bluuebunny/crossref_metadata_2025 huggingface dataset:
Culture of leukocyte-derived cells from human peripheral blood: Increased expression of pluripotent genes OCT4, NANOG, SOX2, self-renewal gene TERT and plasticity
Authors: Lee Yi-Jen , Wang Jehng-Kang , Pai Yu-Ming , Frost Alan , Viprakasit Vip , Ekwattanakit Supachai , Chin Hui-Chieh , Liu Jah-Yao
Published: January 2023

There are few stem cells in human peripheral blood (PB). Increasing the population and plasticity of stem cells in PB and applying it to regenerative medicine require suitable culture methods. In this study, leukocyte populations 250 mL of PB were collected using a blood separator before that were cultured in optimal cell culture medium for 4 to 7 days. After culturing, stemness characteristics were analyzed, and red blood cells were removed from the cultured cells. In our results, stemness markers of the leukocyte populations Sca-1+ CD45+, CD117+ CD45+, and very small embryonic-like stem cells CD34+ Lin− CD45− and CXCR4+ Lin− CD45− were significantly increased. Furthermore, the expression of stem cell genes OCT4 (POU5F1), NANOG, SOX2, and the self-renewal gene TERT was analyzed by quantitative real-time polymerase chain reaction in these cells, and it showed a significant increase. These cells could be candidates for multi-potential cells and were further induced using trans-differentiation culture methods. These cells showed multiple differentiation potentials for osteocytes, nerve cells, cardiomyocytes, and hepatocytes. These results indicate that appropriate culture methods can be applied to increase expression of pluripotent genes and plasticity. Leukocytes of human PB can be induced to trans-differentiate into pluripotent potential cells, which will be an important breakthrough in regenerative medicine.
Reexamining the Impact of Insurance Type on Kidney Transplant Waitlist Status and Posttransplantation Outcomes in the United States After Implementation of the Affordable Care Act
Authors: Morenz Anna , Perkins James , Dick André , Young Bessie , Ng Yue-Harn
Published: January 2023

Background.

Insurance type, a marker of socioeconomic status, has been associated with poor access to kidney transplant (KT) and worse KT outcomes before the implementation of the Affordable Care Act (ACA) and the revised Kidney Allocation System (KAS). In this study, we assessed if insurance type remained a risk marker for worse waitlist and transplant outcomes after ACA and KAS.

Methods.

Using Scientific Registry of Transplant Recipients data, we assessed insurance type of waitlisted candidates pre- (2008–2014) versus post- (2014–2021) KAS/ACA using chi-square tests. Next, we performed a competing risk analysis to study the effect of private versus public (Medicare, Medicaid, or government-sponsored) insurance on waitlist outcomes and a Cox survival analysis to study posttransplant outcomes while controlling for candidate, and recipient and donor variables, respectively.

Results.

The proportion of overall KT candidates insured by Medicaid increased from pre-KAS/ACA to post-KAS/ACA (from 12 667 [7.3%] to 21 768 [8.8%], P < 0.0001). However, KT candidates with public insurance were more likely to have died or become too sick for KT (subdistribution hazard ratio [SHR] = 1.33, confidence interval [CI], 1.30-1.36) or to receive a deceased donor KT (SHR = 1.57, CI, 1.54-1.60) but less likely to receive a living donor KT (SHR = 0.87, CI, 0.85-0.89). Post-KT, KT recipients with public insurance had greater risk of mortality (relative risks = 1.22, CI, 1.15-1.31) and allograft failure (relative risks = 1.10, CI, 1.03-1.29).

Conclusions.

Although the implementation of ACA marginally increased the proportion of waitlisted candidates with Medicaid, publicly insured KT candidates remained at greater risk of being removed from the waitlist, had lower probability of living donor kidney transplantation, and had greater probability of dying post-KT and allograft failure. Concerted efforts to address factors contributing to these inequities in future studies are needed, with the goal of achieving equity in KT for all.
Draft genomes, phylogenomic reconstruction and comparative genome analysis of three Xenorhabdus strains isolated from soil dwelling nematodes in Kenya
Authors: Awori Ryan Musumba , Waturu Charles N. , Pidot Sacha J. , Amugune Nelson O. , Bode Helge B.
Published: January 2023

As a proven source of potent and selective antimicrobials, Xenorhabdus bacteria are important to an age plagued with difficult-to-treat microbial infections. Yet, only twenty-seven species have been described to date. In this study, a new Xenorhabdus species was discovered through genomic studies on three isolates from Kenyan soils. Soils in Western Kenya were surveyed for steinernematids and Steinernema isolates VH1 and BG5 were recovered from red volcanic loam soils from cultivated land in Vihiga and clay soils from riverine land in Bungoma respectively. From the two nematode isolates, Xenorhabdus sp. BG5 and Xenorhabdus sp. VH1 were isolated. The genomes of these two, plus that of X. griffiniae XN45 —this was previously isolated from Steinernema sp. scarpo that also originated from Kenyan soils— were sequenced and assembled. Nascent genome assemblies of the three isolates were of good quality with over 70% of their proteome having known functions. These three isolates formed the X. griffiniae clade in a phylogenomic reconstruction of the genus. Their species were delineated using three overall genome relatedness indices: an unnamed species of the genus, Xenorhabdus sp. BG5, X. griffiniae VH1, and X. griffiniae XN45. A pangenome analysis of this clade revealed that over 70% of species-specific genes encoded unknown functions.  Transposases were linked to genomic islands in Xenorhabdus sp. BG5. Thus, overall genome-related indices sufficiently delineated species of two new Xenorhabdus isolates from Kenya, both of which were closely related to X. griffiniae. The functions encoded by most species specific genes in the X. griffiniae clade remain unknown.
Efficacy of federated learning on genomic data: a study on the UK Biobank and the 1000 Genomes Project
Authors: Kolobkov Dmitry , Sharma Satyarth Mishra , Medvedev Aleksandr , Lebedev Mikhail , Kosaretskiy Egor , Vakhitov Ruslan
Published: January 2023

Combining training data from multiple sources increases sample size and reduces confounding, leading to more accurate and less biased machine learning models. In healthcare, however, direct pooling of data is often not allowed by data custodians who are accountable for minimizing the exposure of sensitive information. Federated learning offers a promising solution to this problem by training a model in a decentralized manner thus reducing the risks of data leak-age. Although there is increasing utilization of federated learning on clinical data, its efficacy on individual-level genomic data has not been studied. This study lays the groundwork for the adoption of federated learning for genomic data by investigating its applicability in two scenarios: phenotype prediction on the UK Biobank data and ancestry prediction on the 1000 Genomes Project data. We show that federated models trained on data split into independent nodes achieve performance close to centralized models, even in the presence of significant inter-node heterogeneity. Additionally, we investigate how federated model accuracy is affected by communication frequency and suggest approaches to reduce computational complexity or communication costs.
Estimations of SARS-CoV-2 endemic characteristics
Authors: Nesteruk Igor
Published: January 2023

The fourth year of the COVID-19 pandemic without decreasing trends in the global numbers of new daily cases, high numbers of circulating SARS-CoV-2 variants and re-infections together with pessimistic predictions for the Omicron wave duration force studies about the endemic stage of the disease. The global trends were illustrated with the use the accumulated numbers of laboratory-confirmed COVID-19 cases and deaths, the percentages of fully vaccinated people and boosters and the results of calculation of the effective reproduction number provided by Johns Hopkins University. The modified SIR model showed the presence of unsteady equilibrium. The global numbers of new daily cases will range between 300 thousand and one million, daily deaths – between one and 3.3 thousand.
HPV and HBV vaccine hesitancy, intention, and uptake in the era of social media and COVID-19: A review
Authors: Vraga Emily K , Brady Sonya S , Gansen Chloe , Khan Euna M , Bennis Sarah L. , Nones Madalyn , Tang Rongwei , Srivastava Jaideep , Kulasingam Shalini
Published: January 2023

Prior to the COVID-19 pandemic, the World Health Organization named vaccine hesitancy as one of the top 10 threats to global health. The impact of hesitancy on uptake of human papillomavirus (HPV) vaccines was of particular concern, given the markedly lower uptake compared to other adolescent vaccines in some countries, notably the United States. With the recent approval of COVID-19 vaccines coupled with the widespread use of social media, concerns regarding vaccine hesitancy have grown. However, the association between COVID-related vaccine hesitancy and cancer vaccines such as HPV is unclear. To examine the potential association, we performed two reviews using Ovid Medline and APA PsychInfo. Our aim was to answer two questions: (1) Is COVID-19 vaccine hesitancy, intention, or uptake associated with HPV or HBV vaccine hesitancy, intention, or uptake? and (2) Is exposure to COVID-19 vaccine misinformation on social media associated with HPV or HBV vaccine hesitancy, intention, or uptake? Our review identified few published empirical studies that addressed these questions. Our results highlight the urgent need for studies that can shift through the vast quantities of social media data to better understand the link between COVID-19 vaccine misinformation and disinformation and its impact on uptake of cancer vaccines.
Electrophysiological signatures of visual recognition memory across all layers of mouse V1
Authors: Hayden Dustin J. , Finnie Peter S.B. , Thomazeau Aurore , Li Alyssa Y. , Cooke Samuel F. , Bear Mark F.
Published: January 2023

In mouse primary visual cortex (V1), familiar stimuli evoke significantly altered responses when compared to novel stimuli. This stimulus-selective response plasticity (SRP) was described originally as an increase in the magnitude of visual evoked potentials (VEPs) elicited in layer (L) 4 by familiar phase-reversing grating stimuli. SRP is dependent on NMDA receptors (NMDAR) and has been hypothesized to reflect potentiation of thalamocortical synapses in L4. However, recent evidence indicates that the synaptic modifications that manifest as SRP do not occur on L4 principal cells. To shed light on where and how SRP is induced and expressed, the present study had three related aims: (1) to confirm that NMDAR are required specifically in glutamatergic principal neurons of V1, (2) to investigate the consequences of deleting NMDAR specifically in L6, and (3) to use translaminar electrophysiological recordings to characterize SRP expression in different layers of V1. We find that knockout of NMDAR in L6 principal neurons disrupts SRP. Current-source density analysis of the VEP depth profile shows augmentation of short latency current sinks in layers 3, 4 and 6 in response to phase reversals of familiar stimuli. Multiunit recordings demonstrate that increased peak firing occurs to in response to phase reversals of familiar stimuli across all layers, but that activity between phase reversals is suppressed. Together, these data reveal important aspects of the underlying phenomenology of SRP and generate new hypotheses for the expression of experience-dependent plasticity in V1.

Significance Statement

Repeated exposure to stimuli that portend neither reward nor punishment leads to behavioral habituation, enabling organisms to dedicate attention to novel or otherwise significant features of the environment. The neural basis of this process, which is so often dysregulated in neurological and psychiatric disorders, remains poorly understood. Learning and memory of stimulus familiarity can be studied in mouse visual cortex by measuring electrophysiological responses to simple phase-reversing grating stimuli. The current study advances knowledge of this process by documenting changes in visual evoked potentials, neuronal spiking activity, and oscillations in the local field potentials across all layers of mouse visual cortex. In addition, we identify a key contribution of a specific population of neurons in layer 6 of visual cortex.
Tissue-specific collagen hydroxylation at GEP/GDP triplets mediated by P4HA2
Authors: Wilhelm Dafné , Wurtz Alison , Abouhelfara Hanane , Sanchez Guillaume , Bui Catherine , Vincourt Jean-Baptiste
Published: January 2023

Collagen, the most abundant organic compound of vertebrate organisms, is a supramolecular, protein-made polymer. Details of its post-translational maturation largely determine the mechanical properties of connective tissues. Its assembly requires massive, heterogeneous prolyl-4-hydroxylation (P4H), catalyzed by Prolyl-4-hydroxylases (P4HA1-3), providing thermostability to its elemental, triple helical building block. So far, there was no evidence of tissue-specific regulation of P4H, nor of a differential substrate repertoire of P4HAs. Here, the post-translational modifications of collagen extracted from bone, skin, and tendon were compared, revealing lower hydroxylation of most GEP/GDP triplets, together with fewer other residue positions along collagen α chains, in the tendon. This regulation is mostly conserved in two distant homeotherm species, mouse and chicken. The comparison of detailed P4H patterns in both species suggests a dual mechanism of specificity.P4ha2expression is low in tendon and its genetic invalidation in the ATDC5 cellular model of collagen assembly specifically mimics the tendon-related P4H profile. Therefore, P4HA2 has a better ability than other P4HAs to hydroxylate the corresponding residue positions. Its local expression participates in determining the P4H profile, a novel aspect of the tissue specificities of collagen assembly.

Data availability

Proteomics data are availableviaProteomeXchange with the identifier PXD039221. Reviewer account details:

login: MSV000091002_reviewer

password: P4HA2tendon.
Reinforcement Learning Is Impaired in the Sub-acute Post-stroke Period
Authors: Branscheidt Meret , Hadjiosif Alkis M. , Anaya Manuel A. , Keller Jennifer , Widmer Mario , Runnalls Keith D. , Luft Andreas R , Bastian Amy J. , Krakauer John W. , Celnik Pablo A.
Published: January 2023

Background

Neurorehabilitation approaches are frequently predicated on motor learning principles. However, much is left to be understood of how different kinds of motor learning are affected by stroke causing hemiparesis. Here we asked if two kinds of motor learning often employed in rehabilitation, (1) reinforcement learning and (2) error-based adaptation, are altered at different times after stroke.

Methods

In a cross-sectional design, we compared learning in two groups of patients with stroke, matched for their baseline motor execution deficit on the paretic side. The early group was tested within 3 months following stroke (N = 35) and the late group was tested more than 6 months after stroke (N = 30). Two types of task were studied: one based on reinforcement learning and the other on error-based learning.

Results

We found that reinforcement learning was impaired in the early but not the late group, whereas error-based learning was unaffected compared to controls. These findings could not be attributed to differences in baseline execution, cognitive impairment, gender, age, or lesion volume and location.

Conclusions

The presence of a specific impairment in reinforcement learning in the first 3 months after stroke has important implications for rehabilitation. It might be necessary to either increase the amount of reinforcement feedback given early or even delay onset of certain forms of rehabilitation training, e.g., like constraint-induced movement therapy, and instead emphasize others forms of motor learning in this early time period. A deeper understanding of stroke-related changes in motor learning capacity has the potential to facilitate the development of new, more precise treatment interventions.
Structural variation across 138,134 samples in the TOPMed consortium
Authors: Jun Goo , English Adam C , Metcalf Ginger A , Yang Jianzhi , Chaisson Mark JP , Pankratz Nathan , Menon Vipin K , Salerno William J , Krasheninina Olga , Smith Albert V , Lane John A , Blackwell Tom , Kang Hyun Min , Salvi Sejal , Meng Qingchang , Shen Hua , Pasham Divya , Bhamidipati Sravya , Kottapalli Kavya , Arnett Donna K. , Ashley-Koch Allison , Auer Paul L. , Beutel Kathleen M , Bis Joshua C. , Blangero John , Bowden Donald W. , Brody Jennifer A. , Cade Brian E. , Chen Yii-Der Ida , Cho Michael H. , Curran Joanne E. , Fornage Myriam , Freedman Barry I. , Fingerlin Tasha , Gelb Bruce D. , Hou Lifang , Hung Yi-Jen , Kane John P , Kaplan Robert , Kim Wonji , Loos Ruth J.F. , Marcus Gregory M , Mathias Rasika A. , McGarvey Stephen T. , Montgomery Courtney , Naseri Take , Nouraie S. Mehdi , Preuss Michael H. , Palmer Nicholette D. , Peyser Patricia A. , Raffield Laura M. , Ratan Aakrosh , Redline Susan , Reupena Sefuiva , Rotter Jerome I. , Rich Stephen S. , Rienstra Michiel , Ruczinski Ingo , Sankaran Vijay G. , Schwartz David A. , Seidman Christine E. , Seidman Jonathan G. , Silverman Edwin K. , Smith Jennifer A. , Stilp Adrienne , Taylor Kent D. , Telen Marilyn J. , Weiss Scott T. , Williams L. Keoki , Wu Baojun , Yanek Lisa R. , Zhang Yingze , Lasky-Su Jessica , Gingras Marie Claude , Dutcher Susan K. , Eichler Evan E. , Gabriel Stacey , Germer Soren , Kim Ryan , Viaud-Martinez Karine A. , Nickerson Deborah A. ,   NHLBI Trans-Omics for Precision Medicine (TOPMed) Consortium, Luo James , Reiner Alex , Gibbs Richard A , Boerwinkle Eric , Abecasis Goncalo , Sedlazeck Fritz J
Published: January 2023

Ever larger Structural Variant (SV) catalogs highlighting the diversity within and between populations help researchers better understand the links between SVs and disease. The identification of SVs from DNA sequence data is non-trivial and requires a balance between comprehensiveness and precision. Here we present a catalog of 355,667 SVs (59.34% novel) across autosomes and the X chromosome (50bp+) from 138,134 individuals in the diverse TOPMed consortium. We describe our methodologies for SV inference resulting in high variant quality and >90% allele concordance compared to long-read de-novo assemblies of well-characterized control samples. We demonstrate utility through significant associations between SVs and important various cardio-metabolic and hemotologic traits. We have identified 690 SV hotspots and deserts and those that potentially impact the regulation of medically relevant genes. This catalog characterizes SVs across multiple populations and will serve as a valuable tool to understand the impact of SV on disease development and progression.
Time resolution in cryo-EM using a novel PDMS-based microfluidic chip assembly and its application to the study of HflX-mediated ribosome recycling
Authors: Bhattacharjee Sayan , Feng Xiangsong , Maji Suvrajit , Dadhwal Prikshat , Zhang Zhening , Brown Zuben P. , Frank Joachim
Published: January 2023

The rapid kinetics of biological processes and associated short-lived conformational changes pose a significant challenge in attempts to structurally visualize biomolecules during a reaction in real time. Conventionally, on-pathway intermediates have been trapped using chemical modifications or reduced temperature, giving limited insights. Here we introduce a novel time-resolved cryo-EM method using a reusable PDMS-based microfluidic chip assembly with high reactant mixing efficiency. Coating of PDMS walls with SiO2 virtually eliminates non-specific sample adsorption and ensures maintenance of the stoichiometry of the reaction, rendering it highly reproducible. In an operating range from 10 to 1000 ms, the device allows us to follow in vitro reactions of biological molecules at resolution levels in the range of 3 Å. By employing this method, we show for the first time the mechanism of progressive HlfX-mediated splitting of the 70SE. coliribosome in the presence of the GTP, via capture of three high-resolution reaction intermediates within 140 ms.
Investigating the roles of reflexes and central pattern generators in the control and modulation of human locomotion using a physiologically plausible neuromechanical model
Authors: Russo Andrea Di , Stanev Dimitar , Sabnis Anushree , Danner Simon M. , Ausborn Jessica , Armand Stéphane , Ijspeert Auke
Published: January 2023

Studying the neural components regulating movement in human locomotion is obstructed by the inability to perform invasive experimental recording. Neuromechanical simulations can provide insights by modeling the locomotor circuits. Past neuromechanical models proposed control of locomotion either driven by central pattern generators (CPGs) with simple sensory commands or by a purely reflex-based network regulated by state-machine mechanisms. However, the physiological interpretation of these state-machines remains unclear. Here, we present a physiologically plausible model to investigate spinal control and modulation of human locomotion. We propose a bio-inspired controller composed of two coupled central pattern generators (CPGs) that produce the rhythm and pattern and a reflex-based network simulating low-level reflex pathways and Renshaw cells. This reflex network is based on leaky-integration neurons, and the whole system does not rely on changing reflex gains according to the gait cycle state. The only component of the controller that maintains a state-machine mechanism is the balance controller of the trunk. The musculoskeletal model is composed of a skeletal structure and 9 muscles per leg generating movement in sagittal plane. After optimizing the open parameters, human locomotion replicating kinematics and muscle activation naturally emerged. Furthermore, when CPGs were not activated, no stable and physiologically plausible gaits could be achieved through optimization, suggesting the necessity of this component to generate rhythmic behavior without a state machine mechanism regulating reflex activation. The controller could reproduce a wide range of speeds from 0.3 to 1.9 m/s. The results also showed that the net influence of feedback on motoneurons during perturbed locomotion is predominantly inhibitory and that the CPG network provides the timing of motoneurons’ activation by exciting or inhibiting muscles in specific gait phases. The proposed bio-inspired controller could contribute to our understanding of locomotor circuits of the intact spinal cord and could be used to study neuromotor disorders.
Timing of behavioral responding to long-duration Pavlovian fear conditioned cues
Authors: Wright Kristina M. , Kantor Claire E. , Moaddab Mahsa , McDannald Michael A.
Published: January 2023

Behavioral responding is most beneficial when it reflects event timing. Compared to reward, there are fewer studies on timing of defensive responding. We gave female and male rats Pavlovian fear conditioning over a baseline of reward seeking. Two 100-s cues predicted foot shock at different time points. Rats acquired timing of behavioral responding to both cues. Suppression of reward seeking was minimal at cue onset and maximal before shock delivery. Rats also came to minimize suppression of reward seeking following cue offset. The results reveal timing as a mechanism to focus defensive responding to shock-imminent, cue periods.
The landscape of m1A modification and its posttranscriptional regulatory functions in primary neurons
Authors: Zhang Chi , Yi Xianfu , Hou Mengfan , Li Qingyang , Li Xueying , Lu Lu , Qi Enling , Wu Mingxin , Qi Lin , Jian Huan , Qi Zhangyang , Lv Yigang , Kong Xiaohong , Bi Mingjun , Feng Shiqing , Zhou Hengxing
Published: January 2023

Cerebral ischaemia‒reperfusion injury, during which neurons undergo oxygen-glucose deprivation/reoxygenation (OGD/R), is a notable pathological process in many neurological diseases. N1-methyladenosine (m1A) is an RNA modification that can affect gene expression and RNA stability. The m1A landscape and potential functions of m1A modification in neurons remain poorly understood. We explored RNA (mRNA, lncRNA, and circRNA) m1A modification in normal and OGD/R-treated neurons and the effect of m1A on diverse RNAs. We investigated the m1A landscape in primary neurons, identified m1A-modified RNAs, and found that OGD/R increased the number of m1A RNAs. m1A modification might also affect the regulatory mechanisms of noncoding RNAs, e.g., lncRNA–RBP interactions and circRNA translation. We showed that m1A modification mediates the circRNA/lncRNA‒miRNA–mRNA ceRNA mechanism and that 3’UTR methylation of mRNAs can hinder miRNA–mRNA binding. Three methylation patterns were identified, and genes with different patterns had intrinsic mechanisms with potential m1A-regulatory specificity. Systematic analysis of the m1A landscape in normal and OGD/R neurons lays a critical foundation for understanding RNA methylation and provides new perspectives and a theoretical basis for treating and developing drugs for OGD/R pathology-related diseases.
Loss of genital epithelial barrier function is greater with depot-medroxyprogesterone acetate than intravaginal rings that release etonogestrel and ethinyl estradiol
Authors: Liu Mohan , Vicetti Miguel Rodolfo D. , Quispe Calla Nirk E. , Aceves Kristen M. , Fritts Linda , Miller Christopher J. , Moss John A. , Baum Marc M. , Cherpes Thomas L.
Published: January 2023

The injectable progestin depot-medroxyprogesterone acetate (DMPA) is a popular contraceptive choice in sub-Saharan Africa although mouse models indicate it weakens genital epithelial integrity and barrier function and increases susceptibility to genital infection. The intravaginal ring NuvaRing® is another contraceptive option that like DMPA suppresses hypothalamic pituitary ovarian (HPO) axis function with local release of progestin (etonogestrel) and estrogen (ethinyl estradiol). As we previously reported that treating mice with DMPA and estrogen averts the loss of genital epithelial integrity and barrier function induced by DMPA alone, in the current investigation we compared genital levels of the cell-cell adhesion molecule desmoglein-1 (DSG1) and genital epithelial permeability in rhesus macaques (RM) treated with DMPA or a NuvaRing®re-sized for RM (N-IVR). While these studies demonstrated comparable inhibition of the HPO axis with DMPA or N-IVR, DMPA induced significantly lower genital DSG1 levels and greater tissue permeability to intravaginally administered low molecular mass molecules. By identifying greater compromise of genital epithelial integrity and barrier function in RM administered DMPA vs. N-IVR, our results add to the growing body of evidence that indicate DMPA weakens a fundamental mechanism of anti-pathogen host defense in the female genital tract.
Hsf1 and the molecular chaperone Hsp90 support a “rewiring stress response” leading to an adaptive cell size increase in chronic stress
Authors: Maiti Samarpan , Bhattacharya Kaushik , Wider Diana , Hany Dina , Panasenko Olesya , Bernasconi Lilia , Hulo Nicolas , Picard Didier
Published: January 2023

Cells are exposed to a wide variety of internal and external stresses. Whereas many studies have focused on cellular responses to acute and severe stresses, little is known about how cellular systems adapt to sublethal chronic stresses. Using mammalian cells in culture, we discovered that they adapt to chronic mild stresses of up to two weeks, notably proteotoxic stresses such as heat, by increasing their size and translation, thereby scaling the amount of total protein. These adaptations render them more resilient to persistent and subsequent stresses. We demonstrate that Hsf1, well known for its role in acute stress responses, is required for the cell size increase, and that the molecular chaperone Hsp90 is essential for coupling the cell size increase to augmented translation. We term this translational reprogramming the “rewiring stress response”, and propose that this protective process of chronic stress adaptation contributes to the increase in size as cells get older, and that its failure promotes aging.
Evaluating the causal relationship between educational attainment and mental health
Authors: Demange Perline A. , Boomsma Dorret I. , van Bergen Elsje , Nivard Michel G.
Published: January 2023

Abstract

We investigate the causal relationship between educational attainment (EA) and mental health using two research designs. First, we compare the relationship between EA and 18 psychiatric diagnoses within sibship in Dutch national registry data (N=1.7 million), thereby controlling for unmeasured familial factors. Second, we apply two-sample Mendelian Randomization, which uses genetic variants related to EA or psychiatric diagnosis as instrumental variables, to test whether there is a causal relation in either direction. Our results suggest that lower levels of EA causally increase the risk of MDD, ADHD, alcohol dependence, GAD and PTSD diagnoses. We also find evidence of a causal effect of ADHD on EA. For schizophrenia, anorexia nervosa, OCD, and bipolar disorder, results were inconsistent across the different approaches, highlighting the importance of using multiple research designs to understand complex relationships such as between EA and mental health.
Cleavable crosslinkers redefined by novel MS3-trigger algorithm
Authors: Kolbowski Lars , Fischer Lutz , Rappsilber Juri
Published: January 2023

Crosslinking MS is currently transitioning from a routine tool in structural biology to enabling structural systems biology. MS-cleavable crosslinkers could substantially reduce the associated search space expansion by allowing an MS3-based approach for identifying crosslinked peptides. However, MS2-based approaches currently outperform approaches utilising MS3. We show here that MS3-trigger sensitivity and specificity were hampered algorithmically. Our four-step MS3-trigger algorithm greatly outperformed currently employed methods and comes close to reaching the theoretical limit.
Single cell RNA sequencing unravels the transcriptional network underlying zebrafish retina regeneration
Authors: Celotto Laura , Rost Fabian , Machate Anja , Bläsche Juliane , Dahl Andreas , Weber Anke , Hans Stefan , Brand Michael
Published: January 2023

In the lesioned zebrafish retina, Müller glia produce multipotent retinal progenitors that generate all retinal neurons, replacing lost cell types. To study the molecular mechanisms linking Müller glia reactivity to progenitor production and neuronal differentiation, we used single cell RNA sequencing of Müller glia, progenitors and regenerated progeny from uninjured and light-lesioned retinae. We discover an injury-induced Müller glia differentiation trajectory that leads into a cell population with a hybrid identity expressing marker genes of Müller glia and progenitors. A glial self-renewal and a neurogenic trajectory depart from the hybrid cell population. We further observe that neurogenic progenitors progressively differentiate to generate retinal ganglion cells first and bipolar cells last, similar to the events observed during retinal development. Our work provides a comprehensive description of Müller glia and progenitor transcriptional changes and fate decisions in the regenerating retina, which are key to tailor cell differentiation and replacement therapies for retinal dystrophies in humans.
Balancing act of a leading strand DNA polymerase-specific domain and its exonuclease domain promotes genome-wide sister replication fork symmetry
Authors: Meng Xiangzhou , Claussin Clémence , Regan-Mochrie Gemma , Whitehouse Iestyn , Zhao Xiaolan
Published: January 2023

Pol2 is the leading-strand DNA polymerase in budding yeast. Here we describe an antagonism between its conserved POPS (Pol2 family-specific catalytic core peripheral subdomain) and exonuclease domain and the importance of this antagonism in genome replication. We show that multiple defects caused by POPS mutations, including impaired growth and DNA synthesis, genome instability, and reliance on other genome maintenance factors, were rescued by exonuclease inactivation. Single-molecule data revealed that the rescue stemmed from allowing sister replication forks to progress at equal rates. Our data suggest that balanced activity of Pol2's POPS and exonuclease domains is vital for genome replication and stability.
How market orientation affects open innovation? Exploring the role of information and communication technology capability
Authors: Yin Miaomiao , Li Jiying
Published: January 2023

Purpose

Based on the organizational learning theory, this study regards market orientation as market-based learning and seeks to advance insight into how proactive and responsive market orientations affect two kinds of open innovation strategies, sourcing and selling. A firm’s information and communication technology (ICT) capability is considered an essential moderator in these relationships.

Design/methodology/approach

This study adopted a quantitative design and used the questionnaire survey method to collect data. The authors finally collected data on samples in China. Multiple regression analysis was used to test the hypotheses.

Findings

The results show that proactive and responsive market orientations act as antecedents of open innovation, showing linear and curvilinear relationships between them. Specifically, responsive market orientation positively affects selling, and proactive market orientation positively affects sourcing. Responsive market orientation has an inverted U-shaped relationship with sourcing, and proactive market orientation has a U-shaped relationship with selling. In addition, ICT capability strengthens the positive effects of market orientation on open innovation and weakens the negative effects.

Originality/value

Drawing on organizational learning theory, this study provides a novel perspective to explain the complex mechanism between market orientation and open innovation. This study also explores the moderating role of ICT capability in this process, which advances research on how to select open innovation strategies under different conditions.
Perceived importance of emotional support provided by health care professionals and social networks: Should we broaden our focus for the delivery of supportive care?
Authors: Taylor Jo , Fradgley Elizabeth A. , Clinton‐McHarg Tara , Hall Alix , Paul Christine L.
Published: January 2023

Introduction

Emotional support provided by health care professionals (HCPs) for people diagnosed with cancer is associated with improved outcomes. Support via social networks may also be important.

Aims

To report among a sample of distressed patients and caregivers, (1) the importance attributed to different sources of emotional support (HCPs and social networks) by distressed cancer patients and caregivers; (2) the proportion who indicate they did not receive sufficient levels of emotional support; and (3) potential associations between respondents’ demographic and clinical characteristics and reported lack of emotional support.

Methods

This study utilised cross‐sectional data from telephone interviews collected during the usual‐care phase of the Structured Triage and Referral by Telephone (START) trial. Participants completed a telephone interview 6 months after their initial call to the Cancer Council Information and Support service and included recall of importance and sufficiency of emotional support.

Results

More than two‐thirds of patients (n = 234) and caregivers (n = 152) reported that family and friends were very important sources of emotional support. Nurses (69% and 42%) and doctors (68% and 47%) were reported very important, while a lower proportion reported that psychologists and psychiatrists were very important (39%, and 43%). Insufficient levels of support were reported by 36% of participants. Perceptions of insufficient support were significantly associated with distress levels (p < .0001) and not having a partner (p = .0115).

Conclusion

Social networks, particularly family, are an important source of emotional support. Higher levels of distress, those without partners, and caregivers may require targeted interventions to increase their access to emotional support.
Total‐evidence phylogeny and evolutionary morphology of New World pitvipers (Serpentes: Viperidae: Crotalinae)
Authors: Carrasco Paola A. , Koch Claudia , Grazziotin Felipe G. , Venegas Pablo J. , Chaparro Juan C. , Scrocchi Gustavo J. , Salazar‐Valenzuela David , Leynaud Gerardo C. , Mattoni Camilo I.
Published: January 2023

Crotalines (pitvipers) in the Americas are distributed from southern Canada to southern Argentina, and are represented by 13 genera and 163 species that constitute a monophyletic group. Their phylogenetic relationships have been assessed mostly based on DNA sequences, while morphological data have scarcely been used for phylogenetic inquiry. We present a total‐evidence phylogeny of New World pitvipers, the most taxon/character comprehensive phylogeny to date. Our analysis includes all genera, morphological data from external morphology, cranial osteology and hemipenial morphology, and DNA sequences from mitochondrial and nuclear genes. We performed analyses with parsimony as an optimality criterion, using different schemes for character weighting. We evaluated the contribution of the different sources of characters to the phylogeny through analyses of reduced datasets and calculation of weighted homoplasy and retention indexes. We performed a morphological character analysis to identify synapomorphies for the main clades. In terms of biogeography, our results support a single colonization event of the Americas by pitvipers, and a cladogenetic event into a Neotropical clade and a North American/Neotropical clade. The results also shed light on the previously unstable position of some taxa, although they could not sufficiently resolve the position of Bothrops lojanus, which may lead to the paraphyly of either Bothrops or Bothrocophias. The morphological character analyses demonstrated that an important phylogenetic signal is contained in characters related to head scalation, the jaws and the dorsum of the skull, and allowed us to detect morphological convergences in external morphology associated with arboreality.
Optimizing CNN‐LSTM hybrid classifier using HCA for biomedical image classification
Authors: Pradhan Ashwini Kumar , Das Kaberi , Mishra Debahuti , Chithaluru Premkumar
Published: January 2023

In medical science, imaging is the most effective diagnostic and therapeutic tool. Almost all modalities have transitioned to direct digital capture devices, which have emerged as a major future healthcare option. Three diseases such as Alzheimer's (AD), Haemorrhage (HD), and COVID‐19 have been used in this manuscript for binary classification purposes. Three datasets (AD, HD, and COVID‐19) were used in this research out of which the first two, that is, AD and HD belong to brain Magnetic Resonance Imaging (MRI) and the last one, that is, COVID‐19 belongs to Chest X‐Ray (CXR) All of the diseases listed above cannot be eliminated, but they can be slowed down with early detection and effective medical treatment. This paper proposes an intelligent method for classifying brain (MRI) and CXR images into normal and abnormal classes for the early detection of AD, HD, and COVID‐19 based on an ensemble deep neural network (DNN). In the proposed method, the convolutional neural network (CNN) is used for automatic feature extraction from images and long‐short term memory (LSTM) is used for final classification. Moreover, the Hill‐Climbing Algorithm (HCA) is implemented for finding the best possible value for hyper parameters of CNN and LSTM, such as the filter size of CNN and the number of units of LSTM while fixing the other parameters. The data‐set is pre‐processed (resized, cropped, and noise removed) before feeding the train images to the proposed models for accurate and fast learning. Forty‐five MR images of AD, Sixty MR images of HD, and 600 CXR images of COVID‐19 were used for testing the proposed model ‘CNN‐LSTM‐HCA’. The performance of the proposed model is evaluated using six types of statistical assessment metrics such as; Accuracy, Sensitivity, Specificity, F‐measure, ROC, and AUC. The proposed model compared with the other three types of hybrid models such as CNN‐LSTM‐PSO, CNN‐LSTM‐Jaya, and CNN‐LSTM‐GWO and also with state‐of‐art techniques. The overall accuracy of the proposed model received was 98.87%, 85.75%, and 99.1% for COVID‐19, Haemorrhage, and Alzheimer's data sets, respectively.
Comprehensive analysis of SARS‐CoV‐2 receptor proteins in human respiratory tissues identifies alveolar macrophages as potential virus entry site
Authors: Bräutigam Konstantin , Reinhard Stefan , Wartenberg Martin , Forster Stefan , Greif Karen , Granai Massimo , Bösmüller Hans , Klingel Karin , Schürch Christian M
Published: January 2023

Aims

COVID‐19 has had enormous consequences on global health‐care and has resulted in millions of fatalities. The exact mechanism and site of SARS‐CoV‐2 entry into the body remains insufficiently understood. Recently, novel virus receptors were identified, and alveolar macrophages were suggested as a potential viral entry cell type and vector for intra‐alveolar virus transmission. Here, we investigated the protein expression of 10 well‐known and novel virus entry molecules along potential entry sites in humans using immunohistochemistry.

Methods and results

Samples of different anatomical sites from up to 93 patients were incorporated into tissue microarrays. Protein expression of ACE2, TMPRSS2, furin, CD147, C‐type lectin receptors (CD169, CD209, CD299), neuropilin‐1, ASGR1 and KREMEN1 were analysed. In lung tissues, at least one of the three receptors ACE2, ASGR1 or KREMEN1 was expressed in the majority of cases. Moreover, all the investigated molecules were found to be expressed in alveolar macrophages, and co‐localisation with SARS‐CoV‐2 N‐protein was demonstrated using dual immunohistochemistry in lung tissue from a COVID‐19 autopsy. While CD169 and CD209 showed consistent protein expression in sinonasal, conjunctival and bronchiolar tissues, neuropilin‐1 and ASGR1 were mostly absent, suggesting a minor relevance of these two molecules at these specific sites.

Conclusion

Our results extend recent discoveries indicating a role for these molecules in virus entry at different anatomical sites. Moreover, they support the notion of alveolar macrophages being a potential entry cell for SARS‐CoV‐2.
High‐purity stoichiometric Si3N4 ceramics through trimethylsilyl‐substituted polysilazanes
Authors: Li Tianhao , Zhang Wei , Duan Liantai , Chen Ke , Huang Qing , Li Yinsheng , Huang Zhengren , He Liu , Song Yujie
Published: January 2023

Trimethylsilyl‐substituted polysilazanes were designed and successfully synthesized. They were used to fabricate high‐purity stoichiometric Si3N4 ceramics through pyrolysis process. Trimethylsilyl groups improved the stability of polysilazanes and easily escaped during pyrolysis, which effectively reduced oxygen and carbon content in the final polymer‐derived Si3N4. The C content of Si3N4 ceramic was below 0.06 wt%, and the O content was below 1.2 wt%. The Si3N4 ceramics remained amorphous up to 1400°C, yet they were completely transformed into α‐Si3N4 at 1500°C. Synergistic effect from low oxygen and carbon content contributed to highly stable amorphous state of Si3N4 till high temperatures. This amorphous Si3N4 ceramics could be used in cutting‐edge technology where high purity is compulsory.
Testing a cost‐affordable microfiltration method to prevent eye formation in cheeses
Authors: Giménez Paula , Bergamini Carina Viviana , Peralta Guillermo Hugo , George Guillermo Andrés , Perotti María Cristina , Hynes Erica Rut
Published: January 2023

The naturally occurring microparticles in the cheesemilk are essential for the eye formation in cheeses because they act as eye nuclei. So, their elimination could be a strategy to avoid the eye formation in cheese varieties in which the eyes are considered a defect. The objective of this work was to test the efficiency of a cost‐affordable method, microfiltration through filter bag with 1 μm pore size, for eliminating microparticles from the cheesemilk and so to prevent the undesirable eye formation. For that, cheesemilk was microfiltrated and used to make experimental and control Swiss‐type cheeses with and without the addition of hay microparticles, respectively. These microparticles were added to act as eye nuclei and to promote the eye formation in experimental cheeses, while the absence of microparticles in control cheeses should avoid the eye development. Cheeses were ripened (60 days) in adequate successive steps to allow the gas production by the propionic bacteria included in the starter. Gross composition, pH, and content of carbohydrates and organic acids including propionate were the same in both treatments indicating that similar amounts of CO2 were produced. Despite microfiltration of the milk, control cheeses developed a considerable number of eyes, as well as experimental cheeses, although the eye volume was higher in the last ones. So, the microfiltration with a filter bag was not efficient to prevent eye formation, probably because it did not eliminate all the native nuclei, and therefore is not suitable to our objective.

Practical Applications

It have been demonstrated that the presence of microparticles is absolutely needed for the eyes formation because they act as eye nuclei. So, the elimination of these microparticles from the cheesemilk could be a strategy to avoid the unwanted eye formation in some cheese varieties, which is a main problem for small and medium cheese factories. In this way, tangential microfiltration of cheesemilk has been proposed as an appropriate technique to removes naturally occurring microparticles. However, it is a costly method and not entirely widespread. In this work, the performance of a more cost affordable and easily adaptable method: microfiltration through filter bag (not tangential), for eliminating microparticles and so to avoid eye formation in cheese varieties in which the eyes are considered a defect was assessed. However, this methodology did not demonstrate a good performance.
Mindfulness through agency in health consumption: Empirical evidence from committed dietary supplement consumers
Authors: Wang Yun , Neilson Leighann C. , Ji Shaobo
Published: January 2023

Due to individuals' increasing demand for health promotion, various health‐related consumer goods, like dietary supplements (DS), have flourished in the marketplace as magical solutions to consumers' life problems. Inevitably influenced by various marketplace stakeholders and information sources such as family, friends, brands, and social media influencers, consumers may encounter difficulties making well‐informed health decisions. Based on empirical evidence gleaned from in‐depth interviews with DS consumers, this research contributes to consumer wellness and health promotion research by confirming the role of mindfulness as an agency in distancing individuals from external social noises and enabling them to respond flexibly to inner experiences and desires. We contribute to mindful consumption research by identifying the positive impact of mindfulness on facilitating conscious and independent DS consumption decisions and health practices. Moreover, the daily practices that enable individuals to accumulate mindfulness and the impact of mindfulness on females' perception of beauty are discussed.