bluuebunny/crossref_metadata_2025 huggingface dataset:
A GWAS of ACE Inhibitor-Induced Angioedema in a South African Population
Authors: Mugo Jacquiline W. , Day Cascia , Choudhury Ananyo , Deetlefs Maria , Freercks Robert , Geraty Sian , Panieri Angelica , Cotchbos Christian , Ribeiro Melissa , Engelbrecht Adelein , Micklesfield Lisa K. , Ramsay Michèle , Pedretti Sarah , Peter Jonny
Published: September 2024

Background

Angiotensin-converting enzyme inhibitor-induced angioedema (AE-ACEI) is a life-threatening adverse event and, globally, the commonest cause of emergency presentations with angioedema. Several large genome-wide association studies (GWAS) have found genomic associations with AE-ACEI. However, despite African Americans having a 5-fold increased risk of AE-ACEI, there are no published GWAS from Africa. The aim of this study was to conduct a case-control GWAS of AE-ACEI in a South African population and perform a meta-analysis with an African American and European American population.

Methods

The GWAS included 202 South African adults with a history of AE-ACEI and 513 controls without angioedema following angiotensin-converting enzyme inhibitor (ACEI) treatment for at least 2 years. A meta-analysis was conducted with GWAS summary statistics from an African American and European American cohort (from Vanderbilt/Marshfield with 174 cases and 489 controls).

Results

No SNPs attained genome-wide significance. However, 26 SNPs in the post-imputation standard GWAS of the South African cohort and 37 SNPs in the meta-analysis were associated to AE-ACEI with suggestive threshold(p-value<5.0×10−06). Some of these SNPs were found to be located close to the genesPRKCQandRIMS1,previously linked with drug-induced angioedema, and also close to theCSMD1gene linked to ACEI cough, providing replication at the gene level, but with novel lead SNPs.

Conclusions

Our results highlight the importance of African populations to detect novel variants in replication studies. Further increased sampling across the continent and matched functional work are needed to confirm the importance of genetic variation in understanding the biology of AE-ACEI.
Focused ultrasound enhanced antibody delivery for the treatment of Parkinson's Disease
Authors: Kwon Nancy , Batts Alec J , Zhang Hairong , Lewis-Jackson Vernice , Konofagou Elisa , Przedborski Serge
Published: September 2024

Treatment of neurological disorders is partly impeded by the size of large pharmacological agents which are thereby unable to bypass the blood brain barrier. Focused ultrasound in conjunction with systemically administered microbubbles has been shown to safely noninvasively and transiently open the BBB allowing the passage of large biomolecules to the brain parenchyma through the otherwise impermeable barrier. This pilot study assessed the feasibility of FUS mediated delivery of an anti alpha synuclein monoclonal antibody in Parkinsons disease mouse models that exhibit aggregates. Mice underwent FUS on a weekly basis over the course of 2 to 3 weeks followed by a one month survival period. MRI and microscopy were performed to confirm BBB opening with FUS and visualize antibody delivery. Safety was assessed in vivo using passive cavitation detection and immunohistochemistry to evaluate microglial and astrocyte activity ex vivo. It was found that treatment sessions for multiple FUS sessions of targeted antibody delivery was feasible in alpha-synuclein models facilitating immunotherapeutics.
BRUCE liver-deficiency potentiates MASLD/MASH in PTEN liver-deficient background by impairment of mitochondrial metabolism in hepatocytes and activation of STAT3 signaling in hepatic stellate cells
Authors: Che Lixiao , Stevenson Camille K. , Plas David R. , Wang Jiang , Du Chunying
Published: September 2024

Metabolic dysfunction-associated steatotic liver disease (MASLD) is currently the most common liver disease, affecting up to 25% of people worldwide, featuring excessive fat accumulation in hepatocytes. Its advanced form, metabolic dysfunction-associated steatohepatitis (MASH), is a serious disease with hepatic inflammation and fibrosis, increasing the need for liver transplants. However, the pathogenic mechanism of MASLD and MASH is not fully understood. We reported that BRUCE (BIRC6)is a liver cancer suppressor and is downregulated in MASLD/MASH patient liver specimens, though the functional role of BRUCE in MASLD/MASH remains to be elucidated. To this end, we generated liver-specific double KO (DKO) mice of BRUCE and PTEN, a major tumor suppressor and MASLD/MASH suppressor. By comparing liver histopathology among 2-3-month-old mice, there were no signs of MASLD or MASH in BRUCE liver-KO mice and only onset of steatosis in PTEN liver-KO mice. Interestingly, DKO mice had developed robust hepatic steatosis with inflammation and fibrosis. Further analysis of mitochondrial function with primary hepatocytes found moderate reduction of mitochondrial respiration, ATP production and fatty acid oxidation in BRUCE KO and the greatest reduction in DKO hepatocytes. Moreover, aberrant activation of pro-fibrotic STAT3 signaling was found in hepatic stellate cells (HSCs) in DKO mice which was prevented by administered STAT3-specific inhibitor (TTI-101). Collectively, the data demonstrates by maintaining mitochondrial metabolism BRUCE works in concert with PTEN to suppress the pro-fibrogenic STAT3 activation in HSCs and consequentially prevent MASLD/MASH. The findings highlight BRUCE being a new co-suppressor of MASLD/MASH.
Exploring American Elderberry Compounds for Antioxidant, Antiviral, and Antibacterial Properties Through High-Throughput Screening Assays Combined with Untargeted Metabolomics
Authors: Dwikarina Amanda , Bayati Mohamed , Efrat Novianus , Roy Anuradha , Lei Zhentian , Ho Khanh-Van , Sumner Lloyd , Greenlief Michael , L.Thomas Andrew , Applequist Wendy , Townesmith Andrew , Lin Chung-Ho
Published: September 2024

American elderberry (Sambucus nigrasubsp.canadensis) is a rapidly emerging new perennial crop for Missouri, recognized for its high level of bioactive compounds with significant health benefits, including antibacterial, antiviral, and antioxidant properties. A high-throughput screening assay combined with untargeted metabolomics analysis was utilized on American elderberry juice from 21 genotypes to explore and characterize these bioactive compounds. Our metabolomics study has identified 32 putative bioactive compounds in the American Elderberry juices. An array of high-throughput screening bioassays was conducted to evaluate 1) total antioxidant capacity, 2) activation of antioxidant response elements (ARE), 3) antiviral activity, and 4) antibacterial activity of the putatively identified compounds. Our results revealed that 14 of the 32 American elderberry compounds exhibited strong antioxidant activity. Four compounds (isorhamnetin 3-O-glucoside, kaempferol, quercetin, and naringenin) activated ARE activity and were found to be non-cytotoxic to cells. Notably, six of the 32 compounds demonstrated significant antiviral activity in anin vitroTZM-bl assay against two strains of HIV-1 virus, CXCR4-dependent NL4-3 virus and CCR5-dependent BaL virus. Luteolin showed the most potent anti-HIV activity against the NL4-3 virus (IC50= 1.49 µM), followed by isorhamnetin (IC50= 1.67 µM). The most potent anti-HIV compound against the BaL virus was myricetin (IC50= 1.14 µM), followed by luteolin (IC50= 4.38 µM). Additionally, six compounds were found to have antibacterial activity against gram-positive bacteriaS. aureus, with cyanidin 3-O-rutinoside having the most potent antibacterial activity in vitro (IC50= 2.9 µM), followed by cyanidin 3-O-glucoside (IC50= 3.7 µM). These findings support and validate the potential health benefits of compounds found in American elderberry juices and highlight their potential for use in dietary supplements as well as innovative applications in health and medicine.
ARHGEF3 Regulates Hair Follicle Morphogenesis
Authors: Kalyanakrishnan Krithika , Beaudin Amy , Jetté Alexandra , Ghezelbash Sarah , Hotea Diana Ioana , Chen Jie , Lefrançois Philippe , Laurin Mélanie
Published: September 2024

During embryogenesis, cells arrange into precise patterns that enable tissues and organs to develop specialized functions. Despite its critical importance, the molecular choreography behind these collective cellular behaviors remains elusive, posing a major challenge in developmental biology and limiting advances in regenerative medicine. By using the mouse hair follicle as a mini-organ system to study the formation of bud-like structures during embryonic development, our work uncovers a crucial role for the Rho GTPase regulator ARHGEF3 in hair follicle morphogenesis. We demonstrate thatArhgef3expression is upregulated at the onset of hair follicle placode formation. InArhgef3knockout animals, we observed defects in placode compaction, leading to impaired hair follicle downgrowth. Through cell culture models, we show that ARHGEF3 promotes F-actin accumulation at the cell cortex and P-cadherin enrichment at cell-cell junctions. Collectively, our study identifies ARHGEF3 as a new regulator of cell shape rearrangements during hair placode morphogenesis, warranting further exploration of its role in other epithelial appendages that arise from similar developmental processes.
Structures of aberrant spliceosome intermediates on their way to disassembly
Authors: Soni Komal , Horvath Attila , Dybkov Olexandr , Schwan Merlin , Trakansuebkul Sasanan , Flemming Dirk , Wild Klemens , Urlaub Henning , Fischer Tamás , Sinning Irmgard
Published: September 2024

Intron removal during pre-mRNA splicing is of extraordinary complexity and its disruption causes a vast number of genetic diseases in humans1. While key steps of the canonical spliceosome cycle have been revealed by combined structure-function analyses2,3, structural information on an aberrant spliceosome committed to premature disassembly is not available. Here, we report two cryo-EM structures of post-Bactspliceosome intermediates fromS. pombeprimed for disassembly. We identify the DEAH-box helicase – G patch protein pair (Gih35-Gpl1, homologous to human DHX35-GPATCH1) and show how it maintains catalytic dormancy. In both structures, Gpl1 recognizes a remodeled active site introduced by an over-stabilization of the U5 loop I interaction with the 5’ exon leading to a single nucleotide insertion at the 5’splice site. Remodeling is communicated to the spliceosome surface and the Ntr1 complex that mediates disassembly is recruited. Our data pave the way for a targeted analysis of splicing quality control.
Altered polyadenylation site usage in SERPINA1 3’UTR in response to cellular stress affects A1AT protein expression
Authors: Jiamutai FNU , Hatfield Abigail , Herbert Austin , Majumdar Debarati , Shankar Vijay , Lackey Lela
Published: September 2024

Alternative polyadenylation results in different 3’ isoforms of messenger RNA (mRNA) transcripts. Alternative polyadenylation in the 3’ untranslated region (3’UTR) can alter RNA localization, stability and translational efficiency. TheSERPINA1mRNA has two distinct 3’ UTR isoforms, both of which express the protease inhibitor α-1-antitrypsin (A1AT). A1AT is an acute phase protein that is expressed and secreted from liver hepatocytes and upregulated during inflammation. Low levels of A1AT in the lung contributes to chronic obstructive pulmonary disease, while misfolding of A1AT in the liver contributes to liver cirrhosis. We analyzed the dynamics of alternative polyadenylation during cellular stress by treating the liver cell line HepG2 with the cytokine interleukin 6 (IL-6), ethanol or peroxide.SERPINA1is transcriptionally upregulated after IL-6 treatment and has altered polyadenylation, resulting in an increase in long 3’UTR isoforms. We find that the long 3’UTR represses endogenous A1AT protein expression even with high levels ofSERPINA1mRNA.SERPINA1expression and 3’ end processing were not affected by ethanol or peroxide. IL-6-induced changes in transcriptome-wide transcriptional regulation suggest changes to the endoplasmic reticulum and in secretory protein processing. Our data suggest that inflammation influences polyA site choice forSERPINA1transcripts, resulting in reduced A1AT protein expression.
Motor learning leverages coordinated low-frequency cortico-basal ganglia activity to optimize motor preparation in humans with Parkinson’s Disease
Authors: Presbrey Kara N. , Wozny Thomas A. , Louie Kenneth H. , Little Simon , Starr Philip A. , Abbasi-Asl Reza , Wang Doris D.
Published: September 2024

Learning dexterous motor sequences is crucial to autonomy and quality of life but can be altered in Parkinson’s Disease (PD). Learning involves optimizing pre-movement planning (preplanning) of multiple sequence elements to reduce computational overhead during active movement. However, it is unclear which brain regions mediate preplanning or how this process evolves with learning. Recording cortico-basal ganglia field potentials during a multi-day typing task in four individuals with PD, we found evidence for network-wide multi-element preplanning that improved with learning, facilitated by functional connectivity. In both cortex and basal ganglia, pre-movement gamma (γ, 30–250 Hz) activity, historically linked to population spiking, distinguished between future action sequences and became increasingly predictive with learning. For motor cortex γ, this increase was tied to learning-related cross-frequency coupling led by cortically-driven network delta (δ, 0.5–4 Hz) synchrony. More generally, coordinated network δ supported a complex pattern of learning-driven cross-frequency couplings within and between cortex and basal ganglia, including striatal lead of cortical beta (β, 12–30 Hz) activity, reflecting the specialized roles of these brain regions in motor preparation. In contrast, impaired learning was characterized by practice-driven decreases in γ’s predictive value, limited cross-frequency coupling and absent network δ synchrony, with network dynamics possibly altered by pathologically high inter-basal ganglia δ synchrony. These results suggest that cortically-led δ phase coordination optimized cortico-basal ganglia multi-element preplanning through enhanced recruitment of higher-frequency neural activity. Neurostimulation that enhances cortico-basal ganglia δ synchrony may thus hold potential for improving skilled fine motor control in PD.
Modelling coordinated nocturnal rhythms in ungulates
Authors: Ukrow Johann , Gübert Jennifer , Hahn-Klimroth Max , Dierkes Paul Wilhelm , Schneider Gaby
Published: September 2024

Studying animal behavior is an important aspect of ethology and behavioral biology and a prerequisite to improving animal management in zoos. As the nocturnal behavior of many ungulate species is, in contrast to the behavior during daylight, poorly studied, a better understanding of nocturnal behavior is necessary to improve animal welfare.

We analyse the nocturnal behavior of ungulates recorded in a large number of German and Dutch zoos. These animals show a switching between standing and lying phases, which can be associated with a certain degree of regularity. Interestingly, this regularity is not always captured in the simple length distributions of behavioral phases but shows in the autocorrelation and in the coordination of standing and lying across animals. Particularly, this phenomenon often occurs in younger animals.

We provide an explanation to this phenomenon by proposing a stochastic model that can describe these processes. For individual behavior, regular standing cycles are assumed to be potentially interrupted by short lying phases, such that a regular background rhythm appears in the autocorrelation but not necessarily in the raw length distribution of the activity phases. For coordinated behavior, crosscorrelation functions allow to analyse the degree to which pairs of animals that are sharing the same stable box show a synchronization of their standing-lying rhythms.

In the data set, our analyses suggest that indeed, baseline regularity does not seem to be reduced in younger animals. Instead, younger animals showed increased probabilities for interruption of standing phases by short lying phases. In addition, the coordination of the standing-lying rhythm between animals in the same box ranged up to 100% and decreased with the distance between boxes. We also found systematic delays between the standing activity of young and adult animals.

Author summary

In this paper, we investigate rhythms observed in the nocturnal behavior of a large number of ungulates housed in zoos. Motivated by the observation that younger individuals, in particular, exhibit irregular standing-lying cycles, we propose and analyze a mathematical model to describe the basic rhythms of the observed animals and quantify the regularity of their standing-lying behavior.

Our model enables us to measure both the regularity and synchronization of behavior among individuals. The results suggest that even individuals initially perceived as highly irregular actually follow a strict base rhythm during the night, but single standing phases may be interrupted. Moreover, we observe that animals stalled together typically synchronize their behavior, particularly in the case of a dam and her calf.
Egocentric anchoring-and-adjustment of social knowledge in the hippocampal formation
Authors: Rodríguez Aramendía Marta , Esposito Mariachiara , Kaplan Raphael
Published: September 2024

Recent work suggests the hippocampal formation(HF) assimilates relational social knowledge similar to how it transforms egocentric spatial cues into map-like representations. Yet whether hippocampal map-like representations of social knowledge still represent lingering egocentric biases is unclear. We test if a prominent egocentric bias involving an implicit reliance on self-knowledge when rating others, anchoring-and-adjustment, is present when the relative attributes of different social entities are assimilated by the HF. Participants provided likelihood ratings of partaking in everyday activities for themselves, fictitious individuals, and familiar social groups. Adapting a functional neuroimaging task from Kaplan and Friston, participants then learned a stranger’s preference for an activity relative to one of the fictitious individuals and inferred how the stranger’s preference related to the groups’ preferences. Egocentric anchoring-and-adjustment was present when participants rated the other entities. Isolating the neural representation of egocentric anchoring-and-adjustment when flexibly comparing different social entities, the HF and dorsomedial prefrontal cortex(dmPFC) represented group-self rating discrepancy. Furthermore, the HF also reflected how well group preferences were remembered, where memory for group preferences correlates with task performance. We found the HF selectively represented group identity over other learned entities, confirming that the HF was primarily engaged by social comparisons in a more ample frame of reference. Taken together, these results imply that self-knowledge influences how the HF assimilates map-like knowledge about others.
A systems model of alternating theta sweeps via firing rate adaptation
Authors: Ji Zilong , Chu Tianhao , Wu Si , Burgess Neil
Published: September 2024

Place and grid cells provide a neural system for self-location and tend to fire in sequences within each cycle of the hippocampal theta rhythm when rodents run on a linear track. These sequences correspond to the decoded location of the animal sweeping forward from its current location (“theta sweeps”). However recent findings in open-field environments show alternating left-right theta sweeps, and propose a circuit for their generation. Here, we present a computational model of this circuit, comprising head direction cells, conjunctive grid x direction cells, and pure grid cells, based on continuous attractor dynamics, firing rate adaptation, and modulated by the medial-septal theta rhythm. Due to firing rate adaptation, the head-direction ring attractor exhibits left-right sweeps coding for internal direction, providing an input to the grid cell attractor network shifted along the internal direction, via an intermediate layer of conjunctive grid x direction cells, producing left-right sweeps of position by grid cells. Our model explains the empirical findings, including the alignment of internal position and direction sweeps and the dependence of sweep length on grid spacing. It makes predictions for thetamodulated head-direction cells, including specific relationships between theta phase precession during turning, theta skipping, anticipatory firing and directional tuning width. These predictions are verified in experimental data from anteroventral thalamus. The model also makes several predictions for the relationships between position and direction sweeps, running speed and dorsal-ventral location within the entorhinal cortex. Overall, a simple intrinsic mechanism explains the complex theta dynamics of the spatial circuit, with testable predictions.
Cav3.1 is a leucine sensor in POMC neurons mediating appetite suppression and weight loss
Authors: Tsang Anthony H. , Heeley Nicholas , Alcaino Constanza , Hwang Eunsang , Lam Brian Y. , Rahman Taufiq , Darwish Tamana , Nuzzaci Danae , Kay Richard G. , Sarkar Amar , Wang Ruiyan , Basha Nihal , Punnoose Austin , Kirwan Peter , Ma Marcella , Yeo Giles S. , Merkle Florian T , Gribble Fiona M. , Reimann Frank , William Kevin , Blouet Clémence
Published: September 2024

Hypothalamic leucine sensing promotes satiety and weight loss but an understanding of how leucine regulates neuronal activity is lacking. Here we show thatCacna1g, encoding the T-type voltage-gated calcium channel Cav3.1, is enriched in hypothalamic leucine-sensing neurons and mediates leucine sensing. Pharmacological inhibition of Cav3.1 blunts leucine-induced activation of POMC neurons as well as the anorectic response to leucine in vivo. In addition, genetic deletion ofCacna1gin POMC neurons abolishes the appetite- and weight-suppressive effects of high-protein feeding. Mechanistically, we show that leucine binds to the voltage-sensing segment of Cav3.1, thereby reducing its threshold for voltage-dependent activation. Last, pharmacological activation of hypothalamic Cav3.1 promotes weight loss in diet-induced obese mice and potentiates the weight loss response to GLP-1 receptor agonism. These results reveal that Cav3.1 is a neuronal leucine sensor and a relevant weight loss target.
High distinctness of circadian rhythm is related to negative emotionality and enhanced neural processing of punishment-related information in men
Authors: Scislewska Patrycja , Zareba Michal Rafal , Lengier Julia , Schirmer Aaron , Bebas Piotr , Szatkowska Iwona
Published: September 2024

For years, research on the human biological clock has focused primarily on chronotype (phase of the circadian rhythm). However, a second dimension - distinctness (subjective amplitude) of the rhythm, has so far been overlooked. This study aimed to explore the intricate interplay between psychometric traits and reward-punishment processing, considering both chronotype and distinctness. Circadian rhythmicity characteristics of 37 healthy men (aged 20-30) were measured using the Morningness-Eveningness-Stability-Scale improved (MESSi) questionnaire. We also employed a battery of psychometric questionnaires and used functional magnetic resonance (fMRI) during the Monetary Incentive Delay task, which is a common method of assessing reward-punishment processing. We found a positive association between distinctness and the activity in the bilateral Superior Frontal Gyrus (SFG), Supplementary Motor Area (SMA), and Ventral Tegmental Area (VTA) during processing of punishment cues. These results are consistent with psychometric findings - a significant positive association between distinctness and sensitivity to punishment, neuroticism, behavioral inhibition system (BIS), attention deficits, and negative emotionality. As regards eveningness, we found its negative association only with sensitivity to punishment and BIS. These results highlight the crucial role of distinctness in human functioning, especially in terms of punishment processing and negative emotionality.
Computational metabolic modeling unveils gut microbiome’s role in metabolic shifts during murine cancer cachexia
Authors: Kuehnast Torben , Pototschnig Isabella , Träger Manuela , Diener Christian , Habisch Hansjörg , Vogel Andrea , Wink Lisa , Mahnert Alexander , Madl Tobias , Weichhart Thomas , Schweiger Martina , Moissl-Eichinger Christine
Published: September 2024

Cancer cachexia is a multifactorial syndrome characterized by involuntary weight loss, muscle wasting, systemic inflammation, and metabolic alterations, affecting up to 87% of pancreatic and gastric cancer patients. Unlike simple starvation, cachexia is driven by metabolic disruption involving both host physiology and the gut microbiome. While microbiome changes in cachexia have been documented, a coherent understanding of how these changes translate into functional metabolic shifts remains elusive.

In this study, we combined in vivo fecal and plasma metabolomic analyses with a novel computational microbiome simulation pipeline to identify cachexia-associated microbial metabolites. Using the murine MCA207 tumor line and its cachectic derivative CHX207, we differentiated microbiome changes driven by cachexia from those induced by tumor growth. Our computational tool, McMurGut, a murine-tailored extension of MICOM, enabled simulation of microbial metabolic interactions specific to the mouse microbiome, covering 91% of identified genera.

We identified significant abundance changes in 35 microbial genera and corresponding shifts in metabolite production, including reductions in short-chain fatty acids (SCFAs) like acetate and butyrate, alongside increased production of galactose, formate, and propionate. Notably, decreases in SCFA production, particularly by genera such asFaecalibaculumandDubosiella, correlated with exacerbated cachectic symptoms. Additionally, the elevated production of formate and galactose, primarily byBacteroidesandLactobacillus, suggested altered fermentation pathways in cachexia, potentially linked to increased mucus degradation.

Validation of our computational predictions via NMR metabolomics highlighted key congruencies between predicted and experimentally observed metabolites, supporting the role of microbiome-driven metabolic shifts in cachexia pathology. These findings provide crucial insights into the microbiome’s involvement in cachexia and suggest future avenues for therapeutic interventions aimed at modulating microbial taxa and their metabolic outputs to improve patient outcomes.
Opponent visuospatial coding structures responses during memory recall and visual perception in medial parietal cortex
Authors: Scrivener Catriona L. , Silson Edward H.
Published: September 2024

The mechanisms linking perceptual and memory representations in the brain are not yet fully understood. In early visual cortex, perception and memory are known to share similar neural representations, but how they interact beyond early visual cortex is less clear. Recent work identified that scene-perception and scene-memory areas on the lateral and ventral surfaces of the brain are linked via a shared but opponent visuospatial coding scheme, suggesting that shared visuospatial coding might provide a framework for perceptual-memory interactions. Here, we test whether the pattern in visuospatial coding within category-selective memory areas of medial parietal cortex structures responses during memory recall and visual perception. Using functional magnetic resonance imaging, we observe signatures of visuospatial coding in the form of population receptive fields (pRFs) with both positive and negative response profiles within medial parietal cortex. Crucially, the more dissimilar the timeseries of a pair of positive/negative pRFs within a region, the more dissimilar their responses during both memory recall and visual perception - tasks that place very different demands on these regions: internally oriented memory recall versus externally oriented visual perception. These data extend recent work to suggest that the interplay between pRFs with opponent visuospatial coding may play a vital role in integrating information across different representational spaces.
On the coupling between membrane bending and stretching in lipid vesicles
Authors: Wennerström Håkan , Sparr Emma , Stenhammar Joakim
Published: September 2024

The formation of a lipid vesicle from a lamellar phase involves a cost in bending energy of 100–1000 times the thermal energy for values of the membrane bending rigidityκtypical for phospholipid bilayers. The bending rigidity of a bilayer is however a strongly decreasing function of its thicknessh, and the bilayer can thus reduce its bending energy by stretching (and thus thinning) the bilayer. In this paper, we construct a simple model to describe this mechanism for the coupling between bending and stretching and analyse its effect on the bending energy and thermal fluctuations of spherical lipid vesicles. We show that the bilayer thinning becomes significant for small vesicles, and for a vesicle with radiusR0∼ 15 nm there is a sizeable thinning of the bilayer compared to the planar state. We furthermore demonstrate how this thinning is associated with a significant decrease in free energy due to the thermally excited bending modes. We argue that this previously unexplored effect can explain the experimentally observed lower limit of achievable vesicle sizes, which eventually become unstable due to the thinning of the bilayer. We also sketch how this effect provides a potential generic mechanism for the strong curvature dependence of protein adsorption to lipid membranes.
In silico analysis reveals differential targeting of enterovirus species by commonly used PCR assays
Authors: Trinh Van N. , Mulakken Nisha , Nelson Kara L. , Be Nicholas , Kantor Rose S.
Published: September 2024

Quantitative polymerase chain reaction (qPCR) assays are sensitive molecular tools commonly used to quantify pathogens in environmental samples. These assays have become a staple of wastewater-based surveillance and often form the basis of quantitative microbial risk assessments. However, PCR assays may fail to capture all of their intended targets due to signature erosion over time. Here, we performed anin silicoanalysis of four human enterovirus PCR assays to assess signature erosion against the NCBI virus database. The predicted number of genomes hit by each assay rose alongside total genomes in the database through 2010 but the proportion of predicted hits began to level off with the emergence of the clinically important enterovirus D-68. We found that although all assays captured a majority of enterovirus species, only one recently developed assay adequately captured enterovirus D species. Some assays also appeared more likely to capture non-human enteroviruses than others, an important consideration for data interpretation. We conclude that broad-spectrum virus assays applied to environmental samples should be regularly checked against expanding sequence databases and provide methods to do so.
BRD4 expression in microglia supports recruitment of T cells into the CNS and exacerbates EAE
Authors: Dey Anup , Butcher Matthew , Gegonne Anne , Singer Dinah S. , Zhu Jinfang , Ozato Keiko
Published: September 2024

In EAE, a mouse model of multiple sclerosis, immunization with MOG autoantigen results in the generation of Th1/Th17 T cells in the periphery. MOG-specific T cells then invade into the central nervous system (CNS), resulting in neuronal demyelination. Microglia, innate immune cells in the CNS are known to regulate various neuronal diseases. However, the role of microglia in EAE has remained elusive. BRD4 is a BET protein expressed in microglia, whether BRD4 in microglia contributes to EAE has not been determined. We show that EAE pathology was markedly reduced with microglia-specific Brd4 conditional knockout (cKO). In these mice, microglia- T cell interactions were greatly reduced, leading to the lack of T cell reactivation. Microglia specific transcriptome data showed downregulation of genes required for interaction with and reactivation of T cells in Brd4 cKO samples. In summary, BRD4 plays a critical role in regulating microglia function in normal and EAE CNS.

This study demonstrates that in a EAE model, microglia-specific Brd4 conditional knockout mice were defective in expressing genes required for microglia- T cells interaction and those involved in neuroinflammation, and demyelination resulting in fewer CNS T cell invasion and display marked reduction in EAE pathology.
Superiority Illusion in Older Adults: Volume and Functional Connectivity of the Precuneus
Authors: Shidei Yuki , Matsuyoshi Daisuke , Isato Ayako , Sugihara Genichi , Takahashi Hidehiko , Yamada Makiko
Published: September 2024

Aim

Positive thinking, which has been known to extend the lifespan, tends to increase with age. One specific form of positive thinking, the superiority illusion (SI), involves the belief that one is better than others. Despite its potential benefits in aging, the neural basis of the SI in elderly populations remains underexplored.

Methods

This study combined a behavioral task, voxel-based morphometry (VBM), and resting-state functional connectivity (rsFC) analyses to investigate the neural substrates of the SI in a cohort of 100 participants, including young (N = 33), middle-aged (N = 33), and older adults (N = 34).

Results

Our findings indicated that higher SI scores in older adults were correlated with greater gray matter volume in the right precuneus and stronger rsFC between the right precuneus and the left lateral occipital cortex. However, these correlations were not evident in younger and middle-aged groups.

Conclusions

Our findings underscore the importance of the right precuneus and its connectivity in the manifestation of the SI, particularly in older adults, highlighting its potential role in adaptive aging processes.
Do editorial board members publish in their own journal? – Review of editorial board members as authors in the main foot and ankle journals
Authors: Fa-Binefa Manel , Fontanellas Fes Albert , González Lucena Gemma , Ginés Cespedosa Albert , Gamba Carlo
Published: September 2024

Background

Scientific publications by editorial board members in their own journals raise questions about potential biases in the peer-review process. This study investigates the prevalence of self-publishing in high-impact factor foot and ankle focused journals.

Methods

A review was performed of the highest impact factor foot and ankle focused journals/:Foot and Ankle International,Foot and Ankle SurgeryyJournal of Foot and Ankle Surgery.In January 2023, the editorial board members were identified, and their names, roles, academic backgrounds, and regions were obtained. For each board member, the number of total published articles listed in PubMed and those for each corresponding journal over their entire history, during the last 5 years and during the last 3 years were compiled. Descriptive statistics analyses were performed using IBM SPSS Statistics v26.0.

Results

The study included 196 editorial board members from the 3 selected journals. Editorial board members have published 1694 articles in their own journals (9.17% of all the articles published in those 3 journals). Editorial board members published 23.4% (SD 23.6) of their overall production in their affiliated journals. Of that production, 39.0% (SD 38.6) have been published in the last 5 years, considering this 5-year period as the baseline for their role on the editorial board in question. Some 10% of editorial board members have published more than 50% of their scientific production in their own affiliated journal in the last 5 years. European editors (51%) have published more in their own journal over the last 5-year period than North Americans (29%) (p<0.001). Being a surgeon is related to greater publication rates in one’s own affiliated journal when compared to other specialist profiles (p=0.003).

Conclusion

The publication scientific articles by editorial board members as authors in journals with which they are affiliated is a present-day phenomenon in the highest impact factor journals with a focus on the foot & ankle. Knowledge of this data could be the key to understanding the prevalence of this phenomenon, and lead to making this data more accessible.
Effectiveness of a booster dose of aerosolized or intramuscular adenovirus type 5 vectored COVID-19 vaccine in adults with hybrid immunity against COVID-19: a multicenter, partially randomized, platform trial in China
Authors: Jia Si-Yue , Liu Yuan-Bao , He Qian , Pan Hong-Xing , Liang Zheng-Lun , Zhou Juan , Pan Ying-Zi , Liu Sheng , Wu Jing-Jing , Yang Kun , Zhang Xuan-Xuan , Zhao Yang , Li Si-Min , Zhang Lei , Chen Li , Yao Ai-Hua , Lu Meng-Yi , Mao Qun-Ying , Zhu Feng-Cai , Li Jing-Xin
Published: September 2024

Background

The primary objective of this research was to assess if a booster dose with COVID-19 vaccines containing ancestral strain could still provide significant protection against symptomatic SARS-CoV-2 infection in a predominantly hybrid-immune population during the period of omicron variant dominance.

Methods

We did a multicenter, partially randomized, platform trial to evaluate the effectiveness of a booster dose of an aerosolized or intramuscular adenovirus type 5 vectored COVID-19 vaccine (Ad5-nCoV) in adults, after the national-wide omicron circulating at the end of year 2022 in China. Participants who were willing to receive a COVID-19 booster dose were randomly assigned to receive one of the booster doses. While, those participants who refused to take a booster dose but consented to participate COVID-19 surveillance were included in a control group. Both participants receiving a booster dose or not were monitored for symptomatic COVID-19 during a six-month surveillance period.

Results

Between May 23, 2023, and August 28, 2023, 4089 eligible participants were equally randomized to receive a booster dose of aerosolized Ad5-nCoV through oral inhalation at 0.1mL (IH Ad5-nCoV, n=2039) or intramuscular injection of Ad5-nCoV at 0.5 mL (IM Ad5-nCoV, n=2050). While, 2008 participants were enrolled in the blank-control group. A total of 79 COVID-19 cases were confirmed, with 22 (0.006%) in the IH Ad5-nCoV group, 23 (0.007%) in the IM Ad5-nCoV group, and 34 (0.01%) in the control group. Adjusted effectiveness of IH Ad5-nCoV and IM Ad5-nCoV from 14 days after the vaccination were 51.6% (95% CI 9.0 to 74.3) and 38.1% (95% CI - 9.6 to 65.1), respectively.

Interpretation

Significant protection against symptomatic COVID-19 caused by the Omicron variant, during the ongoing pandemic of evolving COVID-19 variants, was found to be provided by boosting with the ancestral strain-containing vaccine IH Ad5-nCoV, but not by boosting with IM Ad5-nCoV.
easybio: an R Package for Single-Cell Annotation with CellMarker2.0
Authors: Cui Wei
Published: September 2024

Single-cell RNA sequencing (scRNA-seq) allows researchers to study biological activities at the cellular level, enabling the discovery of new cell types and the analysis of intercellular interactions. However, annotating cell types in scRNA-seq data is a crucial and time-consuming process, with its quality significantly influencing downstream analyses. Accurate identification of potential cell types provides valuable insights for discovering new cell populations or identifying novel markers for known cells, which may be utilized in future research. While various methods exist for single-cell annotation, one of the most common approaches is to use known cell markers. The CellMarker2.0 database, a human-curated repository of cell markers extracted from published articles, is widely used for this purpose. However, it currently offers only a web-based tool for usage, which can be inconvenient when integrating with workflows like Seurat. To address this limitation, we introduceeasybio, an R package designed to streamline single-cell annotation using the CellMarker2.0 database in conjunction with Seurat.easybioprovides a suite of functions for querying the CellMarker2.0 database locally, offering insights into potential cell types for each cluster. In addition to single-cell annotation, the package also supports various bioinformatics workflows, including RNA-seq analysis, making it a versatile tool for transcriptomic research.
Cell cycle-dependent S-sulfenyl proteomics uncover a redox switch in p21-CDK feedback governing the proliferation-senescence decision
Authors: Vorhauser Julia , Roumeliotis Theodoros I. , Leung Jacky K. , Coupe David , Yu Lu , Böhlig Kristin , Nadler André , Choudhary Jyoti S. , Mansfeld Jörg
Published: September 2024

Cells are constantly exposed to reactive oxygen species (ROS) from both intrinsic and extrinsic sources. ROS influence proliferation and cell fate through cysteine oxidation (S-sulfenylation), but specific targets and mechanisms remain unclear. Here, we use redox proteomics to identify cell cycle-coordinated S-sulfenylation and investigate its role in cell cycle decision-making. We find that oxidation of a single cysteine (C41) on the CDK inhibitor p21 during G2 phase determines whether cells continue to proliferate. Preventing C41 oxidation redirects p21 from CDK4-Cyclin D to CDK2-Cyclin A, affecting a negative feedback loop that regulates p21 stability. When C41 cannot be oxidized in G2, daughter cells inherit more p21 from their mother, which decreases proliferation and induces senescence upon irradiation. We therefore identify a redox switch in a core cell cycle regulator that governs the decision to proliferate or exit the cell cycle and present a cell cycle-resolved S-sulfenyl proteome as a valuable resource.
Maltodextrin Transport in the Extremely Thermophilic, Lignocellulose Degrading BacteriumAnaerocellum bescii (f. Caldicellulosiruptor bescii)
Authors: Tjo Hansen , Jiang Virginia , Joseph Jerelle A. , Conway Jonathan M.
Published: September 2024

Sugar transport into microbial cells is a critical, yet understudied step in the conversion of lignocellulosic biomass to metabolic products.Anaerocellum bescii(formerlyCaldicellulosiruptor bescii) is an extremely thermophilic, anaerobic bacterium that readily degrades the cellulose and hemicellulose components of lignocellulosic biomass into a diversity of oligosaccharide substrates. Despite significant understanding of how this microorganism degrades lignocellulose, the mechanisms underlying its highly efficient transport of the resulting oligosaccharides into the cell are comparatively underexplored. Here, we identify and characterize the ATP-Binding Cassette (ABC) transporters inA. besciigoverning maltodextrin transport. Utilizing past transcriptomic studies onAnaerocellumandCaldicellulosiruptorspecies, we identify two maltodextrin transporters inA. besciiand express and purify their substrate-binding proteins (Athe_2310 and Athe_2574) for characterization. Using differential scanning calorimetry and isothermal titration calorimetry, we show that Athe_2310 strongly interacts with shorter maltodextrins such as maltose and trehalose with dissociation constants in the micromolar range, while Athe_2574 binds longer maltodextrins, with dissociation constants in the sub-micro molar range. Using a sequence-structure-function comparison approach combined with molecular modeling we provide context for the specificity of each of these substrate-binding proteins. We propose thatA. besciiutilizes orthogonal ABC transporters to uptake malto-oligosaccharides of different lengths to maximize transport efficiency.

Importance

Here, we reveal the biophysical and structural basis for oligosaccharide transport by two maltodextrin ABC transporters inA. bescii. This is the first biophysical characterization of carbohydrate uptake in this organism and establishes a workflow for characterizing other oligosaccharide transporters inA. besciiand similar lignocellulosic thermophiles of interest for lignocellulosic bioprocessing. By deciphering the mechanisms underlying high affinity sugar uptake inA. bescii, we shed light on an underexplored step between extracellular lignocellulose degradation and intracellular conversion of sugars to metabolic products. This understanding will expand opportunities for harnessing sugar transport in thermophiles to reshape lignocellulose bioprocessing as part of a renewable bioeconomy.
NuRD chromatin remodeling is required to repair exogenous DSBs in theCaenorhabditis elegansgermline
Authors: Ananthaswamy Deepshikha , Funes Kelin , Borges Thiago , Roques Scott , Fassnacht Nina , El Jamal Sereen , Checchi Paula M. , Lee Teresa Wei-sy
Published: September 2024

Organisms rely on coordinated networks of DNA repair pathways to protect genomes against toxic double-strand breaks (DSBs), particularly in germ cells. All repair mechanisms must successfully negotiate the local chromatin environment in order to access DNA. For example, nucleosomes can be repositioned by the highly conserved Nucleosome Remodeling and Deacetylase (NuRD) complex. InCaenorhabditis elegans, NuRD functions in the germline to repair DSBs – the loss of NuRD’s ATPase subunit, LET-418/CHD4, prevents DSB resolution and therefore reduces fertility. In this study, we challenge germlines with exogenous DNA damage to better understand NuRD’s role in repairing DSBs. We find thatlet-418mutants are hypersensitive to cisplatin and hydroxyurea: exposure to either mutagen impedes DSB repair, generates aneuploid oocytes, and severely reduces fertility and embryonic survival. These defects resemble those seen when the Fanconi anemia (FA) DNA repair pathway is compromised, and we find that LET-418’s activity is epistatic to that of the FA component FCD-2/FANCD2. We propose a model in which NuRD is recruited to the site of DNA lesions to remodel chromatin and allow access for FA pathway components. Together, these results implicate NuRD in the repair of both endogenous DSBs and exogenous DNA lesions to preserve genome integrity in developing germ cells.

ARTICLE SUMMARY

Preserving genome integrity in germ cells is critical for the survival of individuals and species. Our previous work shows that nucleosome remodeling plays an important role in repairing meiotic DNA damage. Here, we further challenge genomes with toxic DNA damaging agents to test the requirement for remodeling in the germline. We find that DNA damage accumulates in the absence of remodeling, which drastically reduces oocyte quality, and also show that the requirement for remodeling is epistatic to the Fanconi anemia DNA repair pathway. These findings demonstrate that local chromatin environments must be remodeled in response to DNA damage to maintain oocyte quality.