bluuebunny/crossref_metadata_2025 huggingface dataset:
scCancer2: data-driven in-depth annotations of the tumor microenvironment at single-level resolution
Authors: Chen Zeyu , Miao Yuxin , Tan Zhiyuan , Hu Qifan , Wu Yanhong , Guo Wenbo , Gu Jin
Published: August 2023

Single-cell RNA-seq (scRNA-seq) is a powerful technique for decoding the complex cellular compositions in the tumor microenvironment (TME). As previous studies have defined many meaningful cell subtypes in several tumor types, there is a great need to computationally transfer these labels to new datasets. Also, different studies used different approaches or criteria to define the cell subtypes for the same major cell lineages. The relationships between the cell subtypes defined in different studies should be carefully evaluated. In this updated package scCancer2, designed for integrative tumor scRNA-seq data analysis, we developed a supervised machine learning framework to annotate TME cells with annotated cell subtypes from 15 scRNA datasets with 594 samples in total. Based on the trained classifiers, we quantitatively constructed the similarity maps between the cell subtypes defined in different references by testing on all the 15 datasets. Secondly, to improve the identification of malignant cells, we designed a classifier by integrating large-scale pan-cancer TCGA bulk gene expression datasets and scRNA-seq datasets (10 cancer types, 159 samples, 652,160 cells). This classifier shows robust performances when no internal confidential reference cells are available. Thirdly, this package also integrated a module to process the seq-based spatial transcriptomic data and analyze the spatial features of TME. Software availability:http://lifeome.net/software/sccancer2/.
Frontal hip exoskeleton assistance does not appear promising for reducing the metabolic cost of walking: A preliminary experimental study
Authors: Kim Jinsoo , Raitor Michael , Liu C. Karen , Collins Steven H.
Published: August 2023

Background

During walking, humans exert a substantial hip abduction moment to maintain balance and prevent pelvic drop. This significant torque requirement suggests that assisting the frontal hip muscles could be a promising strategy to reduce the energy expenditure associated with walking. A previous musculoskeletal simulation study also predicted that providing hip abduction assistance through an exoskeleton could potentially result in a large reduction in whole-body metabolic rate. However, to date, no study has experimentally assessed the metabolic cost of walking with frontal hip assistance.

Methods

In this case study involving a single subject (N = 1), a tethered hip exoskeleton emulator was used to assess the feasibility of reducing metabolic expenditure through frontal-plane hip assistance. Human-in-the-loop optimization was conducted separately under torque and position control to determine energetically optimal assistance parameters for each control scheme.

Results

The optimized profiles in both control schemes did not reduce metabolic rate compared to walking with assistance turned off. The optimal peak torque magnitude was found to be close to zero, suggesting that any hip abduction torque would increase metabolic rate. Both bio-inspired and simulation-inspired profiles substantially increased metabolic cost.

Conclusion

Frontal hip assistance does not appear to be promising in reducing the metabolic rate of walking. This could be attributed to the need for maintaining balance, as humans may refrain from relaxing certain muscles as a precaution against unexpected disturbances during walking. An investigation of different control architectures is needed to determine if frontal-plane hip assistance can yield successful results.
Promotion of tumor angiogenesis and growth induced by low-dose antineoplastic agentsviabone-marrow-derived cells
Authors: You Huining , Zhao Peipei , Zhao Xue , Cheng Kai , Li Min , Kou Jianrong , Feng Weiyi
Published: August 2023

More research is needed to solidify the basis for reasonable metronomic chemotherapy regimens due to the inconsistent clinical outcomes from studies on metronomic chemotherapy with antineoplastic agents, along with signs of a nonlinear dose–response relationship at low doses. The present study therefore explored the dose–response relationships of representative antineoplastic agents in low dose ranges and their underlying mechanisms. Cyclophosphamide (CPA) and 5-fluorouracil (5-Fu) were employed to observe the effects of the frequent administration of low-dose antineoplastic agents on tumor growth, tumor angiogenesis, and bone-marrow-derived cell (BMDC) mobilization in mouse models. The effects of antineoplastic agents on tumor and endothelial cell functions with or without BMDCs were analyzedin vitro. Tumor growth and metastasis were significantly promoted after the administration of CPA or 5-Fu at certain low dose ranges, and were accompanied by enhanced tumor angiogenesis and proangiogenic factor expression in tumor tissues, increased proangiogenic BMDC release in the circulating blood, and augmented proangiogenic BMDC retention in tumor tissues. Low concentrations of CPA or 5-Fu were found to significantly promote tumor cell migration and invasion, and enhance BMDC adhesion to endothelial cellsin vitro. These results suggest that there are risks in empirical metronomic chemotherapy using low-dose antineoplastic agents.
Cholinergic control of GnRH neuron physiology and luteinizing hormone secretion: involvement of ACh/GABA co-transmission
Authors: Vastagh Csaba , Farkas Imre , Csillag Veronika , Watanabe Masahiko , Kalló Imre , Liposits Zsolt
Published: August 2023

Gonadotropin-releasing hormone (GnRH)-synthesizing neurons orchestrate reproduction centrally. Early studies have proposed the contribution of acetylcholine (ACh) to hypothalamic control of reproduction, although the causal mechanisms have not been clarified. Here, we report thatin vivopharmacogenetic activation of the cholinergic system increased the secretion of luteinizing hormone (LH) in orchidectomized mice. 3DISCO immunocytochemistry and electron microscopy revealed the innervation of GnRH neurons by cholinergic axons. Retrograde viral labeling initiated from GnRH-Cre neurons identified the medial septum and the diagonal band of Broca as exclusive sites of origin for cholinergic afferents of GnRH neurons. In acute brain slices, ACh and the ACh receptor (AChR) agonist carbachol evoked a biphasic effect on the firing rate in GnRH neurons, first increasing and then diminishing it. In the presence of tetrodotoxin, carbachol induced an inward current, followed by a decline in the frequency of mPSCs, indicating a direct influence on GnRH cells. RT-PCR and whole-cell patch-clamp studies revealed that GnRH neurons expressed both nicotinic (α4β2, α3β4, and α7) and muscarinic (M1-M5) ACh receptors. The nicotinic AChRs contributed to the nicotine-elicited inward current and the rise in firing rate. Muscarine via M1 and M3 receptors increased, while via M2 and M4 reduced the frequency of both miniature postsynaptic currents (mPSCs) and firing. Optogenetic activation of channelrhodopsin-2-tagged cholinergic axons modified GnRH neuronal activity and evoked co-transmission of ACh and GABA from a subpopulation of boutons. These findings confirm that the central cholinergic system immensely regulates GnRH neurons and activates the HPG-axis via ACh and ACh/GABA neurotransmissions.

Significance statement

Cholinergic drugs influence reproduction centrally, although the exact neuronal targets and regulatory mechanisms remain unsettled. We found that pharmacogenetic activation of the cholinergic system in vivo evoked an augmented LH release. The study also identified cholinergic cell groups in the mouse forebrain that innervate gonadotropin-releasing hormone (GnRH) neurons, the main hypothalamic regulators of reproduction. We also determined the subtypes of nicotinic and muscarinic receptors involved in neuronal information transmission and explored how their ligands affect the electrophysiological activity of GnRH neurons. A subset of cholinergic neurons was found to co-transmit GABA, which excites GnRH cells via GABA-A receptors. The findings suggest a novel, cholinergic regulation of the adult GnRH system in male mice that activates the pituitary-gonadal axis.
Visual routines for detecting causal interactions are tuned to motion direction
Authors: Ohl Sven , Rolfs Martin
Published: August 2023

Detecting causal relations structures our perception of events in the world. Here, we determined for visual interactions whether generalized (i.e., feature-invariant) or specialized (i.e., feature-selective) visual routines underlie the perception of causality. To this end, we applied a visual adaptation protocol to assess the adaptability of specific features in classical launching events of simple geometric shapes. We asked observers to report whether they observed a launch or a pass in ambiguous test events (i.e., the overlap between two discs varied from trial to trial). After prolonged exposure to causal launch events (the adaptor) defined by a particular set of features (i.e., a particular motion direction, motion speed, or feature conjunction), observers were less likely to see causal launches in subsequent ambiguous test events than before adaptation. Crucially, adaptation was contingent on the causal impression in launches as demonstrated by a lack of adaptation in non-causal control events. We assessed whether this negative aftereffect transfers to test events with a new set of feature values that were not presented during adaptation. Processing in specialized (as opposed to generalized) visual routines predicts that the transfer of visual adaptation depends on the feature-similarity of the adaptor and the test event. We show that the negative aftereffects do not transfer to unadapted launch directions but do transfer to launch events of different speed. Finally, we used colored discs to assign distinct feature-based identities to the launching and the launched stimulus. We found that the adaptation transferred across colors if the test event had the same motion direction as the adaptor. In summary, visual adaptation allowed us to carve out a visual feature space underlying the perception of causality and revealed specialized visual routines that are tuned to a launch’s motion direction.

Significance statement

We used visual adaptation to carve out the visual feature space critical for detecting collisions in visual launching events. Observers were less likely to report perceiving a collision after the repeated viewing of one disc colliding with and launching the movement of another disc. Importantly, observers’ perception of collisions in the direction opposite to the adaptor remained unaffected. However, provided the test stimulus had the adapted direction of motion, the speed or the color of the objects involved in the launching event did not need to be the same as during adaptation for a negative aftereffect to occur. Thus, visual routines that detect causal interactions are selective for motion direction, providing evidence that the perception of causality in a visual interaction relies on low-level perceptual processes.
Inducible genetic ablation ofImmtinduces a lethal disruption of the MICOS complex
Authors: Rockfield Stephanie M. , Turnis Meghan E. , Rodriguez-Enriquez Ricardo , Bathina Madhavi , Ng Seng Kah , Pelletier Stephane , Vogel Peter , Opferman Joseph T.
Published: August 2023

The mitochondrial contact site and cristae organizing system (MICOS) is important for cristae junctions (CJ) formation and for maintaining inner mitochondrial membrane (IMM) architecture. As the largest member, MIC60 is the primary scaffold protein for this complex. While MIC60 has been well studied in yeast and cell culture models, its function in mammals is poorly understood. To address this, we developed a mouse model conditionally deletingImmt(which encodes MIC60) and found that globalImmtdeletion disrupted the MICOS complex and resulted in lethality within 9 days of tamoxifen treatment. Pathologically, these mice display intestinal defects consistent with paralytic ileus, resulting in dehydration. We also identified bone marrow hypocellularity in tamoxifen-treated mice. However, bone marrow transplants fromImmtWTmice failed to rescue survival. Altogether, this novel mouse model demonstrates the importance of MIC60in vivo, in both hematopoietic and non-hematopoietic tissues, and provides a valuable resource for future mechanistic investigations into the MICOS complex. Such investigations could include anin vivostructure-function analysis of MIC60 functional domains, with characterizations that are relevant to human diseases.
Intersectin and Endophilin condensates prime synaptic vesicles for release site replenishment
Authors: Ogunmowo Tyler , Hoffmann Christian , Pepper Renee , Wang Han , Gowrisankaran Sindhuja , Ho Annie , Raychaudhuri Sumana , Cooper Benjamin H. , Milosevic Ira , Milovanovic Dragomir , Watanabe Shigeki
Published: August 2023

Neurotransmitter is released from dedicated sites of synaptic vesicle fusion within a synapse. Following fusion, the vacated sites are replenished immediately by new vesicles for subsequent neurotransmission. These replacement vesicles are assumed to be located near release sites and used by chance. Here, we find that replacement vesicles are clustered around this region by Intersectin-1. Specifically, Intersectin-1 forms dynamic molecular condensates with Endophilin A1 near release sites and sequesters vesicles around this region. In the absence of Intersectin-1, vesicles within 20 nm of the plasma membrane are reduced, and consequently, vacated sites cannot be replenished rapidly, leading to depression of synaptic transmission. Similarly, mutations in Intersectin-1 that disrupt Endophilin A1 binding result in similar phenotypes. However, in the absence of Endophilin, this replacement pool of vesicles is available but cannot be accessed, suggesting that Endophilin A1 is needed to mobilize these vesicles. Thus, our work describes a distinct physical region within a synapse where replacement vesicles are harbored for release site replenishment.
Distinct cortical correlates of perception and motor function in balance control
Authors: Mirdamadi Jasmine L. , Ting Lena H. , Borich Michael R.
Published: August 2023

Fluctuations in brain state alter how we perceive our body and generate movements but have not been investigated in functional whole-body behaviors. During reactive balance control, we recently showed that evoked brain activity is associated with balance ability in healthy young individuals. Further, in individuals with Parkinson’s disease, impairments in whole-body motion perception in reactive balance are associated with clinical balance impairment. Here we investigated brain activity during whole-body motion perception in reactive balance in healthy young adults. We hypothesized that flexibility in brain states underlies successful perception and movement during whole-body movement. We characterized two cortical sensorimotor signals using electroencephalography localized to the supplementary motor area: 1) the “N1 response”, a perturbation-evoked potential that decreases in amplitude with expectancy and is larger in individuals with lower balance function; and 2) pre-perturbation beta oscillatory activity, a rhythm that favors maintenance of the current sensorimotor state and is inversely associated with perception in seated somatosensory perceptual tasks. In a two-alternative forced choice task, participants judged whether pairs of backward support-surface perturbations during standing were in the “same” or “different” direction. As expected, lower whole-body perception was associated with lower balance ability. Within a perturbation pair, N1 attenuation was larger on correctly perceived trials and associated with better balance, but not perception. In contrast, pre-perturbation beta power was higher on incorrectly perceived trials and associated with poorer perception, but not balance. Taken together, flexibility in different cortical processes influences perceptual accuracy but have distinct associations with balance and perceptual ability.
Movies reveal the fine-grained organization of infant visual cortex
Authors: Ellis C. T. , Yates T. S. , Arcaro M. J. , Turk-Browne N. B.
Published: August 2023

Studying infant minds with movies is a promising way to increase engagement relative to traditional tasks. However, the spatial specificity and functional significance of movie-evoked activity in infants remains unclear. Here we investigated what movies can reveal about the organization of the infant visual system. We collected fMRI data from 15 awake infants and toddlers aged 5–23 months who attentively watched a movie. The activity evoked by the movie reflected the functional profile of visual areas. Namely, homotopic areas from the two hemispheres responded similarly to the movie, whereas distinct areas responded dissim-ilarly, especially across dorsal and ventral visual cortex. Moreover, visual maps that typi-cally require time-intensive and complicated retinotopic mapping could be predicted, albeit imprecisely, from movie-evoked activity in both data-driven analyses (i.e., independent com-ponent analysis) at the individual level and by using functional alignment into a common low-dimensional embedding to generalize across participants. These results suggest that the infant visual system is already structured to process dynamic, naturalistic information and that fine-grained cortical organization can be discovered from movie data.
Social network dynamics and gut microbiota composition during alpha male challenges inColobus vellerosus
Authors: Samartino Shelby , Christie Diana , Penna Anna , Sicotte Pascale , Ting Nelson , Wikberg Eva
Published: August 2023

The gut microbiota of group-living animals is strongly influenced by their social interactions, but it is unclear how it responds to social instability. We investigated whether social instability associated with the immigration of new males and challenges to the alpha male position could explain differences in the gut microbiota in adult femaleColobus vellerosusat Boabeng-Fiema, Ghana. During May-August 2007 and May 2008-May 2009, we collected: 1) 53 fecal samples from adult females in 8 social groups for v4 16S rRNA sequencing to determine gut microbiota composition; and 2) demographic and behavioral dataad libitumto determine male immigration, challenges to the alpha male position, and infant births and deaths. We estimated Sørensen and Bray-Curtis beta diversity indices (i.e., between-sample microbiome variation), and they were predicted by year, alpha male stability, group identity, age, and individual identity. We then created 1-m proximity networks using detailed behavioral data via focal follows of 19 adult females in 3 of these groups. Yearly 1-m proximity ties predicted adult female beta-diversity in the two socially stable groups. An alpha male takeover in the third group was associated with infant mortality and temporal variation in proximity networks. Beta-diversity among adult females was predicted by similarity in infant loss status and short-term (rather than yearly) 1-m proximity ties. Although the mechanism driving this association needs to be further investigated in future studies, our findings indicate that alpha male takeovers and social stability are associated with gut microbiota variation and highlight the importance of taking demographic and social network dynamics into account.
Linear Interaction Between Replication and Transcription Shapes DNA Break Dynamics at Recurrent DNA Break Clusters
Authors: Corazzi Lorenzo , Ionasz Vivien , Andrejev Sergej , Wang Li-Chin , Vouzas Athanasios , Giaisi Marco , Di Muzio Giulia , Ding Boyu , Marx Anna J.M. , Henkenjohann Jonas , Allers Michael M. , Gilbert David M. , Wei Pei-Chi
Published: August 2023

Recurrent DNA break clusters (RDCs) are replication-transcription collision hotspots; many are unique to neural progenitor cells. Through high-resolution replication sequencing and a capture-ligation assay in mouse neural progenitor cells experiencing replication stress, we unraveled the replication features dictating RDC location and orientation. Most RDCs occur at the replication forks traversing timing transition regions (TTRs), where sparse replication origins connect unidirectional forks. Leftward-moving forks generate telomere-connected DNA double-strand breaks (DSBs), while rightward-moving forks lead to centromere-connected DSBs. Strand-specific mapping for DNA-bound RNA revealed co-transcriptional dual-strand DNA:RNA hybrids present at a higher density in RDC than in other actively transcribed long genes. In addition, mapping RNA polymerase activity revealed that head-to-head interactions between replication and transcription machinery resulted in 60% DSB contribution to the head-on compared to 40% for co-directional. Our findings revealed TTR as a novel fragile class and highlighted how the linear interaction between transcription and replication impacts genome stability.
Exploiting the Affimer platform against influenza A virus
Authors: Debski-Antoniak Oliver , Flynn Alex , Klebl David P. , Tiede Christian , Wilson Ian A. , Muench Stephen P. , Tomlinson Darren , Fontana Juan
Published: August 2023

Influenza A virus (IAV) is well known for its pandemic potential. While current surveillance and vaccination strategies are highly effective, therapeutic approaches are short-lived due to the high mutation rates of IAV. Currently, monoclonal antibodies (mAbs) have emerged as a promising approach to tackle future IAV pandemics. Additionally, several antibody-like alternatives exist that aim to improve upon mAbs. Affimers, one such alternative, benefit from a short development time, high expression levels inE. coli, and complete animal-free production. Here we exploited the Affimer platform to isolate and produce specific and potent inhibitors of IAV. Starting from a monomeric version of the IAV trimeric hemagglutinin (HA) fusion protein, we isolated 12 Affimers that inhibit IAV H3 subtype infectionin vitro. Two of these Affimers were characterised in detail: they exhibited binding affinities to the target H3 HA protein in the nM range and bound specifically to the HA1 head domain. Cryo-EM employing a novel spray approach to prepare cryo-grids allowed us to image HA-Affimer complexes. Combined with functional assays, we determined that the mode of inhibition of these Affimers is based on blocking the interaction of HA to the host-cell receptor - sialic acid. Additionally, these Affimers inhibited IAV strains closely related to the one employed for Affimer isolation. Overall, these results support the use of Affimers as an alternative to existing targeted therapies for IAV and pave the way for their use as diagnostic reagents.

Importance

Influenza A virus is one of the few viruses that can cause devastating pandemics. Due to the high mutation rates of this virus, annual vaccination is required and antivirals are short-lived. Monoclonal antibodies present a promising approach to tackle influenza virus infections, but are associated with some limitations. To improve on this strategy, we explored the Affimer platform, which are antibody-like, bacterially made proteins. By performing phage-display against a monomeric version of influenza virus fusion protein, an established viral target, we were able to isolate Affimers that inhibit influenza virus infectionin vitro. We characterised the mechanism of inhibition of the Affimers by challenging with related influenza virus strains. We additionally characterised an HA-Affimer complex structure, using a novel approach to prepare samples for cryo-electron microscopy. Overall, these results show that Affimers are a promising tool against influenza virus infection.
Dominant nitrogen metabolisms of a warm, seasonally anoxic freshwater ecosystem revealed using genome resolved metatranscriptomics
Authors: Fadum J. M. , Borton M. A. , Daly R. A. , Wrighton K. C. , Hall E. K.
Published: August 2023

Reactive nitrogen (N) is one of the principal drivers of primary productivity across aquatic ecosystems. However, the microbial communities and emergent metabolisms which govern N cycling in tropical lakes are both distinct from and poorly understood relative to those found in temperate lakes. This latitudinal difference is largely due to the warm (>20 °C) temperatures of tropical lake anoxic hypolimnions (deepest portion of a stratified water column) which result in unique anaerobic metabolisms operating without the temperature constraints found in lakes at temperate latitudes. As such, tropical hypolimnions provide a platform for exploring microbial membership and functional diversity. To better understand N metabolism in warm anoxic waters, we combined measurements of geochemistry and water column thermophysical structure with genome resolved metatranscriptomic analyses of the water column microbiome in Lake Yojoa, Honduras. We sampled above and below the oxycline in June 2021, when the water column was stratified, and again at the same depths and locations in January 2022, when the water column was mixed. We identified 335 different lineages and significantly different microbiome membership between seasons and, when stratified, between depths. Notably,nrfA(indicative of dissimilatory nitrate reduction to ammonium) was upregulated relative to other N metabolism genes in the June hypolimnion. This work highlights the taxonomic and functional diversity of microbial communities in warm and anoxic inland waters, providing insight into the contemporary microbial ecology of tropical ecosystems as well as inland waters at higher latitudes as water columns continue to warm in the face of global change.

Importance

In aquatic ecosystems where primary productivity is limited by nitrogen (N), whether continuously, seasonally, or in concert with additional nutrient limitations, increased inorganic N availability can reshape ecosystem structure and function, potentially resulting in eutrophication and even harmful algal blooms (HABs). Whereas microbial metabolic processes such as mineralization and dissimilatory nitrate reduction to ammonium (DNRA) increase inorganic N availability, denitrification removes bioavailable N from the ecosystem. Therefore, understanding these key microbial mechanisms is critical to the sustainable management and environmental stewardship of inland freshwater resources. This study identifies and characterizes these crucial metabolisms in a warm, seasonally anoxic ecosystem. Results are contextualized by an ecological understanding of the study system derived from a multi-year continuous monitoring effort. This unique dataset is the first of its kind in this largely understudied ecosystem (tropical lakes) and also provides insight into microbiome function, and associated taxa, in warm anoxic freshwaters.
Crystallographic and thermodynamic evidence of negative cooperativity of flavin and tryptophan binding in the flavin-dependent halogenases AbeH and BorH
Authors: Ashaduzzaman Md , Lingkon Kazi , De Silva Aravinda J. , Bellizzi John J.
Published: August 2023

The flavin-dependent halogenase AbeH produces 5-chlorotryptophan in the biosynthetic pathway of the chlorinated bisindole alkaloid BE-54017. We report thatin vitro, AbeH (assisted by the flavin reductase AbeF) can chlorinate and brominate tryptophan as well as other indole derivatives and substrates with phenyl and quinoline groups. We solved the X-ray crystal structures of AbeH alone and complexed with FAD, as well as crystal structures of the tryptophan-6-halogenase BorH alone, in complex with 6-chlorotryptophan, and in complex with FAD and tryptophan. Partitioning of FAD and tryptophan into different chains of BorH and failure to incorporate tryptophan into AbeH/FAD crystals suggested that flavin and tryptophan binding are negatively coupled in both proteins. ITC and fluorescence quenching experiments confirmed the ability of both AbeH and BorH to form binary complexes with FAD or tryptophan and the inability of tryptophan to bind to AbeH/FAD or BorH/FAD complexes. FAD could not bind to BorH/tryptophan complexes, but FAD appears to displace tryptophan from AbeH/tryptophan complexes in an endothermic entropically-driven process.
IC3 Protocol – A novel digital health method for monitoring cognition after stroke
Authors: Gruia Dragos C. , Trender William , Hellyer Peter , Banerjee Soma , Kwan Joseph , Zetterberg Henrik , Hampshire Adam , Geranmayeh Fatemeh
Published: August 2023

Introduction

Stroke is a major cause of death and disability worldwide, frequently resulting in persistent cognitive deficits among survivors. These deficits negatively impact recovery and therapy engagement, and their treatment is consistently rated as high priority by stakeholders and clinicians. Although clinical guidelines endorse cognitive screening for post-stroke management, there is currently no gold standard approach for identifying cognitive deficits after stroke, and clinical stroke services lack the capacity for long-term cognitive monitoring and care. Currently available assessment tools are either not stroke-specific, not in-depth or lack scalability, leading to heterogeneity in patient assessments.

Methods and Analysis

To address these challenges, a cost-effective, scalable, and comprehensive screening tool is needed to provide a stroke-specific assessment of cognition. The current study presents such a novel digital tool, the Imperial Comprehensive Cognitive Assessment in Cerebrovascular Disease (IC3), designed to detect both domain-general and domain-specific cognitive deficits in patients after stroke with minimal input from a health professional. To ensure its reliability, we will utilise multiple validation approaches, and aim to recruit a large normative sample of age-, gender-, and education-matched UK-based controls. Moreover, the IC3 assessment will be integrated within a larger prospective observational longitudinal clinical trial, where post-stroke cognition will be examined in tandem with brain imaging and blood biomarkers to identify novel multimodal biomarkers of recovery after stroke. This study will enable deeper cognitive phenotyping of patients at a large scale, whilst identifying those with highest risk of progressive cognitive decline, as well as those with greatest potential for recovery.

Ethics and dissemination

This study has been approval by South West - Frenchay Research Ethics Committee (IRAS 299333), and authorized by the UK’s Health Research Authority. Study registration. The study is registered as an observational trial underNCT05885295.
Exploration of Modern Contraceptive Methods Using Patterns among Late Reproductive Aged Women in Bangladesh
Authors: Rana Md Shohel , Alam Md Badsha , Hassen Md Tahir , Kabir Md Iqbal , Khanam Shimlin Jahan , Khan Md Nuruzzaman
Published: August 2023

Background

In light of the increasing population of late reproductive-aged women (aged 35 and above) within the broader demographic of reproductive-aged females, the concern surrounding their contraceptive considerations has escalated to a point of critical importance. This study aims to examine the trends and determinants of modern contraceptive practices among late reproductive-aged women in Bangladesh.

Methods

A total of 17,736 women aged 35 and more were included in the analysis, utilizing data from three consecutives Bangladesh Demographic and Health Surveys conducted in 2011, 2014, and 2017-18. The outcome variable was the use of modern contraceptive methods (yes or no). The explanatory variables encompassed survey years, individual characteristics of the women, as well as characteristics of their partners and the community. To examine the association of the outcome variable with the explanatory variables, a multilevel logistic regression model was used.

Results

Approximately 54% of women aged 35 and older do not utilize modern contraceptive methods, and there have been no significant shifts in their usage observed over the survey years. The probability of using modern contraceptive methods exhibited a notable decline in relation to increasing age, the educational level of women’s partners, and their categorization within the richer or richest wealth quintile. Conversely, women with higher education, increased exposure to mass media, and residing in the Dhaka or Rajshahi division displayed an elevated likelihood of embracing modern contraceptive methods.

Conclusion

The study highlights the relatively stable adoption of modern contraceptive methods among women aged 35 or older in Bangladesh, despite their increasing representation within the population. This raises concerns about the elevated risk of unintended pregnancies and shorter birth intervals, emphasizing the need for targeted interventions to address the specific needs and preferences of this demographic.
A unifying model to explain high nirmatrelvir therapeutic efficacy against SARS-CoV-2, despite low post-exposure prophylaxis efficacy and frequent viral rebound
Authors: Esmaeili Shadisadat , Owens Katherine , Wagoner Jessica , Polyak Stephen J. , White Judith M. , Schiffer Joshua T.
Published: August 2023

In a pivotal trial (EPIC-HR), a 5-day course of oral ritonavir-boosted nirmatrelvir, given early during symptomatic SARS-CoV-2 infection (within three days of symptoms onset), decreased hospitalization and death by 89.1% and nasal viral load by 0.87 log relative to placebo in high-risk individuals. Yet, nirmatrelvir/ritonavir failed as post-exposure prophylaxis in a trial, and frequent viral rebound has been observed in subsequent cohorts. We developed a mathematical model capturing viral-immune dynamics and nirmatrelvir pharmacokinetics that recapitulated viral loads from this and another clinical trial (PLATCOV). Our results suggest that nirmatrelvir’sin vivopotency is significantly lower thanin vitroassays predict. According to our model, a maximally potent agent would reduce the viral load by approximately 3.5 logs relative to placebo at 5 days. The model identifies that earlier initiation and shorter treatment duration are key predictors of post-treatment rebound. Extension of treatment to 10 days for Omicron variant infection in vaccinated individuals, rather than increasing dose or dosing frequency, is predicted to lower the incidence of viral rebound significantly.
Genetically Guided Precision Medicine Clinical Decision Support Tools: A Systematic Review
Authors: Johnson Darren , Del Fiol Guilherme , Kawamoto Kensaku , Romagnoli Katrina , Sanders Nathan , Isaacson Grace , Jenkins Elden , Williams Marc
Published: August 2023

Objective

Patient care using genetics presents complex challenges. Clinical decision support (CDS) tools are a potential solution because they provide patient-specific risk assessments and/or recommendations at the point of care. This systematic review evaluated literature on CDS systems which have been implemented to support genetically guided precision medicine (GPM).

Materials and Methods

A comprehensive search was conducted in MEDLINE and Embase, encompassing Jan 1st, 2011 to March 14th, 2023. The review included primary English peer-reviewed research articles studying humans, focused on use of computers to guide clinical decision making and delivering genetically guided, patient-specific assessments and/or recommendations to healthcare providers and/or patients.

Results

The search yielded 3,832 unique articles. After screening, 41 articles were identified that met the inclusion criteria. Alerts and reminders were the most common form of CDS used. 27 systems were integrated with the electronic health record; 2 of those used standards-based approaches for genomic data transfer. Three studies used a framework to analyze the implementation strategy.

Discussion

Findings include limited use of standards-based approaches for genomic data transfer, system evaluations that do not employ formal frameworks, and inconsistencies in the methodologies used to assess genetic CDS systems and their impact on patient outcomes.

Conclusion

We recommend that future research on CDS system implementation for genetically guided precision medicine should focus on implementing more CDS systems, utilization of standards-based approaches, user-centered design, exploration of alternative forms of CDS interventions, and use of formal frameworks to systematically evaluate genetic CDS systems and their effects on patient care.
COVID-19 Testing and Vaccination among US Older Adults with Vision Impairment: The National Health and Aging Trends Study 2021
Authors: Almidani Louay , Swenor Bonnielin K. , Ehrlich Joshua R. , Varadaraj Varshini
Published: August 2023

Purpose

To examine the associations between vision impairment (VI) and COVID-19 testing and vaccination services in older US adults.

Methods

This cross-sectional study assessed data from adults ≥65 years who participated in the National Health and Aging Trends Study (year 2021), a nationally representative sample of Medicare beneficiaries. Exposure: Distance VI (<20/40), near VI (<20/40), contrast sensitivity impairment (CSI) (<1.55 logCS), and any VI (distance, near, or CSI). Outcomes: Self-reported COVID-19 testing and vaccination.

Results

Of 2,822 older adults, the majority were female (weighted; 55%) and White (82%), and 32% had any VI. In fully-adjusted regression analyses, older adults with any VI had similar COVID-19 vaccination rates to adults without any VI (OR:0.77, 95% CI:0.54–1.09), but had lower odds of COVID-19 testing (OR:0.82, 95% CI:0.68–0.97). Older adults with distance (OR:0.47, 95% CI:0.22–0.99) and near (OR:0.68, 95% CI:0.47–0.99) VI were less likely to be vaccinated for COVID-19, while those with CSI were less likely to test for COVID-19 (OR:0.76, 95% CI:0.61– 0.95), as compared to peers without respective impairments. The remaining associations were not significant (p>.05).

Conclusions and Relevance

These findings highlight inequities in the COVID-19 pandemic response for people with vision disability and emphasize the need for equitable prioritization of accessibility of healthcare services for all Americans.
Loci associated with maturation, migration and appetite control are linked with signals of fine-scale local selection in a large Atlantic salmon population
Authors: Miettinen Antti , Dannewitz Johan , Palm Stefan , Ahi Ehsan Pashay , Romakkaniemi Atso , Vähä Ville , Östergren Johan , Primmer Craig R. , Pritchard Victoria L.
Published: August 2023

Insights into the genetic basis of local adaptation and drivers of population differentiation improve our understanding of evolution and the maintenance of biological diversity. Characterising adaptively important genetic variation also allows more efficient planning of conservation and management actions. We used a genome-wide SNP array to analyse the genetic population structure of a large Atlantic salmon (Salmo salar) population in the interconnected Tornio/Torne and Kalix River system of the Baltic Sea basin, and to identify genomic signatures of fine-scale selection within it. We identified signals of selection and genotype-environment associations (GEA) especially on chromosome (Chr) 9, including on a haploblock containing thesix6gene and other loci that have been earlier suggested to be adaptively important in salmonids. We also detected signals of selection in genome regions including other genes of ecological relevance, such as two known appetite-controlling genes in the melanocortin system (pomcaon Chr 9 andmc4ron Chr 14), and the maturation-associated genetaar13c-like(on Chr 21). Variation in these and other identified candidate genes may potentially reflect differential selective pressures experienced by salmon from different parts of the large river system, regarding traits related to e.g. vision, feeding and growth, age at maturity and/or migratory timing. This indicates a need for management strategies to consider ecologically important genomic regions such as these, in order to protect adaptive genetic diversity in wild salmon populations.
Admixture as a source for HLA variation in Neolithic European farming communities
Authors: da Silva Nicolas Antonio , Özer Onur , Haller Magdalena , Chen Yan-Rong , Kolbe Daniel , Schade-Lindig Sabine , Wahl Joachim , Berszin Carola , Francken Michael , Görner Irina , Schierhold Kerstin , Pechtl Joachim , Grupe Gisela , Rinne Christoph , Müller Johannes , Lenz Tobias L. , Nebel Almut , Krause-Kyora Ben
Published: August 2023

The northern European Neolithic is characterized by two major demographic events: immigration of early farmers (EF) from Anatolia (5500 BCE) and their admixture (from ∼4200 BCE) with western hunter-gatherers (WHG) forming late farmers (LF). The influence of this admixture event on variation in the immune-relevant human leukocyte antigen (HLA) region is understudied. Here, we conducted population and immunogenetic analyses on 83 individuals from six EF and LF sites located in present-day Germany. We observed significant shifts in HLA allele frequencies from EF to LF. The HLA diversity increased from EF to LF, likely due to admixture with WHG. However, it was considerably lower than in modern populations. Both EF and LF exhibited a relatively narrow HLA allele spectrum compared to today. This coincides with sparse traces of pathogen DNA, potentially indicating a lower pathogen pressure at the time. We additionally noted that LF resulted from sex-biased admixture from male WHG.

TEASER

More restricted HLA allele spectrum and lower diversity in Neolithic farmers than in modern populations
The bacterial microbiome of symbiotic and menthol-bleached polyps of long-term aquarium-rearedGalaxea fascicularis
Authors: Puntin Giulia , Wong Jane C. Y. , Röthig Till , Baker David M. , Sweet Michael , Ziegler Maren
Published: August 2023

Abstract

Coral reefs support the livelihood of half a billion people but are at high risk of collapse due to the vulnerability of corals to climate change and local anthropogenic stressors. While understanding coral functioning is essential to guide conservation efforts, research is challenged by the complex nature of corals. They exist as metaorganisms (holobionts), constituted by the association between the (coral) animal host, its obligate endosymbiotic algae (Symbiodiniaceae), and other microorganisms comprising bacteria, viruses, archaea, fungi and other protists. Researchers therefore increasingly turn to model organisms to unravel holobiont complexity, dynamics, and how these determine the health and fitness of corals. The coral Galaxea fascicularis is an emerging model organism for coral symbiosis research with demonstrated suitability to aquarium rearing and reproduction, and to manipulation of the host-Symbiodiniaceae symbiosis. However, little is known about the response of theG. fascicularismicrobiome to menthol bleaching—the experimental removal of the Symbiodiniaceae which represents the first step in coral-algal symbiosis manipulation. For this, we characterized the bacterial microbiome of symbiotic and menthol-bleachedG. fascicularisoriginating from the Red Sea and South China Sea (Hong Kong) that were long-term aquarium-reared in separate facilities. We found that the coral-associated microbiomes were composed of relatively few bacterial taxa (10-78 ASVs). Symbiotic polyps (clonal replicates) from the same colony had similar microbiomes, which were distinct from those of other colonies despite co-culturing in shared aquaria. A pattern of seemingly differential response of the bacterial microbiome to menthol bleaching between the two facilities emerged, warranting further investigation into the role of rearing conditions. Nevertheless, the changes in community composition overall appeared to be stochastic suggesting a dysbiotic state. Considering the importance of bleaching treatment of captive corals for symbiosis research, our results—although preliminary—contribute fundamental knowledge for the development of the Galaxea model for coral symbiosis research.
Evolution of resistance and disease tolerance mechanisms to oral bacterial infection inD. melanogaster
Authors: Paulo Tânia F. , Akyaw Priscilla A. , Paixão Tiago , Sucena Élio
Published: August 2023

Pathogens exert strong selection on hosts, that evolve and deploy different defensive strategies, namely minimizing pathogen exposure (avoidance), directly promoting pathogen elimination (resistance), and/or managing the deleterious effects of illness (disease tolerance). However, how the response to pathogens partitions across these processes has never been directly assessed in a single system, let alone in the context of known adaptive trajectories under controlled selection regimes. Here, an experimental evolution system composed ofD. melanogasterand its natural pathogenP. entomophilais used to independently assess the role of behavioural traits, and of resistance and disease tolerance mechanisms on host evolution. We compare one replicate of a population adapted to oral infection withP. entomophila(BactOral) to a replicate of its control population to find no evidence for behavioural change but measurable differences in both resistance and disease tolerance. In BactOral, we identify a relative decrease in bacterial loads correlated with an increase in gut production of specific AMPs, but no differences in bacterial intake, in gut cell renewal rate, or in the rate of bacterial defecation, pointing to a strengthening in resistance. Additionally, we posit that disease tolerance also contributes to the adaptive response of the BactOral population through a tighter control of its immune response and of the deleterious effects of exposure. This study reveals a genetically complex and mechanistically multi-layered response, possibly reflecting the structure of adaptation to infection in natural populations.
A New Feature of the Laboratory Model PlantNicotiana benthamiana: Dead-End Trap for Sustainable Field Pest Control
Authors: Han Wen-Hao , Wang Jun-Xia , Zhang Feng-Bin , Ji Shun-Xia , Zhong Yu-Wei , Liu Yin-Quan , Liu Shu-Sheng , Wang Xiao-Wei
Published: August 2023

Hemiptera and Thysanoptera insects pose persistent threats to agricultural production. Conventional management strategies involve the release of chemical or plastic agents, causing adverse environmental and global health issues. Notably,Nicotiana benthamiana,a globally utilized model plant, exhibits remarkable lethal effects and attraction towards these pests.

In this study, we explored the potential of usingN. benthamianafor Hemiptera and Thysanoptera pest control in the laboratory and field. Through net cover and three field assays over two years, we demonstrated the efficacy and benefits of usingN. benthamianaas a field-deployed pest control dead-end trap.

N. benthamianademonstrated nearly 100% lethality to whiteflies, aphids, and thrips, with emitted volatiles attracting these insects. Field trials showed that potted and plantedN. benthamianablocks and traps whiteflies and thrips from several Solanaceae and Cucurbitaceae crops effectively, comparable to common commercial yellow and blue sticky boards. Moreover,N. benthamianain the field exhibits robust growth in commercial greenhouses without negatively impacting crop growth, natural enemies, and pollinators.

Our study introduces an innovative, easily implementable, and sustainable approach for controlling Hemiptera and Thysanoptera pests. Moreover, it unveils the novel utility ofN. benthamianain field-based pest management.