bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of cardiopulmonary resuscitation on perfusion in a porcine model of severe hemorrhagic shock
Authors: Greiffenstein Patrick , Cavalea Alexander , Smith Alison , Sharp Thomas , Warren Olivia , Dennis Jenna , Gatterer Mary C. , Danos Denise , Byrne Terrence C. , Scarborough Amy , Deville Paige , VanMeter Keith
Published: October 2024

BACKGROUND

Pulseless electrical activity from hemorrhagic shock has not been shown to benefit from cardiopulmonary resuscitation (CPR). Using a porcine model, our objective was to determine the effects of CPR on brain and skin oxygenation as a measure of perfusion in the setting of severe hemorrhagic shock.

METHODS

Adult swine randomized to non-CPR and CPR were anesthetized. Tissue oxygen sensors were inserted into the parietal cerebral parenchyma and skin. Controlled hemorrhagic shock with mean arterial pressure (MAP) <30 mm Hg was achieved and allowed to persist for 10 minutes. Animals were randomized to either receive automated CPR or no treatment. They were then autotransfused with sufficient blood to achieve MAP >60 mm Hg. Measurements were obtained before, during, and after shock state. Outcomes were modeled using mixed-effects lognormal models.

RESULTS

A total of 12 swine were used, and the results were analyzed (non-CPR, n = 5; CPR, n = 7). One animal in the CPR group died during shock. One cerebral probe sensor malfunctioned, and these data were excluded. Baseline characteristics were similar between groups. MAP during shock was similar between groups; however, the CPR group had significantly higher systolic blood pressure (62.8 vs. 48.8 mm Hg, p = 0.010) and lower diastolic blood pressure (12.8 vs. 27.8 mm Hg, p < 0.001). Both cerebral (pBO2) and skin oxygenation (TcO2) dropped significantly as a result of shock. The CPR group had lower overall measures of tissue perfusion during shock, but only TcO2 at the shoulder was significantly lower during shock (11.5 vs. 21.1 mm Hg, p = 0.027) and recovery (33.3 vs. 62 mm Hg, p = 0.033).

CONCLUSION

Our model showed that adding CPR during hemorrhagic shock did not improve end-organ oxygenation/perfusion, but did significantly diminish skin perfusion. This experiment corroborates existing literature on the potential detrimental effects of CPR during hemorrhagic pulseless electrical activity, but further work is needed to confirm this observation.
Association of NTRK2 gene with suicidality: a meta-analysis
Authors: Ye Wenzhu , Zhang Ruo Su , Hosang Georgina M. , Fabbri Chiara , King Nicole , Strauss John , Jones Ian , Jones Lisa , Breen Gerome , Kennedy James L. , Vincent John B. , Zai Clement C.
Published: October 2024

Background

Previous studies have shown that genes in brain development pathways may have important roles in affecting risk of suicidal behaviors, with our previous meta-analysis supporting a role of the brain-derived neurotrophic factor (BDNF) gene. NTRK2 is a gene that encodes the neurotrophic receptor tyrosine kinase 2, which is a receptor for BDNF. In the current study, we aim to examine the potential association between NTRK2 single nucleotide polymorphism (SNPs) and suicidal ideation/behaviors.

Methods

We first conducted a literature search using keywords like ‘NTRK2’, ‘TRKB’, and ‘suicid*’ to identify papers on NTRK2 SNPs and suicidal ideation/behaviors. In addition, we have individual-level genotype data for all the identified SNPs in literature search. We used the R meta package to perform meta-analyses on both the genotype count and the allele count data. Moreover, we performed meta-analyses on specific haplotypes within each haplotype block.

Main results

Following our literature search and meta-analyses on 20 NTRK2 SNPs across up to 8467 samples, we found three SNPs, rs10868235 [N = 5,318, odds ratio (OR) = 1.34, P = 0.02], rs1867283 (N = 5,134, OR = 0.73, P = 0.04), and rs1147198 (N = 5,132, OR = 1.36, P = 0.03) to be nominally associated with suicidal attempts. Those three findings, however, did not survive multiple-testing corrections. Also, none of the haplotype blocks showed significant involvement in suicidality.

Conclusion

Our results suggest that the NTRK2 gene may not have a major role in suicidality. Future efforts, however, should explore gene–gene interaction and pathway analyses.
An ulvophycean marine green alga produces large parthenogenetic isogametes as predicted by the gamete dynamics model for the evolution of anisogamy
Authors: Togashi Tatsuya , Nomura Kazuei , Mochizuki Kosei , Parker Geoff A. , Horinouchi Yusuke
Published: October 2024

In eukaryotes, gamete size difference between the two sexes (anisogamy) evolved from gametes of equal size in both mating types (isogamy). The gamete dynamics (GD) model for anisogamy evolution combines gamete limitation and competition and predicts that if gametes of both mating types can develop parthenogenetically (i.e. without fusing with the opposite mating type), large isogamy can evolve under gamete-limited conditions. Ulvophycean marine green algae that have been claimed to exhibit various gametic systems from isogamy to anisogamy are important models for testing such theories. However, in most previous papers, whether a species is isogamous or anisogamous has not been examined statistically. Caution is necessary regarding claims of slight anisogamy because of gamete size variation. We reveal (i) that the gametic system of
Struvea okamurae
is large isogamy using a generalized linear mixed model, which accounted for the variation of gamete size among individual gametophytes, and (ii) that gametes of this alga can actually develop parthenogenetically, contrary to a previous report. Its habitat environments and protracted duration of gamete release suggest that this alga might experience gamete-limited conditions.
Struvea okamurae
seems to produce large parthenogenetic isogametes following GD model predictions, as an adaptation to deep waters.
Tail-anchored membrane protein SLMAP3 is essential for targeting centrosomal proteins to the nuclear envelope in skeletal myogenesis
Authors: Dias Ana Paula , Rehmani Taha , Salih Maysoon , Tuana Balwant
Published: October 2024

The positioning and communication between the nucleus and centrosomes are essential in cell division, differentiation and tissue formation. During skeletal myogenesis, the nuclei become evenly spaced with the switch of the microtubule-organizing centre (MTOC) from the centrosome to the nuclear envelope (NE). We report that the tail-anchored sarcolemmal membrane associated protein 3 (SLMAP3), a component of the MTOC and NE, is crucial for myogenesis because its deletion in mice leads to a reduction in the NE-MTOC formation, mislocalization of the nuclei, dysregulation of the myogenic programme and abnormal embryonic myofibres. SLMAP3
−/−
myoblasts also displayed a similar disorganized distribution of nuclei with an aberrant NE-MTOC and defective myofibre formation and differentiation programming. We identified novel interactors of SLMAP3, including pericentrin, PCM1 (pericentriolar material 1), AKAP9 (A-kinase anchoring protein 9), kinesin-1 members Kif5B (kinesin family member 5B), KCL1 (kinesin light chain 1), KLC2 (kinesin light chain 2) and nuclear lamins, and observed that the distribution of centrosomal proteins at the NE together with Nesprin-1 was significantly altered by the loss of SLMAP3 in differentiating myoblasts. SLMAP3 is believed to negatively regulate Hippo signalling, but its loss was without impact on this pathway in developing muscle. These results reveal that SLMAP3 is essential for skeletal myogenesis through unique mechanisms involving the positioning of nuclei, NE-MTOC dynamics and gene programming.
Cell cycle visualization tools to study cardiomyocyte proliferation in real-time
Authors: Salmenov Rustem , Mummery Christine , ter Huurne Menno
Published: October 2024

Cardiomyocytes in the adult human heart are quiescent and those lost following heart injury are not replaced by proliferating survivors. Considerable effort has been made to understand the mechanisms underlying cardiomyocyte cell cycle exit and re-entry, with view to discovering therapeutics that could stimulate cardiomyocyte proliferation and heart regeneration. The advent of large compound libraries and robotic liquid handling platforms has enabled the screening of thousands of conditions in a single experiment but success of these screens depends on the appropriateness and quality of the model used. Quantification of (human) cardiomyocyte proliferation in high throughput has remained problematic because conventional antibody-based staining is costly, technically challenging and does not discriminate between cardiomyocyte division and failure in karyokinesis or cytokinesis. Live cell imaging has provided alternatives that facilitate high-throughput screening but these have other limitations. Here, we (i) review the cell cycle features of cardiomyocytes, (ii) discuss various cell cycle fluorescent reporter systems, and (iii) speculate on what could improve their predictive value in the context of cardiomyocyte proliferation. Finally, we consider how these new methods can be used in combination with state-of-the-art three-dimensional human cardiac organoid platforms to identify pro-proliferative signalling pathways that could stimulate regeneration of the human heart.
Facebook increases political knowledge, reduces well-being and informational treatments do little to help
Authors: Arceneaux Kevin , Foucault Martial , Giannelos Kalli , Ladd Jonathan , Zengin Can
Published: October 2024

Nearly three billion people actively use Facebook, making it the largest social media platform in the world. Previous research shows that the social media platform reduces users’ happiness, while increasing political knowledge. It also may increase partisan polarization. Working to build a scientific consensus, we test whether the potential negative effects of Facebook use can be overcome with the help of minimalist informational interventions that a parallel line of research has shown to be effective at inducing people to be more accurate and civil. We conducted a pre-registered well-powered Facebook deactivation experiment during the 2022 French presidential election. In line with previous research, we find that deactivating Facebook increases subjective well-being and reduces political knowledge. However, deactivating Facebook had no overall effect on the level of political or social polarization during the election. Moreover, we find little evidence that minimalist informational interventions in a field setting helped individuals who deactivated Facebook to become better informed.
Flight initiation distance and bird tolerance to humans in rural and urban habitats
Authors: Nepali Amrit , Katuwal Hem Bahadur , Kc Sabin , Regmi Sandeep , Sharma Hari Prasad
Published: October 2024

Urbanization induces homogenization and changes the behavioural patterns of various bird species, thereby facilitating coexistence and prompting adaptations to disturbances in urban environments. However, there is limited research on the influence of how urbanization affects bird tolerance towards humans, especially in developing sub-tropical regions such as Nepal, which is undergoing rapid unplanned urbanization. This study identified the flight initiation distance (FID) as a proxy for assessing bird tolerance. We focused on evaluating the human tolerance levels of 33 bird species using their FIDs in urban and rural habitats within Kathmandu Valley, a rapidly urbanizing city in South Asia. We found higher tolerance in urban birds than in their rural conspecifics, which varies mainly with dietary guild and season. The positive impact on FID was associated with time of the day and body size, while a negative association was observed with flock size, mean population density of humans and interaction between body size and elevation. Our study highlights the increased tolerance level of birds in urban areas, probably owing to habituation, and emphasizes the imperative need to investigate the potential adverse effect on urban bird population owing to this increased tolerance level.
Effects of the kinematic variable, time delay and data length on test–retest reliability of the maximal Lyapunov exponent of human walking
Authors: Park Ilseung , Lee Jun Hyuk , Ahn Jooeun
Published: October 2024

The maximal Lyapunov exponent (MLE) has been used to quantify the dynamic stability of human locomotion. The method for estimating MLE requires selecting a proper time series of kinematic variables and reconstructing phase space using proper time delay. The data length also affects the reliability of the measured MLE. However, there has been no criterion for the choice of the time series, time delay or data length. Here, we quantified the effect of these factors on the test–retest reliability of MLE estimations. We recruited 15 young and healthy adults and let them walk on a treadmill three times. We calculated MLE employing various lengths of time series of 18 frequently used kinematic variables and two typical choices of time delay: fixed delay and delay selected by average mutual information algorithm. Then, we measured the intraclass correlation coefficient (ICC) of the measured MLE under each condition. Our results show that the choice of time delay does not affect reliability. Five among the 18 kinematic variables enabled excellent reliability with ICC above 0.9 within 450 strides and also enabled ICC above 0.75 even with 60 or less strides. These findings can contribute to establishing the criteria for measuring the dynamic stability of human walking.
Comparing self–other distinction across motor, cognitive and affective domains
Authors: Pronizius Ekaterina , Bukowski Henryk , Lamm Claus
Published: October 2024

The self–other distinction (SOD) is a process by which humans disentangle self from other-related mental representations. This online study investigated two unresolved questions: (i) whether partially the same processes underpin SOD for motor, cognitive and affective representations, and (ii) whether SOD overlaps with domain-general cognitive control processes. Participants (
N
= 243) performed three SOD tasks (motor: automatic imitation inhibition (AIT); cognitive: visual perspective-taking (VPT); affective: emotional egocentricity bias (av-EEB) tasks) and two cognitive control tasks (Stroop and stop-signal reaction time (SSRT) tasks). Correlation analyses showed no associations among the motor, cognitive and affective SOD indexes. Similarly, distinct SOD clusters emerged in the hierarchical clustering dendrogram, indicating clear separations among SODs. However, the results of multidimensional scaling suggested a tendency towards two clusters, as evidenced by the proximity of AIT and VPT indexes in relation to EEB indexes. AIT spatial laterality and Stroop domain-general cognitive control confounded AIT and VPT indexes, albeit slightly differently depending on the analysis method used. SSRT showed neither associations with SODs nor with other domain-general indexes. These findings underscore the complexity of SOD processes and have notable implications for basic and applied research, e.g. in the domain of clinical disorders affected by deficiencies in SOD.
Data-driven two-dimensional stationary quantum droplets and wave propagations in the amended Gross–Pitaevskii equation with two potentials via deep neural networks learning
Authors: Song Jin , Yan Zhenya
Published: October 2024

In this paper, we develop a systematic deep learning approach to solve two-dimensional stationary quantum droplets (QDs) and investigate their wave propagation in the two-dimensional amended Gross–Pitaevskii equation with Lee–Huang–Yang correction and two kinds of potentials. Firstly, we use the initial-value iterative neural network algorithm for two-dimensional stationary QDs of stationary equations. Then, the learned stationary QDs are used as the initial value conditions for physics-informed neural networks to explore their evolutions in the space-time region. Especially, we consider two types of potentials, one is the two-dimensional quadruple-well Gaussian potential and the other is thePT-symmetric harmonic-oscillator (HO)-Gaussian potential, which lead to spontaneous symmetry breaking and the generation of multi-component QDs. The used deep learning method can also be applied to study wave propagations of other nonlinear physical models.
Physically stressed bees expect less reward in an active choice judgement bias test
Authors: Procenko Olga , Read Jenny C. A. , Nityananda Vivek
Published: October 2024

Emotion-like states in animals are commonly assessed using judgment bias tests that measure judgements of ambiguous cues. Some studies have used these tests to argue for emotion-like states in insects. However, most of these results could have other explanations, including changes in motivation and attention. To control for these explanations, we developed a novel judgment bias test, requiring bumblebees to make an active choice indicating their interpretation of ambiguous stimuli. Bumblebees were trained to associate high or low rewards, in two different reward chambers, with distinct colours. We subsequently presented bees with ambiguous colours between the two learnt colours. In response, physically stressed bees were less likely than control bees to enter the reward chamber associated with high reward. Signal detection and drift diffusion models showed that stressed bees were more likely to choose low reward locations in response to ambiguous cues. The signal detection model further showed that the behaviour of stressed bees was explained by a reduction in the estimated probability of high rewards. We thus provide strong evidence for judgement biases in bees and suggest that their stress-induced behaviour is explained by reduced expectation of higher rewards, as expected for a pessimistic judgement bias.
Climate change reduces the tension of conflicting selection pressures on breeding date in a passerine bird
Authors: Moelling Matthew H. , Duckworth Renée A.
Published: October 2024

Unpredictably fluctuating environments create complex selective landscapes that shape the distribution of key life history traits. Identifying the mechanisms behind dynamic patterns of selection is difficult, yet essential for predicting responses to climate change. We combine long-term measures with field manipulation of natural selection on breeding date in a wild bird to investigate whether highly variable spring cold snaps drive fluctuating selection. We show that variation in cold snap intensity leads to fluctuating selection on breeding date—in weak cold snap years, selection was consistently negative; however, in strong cold snap years, its direction reversed. These patterns were mirrored in a field experiment; nests that were food supplemented during cold snaps avoided cold snap mortality leading earlier breeders to have higher fitness. In contrast, in the non-supplemented group earlier breeders had higher cold snap nest mortality and selection was positive. Using nearly a century of climate data, we show that cold snaps are becoming less frequent and paradoxically occurring later which should allow earlier breeders to avoid them, potentially releasing conflicting selection pressures and facilitating a rapid phenological shift. Thus, rather than constraining a species’ ability to adapt, climate change can enable a rapid shift to a new phenotypic optimum.
Relaxed selection in evolution of genes regulating limb development gives clue to variation in forelimb morphology of cetaceans and other mammals
Authors: Telizhenko Valeriia , Kosiol Carolin , McGowen Michael R. , Gol'din Pavel
Published: October 2024

Cetaceans have evolved unique limb structures, such as flippers, due to genetic changes during their transition to aquatic life. However, the full understanding of the genetic and evolutionary mechanisms behind these changes is still developing. By examining 25 limb-related protein-coding genes across various mammalian species, we compared genetic changes between aquatic mammals, like whales, and other mammals with unique limb structures such as bats, rodents and elephants. Our findings revealed significant modifications in limb-related genes, including variations in the Hox,
GDF5
and Evx genes. Notably, a relaxed selection in several key genes was observed, suggesting a lifting of developmental constraints, which might have facilitated the emergence of morphological innovations in cetacean limb morphology. We also uncovered non-synonymous changes, insertions and deletions in these genes, particularly in the polyalanine tract of
HOXD13
, which are distinctive to cetaceans or convergent with other aquatic mammals. These genetic variations correlated with the diverse and specialized limb structures observed in cetaceans, indicating a complex interplay of relaxed selection and specific mutations in mammalian limb evolution.
Brains in sync, friends in empathy: interbrain neural mechanisms underlying the impact of interpersonal closeness on mutual empathy
Authors: Lin Chennan , Lin Xinxin , Lian Weicheng , Zhang Wenting , Peng Weiwei
Published: October 2024

Many everyday empathetic experiences arise within our social interactions and depend significantly on interpersonal closeness. However, the interbrain processes underlying social-oriented empathy by interpersonal closeness remain unclear. To address this gap, we conducted a dyadic social judgement task with dyads of friends and strangers, where targets received social evaluative feedback and empathizers observed the scenario in different experimental trials. Results showed that dyads of friends exhibited greater affect sharing than strangers when witnessing their partners being accepted or rejected. This was supported by the more pronounced event-related potential similarity in friends during the 340−840 ms post-feedback window, mediating the link between interpersonal closeness and affect sharing. Furthermore, witnessing emotional feedback elicited greater interbrain neural synchronization of brain α-oscillation between the empathizer’s left prefrontal cortex and the target’s left temporoparietal junction in dyads of friends compared with those of strangers. This empathy-related synchronization was associated with mutual affect sharing within dyads of friends but not within dyads of strangers. Our findings highlight the sensitivity of empathy to interpersonal closeness, which links to sustained attention and detailed evaluation in social scenarios, along with functional communication between brain regions for mentalizing and emotional regulation. These insights have therapeutic potential for improving social functioning and relationship satisfaction.
Nurseries and garden centres as hubs of alien plant invasions
Authors: Sonkoly Judit , Molnár V Attila , Török Péter , Süveges Kristóf , Takács Attila
Published: October 2024

The growing global horticultural trade is having a steadily increasing impact on the rate at which alien species are introduced into new areas, partly because horticultural trade also entails the unintentional dispersal of many contaminant species. Although there are reports about noteworthy occurrences of alien plant species in garden centres, this phenomenon has hardly been studied systematically. To bridge this knowledge gap, we conducted systematic field surveys in 12 garden centres in Hungary to assess their alien flora. We hypothesised that (i) the number of alien species inhabiting a garden centre is positively correlated with its size, (ii) relative to their size, garden centres host a disproportionately large proportion of the local alien flora, and (iii) alien species inhabiting garden centres differ from the regional alien flora in their traits. We recorded altogether 93,788 individuals of 67 introduced species, seven of which have not yet been reported from the country. There was considerable variability in the number of species and individuals found in each garden centre, but there was no correlation between the size of the garden centres and the number of species they host. Despite their relatively small size, the studied garden centres hosted a considerable proportion of the local alien flora, indicating that they strongly accumulate alien species and that they can act as invasion hubs for several alien species. Alien species inhabiting garden centres differed from the regional alien flora in some of their trait values, indicating that the species that are most successful at establishing populations inside garden centres are both good dispersers and possess an effective resource-acquisitive strategy. We conclude that established alien plant populations in garden centres may induce local invasions, and in the meantime, individuals and seeds inside the containers of ornamental plants are regularly transported to distant areas by the customers. Therefore, plant species dispersed as contaminants of horticultural stock need to be better considered in invasion biology to reduce the threat they may present.
Transcriptional reprogramming and microbiome dynamics in garden pea exposed to high pH stress during vegetative stage
Authors: Thapa Asha , Hasan Md Rokibul , Kabir Ahmad H.
Published: October 2024

High soil pH severely impacts plant growth and productivity, yet the transcriptomic changes and microbial dynamics underlying stress adaptation in garden pea (Pisum sativumssp.hortense) remain unclear. This study demonstrates that high soil pH leads to stunted growth, reduced biomass, impaired photosynthesis, and nutrient status in garden pea. Further, disruption in key nitrogen-fixing bacteria (Rhizobium indicum, R. leguminosarum,andR. redzepovicii), along with the downregulation ofNifAandNifDgenes and upregulation ofNifHin nodules highlight the critical role of micronutrient balance in legume-microbe symbiosis and a compensatory response to maintain nitrogen status. RNA-seq analysis revealed extensive transcriptional reprogramming in roots, characterized by the upregulation of oxidative stress response genes (e.g., oxidoreductase and glutathione transferase activities, metal ion transporters) and the downregulation of genes related to ammonia-lyase activity and ion binding, reflecting broader disruptions in nutrient homeostasis. KEGG pathway analysis identified enrichment of MAPK signaling pathway, likely interacting with other pathways associated with stress tolerance, metabolic adjustment, and structural reorganization as part of adaptive responses to high pH. Root microbiome analysis showed significant enrichment ofVariovorax, Shinella,andChaetomium, suggesting host-driven recruitment under high pH stress. Stable genera such asPseudomonas, Novosphingobium, Mycobacterium, Herbaspirillum,andPaecilomycesdisplayed resilience to stress conditions, potentially forming core microbiome components for adaptation to high pH. In a targeted study, inoculation of plants with an enriched microbiome, particularlyC. globosum, under high pH conditions improved growth parameters and increased the abundance ofStenotrophomonasandPseudomonasin the roots. It suggests that these bacterial genera may act as helper microbes toC. globosum, collectively promoting stress resilience in pea suffering from high pH. These findings provide a foundation for microbiome-aided breeding programs and the development of microbial consortia to enhance the adaptation of pea plants to high pH conditions.
The effect of yoga and aerobic exercise on children’s physical activity in rural India: a randomized controlled trial
Authors: Katapally Tarun Reddy , Patel Jamin , Ibrahim Sheriff Tolulope , Kasture Sonal , Khadilkar Anuradha , Bhawra Jasmin
Published: October 2024

Purpose The objective of this study was to test the effect of both yoga and aerobic exercise on children’s moderate-to-vigorous physical activity (MVPA) in rural India. Methods The study utilized secondary data from a randomized, controlled, open-labelled, single-center, two-site, parallel-group trial. The study was conducted in rural India over a 6-month period between 2018-2019. Children aged 6 to 11 years were randomized into three groups: aerobic exercise (30 minutes, 5 days/week), control (no intervention), and yoga (30 minutes, 5 days/week). MVPA was measured at baseline and at six months using the Quantification of Physical Activity in School Children and Adolescents survey adapted and validated for Indian children. Overall sample and gender-segregated data were analyzed using paired sample t-tests and one-way analysis of variance with post-hoc analyses. Findings In the overall sample (N=151), mean MVPA (minutes/day) increased significantly in both yoga (n=50; p<0.001) and aerobic exercise (n=49; p<0.001) groups from baseline to endline. Among males, mean MVPA increased significantly from baseline to endline in all three groups, including the control group (n=23; p=0.005). Among females, mean MVPA increased only in the yoga group, with baseline to endline change being significant across the three groups (p=0.005), and with the yoga group depicting greater change in comparison to the control group (p=0.004). Conclusions Our findings suggest that both yoga and aerobic exercise can increase MVPA among rural children, with yoga being particularly beneficial for girls – a significant finding to inform culturally-appropriate active living policies to minimize the current physical activity gender gap in India. These findings can have implications for public health programs and policies not only in India but across other rural areas worldwide, where similar challenges in promoting physical activity among children may exist.
Chronic infections can generate SARS-CoV-2-like bursts of viral evolution without epistasis
Authors: Rodriguez-Horta Edwin , Strahan John , Dinner Aaron , Barton John P
Published: October 2024

Multiple SARS-CoV-2 variants have arisen during the first years of the pandemic, often bearing many new mutations. Several explanations have been offered for the surprisingly sudden emergence of multiple mutations that enhance viral fitness, including cryptic transmission, spillover from animal reservoirs, epistasis between mutations, and chronic infections. Here, we simulated pathogen evolution combining within-host replication and between-host transmission. We found that, under certain conditions, chronic infections can lead to SARS-CoV-2-like bursts of mutations even without epistasis. Chronic infections can also increase the global evolutionary rate of a pathogen even in the absence of clear mutational bursts. Overall, our study supports chronic infections as a plausible origin for highly mutated SARS-CoV-2 variants. More generally, we also describe how chronic infections can influence pathogen evolution under different scenarios.
JunB-HBZ nuclear translocation by TGF-β is a key driver in HTLV-1–mediated leukemogenesis
Authors: Zhang Wenyi , Shichijo Takafumi , Chen Xueda , Matsuoka Masao , Yasunaga Jun-ichirou
Published: October 2024

TheHTLV-1 bZIP factor(HBZ) gene, which is the only viral gene conserved and consistently expressed in all adult T-cell leukemia-lymphoma (ATL) cases, is critical for ATL oncogenesis. Although HBZ protein is found in both the nucleus and the cytoplasm, the dynamics of HBZ protein localization and its contribution to oncogenesis have not been fully elucidated. In this study, we analyzed the subcellular expression pattern of HBZ in primary HTLV-1–infected T cells from asymptomatic carriers and leukemic cells of ATL patients using the Proximity Ligation Assay. Nuclear localization of HBZ protein was significantly higher in fresh ATL cells than in HTLV-1–infected cells from carriers. Importantly, translocation of HBZ protein from the cytoplasm to the nucleus after TGF-β activation was observed in ATL patients, but not in HTLV-1 carriers. In ATL cells, the cellular transcription factors JunB and pSmad3 interact with HBZ and facilitate its nuclear translocation upon TGF-β stimulation.JUNBknockdown inhibits cell proliferationin vitroandin vivoand promotes apoptosis in ATL cells but not in HTLV-1–infected non-leukemic cells, indicating that JunB has important roles in maintaining ATL cells. In conclusion, TGF-β-induced nuclear translocation of HBZ-JunB complexes is associated with ATL oncogenesis.
Comparative effectiveness of first line pembrolizumab vs. chemotherapy in aNSCLC: A Norwegian Population-Based Cohort Study
Authors: Brant Simon Boge , Børø Siri , Jonasson Christian , Helland Åslaug , Thoresen Steinar Østerbø
Published: October 2024

The KEYNOTE-042(1,2) trial showed a benefit of treating patients with non-oncogene addicted advanced NSCLC with PD-L1 tumour proportion score over 50% with Pembrolizumab as monotherapy over platinum doublet chemotherapy. To contextualize these results, we undertake a detailed emulation of the inclusion criteria in Keynote–042 using Norwegian health registry data, and discuss both the clinical context, as well as the general utility of such registry data for pharmacoepidemiologic research in oncology. Within the population of patients with PD-L1 tumour proportion score over 50%, an observational analogue of an intention to treat analysis showed similar results to those of the Keynote-042 study.
Frailty and loneliness among community-dwelling older adults: Examining reciprocal associations within a measurement burst design
Authors: Schultz Anna , Mayerl Hannes , Freidl Wolfgang , Stolz Erwin
Published: October 2024

Background

Previous research indicates that frailty and loneliness are interrelated. The aim of this study is to analyze their possible reciprocal relationship while disentangling between- and within-person effects. The separation of these sources of variance is vital for a better understanding of potential causal mechanisms.

Methods

Within the FRequent health Assessment In Later life (FRAIL70+) project, participants aged 70 and over completed two measurement bursts spread one year apart with seven biweekly assessments each. The final sample consisted of 426 individuals at baseline (Mage=77.2;SD=5.4; 64.6% female). A latent curve model with structured residuals was used to examine the potential reciprocal relationship between frailty (37-item deficit accumulation approach) and loneliness (3-item UCLA scale).

Results

No relevant cross-lagged effects over repeated 2-week periods were found between frailty and loneliness at the within-person level, but increases in frailty co-occurred with increases in loneliness. At the between-person level, higher levels of frailty correlated with higher levels of loneliness in each burst.

Conclusion

The findings do not support the assumption that frailty and loneliness share a causal reciprocal relationship over weeks and months. Nonetheless, higher levels of frailty were weakly associated with higher levels of loneliness at the within- and considerably associated at the between-person level, which may indicate a common source of both domains.
NIAGADS: A Comprehensive National Data Repository for Alzheimer’s Disease and Related Dementia Genetics and Genomics Research
Authors: Kuzma Amanda , Valladares Otto , Greenfest-Allen Emily , Nicaretta Heather , Kirsch Maureen , Ren Youli , Katanic Zivadin , White Heather , Wilk Andrew , Bass Lauren , Brettschneider Jascha , Carter Luke , Cifello Jeffrey , Chuang Wei-Hsuan , Clark Kaylyn , Gangadharan Prabhakaran , Haut Jacob , Ho Pei-Chuan , Horng Wenhwai , Iqbal Taha , Jin Yumi , Keskinen Peter , Rose Alexis Lerro , Moon Michelle K , Manuel Joseph , Qu Liming , Robbins Flawless , Saravanan Naveensri , Sha Jin , Tate Sam , Zhao Yi ,   Alzheimer’s Disease Sequencing Project, Cantwell Laura , Gardner Jake , Chou Shin-Yi , Tzeng Jung-Ying , Bush William , Naj Adam , Kuksa Pavel , Lee Wan-Ping , Leung Yuk Yee , Schellenberg Gerard , Wang Li-San
Published: October 2024

NIAGADS is the National Institute on Aging (NIA) designated national data repository for human genetics research on Alzheimer’s Disease and related dementia (ADRD). NIAGADS maintains a high-quality data collection for ADRD genetic/genomic research and supports genetics data production and analysis. NIAGADS hosts whole genome and exome sequence data from the Alzheimer’s Disease Sequencing Project (ADSP) and other genotype/phenotype data, encompassing 209,000 samples. NIAGADS shares these data with hundreds of research groups around the world via the Data Sharing Service, a FISMA moderate compliant cloud- based platform that fully supports the NIH Genome Data Sharing Policy. NIAGADS Open Access consists of multiple knowledge bases with genome-wide association summary statistics and rich annotations on the biological significance of genetic variants and genes across the human genome. NIAGADS stands as a keystone in promoting collaborations to advance the understanding and treatment of Alzheimer’s disease.
B cell immune repertoire sequencing in tobacco cigarette smoking, vaping, and chronic obstructive pulmonary disease in the COPDGene cohort
Authors: Moll Matthew , Xu Zhonghui , Boueiz Adel , Ryu Min Hyung , Silverman Edwin K. , Cho Michael H. , Hersh Craig P. , Sauler Maor , Polverino Francesca , Kinney Gregory L. , Curtis Jeffrey L. , Crotty-Alexander Laura E. , Vollmers Christopher , Castaldi Peter J.
Published: October 2024

Rationale

Cigarette smoking (CS) impairs B cell function and antibody production, increasing infection risk. The impact of e-cigarette use (’vaping’) and combined CS and vaping (’dual-use’) on B cell activity is unclear.

Objective

To examine B cell receptor sequencing (BCR-seq) profiles associated with CS, vaping, dual-use, COPD-related outcomes, and demographic factors.

Methods

BCR-seq was performed on blood RNA samples from 234 participants in the COPDGene study. We assessed multivariable associations of B cell function measures (immunoglobulin heavy chain (IGH) subclass expression and usage, class-switching, V-segment usage, and clonal expansion) with CS, vaping, dual-use, COPD severity, age, sex, and race. We adjusted for multiple comparisons using the Benjamini-Hochberg method, identifying significant associations at 5% FDR and suggestive associations at 10% FDR.

Results

Among 234 non-Hispanic white (NHW) and African American (AA) participants, CS and dual-use were significantly positively associated with increased secretory IgA production, with dual-use showing the strongest associations. Dual-use was positively associated with class switching and B cell clonal expansion, indicating increased B cell activation, with similar trends in those only smoking or only vaping. We observed significant associations between race and IgG antibody usage. AA participants had higher IgG subclass proportions and lower IgM usage compared to NHW participants.

Conclusions

CS and vaping additively enhance B cell activation, most notably in dual-users. Self-reported race was strongly associated with IgG isotype usage. These findings highlight associations between B cell activation and antibody transcription, suggesting potential differences in immune and vaccine responses linked to CS, vaping, and race.
ML-driven design of 3’ UTRs for mRNA stability
Authors: Morrow Alyssa K. , Thornal Ashley , Flynn Elise Duboscq , Hoelzli Emily , Shan Meimei , Garipler Görkem , Kirchner Rory , Reddy Aniketh Janardhan , Tabchouri Sophia , Gupta Ankit , Michel Jean-Baptiste , Laserson Uri
Published: October 2024

Using mRNA as a therapeutic has received enormous attention in the last few years, but instability of the molecule remains a hurdle to achieving long-lasting therapeutic levels of protein expression. In this study, we describe our approach for designing stable mRNA molecules by combining machine learning-driven sequence design with high-throughput experimental assays. We developed a high-throughput massively parallel reporter assay (MPRA) that, in a single experiment, measures the half-life of tens of thousands of unique mRNA sequences containing designed 3’ UTRs. Over multiple design-build-test iterations, we have accumulated 180,000 unique measurements of mRNA stability covering unique genomic and synthetic 3’ UTRs, representing the largest such dataset of sequences. We trained highly-accurate machine learning models to map from 3’ UTR sequence to mRNA stability, and used them to guide the design of synthetic 3’ UTRs that increase mRNA stability in cell lines. Finally, we validated the function of several ML-designed 3’ UTRs in mouse models, resulting in up to 2-fold more protein production over time and 30–100-fold higher protein output at later time points compared to a commonly used benchmark. These results highlight the potential of ML-driven sequence design for mRNA therapeutics.
A clinical mutation inuvrA, a DNA repair gene, confers survival advantage toMycobacterium tuberculosisin the host
Authors: Naz Saba , Datta Dipanwita , Khan Sidra , Singh Yogendra , Nandicoori Vinay Kumar , Kumar Dhiraj
Published: October 2024

DNA repair pathways play an essential role in maintaining the genomic integrity of bacteria, and a perturbation in their biological activity helps bacteria survive under duress. In drug-resistant clinical strains, we identified a Q135K mutation in theuvrAgene, a DNA repair pathway gene. To delineate the role ofuvrAand the Q135K mutation, we generated the gene replacement mutant of UvrA (RvΔuvrA) inMycobacterium tuberculosis H37Rv(Mtb-Rv). While the lack of UvrA function inRvΔuvrAcould be restored upon complementation withuvrA, theuvrA-Q135Kmutant identified in clinical drug-resistant strains failed to do so. This was reflected in higher mutation rates inRvΔuvrAandRvΔuvrA::uvrAQ135A,compared with wild-typeRvorRvΔuvrA::uvrAcomplemented strains in the presence and absence of oxidative stress. Killing kinetics experiments with anti-TB drugs showed increased survival ofRvΔuvrAandRvΔuvrA::uvrAQ135K,strains compared withRvorRvΔuvrA::uvrA. Importantly,RvΔuvrAandRvΔuvrA::uvrAQ135Kshowed enhanced survival in peritoneal macrophages and murine infection model of infection. Together, data suggests that acquiring Q135K mutation benefits the pathogen, which helps enhance the host’s survival adaptability.

Author Summary

DNA repair mechanisms in an organism are necessary for correcting the errors generated during replication or when it is damaged/modified due to insults. As a GC organism, Mtb is highly prone to host-mediated attacks on its genome, which, if uncorrected, can impact its genome integrity. The drug-resistant clinical strains ofMtbharbor Q135K mutation inuvrA, the first enzyme in the nucleotide excision repair pathway. With the help of genetic, molecular, and murine challenge experiments, we show that the UvrA-Q135K mutation abrogates the enzyme’s activity, compromising theMtbstrain harboring the mutation in the oxidative and nitrosative stress. On the contrary, the mutation in UvrA imparts survival advantage in activated macrophages and murine infection models. Results presented argue that identified mutation helps in better adaptability in the host, which may include faster acquisition of drug resistance.
Predicting near-future deforestation in West African Key Biodiversity Areas to inform conservation urgency
Authors: Trew Brittany T. , Buchanan Graeme M. , Edwards Felicity A. , Sanderson Fiona J.
Published: October 2024

Site-based protection is a cornerstone of 21stcentury conservation and a core component of global biodiversity conservation targets. However, loss of tropical forests, the most biodiverse of habitats, is a major threat to such sites. Here, we predict near-future deforestation risk in 113 Key Biodiversity Areas (KBAs) - sites of objectively defined global conservation importance - in the Guinean Forest biodiversity hotspot and identify those factors associated with loss. We find that (i) KBAs in the Guinean Forests have lost over 265,000 hectares of forest cover over the past decade, with those in Côte d’Ivoire experiencing the highest forest loss; (ii) future deforestation risk is highest among KBAs in Liberia and Côte d’Ivoire (on average 10% predicted loss across KBAs), where some are predicted to lose over a fifth of remaining forest cover by 2033. Models indicate that deforestation is highly contagious, with historical forest loss effectively predicting further adjacent loss, and that forest fragmentation and ease of human access also increased the localised deforestation risk. Conversely, predicted forest loss was lower in sites under some form of conservation protection. Our methods to predict near-future hotspots of deforestation risk in KBAs are reproducible and therefore applicable to other biodiversity hotspots. In the Guinean forests, our results highlight where conservation interventions to mitigate forest loss should be urgently prioritised.
Estimating the effective population size across space and time in the Critically Endangered western chimpanzee in Guinea-Bissau: challenges and implications for conservation management
Authors: Ferreira da Silva Maria Joana , Borges Filipa , Gerini Federica , Sá Rui M. , Silva Francisco , Maié Tiago , Hernández-Alonso Germán , Ramos-Madrigal Jazmín , Gopalakrishnan Shyam , Aleixo-Pais Isa , Djaló Mohamed , Fernandes Nelson , Camará Idrissa , Regalla Aissa , Casanova Catarina , Costa Mafalda , Colmonero-Costeira Ivo , Fernandes Carlos Rodríguez , Chikhi Lounès , Minhós Tânia , Bruford Michael W.
Published: October 2024

Effective population size (Ne) is a key concept in evolutionary and conservation biology. The western chimpanzee (Pan troglodytes verus) is a Critically Endangered taxon. In Guinea-Bissau, chimpanzees are mainly threatened by habitat loss, hunting and diseases. Guinea-Bissau is considered a key area for its conservation. Genetic tools have not yet been applied to inform management and no estimates ofNehave been obtained. In this study, we use country’s range-wide microsatellite data and five whole-genome sequences to estimate severalNeand infer the recent and ancient demographic history of populations using different methods. We also aim to integrate the differentNeestimates to improve our understanding of the evolutionary history and current demography of this great ape and to discuss strengths and limitations of each estimator and their complementarity in informing conservation decisions. Results from the PSMC method suggest a large ancestralNe, likely due to ancient structure over the whole subspecies distribution until approximately 10-15,000 years ago. After that, a change in connectivity, a real decrease in size or a combination of both occurred, which reduced the then still large ancestral population to a smaller size (MSVAR: ∼10,000 decreasing to 1,000-6,000 individuals), possibly indicating a fragmentation into coastal and inner subpopulations. In the most recent past, contemporaryNeis below or close to 500 (GONE: 116-580, NeEstimator: 107-549), suggesting a high risk of extinction. The populations at coastal Parks may have been small or isolated for several generations whereas the Boé Park one exhibit higher long-termNeestimates and can be considered a stronghold of chimpanzee conservation. Through combining different types of molecular markers and analytical methodologies, we try to overcome the limitations of obtaining high quality DNA sampling from wild threatened populations and estimateNeat different temporal and spatial scales, which is crucial information to make informed conservation decisions at local and regional scales.
Electrical diversity of neurons in sensory cortices
Authors: Calcini Niccolò , Zeldenrust Fleur , Celikel Tansu
Published: October 2024

The classification of neuronal types is a complex task with numerous molecular, anatomical, and functional (electrical) features have been identified as informative in discriminating neuronal populations. The functional characterization of neurons has traditionally been carried out with predefined sets of parameters such as firing rate and action potential generation threshold. Here we provide an objective method to choose what parameters are most informative about a neuron’s functional cell type. Using this method we show that despite the significant molecular and anatomical variability across neurons, functional characterization of neuronal activity identifies 9 and 11 distinct neuronal subpopulations in the upper layers of the somatosensory and visual cortices respectively. This novel classification method will help to unravel the functional (electrophysiological) diversity of cellular classes throughout the nervous system. Further, the thorough comparison between the different classes of cells will provide a solid building block for the study of the sensory cortices.