bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of membrane estrogen receptor alpha on the positive feedback of estrogens on LH secretion
Authors: Faure Mélanie C. , Corona Rebeca , de Bournonville Catherine , Lenfant Françoise , Foidart Jean-Michel , Cornil Charlotte A.
Published: March 2023

Estrogens act through nuclear and membrane-initiated signaling. Estrogen receptor alpha (ERα) is critical for reproduction, but the relative contribution of its nuclear and membrane signaling is unclear. To address this question, we used two complementary approaches: estetrol (E4) a natural estrogen described to act as an agonist of nuclear ERα and a mERα antagonist and the C451A-ERα mouse lacking mERα. E4dose-dependently blocks ovulation in female rats, but the mechanism underlying this effect is unknown. To determine whether E4acts centrally to control ovulation, we tested its effect on the positive feedback of estradiol (E2) on LH secretion. In ovariectomized females chronically exposed to a low dose of E2, estradiol benzoate (EB) alone or combined with progesterone (P) induced a LH surge and the associated increase in the number of activated kisspeptin (Kp) and gonadotropin-releasing hormone (GnRH) neurons. However, E4blocked these effects of EB when provided alone, but not when combined to P. These results indicate that E4blocked the induction of the positive feedback and the associated neuronal activation in the absence of P, suggesting an antagonistic effect of E4on mERα as shown in peripheral tissues. In parallel, C451A-ERα females do not show a pre-ovulatory LH surge and the associated activation of Kp and GnRH neurons in response to EB unless they are treated with P. The similarity of the responses of C451A-ERα mice and wild-type females treated with E4 supports a role for membrane-initiated estrogen signaling in the EB-induced LH surge.
Understanding the Divergent Evolution and Epidemiology of H3N8 Influenza Viruses in Dogs and Horses
Authors: Wasik Brian R. , Rothschild Evin , Voorhees Ian E.H. , Reedy Stephanie E. , Murcia Pablo R. , Pusterla Nicola , Chambers Thomas M. , Goodman Laura B. , Holmes Edward C. , Kile James C. , Parrish Colin R.
Published: March 2023

Cross-species virus transmission events can lead to dire public health emergencies in the form of epidemics and pandemics. One example in animals is the emergence of the H3N8 equine influenza virus (EIV), first isolated in 1963 in Miami, Florida, USA, after emerging among horses in South America. In the early 21stcentury the American lineage of EIV diverged into two ‘Florida’ clades that persist today, while an EIV transferred to dogs around 1999 and gave rise to the H3N8 canine influenza virus (CIV), first reported in 2004. Here, we compare CIV in dogs and EIV in horses to reveal their host-specific evolution, to determine the sources and connections between significant outbreaks, and to gain insight into the factors controlling their different evolutionary fates. H3N8 CIV only circulated in North America, was geographically restricted after the first few years, and went extinct in 2016. Of the two EIV Florida clades, clade 1 circulates widely and shows frequent transfers between the USA and South America, Europe and elsewhere, while clade 2 was globally distributed early after it emerged, but since about 2018 has only been detected in Central Asia. Any potential zoonotic threat of these viruses to humans can only be determined with an understanding of its natural history and evolution. Our comparative analysis of these three viral lineages reveals distinct patterns and rates of sequence variation yet with similar overall evolution between clades, suggesting epidemiological intervention strategies for possible eradication of H3N8 EIV. (242 words)

IMPORTANCE

The emergence of viruses in new hosts is a threat to human and animal health. The H3N8 equine influenza virus (EIV) emerged in 1963 by transfer of an avian influenza virus, and the H3N8 canine influenza virus (CIV) subsequently emerged in 1999 when EIV transferred to dogs. H3N8 CIV persistently circulated in only a few locations in the USA, and has not been detected since 2016. In the same period H3N8 EIV has circulated as two separate clades, one in North America and other regions of the world, while the other currently appears to be found only in Central Asia. By comparing the hosts, epidemiology, and evolution of these influenza viruses we explain how these lineages had different evolutionary fates, and show why elucidating these evolutionary processes is key to understanding zoonotic disease and viral emergence. (137 words)
Spinal control of locomotion before and after spinal cord injury
Authors: Danner Simon M. , Shepard Courtney T. , Hainline Casey , Shevtsova Natalia A. , Rybak Ilya A. , Magnuson David S.K.
Published: March 2023

Thoracic spinal cord injury affects long propriospinal neurons that interconnect the cervical and lumbar enlargements. These neurons are crucial for coordinating forelimb and hindlimb locomotor movements in a speed-dependent manner. However, recovery from spinal cord injury is usually studied over a very limited range of speeds that may not fully expose circuitry dysfunction. To overcome this limitation, we investigated overground locomotion in rats trained to move over an extended distance with a wide range of speeds both pre-injury and after recovery from thoracic hemisection or contusion injuries. In this experimental context, intact rats expressed a speed-dependent continuum of alternating (walk and trot) and non-alternating (canter, gallop, half-bound gallop, and bound) gaits. After a lateral hemisection injury, rats recovered the ability to locomote over a wide range of speeds but lost the ability to use the highest-speed gaits (half-bound gallop and bound) and predominantly used the limb contralateral to the injury as lead during canter and gallop. A moderate contusion injury caused a greater reduction in maximal speed, loss of all non-alternating gaits, and emergence of novel alternating gaits. These changes resulted from weak fore–hind coupling together with appropriate control of left–right alternation. After hemisection, animals expressed a subset of intact gaits with appropriate interlimb coordination even on the side of the injury, where the long propriospinal connections were severed. These observations highlight how investigating locomotion over the full range of speeds can reveal otherwise hidden aspects of spinal locomotor control and post-injury recovery.
Spotless: a reproducible pipeline for benchmarking cell type deconvolution in spatial transcriptomics
Authors: Sang-aram Chananchida , Browaeys Robin , Seurinck Ruth , Saeys Yvan
Published: March 2023

Spatial transcriptomics (ST) is an emerging field that aims to profile the transcriptome of a cell while keeping its spatial context. Although the resolution of non-targeted ST technologies has been rapidly improving in recent years, most commercial methods do not yet operate at single-cell resolution. To tackle this issue, computational methods such as deconvolution can be used to infer cell type proportions in each spot by learning cell type-specific expression profiles from reference single-cell RNA-sequencing (scRNA-seq) data. Here, we benchmarked the performance of 11 deconvolution methods using 63 silver standards, three gold standards, and two case studies on liver and melanoma tissues. The silver standards were generated using our novel simulation enginesynthspot, where we used seven scRNA-seq datasets to create synthetic spots that followed one of nine different biological tissue patterns. The gold standards were generated using imaging-based ST technologies at single-cell resolution. We evaluated method performance based on the root-mean-squared error, area under the precision-recall curve, and Jensen-Shannon divergence. Our evaluation revealed that method performance significantly decreases in datasets with highly abundant or rare cell types. Moreover, we evaluated the stability of each method when using different reference datasets and found that having sufficient number of genes for each cell type is crucial for good performance. We conclude that while cell2location and RCTD are the top-performing methods, a simple off-the-shelf deconvolution method surprisingly outperforms almost half of the dedicated spatial deconvolution methods. Our freely available Nextflow pipeline allows users to generate synthetic data, run deconvolution methods and optionally benchmark them on their dataset (https://github.com/saeyslab/spotless-benchmark).
Dynamic control of sequential retrieval speed in networks with heterogeneous learning rules
Authors: Gillett Maxwell , Brunel Nicolas
Published: March 2023

Temporal rescaling of sequential neural activity has been observed in multiple brain areas during behaviors involving time estimation and motor execution at variable speeds. Temporally asymmetric Hebbian rules have been used in network models to learn and retrieve sequential activity, with characteristics that are qualitatively consistent with experimental observations. However, in these models sequential activity is retrieved at a fixed speed. Here, we investigate the effects of a heterogeneity of plasticity rules on network dynamics. In a model in which neurons differ by the degree of temporal symmetry of their plasticity rule, we find that retrieval speed can be controlled by varying external inputs to the network. Neurons with temporally symmetric plasticity rules act as brakes and tend to slow down the dynamics, while neurons with temporally asymmetric rules act as accelerators of the dynamics. We also find that such networks can naturally generate separate ‘preparatory’ and ‘execution’ activity patterns with appropriate external inputs.
Convergence of resistance and evolutionary responses inEscherichia coliandSalmonella entericaco-inhabiting chicken farms in China
Authors: Baker Michelle , Zhang Xibin , Guerra Alexandre Maciel , Babaarslan Kubra , Dong Yinping , Wang Wei , Hu Yujie , Renney David , Liu Longhai , Li Hui , Tong Zhiqin , Pearcy Nicole , Zhang Meimei , Geng Yingzhi , Zhao Li , Hao Zhihui , Chen Junshi , Peng Zixin , Li Fengqin , Dottorini Tania
Published: March 2023

Sharing among different pathogens and commensals inhabiting same hosts and environments has significant implications for antimicrobial resistance (AMR), especially in settings with high antimicrobial exposure. We analysed 661E. coliandS. entericaisolates collected within and across hosts and environments, in 10 Chinese chicken farms over 2.5 years using novel data-mining methods. Most isolates within same hosts possessed same clinically relevant AMR-carrying mobile genetic elements (plasmids: 70.6%, transposons: 78%), which also showed recent common evolution. Machine learning revealed known and novel AMR-associated mutations and genes underlying resistance to 28 antimicrobials and primarily associated with resistance inEscherichia coliand susceptibility inSalmonella enterica. Many of these genes were essential and affected same metabolic processes in both species, albeit with varying degrees of phylogenetic penetration. Multi-modal strategies are crucial to investigate the interplay of mobilome, resistance and metabolism in cohabiting bacteria, especially in ecological settings where community-driven resistance selection occurs.
Contrasting the form and strength of pre- and postcopulatory sexual selection in a transparent worm with fluorescent sperm
Authors: Marie-Orleach Lucas , Hall Matthew D. , Schärer Lukas
Published: March 2023

Sexual traits may be selected during multiple consecutive episodes of selection, occurring before, during, or after copulation. The overall strength and shape of selection acting on sexually selected traits may thus be determined by how selection (co-)varies along different episodes. However, it is challenging to measure pre- and postcopulatory phenotypic traits alongside variation in fitness components at each different episode. Here, we used a transgenic line of the transparent flatwormMacrostomum lignanoexpressing green fluorescent protein (GFP) in all cell types, including sperm cells, enablingin vivosperm tracking. We exposed GFP(+) focal worms to three groups in which we assessed their mating success, sperm-transfer efficiency, and sperm fertilising efficiency. Moreover, we measured 13 morphological traits on the focal worms to study the fitness landscape in multivariate trait space. We found linear selection on sperm production rate arising from pre- and postcopulatory components, and on copulatory organ shape arising from sperm fertilising efficiency. We further found nonlinear (mostly concave) selection on combinations of copulatory organ and sperm morphology traits arising mostly from sperm-transfer efficiency and sperm fertilising efficiency. Our study shows that contrasting patterns of phenotypic selection are observed by measuring how sexual selection builds-up over consecutive episodes of selection.
“It’s no use saying it in English”: A qualitative study exploring community leaders’ perceptions of the challenges and opportunities with translating and interpreting COVID-19 related public health messaging to reach ethnic minorities in Australia
Authors: Seale Holly , Harris-Roxas Ben , Heywood Anita , Abdi Ikram , Mahimbo Abela , Woodland Lisa , Waller Emily
Published: March 2023

Background

The Australian Government implemented a range of public health response strategies and communication approaches to reduce the spread of COVID-19; however, concerns have been raised around a failure to consider culturally and linguistically diverse (CaLD) communities sufficiently in these processes. This research aimed to understand the factors that have impacted COVID-19 communication and engagement efforts during the pandemic from the perspective of key CaLD community stakeholders and community members. A further aim was to understand the processes that could be adopted to support future communication strategies, including the promotion of pandemic-related vaccines.

Approach

This study included 29 key informant interviews with community and faith-based leaders in New South Wales, Australia.

Results

The overwhelming message from community leaders was a sense of shared responsibility between their organisations and the government in communicating pertinent and accurate COVID-19 related information to CaLD communities. They expressed a sense of duty to keep their community members safe. While acknowledging this shared responsibility, community leaders and others shouldered significant costs related to resources and time that need to be acknowledged by governments in preparing for future disease outbreaks. They felt that governments should consider: 1) improving communication between governments and CaLD organisations; 2) responding to the specific CaLD needs with greater agility; 3) foregrounding social media in their communication strategy; 4) reinvesting in local public health units to know their population; 5) investing in a health ambassadors model program; 6) preparing a hybrid model of translators/interpreters to fill the gap; and, 7) reimagining vaccine information campaigns to better target CaLD communities.

Conclusion

Given the technical details about the COVID-19 virus conveyed in government information campaigns and the media, ensuring the most vulnerable populations, including people from CaLD backgrounds, access clear, concise and timely public health messaging from both governments and community organisations requires further attention.
Plasma concentrations of curcumin in individuals using curcumin with adjuvants or lipid formulated curcumin supplements: a real world cohort
Authors: Kroon Maurice A.G.M. , Berbee Jacqueline K. , Majait Soumia , Swart Noortje E.L. , van Tellingen Olaf , van Laarhoven Hanneke W.M , Kemper E. Marleen
Published: March 2023

The spice curcumin and its metabolites have been linked to many beneficial health effects. These effects have, thus far, not been duplicated in independent research most likely due to low plasma concentrations of curcumin. Despite the many reports, the public’s interest in curcumin continues to grow and many people use curcumin in daily life. Moreover, companies seize the popularity of curcumin and claim that their formulations increase systemic expose of curcumin. In this independent study we determined the plasma concentration of curcumin after oral intake in daily life to determine if the systemic exposure is sufficient to achieve beneficial health effects.

We used a validated HPLC-MS/MS assay to determine the plasma concentration of curcumin and its metabolites in 47 individuals (patient or healthy) using their own curcumin formulations. Through questionnaires, we assessed which other supplements and (self-)medication(s) were used. The concentrations of curcumin and its metabolites were analyzed in plasma samples collected just before and 1.5 h after curcumin intake. Each sample was pretreated with and without β-glucuronidase to determine the levels of conjugated and unconjugated curcumin.

After oral intake of the curcumin supplement, plasma concentrations of curcumin, demethoxycurcumin, bisdemethoxycurcumin and tetrahydrocurcumin ranged between 2 and 4 nM. Use of adjuvants like piperine did not result in higher curcumin plasma concentrations. Adding β-glucuronidase to the plasma sample increased curcumin plasma levels from below LLQ to 25.3 ng/mL, however still below any plasma concentration to which a beneficial health effect can be expected.

The observed plasma concentration of unchanged curcumin remained several orders below the concentration of 2-100 μg/mL used inin vitrostudies. Therefore, our study confirms the low plasma levels of curcumin and indicates the need to be critical towards the claimed beneficial systemic health effects of current curcumin supplement use in daily life among patients and healthy individuals.
Spatial variation in the non-use of modern contraception and its predictors in Bangladesh
Authors: Khan Md Nuruzzaman , Harris Melissa L.
Published: March 2023

Objective

We assessed spatial variations in the non-use of modern contraception in Bangladesh, and identified associated individual, household and community level factors.

Methods

We analysed data from 16,135 women extracted from the 2017/18 Bangladesh Demographic and Health Survey. The study outcome was non-use of modern contraception (yes, no), and the explanatory variables were factors at the individual (e.g., women’s education), household (e.g., husband education) and community level (e.g., community level poverty and illiteracy). Moran’s I statistics was applied to examine whether any geographical heterogeneity in non-use of modern contraception exists in Bangladesh. The Gettis-ord Gi*was calculated to measure how spatial autocorrelation differed across study locations. A geographically weighted regression model was used to assess the relationship of non-use of modern contraception at the cluster level.

Results

Overall, 42.8% (95% CI, 41.6-43.8) of respondents reported non-use of modern contraception in Bangladesh with a significant variation across geographical locations (p<0.001). Clusters of high non-use of modern contraception (hot spots) were found mostly located in the Sylhet, Barishal and part of the Chattogram divisions while clusters of low use of modern contraception(cold spots) were mostly located in the Rangpur, Mymensingh and part of the Rajshahi divisions. The likelihood of non-use of modern contraception was strongest among women and parteners with low levels of education. Other risk factors analysed including partner’s occupation, community-level illiteracy and poverty had varying effects on the non-use of modern contraception across the locations (clusters) of the country included in the survey.

Conclusion

Prevalence of, and risk factors for, modern contraception non-use in Bangladesh differed depending on geographical location. This suggests a need for targeted area-specific policies and programs to improve knowledge and uptake of modern contraception.
Statistical learning shapes pain perception and prediction independently of external cues
Authors: Onysk Jakub , Gregory Nicholas , Whitefield Mia , Jain Maeghal , Turner Georgia , Seymour Ben , Mancini Flavia
Published: March 2023

The placebo and nocebo effects highlight the importance of expectations in modulating pain perception, but in everyday life we don’t need an external source of information to form expectations about pain. The brain can learn to predict pain in a more fundamental way, simply by experiencing fluctuating, non-random streams of noxious inputs, and extracting their temporal regularities. This process is called statistical learning. Here we address a key open question: does statistical learning modulate pain perception? We asked 27 participants to both rate and predict pain intensity levels in sequences of fluctuating heat pain. Using a computational approach, we show that probabilistic expectations and confidence were used to weight pain perception and prediction. As such, this study goes beyond well-established conditioning paradigms associating non-pain cues with pain outcomes, and shows that statistical learning itself shapes pain experience. This finding opens a new path of research into the brain mechanisms of pain regulation, with relevance to chronic pain where it may be dysfunctional.
Social Determinants of Health and Cardiologist Involvement in the Care of Adults Hospitalized for Heart Failure
Authors: Zhang David T. , Onyebeke Chukwuma , Nahid Musarrat , Balkan Lauren , Musse Mahad , Pinheiro Laura C. , Sterling Madeline R. , Durant Raegan W. , Brown Todd M. , Levitan Emily B. , Safford Monika M. , Goyal Parag
Published: March 2023

Introduction

The involvement of a cardiologist in the care of adults during a hospitalization for heart failure (HF) is associated with reduced rates of in-hospital mortality and hospital readmission. However, not all patients see a cardiologist when they are hospitalized for HF. Since reasons for this are not entirely clear, we sought to determine whether social determinants of health (SDOH) are associated with cardiologist involvement in the management of adults hospitalized for HF. We hypothesized that SDOH would be inversely associated with cardiologist involvement in the care of adults hospitalized for HF.

Methods

We included adult participants from the national REasons for Geographic And Racial Difference in Stroke (REGARDS) cohort, who experienced an adjudicated hospitalization for HF between 2009 and 2017. We excluded participants who were hospitalized at institutions that lacked cardiology services (n=246). We examined nine candidate SDOH, which align with the Healthy People 2030 conceptual model: Black race, social isolation (0–1 visits from a family or friend in the past month), social network/caregiver availability (having someone to care for them if ill), educational attainment < high school, annual household income < $35,000, living in rural areas, living in a zip code with high poverty, living in a Health Professional Shortage Area, and residing in a state with poor public health infrastructure. The primary outcome was cardiologist involvement, a binary variable which was defined as involvement of a cardiologist as the primary responsible clinician or as a consultant, collected via chart review. We examined associations between each SDOH and cardiologist involvement using Poisson regression with robust standard errors. Candidate SDOH with statistically significant associations (p<0.10) were retained for multivariable analysis. Potential confounders/covariates for the multivariable analysis included age, race, sex, HF characteristics, comorbidities, and hospital characteristics.

Results

We examined 876 participants hospitalized at 549 unique US hospitals. The median age was 77.5 years (IQR 71.0-83.7), 45.9% were female, 41.4% were Black, and 56.2% had low income. Low household income (<$35,000/year) was the only SDOH that had a statistically significant association with cardiologist involvement in a bivariate analysis (RR: 0.88 [95% CI: 0.82-0.95]). After adjusting for potential confounders, low income remained inversely associated (RR: 0.89 [95% CI: 0.82-0.97]).

Conclusions

Adults with low household income were 11% less likely to have a cardiologist involved in their care during a hospitalization for HF. This suggests that socioeconomic status may implicitly bias the care provided to patients hospitalized for HF.
Golgi organization is a determinant of stem cell function in the small intestine
Authors: Scharaw Sandra , Sola-Carvajal Agustin , Belevich Ilya , Webb Anna T. , Das Srustidhar , Andersson Simon , Pentinmikko Nalle , Villablanca Eduardo J. , Goldenring James R. , Jokitalo Eija , Coffey Robert J. , Katajisto Pekka
Published: March 2023

Cell-to-cell signalling between niche and stem cells regulates tissue regeneration. While the identity of many mediating factors is known, it is largely unknown whether stem cells optimize their receptiveness to niche signals according to the niche organization. Here, we show that Lgr5+ small intestinal stem cells (ISCs) regulate the morphology and orientation of their secretory apparatus to match the niche architecture, and to increase transport efficiency of niche signal receptors. Unlike the progenitor cells lacking lateral niche contacts, ISCs orient Golgi apparatus laterally towards Paneth cells of the epithelial niche, and divide Golgi into multiple stacks reflecting the number of Paneth cell contacts. Stem cells with a higher number of lateral Golgi transported Epidermal growth factor receptor (Egfr) with a higher efficiency than cells with one Golgi. The lateral Golgi orientation and enhanced Egfr transport required A-kinase anchor protein 9 (Akap9), and was necessary for normal regenerative capacityin vitro. Moreover, reduced Akap9 in aged ISCs renders ISCs insensitive to niche-dependent modulation of Golgi stack number and transport efficiency. Our results reveal stem cell-specific Golgi complex configuration that facilitates efficient niche signal reception and tissue regeneration, which is compromised in the aged epithelium.
Antiviral activities of two nucleos(t)ide analogs against vaccinia and mpox viruses in primary human fibroblasts
Authors: Dsouza Lara , Pant Anil , Offei Samuel , Priyamvada Lalita , Pope Blake , Satheshkumar Panayampalli S. , Wang Zhengqiang , Yang Zhilong
Published: March 2023

Many poxviruses are significant human and animal pathogens, including viruses that cause smallpox and mpox. Identification of inhibitors of poxvirus replication is critical for drug development to manage poxvirus threats. Here we tested two compounds, nucleoside trifluridine and nucleotide adefovir dipivoxil, for antiviral activities against vaccinia virus (VACV) and mpox virus (MPXV) in physiologically relevant primary human fibroblasts. Both trifluridine and adefovir dipivoxil potently inhibited replication of VACV and MPXV (MA001 2022 isolate) in a plaque assay. Upon further characterization, they both conferred high potency in inhibiting VACV replication with half maximal effective concentrations (EC50) at low nanomolar levels in our recently developed assay based on a recombinant VACV secreted Gaussia luciferase. Our results further validated that the recombinant VACV with Gaussia luciferase secretion is a highly reliable, rapid, non-disruptive, and simple reporter tool for identification and chracterization of poxvirus inhibitors. Both compounds inhibited VACV DNA replication and downstream viral gene expression. Given that both compounds are FDA-approved drugs, and trifluridine is used to treat ocular vaccinia in medical practice due to its antiviral activity, our results suggest that it holds great promise to further test trifluridine and adefovir dipivoxil for countering poxvirus infection, including mpox.
An extended Tudor domain within Vreteno interconnects Gtsf1L and Ago3 for piRNA biogenesis inBombyx mori
Authors: Bronkhorst Alfred W. , Lee Chop Y. , Möckel Martin M. , Ruegenberg Sabine , de Jesus Domingues Antonio M. , Sadouki Shéraz , Sumiyoshi Tetsutaro , Siomi Mikiko C. , Stelzl Lukas , Luck Katja , Ketting René F.
Published: March 2023

Piwi-interacting RNAs (piRNAs) direct PIWI proteins to transposons to silence them, thereby preserving genome integrity and fertility. The piRNA population can be expanded in the ping-pong amplification loop. Within this process, piRNA-associated PIWI proteins (piRISC) enter the nuage to cleave target RNA, which is stimulated by Gtsf proteins. The resulting cleavage product gets loaded into an empty PIWI protein to form a new piRISC complex. However, for piRNA amplification to occur, it is required that new RNA substrates, Gtsf-piRISC and empty PIWI proteins are all in physical proximity. In this study we show that BmGtsf1L binds to piRNA-loaded BmAgo3 and co-localizes to BmAgo3-BmVreteno positive granules. Biochemical assays further revealed that conserved residues within the unstructured tail of BmGtsf1L directly interact with BmVreteno. Using a combination of AlphaFold modeling, atomistic molecular dynamics simulations and in vitro assays we identified a novel binding interface on a BmVreteno-eTudor domain, which is required for BmGtsf1L binding. Our study reveals that a single eTudor domain within BmVreteno provides two binding interfaces and thereby interconnects piRNA-loaded BmAgo3 and BmGtsf1L.
Hearing what is being said: The distributed neural substrate for early speech interpretation
Authors: Clarke Alex , Tyler Lorraine K. , Randall Billi , Marslen-Wilson William
Published: March 2023

Human speech comprehension is remarkable for the immediacy with which the listener hears what is being said. Here, we focus on the neural underpinnings of this process in isolated spoken words, to define the intrinsic properties of these core mechanisms independent of contextual constraints or predictions. We analysed source-localised MEG data for a set of 218 spoken nouns heard in isolation, using Representational Similarity Analysis to probe the spatiotemporal coordinates of processes sensitive to speech phonology, lexical form, and the semantics of emerging word candidates. Phonological model fit was detectable within 40-50 ms from onset, rapidly engaging a bilateral network including superior and middle temporal cortex and extending into anterior temporal and inferior parietal regions. Model fit to lexical form emerged within 60-70 ms, and model fit to cohort semantics from 100-110 ms, both overlapping strongly with the spatial pattern of phonological model fit in bilateral temporo-parietal cortices. Strikingly, the majority of vertices in a central core of brain regions showed significant model fit to all three dimensions tested, consistent with a fully distributed neural substrate for early speech analysis. The early interpretation of speech seems to be conducted in a unified integrative representational space, in conflict with the conventional view that speech analysis is underpinned by a linguistically stratified representational hierarchy.
Metabolomic, proteomic and single cell proteomic analysis of cancer cells treated with the KRASG12Dinhibitor MRTX1133
Authors: Orsburn Benjamin C.
Published: March 2023

Mutations in KRAS are common drivers of human cancers and are often those with the poorest overall prognosis for patients. A recently developed compound, MRTX1133, has shown promise in inhibiting the activity of KRASG12Dmutant proteins, one of the main drivers in pancreatic cancer. To better understand the mechanism of action of this compound I performed both proteomics and metabolomics on four KRASG12Dmutant pancreatic cancer cell lines. To obtain increased granularity in the proteomic observations, single cell proteomics was successfully performed on two of these lines. Following quality filtering, a total of 1,498 single cells were analyzed. From these cells 3,140 total proteins were identified with approximately 953 proteins quantified per cell. At 48 hours of treatment, two distinct populations of cells can be observed based on the level of effectiveness of the drug in decreasing total abundance of the KRAS protein in each respective cell, results that are effectively masked in the bulk cell analysis. All mass spectrometry data and processed results are publicly available at thewww.massive.ucsd.eduat accessions PXD039597, PXD039601 and PXD039600.

Abstract Graphic
Nuclease genes occupy boundaries of genetic exchange between bacteriophages
Authors: Barth Zachary K , Dunham Drew T , Seed Kimberley D
Published: March 2023

Homing endonuclease genes (HEGs) are ubiquitous selfish elements that generate targeted double-stranded DNA breaks, facilitating the recombination of the HEG DNA sequence into the break site and contributing to the evolutionary dynamics of HEG-encoding genomes. Bacteriophages (phages) are well-documented to carry HEGs, with the paramount characterization of HEGs being focused on those encoded by coliphage T4. Recently, it has been observed that the highly sampled vibriophage, ICP1, is similarly enriched with HEGs distinct from T4’s. Here, we examined the HEGs encoded by ICP1 and diverse phages, proposing HEG-driven mechanisms that contribute to phage evolution. Relative to ICP1 and T4, we found a variable distribution of HEGs across phages, with HEGs frequently encoded proximal to or within essential genes. We identified large regions (> 10kb) of high nucleotide identity flanked by HEGs, deemed HEG islands, which we hypothesize to be mobilized by the activity of flanking HEGs. Finally, we found examples of domain swapping between phage-encoded HEGs and genes encoded by other phages and phage satellites. We anticipate that HEGs have a larger impact on the evolutionary trajectory of phages than previously appreciated and that future work investigating the role of HEGs in phage evolution will continue to highlight these observations.
Syndromic surveillance as a predictive tool for health-related school absences in COVID-19 Sentinel Schools in Catalonia, Spain
Authors: Ganem Fabiana , Alonso Lucia , Colom-Cadena Andreu , Bordas Anna , Folch Cinta , Soriano-Arandes Antoni , Casabona Jordi
Published: March 2023

Monitoring influenza-like illness through syndromic surveillance could be an important strategy in the COVID-19 emergence scenario. The study aims to implement syndromic surveillance for children aged 6-11 years in COVID-19 sentinel schools in Catalonia. Data collection was made by self-applied survey to collect daily health status and symptoms. We proceed logistic mixed models and a Latent Class Analysis to investigate associations with syndromes and school absence. Were enrolled 135 students (2163 person-days) that filled 1536 surveys and 60 participants reported illness (29.52 by 100 person/day) and registered 189 absence events, 62 of them (32.8%) related to health reasons. Subgroups of influenza-like illness were founded such as a significantly and positively association with school absences. The findings of this study can be applied to the detection of health events, and association with school absences, offering an opportunity for quick action, or simply for monitoring and understanding the students’ health situation.

ARTICLE SUMMARY LINE

This study confirms the relevance of syndromic surveillance in students from 6 to 11 years of age as a strategy to timely detect events that can cause school absence, either to support public health actions by applying analytical models that improve their potential in providing systematized information, or to monitor and understand the health situation of students, thus offering an opportunity for rapid action.
MAPTallele and haplotype frequencies in Nigerian Africans: population distribution and association with Parkinson’s disease risk and age at onset
Authors: Okunoye Olaitan , Ojo Oluwadamilola , Abiodun Oladunni , Abubakar Sani , Achoru Charles , Adeniji Olaleye , Agabi Osigwe , Agulanna Uchechi , Akinyemi Rufus , Ali Mohammed , Ani-Osheku Ifeyinwa , Arigbodi Owotemu , Bello Abiodun , Erameh Cyril , Farombi Temitope , Fawale Michael , Imarhiagbe Frank , Iwuozo Emmanuel , Komolafe Morenikeji , Nwani Paul , Nwazor Ernest , Nyandaiti Yakub , Obiabo Yahaya , Odeniyi Olanike , Odiase Francis , Ojini Francis , Onwuegbuzie Gerald , Osaigbovo Godwin , Osemwegie Nosakhare , Oshinaike Olajumoke , Otubogun Folajimi , Oyakhire Shyngle , Ozomma Simon , Samuel Sarah , Taiwo Funmilola , Wahab Kolawole , Zubair Yusuf , Hernandez Dena , Bandres-Ciga Sara , Blauwendraat Cornelis , Singleton Andrew , Houlden Henry , Hardy John , Rizig Mie , Okubadejo Njideka
Published: March 2023

Background

The microtubule-associated protein tau (MAPT) gene is critical because of its putative role in the causal pathway of neurodegenerative diseases including Parkinson’s disease (PD). However, there is a lack of clarity regarding the link between the main H1 haplotype and risk of PD. Inconsistencies in reported association may be driven by genetic variability in the populations studied to date. Data onMAPThaplotype frequencies in the general population and association studies exploring the role ofMAPThaplotypes in conferring PD risk in black Africans are lacking.

Objectives

To determine the frequencies ofMAPThaplotypes and explore the role of the H1 haplotype as a risk factor for PD risk and age at onset in Nigerian Africans.

Methods

The haplotype and genotype frequencies ofMAPTrs1052553 were analysed using PCR-based KASP™ in 907 individuals with PD and 1,022 age-matched neurologically normal controls from the Nigeria Parkinson’s Disease Research (NPDR) network cohort. Clinical data related to PD included age at study, age at onset, and disease duration.

Results

The frequency of the mainMAPTH1 haplotype in this cohort was 98.7% in individuals with PD, and 99.1% in healthy controls (p=0.19). The H2 haplotype was present in 41/1929 (2.1%) of the cohort (PD - 1.3%; Controls - 0.9%; p=0.24). The most frequentMAPTgenotype was H1H1 (PD - 97.5%, controls - 98.2%). The H1 haplotype was not associated with PD risk after accounting for gender and age at onset (Odds ratio for H1/H1 vs H1/H2 and H2/H2: 0.68 (95% CI:0.39-1.28); p=0.23).

Conclusions

Our findings support previous studies that report a low frequency of theMAPTH2 haplotype in black ancestry Africans, but document its occurrence in the Nigerian population (2.1%). In this cohort of black Africans with PD, theMAPTH1 haplotype was not associated with an increased risk or age at onset of PD.
Associations of polygenic inheritance of physical activity with aerobic fitness, cardiometabolic risk factors and diseases: the HUNT Study
Authors: Tynkkynen Niko Paavo , Törmäkangas Timo , Palviainen Teemu , Hyvärinen Matti , Klevjer Marie , Joensuu Laura , Kujala Urho , Kaprio Jaakko , Bye Anja , Sillanpää Elina
Published: March 2023

Background

Physical activity (PA), aerobic fitness, and cardiometabolic diseases (CMD) are highly heritable multifactorial phenotypes. Shared genetic factors may underlie the associations between higher levels of PA and better aerobic fitness and a lower risk for cardiometabolic CMDs. Our aim was first to validate PA genotype against self-reported leisure-time PA (LTPA) and second to study how PA genotype associates with aerobic fitness and CMD risk factors. Finally, we investigated if PA genotype predicts CMD endpoints. We expected that these analyses would provide evidence for pleiotropic effects (same gene variants explaining both phenotypes) of PA and CMDs.

Methods and findings

Polygenic risk score (PRS) for PA was constructed in the Trøndelag Health Study (N=47,148) using UK Biobank single nucleotide polymorphism-specific weights (N=400,124). The results showed that genotypes predisposing to higher PA were associated with greater self-reported PA (Beta [B]=0.282 MET-h·wk-1per SD of PRS for PA, 95% confidence interval [CI]=0.211, 0.354) but not with aerobic fitness. These genotypes were also associated with healthier profile in CMD risk factors (waist circumference [B=-0.003 cm, 95% CI=-0.004, -0.002], body mass index [B=-0.002 kg·(m2)-1, 95% CI=-0.004, -0.001], high-density lipoprotein cholesterol [B=0.004 mmol·L-1, 95% CI=0.002, 0.006]) and lower incidence of hypertensive diseases (HR=0.97, 95% CI=0.951, 0.990), stroke (HR=0.94, 95% CI=0.903, 0.978) and type 2 diabetes (HR=0.94, 95% CI=0.902, 0.970). When accounting for self-reported PA, the associations between PA genotypes and CMD risk factors remained statistically significant.

Conclusions

Genotypes predisposing to higher PA were associated with higher amount of PA. However, in general the predictive value of the PRS for PA in predicting self-reported PA was low, possibly because of the acknowledged inconsistencies in assessing PA in cohort studies. Genotypes predisposing to higher PA were also associated with better cardiometabolic health and lower incidence of CMDs, and the observed associations were independent of self-reported PA. These results support earlier findings suggesting small pleiotropic effects between PA and CMDs and provide new evidence about associations with polygenic inheritance of PA and intermediate CMD risk factors. The observed association were however small, and results do not suggest clinical relevance in health promotion.
Neurophysiological and computational mechanisms of non-associative and associative memories during complex human behavior
Authors: Xiao Yuchen , López Paula Sánchez , Wu Ruijie , Srinivasan Ravi , Wei Peng-Hu , Shan Yong-Zhi , Weisholtz Daniel , Cosgrove Garth Rees , Madsen Joseph R , Stone Scellig , Zhao Guo-Guang , Kreiman Gabriel
Published: March 2023

The ability to transiently remember what happened where and when is a cornerstone of cognitive function. Forming and recalling working memories depends on detecting novelty, building associations to prior knowledge, and dynamically retrieving context-relevant information. Previous studies have scrutinized the neural machinery for individual components of recognition or associative memory under laboratory conditions, such as recalling elements from arbitrary lists of words or pictures. In this study, we implemented a well-known card- matching game that integrates multiple components of memory formation together in a naturalistic setting to investigate the dynamic neural processes underlying complex natural human memory. We recorded intracranial field potentials from 1,750 depth or subdural electrodes implanted in 20 patients with pharmacologically-intractable epilepsy while they were performing the task. We leveraged generalized linear models to simultaneously assess the relative contribution of neural responses to distinct task components. Neural activity in the gamma frequency band signaled novelty and graded degrees of familiarity, represented the strength and outcome of associative recall, and finally reflected visual feedback on a trial-by-trial basis. We introduce an attractor-based neural network model that provides a plausible first-order approximation to capture the behavioral and neurophysiological observations. The large-scale data and models enable dissociating and at the same time dynamically tracing the different cognitive components during fast, complex, and natural human memory behaviors.
Direct Thalamic Inputs to Hippocampal CA1 Transmit a Signal That Suppresses Ongoing Contextual Fear Memory Retrieval
Authors: Ratigan Heather C. , Krishnan Seetha , Smith Shai , Sheffield Mark E. J.
Published: March 2023

Memory retrieval of fearful experiences is essential for survival but can be maladaptive if not appropriately suppressed. Fear memories can be acquired through contextual fear conditioning (CFC) which relies on the hippocampus. The thalamic subregion Nucleus Reuniens (NR) is necessary for contextual fear extinction and strongly projects to hippocampal subregion CA1. However, the NR-CA1 pathway has not been investigated during behavior, leaving unknown its role in contextual fear memory retrieval. We implement a novel head-restrained virtual reality CFC paradigm and show that inactivation of the NR-CA1 pathway prolongs fearful freezing epochs, induces fear generalization, and delays extinction. We usein vivosub-cellular imaging to specifically record NR-axons innervating CA1 before and after CFC. We find NR-axons become selectively tuned to freezing only after CFC, and this activity is well-predicted by an encoding model. We conclude that the NR-CA1 pathway actively suppresses fear responses by disrupting ongoing hippocampal-dependent contextual fear memory retrieval.
Accountability, emergency and liberty during COVID-19 in the UK 2020–22
Authors: Ferry Laurence , Midgley Henry , Green Stuart
Published: March 2023

Purpose

The study explains why Parliamentarians in the United Kingdom (UK) focused on accountability through data during the COVID-19 pandemic, as well as on how data could be used to improve the government’s response to the pandemic.

Design/methodology/approach

Understanding the implications of accountability for COVID-19 is crucial to understanding how governments should respond to future pandemics. This article provides an account of what a select committee in the UK thought were the essential elements of these accountability relationships. To do so, the authors use a neo-Roman concept of liberty to show how Parliamentary oversight of the pandemic for accountability was crucial to maintaining the liberty of citizens during the crisis and to identify what lessons need to be learnt for future crises.

Findings

The study shows that Parliamentarians were concerned that the UK government was not meeting its obligations to report openly about the COVID-19 pandemic to them. It shows that the government did make progress in reporting during the pandemic but further advancements need to be made in future for restrictions to be compatible with the protection of liberty.

Research limitations/implications

The study extends the concept of neo-Roman liberty showing how it is relevant in an emergency situation and provides an account of why accountability is necessary for the preservation of liberty when the government uses emergency powers.

Practical implications

Governments and Parliaments need to think about how they preserve liberty during crises through enhanced accountability mechanisms and the publication of data.

Originality/value

The study extends previous work on liberty and calculation, providing a theorisation of the role of numbers in the protection of liberty.