatObp56gshows high male reproductive tract expression only in species of themelanogasterandobscuragroups, though conserved head expression in all species tested. Together, these functional and expression data suggest thatObp56gmay have been co-opted for a reproductive function over evolutionary time.
SaLTy: a novelStaphylococcus aureusLineage Typer
Authors: Cheney Liam , Payne Michael , Kaur Sandeep , Lan Ruiting
Published: February 2023

Staphylococcus aureusasymptomatically colonises 30% of humans and in 2017 was associated with 20,000 deaths in the USA alone. DividingS. aureusinto smaller sub-groups can reveal the emergence of distinct sub-populations with varying potential to cause infections. Despite multiple molecular typing methods categorising such sub-groups, they do not take full advantage ofS. aureusWGS when describing the fundamental population structure of the species.

In this study, we developedStaphylococcus aureusLineage Typing (SaLTy), which rapidly divides the species into 61 phylogenetically congruent lineages. Alleles of three core genes were identified that uniquely define the 61 lineages and were used for SaLTy typing. SaLTy was validated on 5,000 genomes and 99.12% (4,956/5,000) of isolates were assigned the correct lineage.

We compared SaLTy lineages to previously calculated clonal complexes (CCs) from BIGSdb (n=21,173). SALTy improves on CCs by grouping isolates congruently with phylogenetic structure. SaLTy lineages were further used to describe the carriage ofStaphylococcalchromosomal cassette containingmecA(SCCmec) which is carried by methicillin-resistantS. aureus(MRSA). Most lineages had isolates lacking SCCmecand the four largest lineages varied in SCCmecover time. Classifying isolates into SaLTy lineages, which were further SCCmectyped, allowed SaLTy to describe high-level MRSA epidemiology

We provide SALTy as a simple typing method that defines phylogenetic lineages (https://github.com/LanLab/SaLTy). SALTy is highly accurate and can quickly analyse large amounts ofS. aureusWGS. SALTy will aid the characterisation ofS. aureuspopulations and the ongoing surveillance of sub-groups that threaten human health.
Evidence for a sensorimotor prediction process in action observation
Authors: Hilt Pauline M. , Gueugneau Nicolas , Fadiga Luciano , Pozzo Thierry , Papaxanthis Charalambos
Published: February 2023

The mirror neurons network in the human brain is activated both during the observation of action and the execution of the same action, facilitating thus the transformation of visual information into motor representations, to understand the actions and intentions of others. How this transformation takes place, however, is still under debate. One prevailing theory,direct matching, assumes a direct correspondence between the visual information of the actor’s movement and the activation of the motor representations in the observer’s motor cortex that would produce the same movement. Alternatively, thepredictive codingtheory postulates that, during action observation, motor predictions (e.g., position, velocity) are generated and compared to the visual information of the actor’s movement. Here, we experimentally interrogate these two hypotheses during a locomotion task. The motor prediction process was assessed by measuring the timing of imagined movements: the participants had to imagine walking, forward or backward, for 9 m (linear path). Action observation was assessed by measuring time estimation in an inference locomotor task (the same 9 m linear path): after perceiving an actor walking forward or backward for 3 m, the vision of the observer was occluded and he/she had to estimate when the actor would reach the end of the 9 m path. We manipulated the timing processes during the two tasks by creating sensory illusions via peripheral mechanical muscle vibration on leg muscles, which has provided consistent results in the literature (acceleration of forward and deceleration of backward locomotion). We found that sensory illusions specifically affected the timing processes of both locomotion inference and mental locomotion, suggesting the involvement of sensorimotor predictions, common to both tasks. These findings seem to support the predictive coding hypothesis.
A novel cryopreservation and biobanking strategy to study lymphoid tissue stromal cells in human disease
Authors: Brandstadter Joshua D , De Martin Angelina , Lütge Mechthild , Ferreira Antonio , Gaudette Brian T , Stanossek Yves , Wang Shumei , Gonzalez Michael V , Camiolo Edward , Wertheim Gerald , Austin Bridget , Allman David , Lim Megan S , Fajgenbaum David C , Aster Jon C , Ludewig Burkhard , Maillard Ivan
Published: February 2023

Non-hematopoietic lymph node stromal cells (LNSCs) regulate lymphocyte trafficking, survival, and function for key roles in host defense, autoimmunity, alloimmunity, and lymphoproliferative disorders. However, study of LNSCs in human diseases is complicated by a dependence on viable lymphoid tissues, which are most often excised prior to establishment of a specific diagnosis. Here, we demonstrate that cryopreservation can be used to bank lymphoid tissue for the study of LNSCs in human disease. Using human tonsils, lymphoid tissue fragments were cryopreserved for subsequent enzymatic digestion and recovery of viable non-hematopoietic cells. Flow cytometry and single-cell transcriptomics identified comparable proportions of LNSC cell types in fresh and cryopreserved tissue. Moreover, cryopreservation had little effect on transcriptional profiles, which showed significant overlap between tonsils and lymph nodes. The presence and spatial distribution of transcriptionally defined cell types was confirmed by in situ analyses. Our broadly applicable approach promises to greatly enable research into the roles of LNSC in human disease.
Marine Picoplankton Metagenomes from Eleven Vertical Profiles Obtained by the Malaspina Expedition in the Tropical and Subtropical Oceans
Authors: Sánchez Pablo , Sebastián Marta , Pernice Massimo , Rodríguez-Martínez Raquel , Pesant Stephane , Agustí Susana , Gojobori Takashi , Logares Ramiro , Sala María Montserrat , Vaqué Dolors , Massana Ramon , Duarte Carlos M. , Acinas Silvia G. , Gasol Josep M.
Published: February 2023

The Ocean microbiome has a crucial role on Earth’s biogeochemical cycles, but also represents a tremendous potential for biological applications as part of the bluebiotechnology. During the last decade, global cruises such asTaraOceans or the Malaspina Expedition have expanded our knowledge on the diversity and genetic repertoire of marine microbes. Nevertheless, there is still a gap of knowledge on broad scale patterns between photic and bathypelagic dark ocean microbes derived from the lack of detailed vertical profiles covering contrasting oceans depth regions. Here we present a dataset of 76 microbial metagenomes of the picoplankton size fraction (0.2-3.0 μm) collected in 11 stations along the Malaspina Expedition circumnavigation that cover vertical profiles sampling at 7 depths, from the surface to the 4000 m deep (or the sea floor in shallower waters). This Malaspina Microbial Vertical Profiles metagenomes (MProfile) dataset produced 1.66 Tbp of raw DNA sequences that assembled into a total 25.3 Gbp. After gene prediction and annotation, we built a 46.3 million non-redundant gene compendium with their corresponding annotations (M-GeneDB-VP), clustered at 95% sequence similarity. This dataset will be a valuable resource for exploring the functional and taxonomic connectivity between the photic and bathypelagic tropical and subtropical ocean at a global scale, while increasing our general knowledge on the Ocean microbiome.
Sulcal morphology of posteromedial cortex substantially differs between humans and chimpanzees
Authors: Willbrand Ethan H. , Maboudian Samira A. , Kelly Joseph P. , Parker Benjamin J. , Foster Brett L. , Weiner Kevin S.
Published: February 2023

Recent studies identify a surprising coupling between evolutionarily new sulci and the functional organization of human posteromedial cortex (PMC). Yet, no study has compared this modern PMC sulcal patterning between humans and non-human hominoids. To fill this gap in knowledge, we first manually defined 918 sulci in 120 chimpanzee (Pan Troglodytes) hemispheres and 1619 sulci in 144 human hemispheres. We uncovered four new PMC sulci, and quantitatively identified species differences in incidence, depth, and surface area. Interestingly, some PMC sulci are more common in humans and others, in chimpanzees. Further, we found that the prominent marginal ramus of the cingulate sulcus differs significantly between species. Contrary to classic observations, the present results reveal that the surface anatomy of PMC substantially differs between humans and chimpanzees — findings which lay a foundation for better understanding the evolution of neuroanatomical-functional and neuroanatomical-behavioral relationships in this highly expanded region of the human cerebral cortex.
Medial prefrontal cortex stimulation abolishes implicit reactions to threats and prevents the return of fear
Authors: Manassero Eugenio , Concina Giulia , Caraig Maria Clarissa Chantal , Sarasso Pietro , Salatino Adriana , Ricci Raffaella , Sacchetti Benedetto
Published: February 2023

Down-regulating emotional overreactions toward threats is fundamental for developing treatments for anxiety and post-traumatic disorders. The prefrontal cortex (PFC) is critical for top-down modulatory processes, and despite previous studies adopting repetitive Transcranial Magnetic Stimulation (rTMS) over this region provided encouraging results in enhancing extinction, no studies have hitherto explored the effects of stimulating the medial PFC (mPFC) on threat memory and generalization. Here we showed that rTMS applied before threat memory retrieval abolishes implicit reactions to learned and novel stimuli in humans. These effects were not due to inhibition of electrodermal reactivity and enduringly persisted one week later in the absence of rTMS. No effects were detected on explicit recognition. Critically, we observed stronger attenuation of defensive responses in subjects stimulated over the mPFC than the dlPFC. Our findings uncover a prefrontal region whose modulation can permanently hamper implicit reactions to learned dangers, representing an advance to long-term deactivating overreactions to threats.
The anti-leprosy drug clofazimine reduces polyQ toxicity through activation of PPARγ
Authors: Li Xuexin , Hernandez Ivo , Häggblad Maria , Lidemalm Louise , Brautigam Lars , Lucas Jose J. , Carreras-Puigvert Jordi , Hühn Daniela , Fernandez-Capetillo Oscar
Published: February 2023

PolyQ diseases are autosomal dominant neurodegenerative disorders caused by the expansion of CAG repeats. While of slow progression, these diseases are ultimately fatal and lack effective therapies. Here, we present our results from a High-Throughput chemical screen oriented to find drugs that lower the toxicity of a protein containing the first exon from the Huntington’s disease protein huntingtin (HTT) harboring 94 glutamines (Htt-Q94). Our screening identified the anti-leprosy drug clofazimine as a hit, which was subsequently validated in several in vitro models as well as in a zebrafish model of polyQ toxicity. Computational analyses of transcriptional signatures, together with molecular modeling and biochemical assays revealed that clofazimine is an agonist of the peroxisome proliferator activated receptor gamma (PPARγ), previously suggested as a potential therapy for HD by stimulating mitochondrial biogenesis. Accordingly, clofazimine rescued the mitochondrial dysfunction triggered by Htt-Q94expression. Together, our results support the potential of clofazimine repurposing for the treatment of PolyQ diseases.
Mechanism of sensor kinase CitA transmembrane signaling
Authors: Zhang Xizhou Cecily , Xue Kai , Salvi Michele , Schomburg Benjamin , Mehrens Jonas , Giller Karin , Stopp Marius , Weisenburger Siegfried , Böning Daniel , Sandoghdar Vahid , Unden Gottfried , Becker Stefan , Andreas Loren B. , Griesinger Christian
Published: February 2023

Membrane bound histidine kinases (HKs) are ubiquitous sensors of extracellular stimuli in bacteria. Here, we used solid-state NMR in conjunction with crystallography, solution NMR and distance measurements to investigate the transmembrane signaling mechanism of a paradigmatic citrate sensing membrane embedded HK, CitA. Citrate binding in the sensory extracytoplasmic PAS domain (PASp) causes the linker to transmembrane helix 2 (TM2) to adopt a helical conformation. This triggers a piston-like pulling of TM2 and a quaternary structure rearrangement in the cytosolic PAS domain (PASc). Crystal structures of PASc reveal both anti-parallel and parallel dimer conformations. An anti-parallel to parallel transition upon citrate binding agrees with interdimer distances measured in the lipid embedded protein using a site-specific19F label in PASc. These data show how Angstrom scale structural changes in the sensor domain are transmitted across the membrane to be converted and amplified into a nm scale shift in the linker to the phosphorylation subdomain of the kinase.

One-Sentence Summary

Transmembrane signal transduction of a PAS-domain containing histidine kinase occurs via a piston-like pulling of a transmembrane helix, and amplification by cytoplasmic PAS domain dimer rearrangement.
BiGPICC: a graph-based approach to identifying carcinogenic gene combinations from mutation data
Authors: Oles Vladyslav , Dash Sajal , Anandakrishnan Ramu
Published: February 2023

Genome data from cancer patients represents relationships between the presence of a gene mutation and cancer occurrence in a patient. Different types of cancer in human are thought to be caused by combinations of two to nine gene mutations. Identifying these combinations through traditional exhaustive search requires the amount of computation that scales exponentially with the combination size and in most cases is intractable even for cutting-edge supercomputers.

We propose a parameter-free heuristic approach that leverages the intrinsic topology of gene-patient mutations to identify carcinogenic combinations. The biological relevance of the identified combinations is measured by using them to predict the presence of tumor in previously unseen samples. The resulting classifiers for 16 cancer types perform on par with exhaustive search results, and score the average of 80.1% sensitivity and 91.6% specificity for the best choice of hit range per cancer type. Our approach is able to find higher-hit carcinogenic combinations targeting which would take years of computations using exhaustive search.
TLR7 activation at epithelial barriers promotes emergency myelopoiesis and lung anti-viral immunity
Authors: Jackson William D , Giacomassi Chiara , Ward Sophie , Owen Amber , Luis Tiago C. , Spear Sarah , Woollard Kevin J , Johansson Cecilia , Strid Jessica , Botto Marina
Published: February 2023

Monocytes are heterogeneous innate effector leukocytes generated in the bone marrow and released into circulation in a CCR2-dependent manner. During infection or inflammation myelopoiesis is modulated to rapidly meet demand for more effector cells. Danger signals from peripheral tissues can influence this process. Herein we demonstrate that repetitive TLR7 stimulation via the epithelial barriers drove a potent emergency bone marrow monocyte response. This process was unique to TLR7 activation and occurred independently of the canonical CCR2 and CX3CR1 axes or prototypical cytokines. The monocytes egressing the bone marrow had an immature Ly6C-high profile and differentiated into vascular Ly6C-low monocytes and tissue macrophages in multiple organs. They displayed a blunted cytokine response to further TLR7 stimulation and reduced lung viral load after RSV and influenza virus infection. These data provide insights into the emergency myelopoiesis likely to occur in response to the encounter of single-stranded RNA viruses at barrier sites.