bluuebunny/crossref_metadata_2025 huggingface dataset:
Mother’s childhood adversity is associated with accelerated epigenetic aging in pregnancy and in male newborns
Authors: Dye Christian K. , Wu Haotian , Monk Catherine , Belsky Daniel W. , Alschuler Daniel , Lee Seonjoo , O’Donnell Kieran , Scorza Pamela
Published: March 2023

Background

Adverse childhood experiences (ACEs) are correlated with accelerated epigenetic aging, but it is not clear whether altered epigenetic aging from childhood adversities persists into adulthood and can be transmitted to the next generation. Thus, we tested whether mothers’ childhood adversity is associated with accelerated epigenetic aging during pregnancy and in their newborn offspring.

Methods

Data were from the Avon Longitudinal Study of Parents and Children (ALSPAC) sub-study, Accessible Resource for Integrated Epigenomic Studies (ARIES). Women provided retrospective self-reports during pregnancy of ACE exposure. DNA methylation was measured in mothers during pregnancy and cord blood at birth. Estimates of epigenetic age acceleration were calculated using Principal Components of Horvath, Hannum skin & blood, GrimAge, PhenoAge, and DunedinPACE epigenetic clocks for mothers; and the Knight and Bohlin cord blood clocks for newborns. Associations between a cumulative maternal ACE score and epigenetic age acceleration were estimated using linear regression models, adjusting for maternal age at pregnancy, smoking during pregnancy, education, and pre-pregnancy BMI. Models for offspring were stratified by sex and additionally adjusted for gestation age.

Results

Mothers’ total ACE score was positively associated with accelerated maternal PhenoAge and GrimAge. In newborn offspring, mothers’ total ACE score was positively associated with accelerated epigenetic aging in males using the Bohlin clock, but not in females using either epigenetic clock. We found male offsprings’ epigenetic age was accelerated in those born to mothers exposed to neglect using the Knight clock; and parental substance abuse using the Bohlin clock.

Conclusion

Our results show that mothers’ ACE exposure is associated with DNAm age acceleration in male offspring, supporting the notion that DNAm age could be a marker of intergenerational biological embedding of mothers’ childhood adversity. This is consistent with findings on vulnerability of male fetuses to environmental insults.
Improvements in diarrheal disease prevalence with point-of-use water filter implementation in the informal settlement of Kibera, Kenya
Authors: Tintle Nathan L. , Westra Jason , Van De Griend Kristin , Beard Virginia , Turner Benjamin N. , Huisman Natalie L.H. , Dawson Nicholas , Droscha Lillian , Ihle Clay , Moore Matthew , Orellana Marilyn , Schutter Luke , Snyder Lydia , White Devin , Wilson Makayla , Goszkowicz Grace K. , Krueger Brent P. , Best Aaron A.
Published: March 2023

Background

There is increasing evidence of the efficacy of point-of-use water filters on diarrhea prevalence in numerous global settings, in both observational studies and randomized experiments. Most studies, however, are focused on rural locations. Methods We use self-report household surveys to monitor a set of approximately 10,000 households receiving point-of-use water filters and WASH training in Kibera, Kenya. Twenty-five drinking water sources throughout the 7 neighborhoods were also selected for testing of E. coli, total coliform, bacterial 16S rRNA community sequencing and metals. Albendazole was provided to all households at distribution as part of the standard filter distribution protocol, with a subset of 2,642 households not receiving Albendazole at distribution, instead receiving it at the second follow-up (approximately 5 weeks after filter distribution).

Results

After data cleaning, a sample of 6,795 households were analyzed using mixed effects generalized linear models to account for repeated household measurements, geospatial and temporal effects, interviewer and other household covariates. Models predicted self-reported, 2-week prevalence of diarrhea. After accounting for confounding factors, self-reported diarrhea rates dropped from 52.7% to 2.2% after approximately 70 days of filter use. Field testing characterized most water sources (18 out of 25) as unsafe for Total coliforms, many for E. coli (6 out of 25), and one source above WHO health guidelines for arsenic. There was no evidence of a difference in self-reported diarrhea prevalence between households receiving Albendazole at distribution vs. those that didn’t (p>0.05).

Conclusions

The introduction of Sawyer filters to households in a densely populated informal settlement reduced diarrhea and other health related problems. Representative water quality testing indicates a high frequency of drinking water source contamination with E. coli and Total Coliforms but a very low frequency of dissolved metals present, above WHO guidelines for drinking water. Anti-parasitic medication distribution had little to no impact on the results. Future randomized controlled studies with objective health measures are needed to ensure cause-effect impact of the filters, and study of filter longevity in the field continues to be a critical need.
The biosynthesis, degradation, and function of cell wall β-xylosylated xyloglucan mirrors that of arabinoxyloglucan
Authors: Wilson L. F. L. , Neun S. , Yu L. , Tryfona T. , Stott K. , Hollfelder F. , Dupree P.
Published: March 2023

Xyloglucan is an abundant polysaccharide in many primary cell walls and in the human diet. Decoration of its α-xylosyl side chains with further sugars is critical for plant growth, even though the sugars themselves vary considerably between species. Plants in the Ericales order—prevalent in human diets—exhibit β1,2-linked xylosyl decorations. The biosynthetic enzymes responsible for adding these xylosyl decorations, as well as the hydrolases that remove them in the human gut, are unidentified.

GT47 xyloglucan glycosyltransferase candidates were expressed in Arabidopsis andendo-xyloglucanase products from transgenic wall material were analysed by electrophoresis, mass spectrometry, and NMR. The activities of gut bacterial hydrolasesBoGH43A andBoGH43B on synthetic glycosides and xyloglucan oligosaccharides were measured by colorimetry and electrophoresis.

CcXBT1 is a xyloglucan β-xylosyltransferase from coffee that can modify Arabidopsis xyloglucan and restore the growth of galactosyltransferase mutants. RelatedVmXST1 is a weakly active xyloglucan α-arabinofuranosyltransferase from cranberry.BoGH43A hydrolyses both α-arabinofuranosylated and β-xylosylated oligosaccharides.

CcXBT1’s presence in coffee andBoGH43A’s promiscuity suggest that β-xylosylated xyloglucan is not only more widespread than thought, but might also nourish beneficial gut bacteria. The evolutionary instability of transferase specificity and lack of hydrolase specificity hint that, to enzymes, xylosides and arabinofuranosides are closely resemblant.
Computational Methods for Biofabrication in Tissue Engineering and Regenerative Medicine - a literature review
Authors: Bardini Roberta , Di Carlo Stefano
Published: March 2023

This literature review rigorously examines the growing scientific interest in computational methods for Tissue Engineering and Regenerative Medicine biofabrication, a leading-edge area in biomedical innovation, emphasizing the need for accurate, multi-stage, and multi-component biofabrication process models. The paper presents a comprehensive bibliometric and contextual analysis, followed by a literature review, to shed light on the vast potential of computational methods in this domain. It reveals that most existing methods focus on single biofabrication process stages and components, and there is a significant gap in approaches that utilize accurate models encompassing both biological and technological aspects. This analysis underscores the indispensable role of these methods in under-standing and effectively manipulating complex biological systems and the necessity for developing computational methods that span multiple stages and components. The review concludes that such comprehensive computational methods are essential for developing innovative and efficient Tissue Engineering and Regenerative Medicine biofabrication solutions, driving forward advancements in this dynamic and evolving field.

Graphical Abstract
Differential increase of hippocampal subfield volume after socio-affective mental training relates to reductions in diurnal cortisol
Authors: Valk Sofie L. , Engert Veronika , Puhlman Lara , Linz Roman , Caldirou Benoit , Bernasconi Andrea , Bernasconi Neda , Bernhardt Boris C. , Singer Tania
Published: March 2023

The hippocampus is a central modulator of the HPA-axis, impacting the regulation of stress on brain structure, function, and behavior. The current study assessed whether three different types of 3-months mental Training Modules geared towards nurturing a) attention-based mindfulness, b) socio-affective or c) socio-cognitive skills may impact hippocampal organization by reducing stress. We evaluated mental training-induced changes in hippocampal subfield volume and intrinsic functional connectivity, by combining longitudinal structural and resting-state fMRI connectivity analysis in 332 healthy adults. We related these changes to changes in diurnal and chronic cortisol levels. We observed increases in bilateral cornu ammonis volume (CA1-3) following the 3-months compassion-based module targeting socio-affective skills (Affectmodule), as compared to socio-cognitive skills (Perspectivemodule) or a waitlist cohort with no training intervention. Structural changes were paralleled by relative increases in functional connectivity of CA1-3 when fostering socio-affective as compared to socio-cognitive skills. Furthermore, training-induced changes in CA1-3 structure and function consistently correlated with reductions in cortisol output. Notably, using a multivariate approach, we found that other subfields that did not show group-level changes also contributed to changes in cortisol levels. Overall, we provide a link between a socio-emotional behavioural intervention, changes in hippocampal subfield structure and function, and reductions in cortisol in healthy adults.
Viral diversity and dynamics, and CRISPR-Cas mediated immunity in a robust alkaliphilic Cyanobacterial consortium
Authors: Khot Varada , Strous Marc , Dong Xiaoli , Kiesser Alyse K.
Published: March 2023

In many industries, from food to biofuels, contamination of production systems with predators is a costly problem and requires the maintenance of sterile operating conditions. In this study, we look at the robustness of one such alkaliphilic consortium, comprised largely of a cyanobacteriumCandidatusPhormidium alkaliphilum, to viral predation. This consortium has existed without a community crash over several years in laboratory and pilot scale environments. We look at CRISPR-Cas systems and viral dynamics in this consortium at four conditions using metagenomic analyses. Results show that while there are active viral members in this community, viral predation of the cyanobacteria is low and does not affect the community dynamics. The multiple CRISPR arrays within the Phormidium were found to be static following initial lab establishment of consortium. Multiple cryptic CRISPR-Cas systems were detected with uncertain viral protection capacity. Our results suggest that dynamics of potential viruses and CRISPR-Cas mediated immunity likely play an important role in the initial establishment of consortia and may continue to support the functional robustness of engineered microbial communities throughout biotechnology applications.

Importance

Biotechnology applications utilizing the function of microbial communities have become increasingly important solutions as we strive for sustainable applications. Although viral infections are known to have significant impact on microbial turnover and nutrient cycling, viral dynamics have remained largely overlooked in these engineered communities. Predatory perturbations to the functional stability of these microbial biotechnology applications must be investigated in order to design more robust applications. In this study, we closely examine virus-microbe dynamics in a model microbial community used in a biotechnology application. Our findings suggest that viral dynamics change significantly with environmental conditions and that microbial immunity may play an important role in maintaining functional stability. We present this study as a comprehensive template for other researchers interested in exploring predatory dynamics in engineered microbial communities.
S100A1ct: a synthetic peptide derived from human S100A1 protein improves cardiac contractile performance and survival in pre-clinical heart failure models
Authors: Kehr Dorothea , Ritterhoff Julia , Glaser Manuel , Jarosch Lukas , Salazar Rafael E. , Spaich Kristin , Varadi Karl , Birkenstock Jennifer , Egger Michael , Gao Erhe , Koch Walter J. , Katus Hugo A. , Frey Norbert , Jungmann Andreas , Busch Cornelius , Mather Paul J. , Ruhparwar Arjang , Völkers Mirko , Wade Rebecca C. , Most Patrick
Published: March 2023

Background

The EF-hand Ca2+sensor protein S100A1 has been identified as a molecular regulator and enhancer of cardiac performance. S100A1’s ability to recognize and modulate the activity of targets such as SERCA2a and RyR2 in cardiomyocytes has mostly been ascribed to its hydrophobic C-terminalα-helix (residues 75-94).Objective:We therefore hypothesized that a synthetic peptide consisting of residues 75-94 of S100A1 and an N-terminal solubilization tag (S100A1ct) could mimic the performance enhancing effects of S100A1 and may be suitable as a peptide therapeutic to improve the function of diseased hearts.Methods and Results:Applying an integrative translational research pipeline, ranging from computational molecular modeling to large animal cardiac disease models, we characterize S100A1ct as a cell-penetrating peptide with positive inotropic and antiarrhythmic properties in normal and failing myocardiumin vitroandin vivo. This activity translates into improved contractile performance and survival in pre-clinical heart failure models with reduced ejection fraction after S100A1ct systemic administration. Mechanistically, S100A1ct exerts a fast and sustained dose-dependent enhancement of cardiomyocyte Ca2+cycling and prevents ß-adrenergic receptor triggered Ca2+imbalances by targeting SERCA2a and RyR2 activity. Modeling suggests that S100A1ct may stimulate SERCA2a by interacting with the sarcoplasmic transmembrane segments of the multi-span integral membrane Ca2+pump. Incorporation of a cardiomyocyte targeting peptide tag into S100A1ct (cor-S100A1ct) further enhanced its biological and therapeutic potencyin vitroandin vivo.Conclusion:S100A1ct peptide is a promising lead for the development of a novel peptide-based therapeutic against heart failure with reduced ejection fraction.
Inferring B-cell derived T-cell receptor induced multi epitope-based vaccine candidate against enterovirus 71 (EV 71): A reverse vaccinology approach
Authors: Swain Subrat Kumar , Panda Subhasmita , Sahu Basanta Pravas , Mahapatra Soumya Ranjan , Dey Jyotirmayee , Misra Namrata , Sarangi Rachita
Published: March 2023

In addition to Coxsackie virus (CV), another pathogen that causes Hand-foot and mouth disease (HFMD), Enterovirus 71 (EV 71) is currently regarded as an increasing neurotropic virus in Asia and can cause severe complications in paediatric patients with blister like sores or rashes on the hand, feet and mouth. Not withstanding the significant burden of the disease, few treatments are currently available, and there is no authorised vaccine available for the disease prevention. Several vaccinations based on attenuated and inactivated vaccines have previously been identified, however they become worthless over time owing to changes in the viral genome. As a result, the goal of the study is to create an immunoinformatics and reverse vaccinology pipeline for predicting a multi epitope vaccine. A novel vaccine construct using B-cell derived T-cell epitopes from the virulent polyprotein and found the induction of possible immune response, in order to boost the immune system, aBeta-defensin 1 preproprotein adjuvant with EAAAK linker was added at the N-terminal end of the vaccine sequence. The immunogenicity of the designed, refined, and verified prospective 3D- structure of multi-epitope vaccine was found to be quite high with non-allergen, and antigenic property. The vaccine candidates bound to the TLR-3 in a molecular docking analysis and the efficacy of the potential vaccine to generate a strong immune response was assessed by means of an in silico immunological simulation. Computational analysis has shown that the proposed multi epitope vaccine possibility safe for use in humans and elicit an immune response, making it a promising tool against HFMD viral genome.
Sexual Dimorphic Gene Expression Profile of Perirenal Adipose Tissue in Ovine Fetuses with Growth Restriction
Authors: Blomberg Jack , Luna Ramirez Rosa I. , Goyal Dipali , Limesand Sean W. , Goyal Ravi
Published: March 2023

Worldwide, fetal growth restriction (FGR) affects 7 to 10% of pregnancies, or roughly 20.5 million infants, each year. FGR not only increases neonatal mortality and morbidity but also the risk of obesity in later life. Currently, the molecular mechanisms by which FGR “programs” an obese phenotype are not well understood. Studies demonstrate that FGR females are more prone to obesity compared to males; however, the molecular mechanisms that lead to the sexually dimorphic programming of FGR are not known. Thus,we hypothesized that FGR leads to the sexually dimorphic programming of preadipocytes and reduces their ability to differentiate into mature adipocytes. To test the hypothesis, we utilized a maternal hyperthermia-induced placental insufficiency to restrict fetal growth in sheep. We collected perirenal adipose tissue from male and female near-term FGR and normal-weight fetal lambs (N=4 in each group, 16 total), examined the preadipocytes’ differentiation potential, and identified differential mRNA transcript expression in perirenal adipose tissue. Male FGR fetuses have lower cellular density compared to control male fetuses. However, no difference was observed in female FGR fetuses compared to control female fetuses. In addition, the ability of preadipocytes to differentiate into mature adipocytes with fat accumulation was impaired in male FGR fetuses, but this was not observed in female FGR fetuses. Finally, we examined the genes and pathways involved in the sexually dimorphic programming of obesity by FGR. On enrichment of differentially expressed genes in males compared to females, the Thermogenesis KEGG Pathway was downregulated, and the Metabolic and Steroid Biosynthesis KEGG pathways were upregulated. On enrichment of differentially expressed genes in male FGR compared to male control, the Steroid Biosynthesis KEGG Pathway was downregulated, and the PPAR Signaling KEGG pathway was upregulated. No pathways were altered in females in response to growth restriction in perirenal adipose tissue. Thus, the present study demonstrates a sexually dimorphic program in response to growth restriction in sheep fetal perirenal adipose tissue.
Mapping cell types in the tumor microenvironment from tissue images via deep learning trained by spatial transcriptomics of lung adenocarcinoma
Authors: Na Kwon Joong , Koh Jaemoon , Choi Hongyoon , Kim Young Tae
Published: March 2023

Profiling heterogeneous cell types in the tumor microenvironment (TME) is important for cancer immunotherapy. Here, we propose a method and validate in independent samples for mapping cell types in the TME from only hematoxylin and eosin (H&E)-stained tumor tissue images using spatial transcriptomic data of lung adenocarcinoma. We obtained spatial transcriptomic data of lung adenocarcinoma from 22 samples. The cell types of each spot were estimated using cell type inference based on a domain adaptation algorithm with single-cell RNA-sequencing data. They were used to train a convolutional neural network with a corresponding H&E image patch as an input. Consequently, the five predicted cell types estimated from the H&E images were significantly correlated with those derived from the RNA-sequencing data. We validated our model using immunohistochemical staining results with marker proteins from independent lung adenocarcinoma samples. Our resource of spatial transcriptomics of lung adenocarcinoma and proposed method with independent validation can provide an annotation-free and precise profiling method of tumor microenvironment using H&E images.
BuTT-Seq: a new method for facile profiling of transcription
Authors: Yu Albert D. , Rosbash Michael
Published: March 2023

A wide range of sequencing methods have been developed to assess nascent RNA transcription and resolve the single-nucleotide position of RNA polymerase genome-wide. These techniques are often burdened with high input material requirements and lengthy protocols. We leveraged the template-switching properties of thermostable group II intron reverse transcriptase (TGIRT) and developed BuTT-Seq (BUlk analysis of nascent Transcript Termini sequencing), which can produce libraries from purified nascent RNA in 6 hours and from as few as 10,000 cells – an improvement of at least 25-fold over existing techniques. BuTT-Seq shows that inhibition of the superelongation complex (SEC) causes promoter-proximal pausing to move upstream in a fashion correlated with subnucleosomal fragments. To address transcriptional regulation in a tissue, BuTT-Seq was used to measure the circadian regulation of transcription from fly heads. All the results indicate that BuTT-Seq is a simple and powerful technique to analyze transcription at a high level of resolution.
Application of DNA forensic to identify a problem leopard and its implications for human-leopard conflict mitigation
Authors: Manandhar Prajwol , Manandhar Ajaya , Joshi Jyoti , Karmacharya Dibesh
Published: March 2023

Attacks on humans by leopardsPanthera pardusoften escalate human-leopard conflict, influence extreme negative tolerance and encourage retaliatory killings. In the rural hilly region of Arghakhanchi district, mid-western Nepal, a leopard killed a child in November 2018. Government authorities captured a leopard a week later which was immediately killed by the villagers. We collected the predator’s salivary DNA from the victim’s bite wound and compared its DNA fingerprint profile with the killed leopard’s profile to resolve the case using 13 microsatellite markers for leopard individualization. Our genetic analysis confirmed that the leopard persecuted by the villagers was the same leopard that had killed the victim. We urge the government to devise dedicated policy and guidelines for human-leopard conflict management and mitigation in Nepal, and to incorporate protocols, including leopard individualization microsatellite panel we have standardized, that mandate correct identification of captured leopard before any interventions such as persecutions and translocations are attempted. We also recommend steering community programs to proactively safeguard children, people and livestock to avoid conflicts and to influence positive tolerance towards leopards. This will benefit leopard conservation and save human lives and livelihoods leading to a healthy coexistence.
Leaf hydration status under drought is predominantly linked to stomatal regulation and leaf roll but not osmotic adjustment in Canadian hard red spring wheat (Triticum aestivum) cultivars
Authors: Sharma G , Brar GS , Knipfer T
Published: March 2023

For wheat (Triticum aestivum), sustained crop yield at limited soil water has been linked to osmotic adjustment (OA) as one of the main drivers to minimize drought-induced reductions in leaf hydration status and growth. Canada Western Red Spring (CWRS) cultivars are typically grown in rainfed areas in northern regions with milder climates, but ongoing climate change has increased the frequency and intensity of drought event questioning how successful they are in tolerating drought. The extent of OA and its relation to stomatal behavior, leaf roll, and kernel development under periods of drought remain elusive for CWRS. For several commercially used Canada Western Red Spring (CWRS) wheat cultivars (‘Superb’, ‘Stettler’, ‘AAC Viewfield’), OA was not found to be a mechanism contributing to drought tolerance. In contrast, we found that sustained kernel weight during periods of relatively low soil water content was linked to ‘tight’ stomatal behavior (i.e., efficient transition from onset to full stomatal closure) and ‘early’ leaf roll (i.e., reductions in flag leaf width). Moreover, leaf hydration status (ΘRWC) marked the onset of drought-induced losses in kernel weight in all three cultivars. In conclusion, CWRS wheat lacks OA but leaf stomatal behavior and leaf rolling aid in securing leaf hydration status and kernel weight under drought.

One-sentence summary

Select wheat cultivars maintain leaf hydration status and yield by early leaf roll and rapid stomatal closure in the absence of osmotic adjustment and isohydric behavior.
Cryopreservation and revival of Hawaiian stony corals via isochoric vitrification
Authors: Powell-Palm Matthew J. , Henley E. Michael , Consiglio Anthony N. , Lager Claire , Chang Brooke , Perry Riley , Fitzgerald Kendall , Daly Jonathan , Rubinsky Boris , Hagedorn Mary
Published: March 2023

Corals are under siege by both local and global threats, creating a wordwide reef crisis. Cryopreservation is an important intervention measure and a vital component of the modern coral conservation toolkit, but preservation techniques are currently limited to sensitive reproductive materials that can only be obtained a few nights per year during spawning. Here, we report the first successful cryopreservation and revival of cm-scale coral fragments via mL-scale isochoric vitrification. We demonstrate coral viability at 24h post-thaw using a calibrated oxygen-uptake respirometry technique, and further show that the method can be applied in a passive, electronics-free configuration. Finally, we detail a complete prototype coral cryopreservation pipeline, which provides a platform for essential next steps in modulating postthaw stress and initiating long-term growth. These findings pave the way towards an approach that can be rapidly deployed around the world to secure the biological genetic diversity of our vanishing coral reefs.
An Integrated Analysis of Network Pharmacology, Molecular Docking, and Experiment Validation to Explore the Mechanism of Danbai Granules in Treating Sequelae of Pelvic Inflammatory Disease
Authors: Zhu Yuying , Xue Xiaoou , Li Jun , Long Zilin , Zhang Jiawei , Zhao Baohua
Published: March 2023

Purpose

To explore the possible pharmacological mechanisms of Danbai Granules (DBG) against sequelae of pelvic inflammatory disease (SPID) by the method of network pharmacology and molecular docking combined with experimental validation.

Methods

Firstly, biologically active compounds, targets of DBG, and related targets of SPID were collected from public databases. The protein– protein interaction (PPI) network, Gene GO and KEGG enrichment analysis were carried out via R language to find the potential biological processes and pathways of DBG against SPID. Subsequently, molecular docking was used to calculate the affinity between the top six targets and the top ten compounds, respectively. Finally, the above analysis results were verified by in vivo experiments.

Results

A total of 106 crossover genes were selected from 220 potential medicine genes and 952 SPID-related genes. PPI network analysis indicated that IL-6, IL-1β, VEGFA, CASP3, PTGS2, JUN, etc., were core targets. GO and KEGG enrichment analysis revealed that PI3K-Akt, AGE–RAGE, IL-17, TNF, HIF-1 and Toll-like receptors signaling pathways were the main signaling pathways. Molecular docking showed that 15 pairs of target-ingredient combinations have good binding activity. The animal experiments showed that DBG administration inhibited the expression of TLR4/MyD88/NF-κB p65 signaling pathway-related proteins expression, altered the high expression of IL-6, IL-1β, and low level of IL-4, IL-10, thereby relieving the pelvic inflammation of SPID.

Conclusion

Through the network pharmacology and molecular docking, our findings predicted the active ingredients and potential targets of DBG in treating SPID. The experimental verification preliminarily revealed that DBG may inhibit the inflammatory response of SPID rats by regulating the TLR4/MyD88/NF-κB p65 signaling pathway. which provides a theoretical basis for the study of the pharmacodynamic material basis and mechanism of DBG against SPID at the comprehensive level.
Deep neural generation of neuronal spikes
Authors: Nakajima Ryota , Shirakami Arata , Tsumura Hayato , Matsuda Kouki , Nakamura Eita , Shimono Masanori
Published: March 2023

In the brain, many regions work in a network-like association, yet it is not known how durable these associations are in terms of activity and could survive without structural connections. To assess the association or similarity between brain regions with a new “generating” approach, this study evaluated the similarity of activities of neurons at the cellular level within each region after disconnecting between regions. To this end, a multi-layer LSTM (Long-Short Term Memory) model was used. Surprisingly, the results revealed that generation of activity from one region to other regions that had been disconnected was possible with similar reproduction accuracy as generation between the same regions in many cases. Notably, not only firing rates but also synchronization of firing between neuron pairs, which is often used as neuronal representations, could be reproduced with considerable precision. Additionally, their accuracies were associated with the relative distance between brain regions and the strength of the structural connections that initially connected them. This outcome not only enables us to look into principles in neuroscience based on the potential to generate new informative data, but also creates neural activity that has not been measured in adequate amounts and could potentially lead to reduced animal experiments.
Mainly Heterosexual, Bisexual, or Other?: the measurement of sexual minority status and its impact on analytic sample, demographic distribution and health outcomes
Authors: Tabor Evangeline , Kneale Dylan , Patalay Praveetha
Published: March 2023

Background

Sexual orientation has been measured in a wide variety of ways which reflect both theoretical and practical considerations. However, choice of sexual orientation measure and recoding strategy can impact analytic sample, as well as demographic and health profiles, in analyses of sexual minority populations. We aimed to examine how choice of sexual orientation dimension and recoding decisions impact estimates in the sexual minority population in two population-based studies in the UK.

Methods

We used data collected at age 17 (2018) in the UK Millennium Cohort Study and at wave six (2012-13) and eight (2017-18) of the English Longitudinal Study of Ageing. Descriptive statistics were used to examine the impact of choice of sexual orientation dimension (i.e. identity, attraction and experience) and recoding decisions on achieved analytic sample and composition by selected demographic and health measures within and between datasets.

Results

Dimension choice and recoding decisions resulted in variation in analytic sample. For example, more respondents reported some same-sex sexual attraction than reported a non-heterosexual identity (adolescents: 20.77% vs 8.97%, older adults: 4.77% vs 1.04%). Demographic distributions varied, but not substantially by dimension choice or recoding strategy. Overall, in both datasets sexual minority respondents were more likely to be White and in the highest quintiles for income and education than heterosexual respondents. Health status did not vary substantially by dimension choice or recoding strategy, however sexual minority respondents reported worse health than their heterosexual peers.

Conclusions

This study explores a range of practical and theoretical considerations when analysing sexual minority respondents using survey data. We highlight the impact recoding decisions may have on the numbers of sexual minority respondents identified within a dataset and demographic and health distributions in this understudied population. We also demonstrate the benefits of including multiple dimensions for capturing mechanisms of interest in elucidating ambiguous responses and exploring sexual diversity.
Bone marrow from focal segmental glomerulosclerosis displays activation of inflammatory pathway
Authors: Rashmi Priyanka , Boada Patrick , Soni Arvind , Sigdel Tara K , Rychkov Dmitry , Hahm Eunsil , Da Silva Andrea Alice , Damm Izabella , Paul Rohan , Vincenti Flavio , Ye Jimmie , Reiser Jochen , wolf Jeffrey , Sarwal Minnie M.
Published: March 2023

Circulating factors resulting from immune dysfunction have been proposed as one of the causes for increased risk of graft loss associated with recurrence of focal segmental glomerulosclerosis (FSGS) after kidney transplant. However, the precise identity of the circulating factors and their sources remain incompletely characterized.In vivostudies in mouse models have implicated a role for immature bone marrow cells in the development of FSGS. Using single-cell RNA sequencing we have profiled >50,000 cells from bone marrow of FSGS patients with or without recurrence after kidney transplant and controls including healthy individuals and patients with end-stage renal disease due to non-FSGS causes. Bone marrow mononuclear cells from patients with recurrence of FSGS after transplant display an inflammatory phenotype with activation of cytokine and interferon signaling in neutrophils, T cells and B cells. We also observe a dramatically depleted B cell population in R-FSGS patients. Conditioned media from BMNCs of R-FSGS patients have higher levels of pro-inflammatory cytokine MIP-1α/CCL3, reduced anti-inflammatory chemokine CCL22 and cause injury in a human podocyte cell culture model. Our studies provide evidence for the role of bone marrow cells in FSGS associated inflammatory milieu and elucidate the transcriptional changes associated with the disease.
Assessment of Erectile Dysfunction in Patients with Benign Prostate Hyperplasia Using the Sexual Function Index at Muhimbili National Hospital, Dar es Salaam, Tanzania
Authors: Mawji Said Ali , Mkony Charles , Nyongole Obadia , Msinde Peter , Mahenda Deogratius
Published: March 2023

Background

Erectile dysfunction (ED) is the inability to achieve and maintain a steady erection for sexual performance. Erectile dysfunction (ED) is becoming more common in the general population, particularly among elderly men with lower urinary tract symptoms and those with benign prostatic hyperplasia. This rise in erectile dysfunction has also been attributed by several other etiologies, which includes inflammatory, mechanical, psychological, occlusive vascular, trauma, endocrine, neurologic, chemical and extra factors (prostatectomy, old age). The purpose of the study was to assess erectile dysfunction in patients with benign prostate hyperplasia before treatment using international index of erectile function (IIEF) tool.

Methodology

Hospital-based cross-sectional study from March 2021 to June 2022, which involved 188 patients clinically diagnosed with benign prostatic enlargement. Convenient sampling method was used to recruit participants and structured questionnaires were used to attain social demographic characteristics. The international prostate symptom score (IPSS) was used to assess, diagnose patients with BPH as well as the severity of LUTS and international index of erectile function (IIEF) was used to assess erectile dysfunction. Data was analyzed using SPSS software version 27.

Results

The proportion of ED in patients with benign prostate hyperplasia/LUTS using IIEF tool was found to be 154(82%) and those with no erectile dysfunction was 34(18%). The factors that were statistically associated with erectile dysfunction were age, marital status, cigarette smoking, and diabetes mellitus.

Conclusion

Erectile dysfunction is very common in men who have Benign Prostate Hyperplasia. The prevalence and severity of ED increased with age, diabetes, cigarette smoking, lower urinary tract symptoms, and hypertension, according to the study.
Multicellular dynamics on structured surfaces: Stress concentration is a key to controlling complex microtissue morphology on engineered scaffolds
Authors: Matsuzawa Ryosuke , Matsuo Akira , Fukamachi Shuya , Shimada Sho , Takeuchi Midori , Nishina Takuya , Kollmannsberger Philip , Sudo Ryo , Okuda Satoru , Yamashita Tadahiro
Published: March 2023

Tissue engineers have utilized a variety of three-dimensional (3D) scaffolds for controlling multicellular dynamics and the resulting tissue microstructures. In particular, cutting-edge microfabrication technologies, such as 3D bioprinting, provide increasingly complex structures. However, unpredictable microtissue detachment from scaffolds, which ruins desired tissue structures, is becoming an evident problem. To overcome this issue, we elucidated the mechanism underlying collective cellular detachment by combining a new computational simulation method with quantitative tissue-culture experiments. We first quantified the stochastic processes of cellular detachment shown by vascular smooth muscle cells on model curved scaffolds and found that microtissue morphologies vary drastically depending on cell contractility, substrate curvature, and cell-substrate adhesion strength. To explore this mechanism, we developed a new particle-based model that explicitly describes stochastic processes of multicellular dynamics, such as adhesion, rupture, and large deformation of microtissues on structured surfaces. Computational simulations using the developed model successfully reproduced characteristic detachment processes observed in experiments. Crucially, simulations revealed that cellular contractility-induced stress is locally concentrated at the cell-substrate interface, subsequently inducing a catastrophic process of collective cellular detachment, which can be suppressed by modulating cell contractility, substrate curvature, and cell-substrate adhesion. These results show that the developed computational method is useful for predicting engineered tissue dynamics as a platform for prediction-guided scaffold design.
Laser-based killing of a macroparasite inside its live invertebrate host
Authors: Musset Olivier , Balourdet Aude , Perrot-Minnot Marie-Jeanne
Published: March 2023

Abstract

Whether host phenotypic alterations induced by parasites are reversible or not is a core issue to understand underlying mechanisms as well as the fitness costs of infection and recovery to the host. Clearing infection is an essential step to address this issue, which turns out to be challenging with endoparasites of large size relative to that of their host. Here, we took advantage of the lethality, contactless and versatility of high-energy laser beam to design such tool, using thorny-headed worms and their amphipod intermediate host as a model system. We show that laser-based de-parasitization can be achieved using blue laser targeting carotenoid pigments inPolymorphus minutusbut not in the larger and less pigmentedPomphorhynchus tereticollis. Using DNA degradation to establish parasite death, we found that 80%P. minutusdied from within-host exposure to 5 pulses of 50 ms duration, 1.4W power and 450 nm wavelength. Survival rate of infected gammarids to laser treatment was higher than uninfected ones (62% and 33% at 11 days after exposure, respectively). The failure to killP. tereticolliswas also observed with nanosecond-green laser, an alternative laser source targeting lipid. We discuss the possible causes of amphipod death following parasite treatment and highlight the perspectives that this technology offers.
Continued dysfunction of capillary pericytes promotes no-reflow after experimental strokein vivo
Authors: Shrouder J , Filser S , Varga DP , Besson-Girard S , Mamrak U , Bulut B , Seker FB , Geserich B , Laredo F , Wehn A , Khalin I , Bayer P , Liesz A , Gökce O , Plesnila N
Published: March 2023

Incomplete reperfusion of the microvasculature (“no-reflow”) after ischemic stroke damages salvageable brain tissue. Previous ex-vivo studies suggest pericytes are vulnerable to ischemia and may exacerbate no-reflow, but the viability of pericytes and their association with no-reflow remains underexplored in vivo. Using longitudinalin vivo2-photon single-cell imaging over seven days we show 87% of pericytes constrict during cerebral ischemia, remain constricted post-reperfusion and 50% of the pericyte population are acutely damaged. Moreover, we reveal ischemic pericytes are fundamentally implicated in capillary no-reflow by limiting and arresting blood flow within the first 24 hours post-stroke. Despite sustaining acute membrane damage, we observe up to 80% of cortical pericytes survive ischemia, upregulate unique transcriptomic profiles and replicate. Finally, we demonstrate delayed recovery of capillary diameter by ischemic pericytes after reperfusion predicts vessel reconstriction in the sub-acute phase of stroke. Cumulatively, these findings demonstrate surviving cortical pericytes remain both viable and promising therapeutic targets to counteract no-reflow after ischemic stroke.
Hyperactive Ras disrupts cell size control and a key step in cell cycle entry in budding yeast
Authors: DeWitt Jerry T. , Chinwuba Jennifer C. , Kellogg Douglas R.
Published: March 2023

Severe defects in cell size are a nearly universal feature of cancer cells. However, the underlying causes are unknown. A previous study suggested that a hyperactive mutant of yeast Ras (ras2G19V) that is analogous to the human Ras oncogene causes cell size defects, which could provide clues to how oncogenes influence cell size. However, the mechanisms by whichras2G19Vinfluences cell size are unknown. Here, we found thatras2G19Vinhibits a critical step in cell cycle entry, in which an early G1 phase cyclin induces transcription of late G1 phase cyclins. Thus,ras2G19Vdrives overexpression of the early G1 phase cyclin Cln3, yet Cln3 fails to induce normal transcription of late G1 phase cyclins, leading to delayed cell cycle entry and increased cell size.ras2G19Vinfluences transcription of late G1 cyclins via a poorly understood step in which Cln3 inactivates the Whi5 transcriptional repressor. Previous studies found that Ras relays signals via protein kinase A (PKA) in yeast; however,ras2G19Vappears to influence G1 phase cyclin expression via novel PKA-independent signaling mechanisms. Together, the data define new mechanisms by which hyperactive Ras influences cell cycle entry and cell size in yeast. Expression of G1 phase cyclins is also strongly influenced by mammalian Ras via mechanisms that remain unclear. Therefore, further analysis of PKA-independent Ras signaling in yeast could lead to discovery of conserved mechanisms by which Ras family members control expression of G1 phase cyclins.
Variant-specific Mendelian Risk Prediction Model
Authors: Bae Eunchan , Dias Julie-Alexia , Huang Theodore , Chen Jinbo , Parmigiani Giovanni , Rebbeck Timothy R. , Braun Danielle
Published: March 2023

Many pathogenic sequence variants (PSVs) have been associated with increased risk of cancers. Mendelian risk prediction models use Mendelian laws of inheritance to predict the probability of having a PSV based on family history, as well as specified PSV frequency and penetrance (agespecific probability of developing cancer given genotype). Most existing models assume penetrance is the same for any PSVs in a certain gene. However, for some genes (for example, BRCA1/2), cancer risk does vary by PSV. We propose an extension of Mendelian risk prediction models to relax the assumption that risk is the same for any PSVs in a certain gene by incorporating variant-specific penetrances and illustrating these extensions on two existing Mendelian risk prediction models, BRCAPRO and PanelPRO. Our proposed BRCAPRO-variant and PanelPRO-variant models incorporate variant-specific BRCA1/2 PSVs through the region classifications. Due to the sparsity of the variant information we classify BRCA1/2 PSVs into three regions; the breast cancer clustering region (BCCR), the ovarian cancer clustering region (OCCR), and an other region. Simulations were conducted to evaluate the performance of the proposed BRCAPRO-variant model compared to the existing BRCAPRO model which assumes the penetrance is the same for any PSVs in BRCA1 (and respectively BRCA2). Simulation results showed that the BRCAPRO-variant model was well calibrated to predict region-specific BRCA1/2 carrier status with high discrimination and accuracy on the region-specific level. In addition, we showed that the BRCAPRO-variant model achieved performance gains over the existing risk prediction models in terms of calibration without loss in discrimination and accuracy. We also evaluated the performance of the two proposed models, BRCAPRO-variant and PanelPRO-variant, on a cohort of 1,961 families from the Cancer Genetics Network (CGN). We showed that our proposed models provide region-specific PSV carrier probabilities with high accuracy, while the calibration, discrimination and accuracy of gene-specific PSV carrier probabilities were comparable to the existing gene-specific models. As more variant-specific PSV penetrances become available, we have shown that Mendelian risk prediction models can be extended to integrate the additional information, providing precise variant or region-specific PSV carrier probabilities and improving future cancer risk predictions.
Stochasticity explains non-genetic inheritance of lifespan and apparent trade-offs between reproduction and ageing
Authors: Drake Elizabeth D , Simons Mirre J P
Published: March 2023

Stochastic effects are central to the biology and demography of ageing. Genetically identical individuals do not all die at the exact same time but show a distribution of lifespan. Although such effects are appreciated, any cascading effects from stochastic effects of ageing are underappreciated. We show here that genetically identical female flies (Drosophila melanogaster) that live long, produce longer lived daughters. In line with previous work, we also find that daughters born to older mothers are shorter lived, also termed the Lansing effect. We further show that longer-lived flies produce less offspring, suggesting an apparent trade-off due to stochastic effects alone. We explain these effects using an extension of the reliability theory of ageing by dichotomising ageing physiology in reproduction and lifespan supporting units. These simple models reproduce non-genetic inheritance of lifespan, the Lansing effect and trade-offs between reproduction and lifespan. Our work implies that if non-genetic inheritance of lifespan is widespread it explains the generally low heritability of this trait. Furthermore, trade-offs between performance, e.g. reproduction, and lifespan may be less widespread than predicted by evolutionary biology of ageing, stemming from stochasticity rather than differential investment. Anti-ageing treatments therefore come without any unintended costs to other physiology, a perceived risk that limits translation of these treatments to humans.