bluuebunny/crossref_metadata_2025 huggingface dataset:
Learning phenotype associated signature in spatial transcriptomics with PASSAGE
Authors: Guo Chen-Kai , Xia Chen-Rui , Peng Guangdun , Cao Zhi-Jie , Gao Ge
Published: September 2024

Spatially resolved transcriptomics (SRT) is poised to advance our understanding of cellular organization within complex tissues under various physiological and pathological conditions at unprecedented resolution. Despite the development of numerous computational tools that facilitate the automatic identification of statistically significant intra-/inter-slice patterns (like spatial domains), these methods typically operate in an unsupervised manner, without leveraging sample characteristics like physiological/pathological states. Here we presentPASSAGE(PhenotypeAssociatedSpatialSignatureAnalysis withGraph-basedEmbedding), a rationally-designed deep learning framework for characterizing phenotype-associated signatures across multiple heterogeneous spatial slices effectively. In addition to its outstanding performance in systematic benchmarks, we have demonstrated PASSAGE’s unique capability in identifying sophisticated signatures in multiple real-world datasets. The full package of PASSAGE is available athttps://github.com/gao-lab/PASSAGE.
Bioengineering Fascicle-like Skeletal Muscle Bioactuators via Pluronic-Assisted Co-axial 3D Bioprinting
Authors: Fuentes Judith , Mestre Rafael , Guix Maria , Ghailan Ibtissam , Ruiz-González Noelia , Patiño Tania , Sánchez Samuel
Published: September 2024

Advances in 3D bioprinting have opened new possibilities in the development of bioengineered muscle models that mimic the structure and functionality of native tissues. The combination of skeletal muscle tissue and artificial elements promotes diverse innovative solutions of interest in both the biomedical field and the development of biohybrid actuators. However, current bioengineering approaches do not fully recreate the complex fascicle-like hierarchical organization of skeletal muscle, impacting on the muscle maturation process due to a lack of oxygen and nutrients supply in the scaffold inner regions. Here we explored co-axial 3D bioprinting as a strategy towards overcoming this challenge, creating individual/non-fused filaments with controlled thickness that present a fascicle-like organization. Compared to conventional 3D-bioprinting, where cell-laden bioink is disposed by a single syringe, our Pluronic-assisted co-axial 3D-bioprinting system (PACA-3D) creates a physical confinement of the bioink during the extrusion process, effectively obtaining thin and independent printed fibers with controlled shape. Fabrication of skeletal muscle-based actuators with PACA-3D resulted in improved cell differentiation, obtaining stronger bioactuators with increased force output when compared to bioactuators fabricated by conventional 3D bioprinting. The versatility of our technology has been demonstrated using different biomaterials, showing its potential to develop more complex biohybrid tissue-based architectures with improved functionality.
EHZ2 inhibition enhances the activity of platinum chemotherapy in aggressive-variant prostate cancer
Authors: Latarani Maryam , Pucci Perla , Eccleston Mark , Manzo Massimiliano , Gangadharannambiar Priyadarsini , Alborelli Ilaria , Mongiardini Vera , Mahmood Namra , Colombo Mario Paolo , Grimaldi Benedetto , Rigas Sushila , Akamatsu Shusuke , Hawkes Cheryl , Wang Yuzhuo , Jachetti Elena , Crea Francesco
Published: September 2024

Background

EZH2 promotes aggressive-variant prostate cancer (AVPC) progressionviahistone H3-Lysine-27 tri-methylation (H3K27me3). We hypothesize that epigenetic reprogrammingviaEZH2 inhibitors (EZH2i) improves the efficacy of chemotherapy in AVPC.

Methods

We studied the expression of EZH2 in clinical prostate cancer cohorts (bioinformatics). We determined the effect of EZH2i on both cellular- and cell-free-H3K27me3 levels. We measured effects of carboplatin with/without EZH2i on AVPC cell viability (IC50). We studied how EZH2i modulate gene expression (RNA Seq).

Results

EZH2 was significantly up-regulated in AVPCvsother prostate cancer types. EZH2i reduced both cellular and cell free-H3K27me3 levels. EZH2i significantly reduced carboplatin IC50. EZH2i reduced the expression of DNA repair and increased the expression of pro-apoptotic genes.

Article Highlights

Polycomb-mediated gene silencing promotes prostate cancer progression

Aggressive-variant prostate cancers (AVPCs) are characterized by increased activity of the Polycomb-Repressive Complex 2 (PRC2)

Here we show that PRC2 inhibitors are scarcely effective as monotherapy in ACPC cells

However the combination of PRC2 inhibitors and carboplatin is highly synergistic

RNA Seq studies revealed that PRC2 inhibitors enhance carboplatin activity by modulating several key pathways, including DNA repair and apoptosis.
Variation in moment-to-moment brain state engagement changes across development and contributes to individual differences in executive function
Authors: Ye Jean , Tejavibulya Link , Dai Wei , Cope Lora M. , Hardee Jillian E. , Heitzeg Mary M. , Lichenstein Sarah , Yip Sarah W. , Banaschewski Tobias , Baker Gareth J. , Bokde Arun L.W. , Brühl Rüdiger , Desrivières Sylvane , Flor Herta , Gowland Penny , Grigis Antoine , Heinz Andreas , Martinot Jean-Luc , Paillère Martinot Marie-Laure , Artiges Eric , Nees Frauke , Orfanos Dimitri Papadopoulos , Poustka Luise , Hohmann Sarah , Holz Nathalie , Baeuchl Christian , Smolka Michael N. , Vaidya Nilakshi , Walter Henrik , Whelan Robert , Schumann Gunter , Garavan Hugh , Chaarani Bader , Gee Dylan G. , Baskin-Sommers Arielle , Casey BJ ,   IMAGEN consortium, Scheinost Dustin
Published: September 2024

Neural variability, or variation in brain signals, facilitates dynamic brain responses to ongoing demands. This flexibility is important during development from childhood to young adulthood, a period characterized by rapid changes in experience. However, little is known about how variability in the engagement of recurring brain states changes during development. Such investigations would require the continuous assessment of multiple brain states concurrently. Here, we leverage a new computational framework to study state engagement variability (SEV) during development. A consistent pattern of SEV changing with age was identified across cross-sectional and longitudinal datasets (N>3000). SEV developmental trajectories stabilize around mid-adolescence, with timing varying by sex and brain state. SEV successfully predicts executive function (EF) in youths from an independent dataset. Worse EF is further linked to alterations in SEV development. These converging findings suggest SEV changes over development, allowing individuals to flexibly recruit various brain states to meet evolving needs.
Neural Correlates of the Embodied Sense of Agency
Authors: Regev Krugwasser Amit , van der Goot Reina , Markusfeld Geffen , Zvilichovsky Yair , Salomon Roy
Published: September 2024

The Sense of Agency (SoA) is the subjective experience that ‘I am in control of my actions’. Recent accounts have distinguished two levels in the formation of SoA - early implicit sensorimotor processes (feeling of agency) and later explicit higher-level processes, incorporating one’s thoughts and beliefs (judgment of agency). Even though SoA is fundamental to our interactions with the external world and the construct of the self, its underlying neural mechanism remains elusive. In the current pre-registered electroencephalography (EEG) study, we used time-frequency analysis and Multivariate Pattern Analysis (MVPA) to investigate the electrophysiological characteristics associated with SoA. We used an established embodied virtual reality paradigm in which visual feedback of a movement is modulated to examine the effect of conflicts between the predicted and perceived sensory feedback. Participants moved their finger and were shown a virtual hand that either mimicked their movement or differed anatomically (different finger) or spatially (angular shift), then judged their SoA over the observed movement while their brain activity was recorded. In accordance with our pre-registered hypothesis, we found that a reduction of SoA is associated with decreased attenuation in the alpha frequency band. Increased power in the theta frequency band was also associated with SoA reduction. Importantly, we show that trials containing a sensorimotor alteration vs. trials containing no alteration can reliably be decoded with up to 68% accuracy starting around 200ms after the movement onset. Finally, cross-decoding analyses revealed similar neural patterns for reduced SoA in the anatomical and spatial conditions, starting around 500ms after the movement onset. Together, our results reveal a cortical signature of loss of SoA and provide neural evidence supporting the hypothesis of a two-level formation of SoA - an early domain-specific component, possibly the equivalent of the implicit feeling of agency, and a late domain-general component, possibly the equivalent of the explicit judgment of agency.
Mpox vaccination uptake in a UK community sample of gay, bisexual, and other men who have sex with men (GBMSM) the year following the 2022 Clade IIb mpox outbreak
Authors: Mullen Dolores , Edney Jessica , Phillips Dawn , Wilkie Ruth , Reid David , Lowndes Catherine M , Buitendam Erna , Sinka Katy , Mandal Sema , Mercer Catherine H , Saunders John , Mohammed Hamish , Ogaz Dana
Published: September 2024

Mpox is an infectious disease transmitted through close contact. It is caused by the monkeypox virus, which is endemic to some countries of West and Central Africa. A multi-country outbreak of mpox occurred in 2022, and the UK experienced rapid community transmission associated with sexual contact, mainly, but not exclusively among networks of gay, bisexual, and other men who have sex with men (GBMSM). In response to the outbreak in the UK, a reactive mpox vaccination programme was targeted to those most at risk. We explore the uptake and course completion of mpox vaccination in GBMSM taking part in an online survey in 2023. Findings from this community sample indicate vaccination uptake in around two-thirds of participants meeting mpox proxy eligibility criteria with high levels of course completion among all and eligible participants that were ever vaccinated. Vaccine non-offer was a barrier to uptake, as nearly a third of those eligible but unvaccinated reported never having received an mpox vaccine offer. Continued targeting of vaccination to GBMSM at highest risk of mpox at SHS, with community-support, will help facilitate equitable uptake of vaccination.
A Qualitative Study on Food Taboos Among Rural Pregnant Women in Bangladesh: Motivators for Adherence and Influencers of Taboo-Breaking Behavior
Authors: Rayna Shahrin Emdad , Khan Fahmida Afroz , Samin Sharraf , Siraj Saiqa , Nizam Saika , Islam Syed Shariful , Khalequzzaman Md.
Published: September 2024

Understanding the influence of cultural practices on maternal health is crucial in addressing the nutritional challenges faced by pregnant women in rural Bangladesh. Despite significant improvements in maternal and child health indicators, food taboos remain prevalent, impacting the nutritional well-being and health outcomes of vulnerable populations. This study explored food taboos and factors related to their adherence or violation, among rural pregnant women in four districts of Bangladesh: Habiganj, Bhola, Rajshahi, and Cumilla. A qualitative cross-sectional study was conducted with 90 participants through 29 in-depth interviews and 11 focus group discussions. Participants included 21 pregnant women, 23 mothers-in-law, 20 husbands, and 26 healthcare workers. The data were thematically coded and the narrative was analyzed. All participants identified at least one food item restricted by family elders, often based on beliefs about the negative effects of certain foods on pregnancy and the baby’s health. Commonly restricted animal source foods included white carp, trout, duck meat, and mutton, due to fears of convulsions, speech disorders, or undesirable traits in the baby. Raw papayas and pineapples were avoided due to beliefs they could cause miscarriage. Adherence to these taboos was related to the pregnant mother’s preference for vaginal delivery, desire to avoid harm to her child, and profound respect for her elders. Factors enabling the breaking of food taboos included nutritional counseling by health care workers, increased family understanding of maternal nutrition, reduced reinforcement of taboos, and the lack of negative consequences from consuming tabooed foods. The findings highlight the importance of utilizing scientific evidence to challenge food taboos by developing new strategies or updating community-based nutritional counseling programs. Furthermore, including family members and community elders in these efforts is crucial for creating a conducive environment that facilitates dietary changes for pregnant women.
Spatial and Single Cell Mapping of Castleman Disease Reveals Key Stromal Cell Types and Cytokine Pathways
Authors: Smith David , Eichinger Anna , Rech Andrew , Wang Julia , Esteva Eduardo , Seyedian Arta , Yang Xiaoxu , Zhang Mei , Martinez Dan , Tan Kai , Luo Minjie , Park Christopher , Reizis Boris , Pillai Vinodh
Published: September 2024

Castleman disease (CD) is inflammatory lymphoproliferative disorder of unclear etiology. To determine the cellular and molecular basis of CD, we analyzed the spatial proteome of 4,485,009 single cells, transcriptome of 50,117 single nuclei, immune repertoire of 8187 single nuclei, and pathogenic mutations in Unicentric CD, idiopathic Multicentric CD, HHV8-associated MCD, and reactive lymph nodes. CD was characterized by increased non-lymphoid and stromal cells that formed unique microenvironments where they interacted with lymphoid cells. Interaction of activated follicular dendritic cell (FDC) cytoplasmic meshworks with mantle zone B cells was associated with B cell activation and differentiation. VEGF, IL-6, MAPK, and extracellular matrix pathways were elevated in stromal cells of CD. CXCL13+ FDCs, PDGFRA+ T-zone reticular cells (TRC), and ACTA2-positive perivascular reticular cells (PRC) were identified as the predominant source of increased VEGF expression and IL-6 signaling in CD. VEGF expression by FDCs was associated with peri-follicular neovascularization. FDC, TRC and PRC of CD activated JAK-STAT, TGFβ, and MAPK pathways via ligand-receptor interactions involving collagen, integrins, complement components, and VEGF receptors. T, B and plasma cells were polyclonal but showed class-switched and somatically hypermutated IgG1+ plasma cells consistent with stromal cell-driven germinal center activation. In conclusion, our findings show that stromal cell activation and associated B-cell activation and differentiation, neovascularization and stromal remodeling underlie CD and suggest new targets for treatment.

Key points

Castleman Disease is characterized by activation and proliferation of CXCL13+ FDCs, PDGFRA+ reticular cells, and ACTA2-positive PRCs.

VEGF and IL-6 from lymph node stromal cells are associated with B-cell activation and differentiation, endothelial proliferation, and inflammation in CD
Andexanet alfa-associated heparin resistance in cardiac surgery: mechanism andin vitroperspectives
Authors: Chabata Charlene V. , Yu Haixiang , Ke Lei , Frederiksen James W. , Patel Prakash A. , Sullenger Bruce A. , Thalji Nabil K.
Published: September 2024

Background

Andexanet alfa (andexanet) is the only FDA-approved antidote for direct factor Xa (FXa) inhibitors but has been reported to cause resistance to unfractionated heparin (UFH). This has delayed anticoagulation for procedures requiring cardiopulmonary bypass (CPB). The mechanism, andexanet and UFH dose dependence, and thrombotic risk of andexanet-associated heparin resistance are unknown.

Methods

The effect of andexanetin vitrowas determined using activated clotting times (ACT) and thromboelastography (TEG).Ex vivoCPB circuits were used to determine whether andexanet impaired anticoagulation for extracorporeal circulation. Kinetics of antithrombin (AT) inhibition of FXa and thrombin were measured in the presence of andexanet. Equilibrium modeling and thrombin generation assay (TGA) validation were used to predict the role of andexanet, AT, and UFH concentrations in andexanet-associated heparin resistance.

Results

Andexanet prevented UFH-mediated prolongation of ACT and TEG times. At lower concentrations of andexanet, heparin resistance could be overcome with suprapharmacologic doses of UFH, but not at higher andexanet concentrations. Andexanet rendered standard doses of UFH inadequate to prevent circuit thrombosis, and suprapharmacologic UFH doses were only partially able to overcome this. Scanning electron microscopy demonstrated coagulation activation in circuits. Andexanet prevented UFH enhancement of AT-mediated inhibition of FXa and thrombin. Equilibrium modeling and TGA validation demonstrated that andexanet creates a triphasic equilibrium with UFH and AT: initial UFH unresponsiveness, normal UFH responsiveness when andexanet is depleted, and finally AT depletion. Sufficient CPB heparinization can only occur at low therapeutic andexanet doses and normal AT levels. Higher andexanet doses or AT deficiency may require both AT supplementation and very high UFH doses.

Conclusions

Andexanet causes heparin resistance due to redistribution of UFH-bound AT. If andexanet cannot be avoided prior to heparinization and direct thrombin inhibitors are undesirable, ourin vitrostudy suggests excess UFH should be considered as a potential strategy prior to AT supplementation.

Highlights

Andexanet alfa causes heparin resistance not by depleting antithrombin, but rather by sequestering heparin-bound antithrombin such that it cannot act as an anticoagulant.

Heparin responsiveness in the presence of Andexanet alfa is triphasic such that the effect of a dose of heparin can now be predicted in vitro based on the relative concentrations of andexanet, heparin, and antithrombin.

The in vitro insights provided by this work provide a rational starting point for further clinical elucidation of the problem and management of andexanet-associated heparin resistance
Omission-responsive neurons encode negative prediction error and probability in the auditory cortex
Authors: Yaron Amit , Shiramatsu-Isoguchi Tomoyo , Kern Felix B. , Ohki Kenichi , Takahashi Hirokazu , Chao Zenas C.
Published: September 2024

Predictive coding posits the brain predicts incoming sensory information and signals prediction errors when actual input differs from expectations. Positive prediction errors occur when input exceeds predictions, while negative prediction errors arise when input falls short. Specific neurons are theorized to encode negative prediction errors, linked to responses to omitted expected inputs. However, the information encoded in omission responses remains unclear. We recorded single-unit activity in rat auditory cortex during an omission paradigm with varying tone probabilities. We identified neurons selectively responding to omissions, with responses increasing with evidence accumulation and correlating with tone predictability—key characteristics of negative prediction-error neurons. Interestingly, these neurons showed selective omission responses but broad tone responses, revealing an asymmetry in error signaling. We propose a circuit model with laterally interconnected prediction-error neurons reproducing this asymmetry. Our model demonstrates that lateral connections enhance precision and efficiency of prediction encoding, supported by the free energy principle.
The Human T-cell Leukemia Virus capsid protein is a potential drug target
Authors: Yu Ruijie , Phalora Prabhjeet , Li Nan , Böcking Till , Jacques David Anthony
Published: September 2024

Human T-cell Leukemia Virus type 1 (HTLV-1) is an untreatable retrovirus that causes lethal malignancies and degenerative inflammatory conditions. Effective treatments have been delayed by substantial gaps in our knowledge of the fundamental virology, especially when compared to the closely related virus, HIV. A recently developed and highly effective anti-HIV strategy is to target the virus with drugs that interfere with capsid integrity and interactions with the host. Importantly, the first in class anti-capsid drug approved, lenacapavir, can provide long-acting pre-exposure prophylaxis. Such a property would provide a means to prevent the transmission of HTLV-1, but its capsid has not previously been considered as a drug target. Here we describe the first high-resolution crystal structures of the HTLV-1 capsid protein, define essential lattice interfaces, and identify a previously unknown ligand-binding pocket. We show that this pocket is essential for virus infectivity, providing a potential target for future anti-capsid drug development.
Ketamine treatment effects on DNA methylation and Epigenetic Biomarkers of aging
Authors: Dawson Kristin , Carangan Athena May Jean M. , Klunder Jessica , Carreras-Gallo Natalia , Sehgal Raghav , Megilligan Samantha , Askins Benjamin C. , Perkins Nicole , Mendez Tavis L. , Smith Ryan , Dawson Matthew , Mallin Michael , Higgins-Chen Albert T. , Dwaraka Varun B.
Published: September 2024

Major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) are debilitating psychiatric conditions associated with poor health outcomes similarly observed in non-pathological aging. Ketamine is a dissociative anesthetic and NMDA receptor antagonist with demonstrated rapid reduction in symptoms associated with Treatment Resistant Depression (TRD) and PTSD. Ketamine’s effects on biological aging have not been extensively studied among patients with moderate to severe symptoms of depression and/or trauma. To address this gap, this study looked at the changes in non-epigenetic measures, DNA methylation levels, immune cell composition, and biological age based on various epigenetic biomarkers of aging, of 20 participants at baseline and after completion of a 2-3 week treatment course of 0.5 mg/kg ketamine infusions in individuals with MDD or PTSD. As expected, depression and PTSD scores decreased in participants following ketamine infusion treatments as measured by the PHQ-9 and PCL-5. We observed a reduction in epigenetic age in the OMICmAge, GrimAge V2, and PhenoAge biomarkers. In order to better understand the changes in epigenetic age, we also looked at the underlying levels of various Epigenetic Biomarker Proxies (EBPs) and surrogate protein markers and found significant changes following ketamine treatment. The results are consistent with existing literature on ketamine’s effects on different biomarkers. These results underline the ability of GrimAge V2, PhenoAge, and OMICmAge in particular, to capture signals associated with key clinical biomarkers, and add to the growing body of literature on ketamine’s epigenetic mechanisms and their effect on biological aging.
Antibiotic prescribing patterns by age and sex in England: why we need to take this variation into account to evaluate antibiotic stewardship and AMR selection
Authors: Waterlow Naomi R , Ashfield Tom , Knight Gwenan M
Published: September 2024

Structured Abstract

Objectives

The drivers of antimicrobial resistance (AMR) likely vary substantially by diKerent demographics. However, few complete open national detailed data exist on how antibiotic use (ABU) varies by both age and sex.

Methods

Here, prescriptions of antibiotics from General Practices in England for 2015-2023 disaggregated by 5-year age bands and sex were analysed at the national and Integrated Care Board (ICB) level. From a total of 249,578,795 prescriptions (across 9 years), 63% were given to women and the most prescribed were amoxicillin, nitrofurantoin and flucloxacillin sodium. Prescriptions per 100K population varied substantially across sex, age, geographical region, season, year, COVID-19 pandemic period and drug.

Results

Most antibiotics were prescribed more to women across most age bands (84% of antibiotics had more prescriptions to females across 50% of age bands). We show how this variation requires a more nuanced approach to comparing ABU across geographies and highlight that AWaRe targets are not met uniformly (young men have a higher proportion of “Watch” antibiotic prescriptions). We also show the impact on ABU of time-sensitive interruptions, including diKerential age-targeted influenza vaccination, COVID-19 restrictions and a shortage of amoxicillin combined with a Streptococcus A outbreak. Comparing to open access AMR data (MRSA in bloodstream infections) highlights the complexity of the link between ABU and AMR.

Conclusions

These detailed diKerences in ABU across England suggest that there should be large variation in AMR burden by age and sex, which now need to be quantified with detailed open access AMR data for a better intervention design.
Non-pharmaceutical interventions to reduce influenza transmission in households: a systematic review and meta-analysis
Authors: Wong Jessica Y. , Lim Wey Wen , Cheung Justin K. , Murphy Caitriona , Shiu Eunice Y. C. , Xiao Jingyi , Chen Dongxuan , Xie Yanmin , Li Mingwei , Xin Hualei , Szeto Michelle , Choi Sammi , Cowling Benjamin J.
Published: September 2024

Background

Influenza pandemic plans often recommend non-pharmaceutical interventions (NPIs) in household settings, including hand hygiene and face masks. We reviewed the evidence supporting the recommendations of these measures to prevent the spread of influenza in households.

Methods

We performed systematic reviews between 26 May and 30 August 2022 in Medline, PubMed, EMBASE, and CENTRAL to identify evidence for the effectiveness of selected measures recommended by representative national influenza pandemic plans. We prioritized evidence from randomized controlled trials. Fixed-effects models were used to estimate the overall effects. Systematic reviews were registered in the OSF registry (https://osf.io/8kyth).

Results

We selected 9 NPIs for evidence review. We identified 9 randomized-controlled trials related to hand hygiene and face masks in household settings. 2 studies reported that measures could delay the introduction of influenza virus infections into households. However, we did not identify evidence from randomized controlled trials that indicated a substantial effect of hand hygiene and face masks in preventing the spread of pandemic influenza within households.

Conclusion

Limited evidence indicated that within-household measures may likely be effective only when implemented before or as soon as possible after symptom onset in an infected case. Improving the evidence base for NPIs in households and elsewhere is a continuing priority.

Funding

World Health Organization and the Strategic Topic Grants Scheme
Performance of the Verily Study Watch for Measuring Sleep Compared to Polysomnography
Authors: Saeb Sohrab , Nelson Benjamin W. , Barman Poulami , Verma Nishant , Allen Hannah , de Zambotti Massimiliano , Baker Fiona C. , Arra Nicole , Sridhar Niranjan , Sullivan Shannon S. , Plowman Scooter , Rainaldi Erin , Kapur Ritu , Shin Sooyoon
Published: September 2024

Introduction

This study evaluated the performance of a wrist-worn wearable, Verily Study Watch (VSW), in detecting key sleep measures against polysomnography (PSG).

Methods

We collected data from 41 adults without obstructive sleep apnea or insomnia during a single overnight laboratory visit. We evaluated epoch-by-epoch performance for sleep versus wake classification, sleep stage classification and duration, total sleep time (TST), wake after sleep onset (WASO), sleep onset latency (SOL), sleep efficiency (SE), and number of awakenings (NAWK). Performance metrics included sensitivity, specificity, Cohen’s kappa, and Bland-Altman analyses.

Results

Sensitivity and specificity (95% CIs) of sleep versus wake classification were 0.97 (0.96, 0.98) and 0.70 (0.66, 0.74), respectively. Cohen’s kappa (95% CI) for 4-class stage detection was 0.64 (0.18, 0.82). Most VSW sleep measures had proportional bias. The mean bias values (95% CI) were 14.0 minutes (5.55, 23.20) for TST, - 13.1 minutes (-21.33, -6.21) for WASO, 2.97% (1.25, 4.84) for SE, -1.34 minutes (-7.29, 4.81) for SOL, 1.91 minutes (-8.28, 11.98) forlight sleepduration, 5.24 minutes (-3.35, 14.13) fordeep sleepduration, and 6.39 minutes (-0.68, 13.18) forREM sleepduration. Mean and median NAWK count differences (95% CI) were 0.05 (-0.42, 0.53) and 0.0 (0.0, 0.0), respectively.

Discussion

Results support applying the VSW to track overnight sleep measures in free-living settings. Registered atclinicaltrials.gov(NCT05276362).
Risk factors for typhoid fever: A desk review
Authors: Boakye Okyere Portia , Twumasi-Ankrah Sampson , Newton Sam , Darko Samuel Nkansah , Owusu Ansah Michael , Darko Eric , Agyapong Francis Opoku , Jin Jeon Hyon , Adu-Sarkodie Yaw , Marks Florian , Owusu-Dabo Ellis
Published: September 2024

Background and Aim

Typhoid fever, a significant global health problem, demonstrates a multifaceted transmission pattern. Knowledge of the factors driving the transmission of infection is critical for developing effective control strategies and resource allocation. This comprehensive desk review aimed at synthesizing evidence from 1928 to 2023 on risk factors associated with typhoid fever transmission.

Method

We conducted article searches in PubMed, Scopus, Google Scholar, and Semantic Scholar, using keywords related to risk, contributors, determinants, causes etc. associated with typhoid fever. We followed a registered protocol to support our search and triangulated the results.

Results

In all, we retrieved 1614 articles, of which 216 were reviewed. Of these articles reviewed, 106 provided data on typhoid fever risk factors. Unsurprisingly, of the total articles reviewed on risk factors, about 72% (76/106) originated from the Asian (48.1%, 51/106) and African (23.6%, 25/106) continents. A higher proportion, 47.2% (50/106) of the articles indicated risk factors related to socio-economic and housing transmission. Additional risk factors included foodborne transmissions (45.3%, 48/106), WASH:Waterborne transmissions (42.5%, 45/106),Sanitation andHygiene practices (32.1%, 34/106), travel-related risk (16.0%, 17/106), antimicrobial agents (13.2%, 14/106), climate (13.2%, 14/106), environmental (8.5%, 9/106), typhoid carriers (10.4%, 11/106), and host risk (5.7%, 6/106) factors to disease transmission.

Conclusion

These findings highlight the necessity for targeted and combined interventions including improved sanitation infrastructure, enhanced WASH practices and the use of vaccines in endemic areas. Implementing effective strategies informed by this review can aid clinicians, public health experts, and policymakers in efficiently mitigating the burden of typhoid fever.
Epistasis drives rapid divergence across multiple traits during the adaptive evolution of a carbapenemase
Authors: Dabos Laura , Nedjari Inssaf , Couce Alejandro
Published: September 2024

Interactions among beneficial mutations (i.e., epistasis) are often strong enough as to direct adaptation through alternative mutational paths. While alternative solutions should display similar fitness under the primary selective conditions, their properties across secondary environments may differ widely. The extent to which these cryptic differences are to be expected is largely unknown, despite their fundamental and practical importance, such as in the search for exploitable collateral sensitivities among antibiotic resistance mutations. Here we use directed evolution to characterize the diversity of mutational paths through which the prevalent carbapenemase KPC-2 can evolve high activity against the clinically-relevant antibiotic ceftazidime, an initially poor substrate. We identified 40 different substitutions, including many common clinical settings, spread along 18 different mutational trajectories. Initial mutations determined four major groups into which the trajectories can be classified, a signature of strong epistasis. Of note, despite minor variation in final ceftazidime resistance, groups diverged markedly across multiple phenotypic dimensions, from molecular traits such as stability and hydrolitic efficiency to macroscopic traits such as growth rate and activity against other β-lactam antibiotics. Our results indicate that cryptic yet consequential phenotypic differences can readily accumulate under strong selective pressures, bearing implications for efforts to prevent unwanted evolution in microbes.
Highly Iterated Palindrome 1 (HIP1) sequence improvesSynechococcussp. PCC 7002 transformation efficiencies in a homology- and methylation-dependent manner
Authors: Kamoku Cody , Nielsen David R.
Published: September 2024

The ability to precisely control cyanobacterial metabolism first requires the ability to efficiently deliver engineered DNA constructs. Here, we investigate how natural transformation efficiencies inSynechococcussp. PCC 7002 can be greatly improved by leveraging the native and abundant cyanobacterial Highly Iterated Palindrome 1 (HIP1) sequence. While including at least one homologous HIP1 site within the homology arms of an integrating plasmid increased integration efficiency by up to 7-fold, methylation of those sites by HIP1 methyltransferase (encoded byslr0214fromSynechococcussp. PCC 6803) boosted this to greater than a 100-fold improvement overall. Non-homologous HIP1 sites also improved transformation efficiencies of both integrating and replicating episomal plasmids (by up to 60- and 9-fold, respectively), but only when methylated. The collective data further reveal that HIP1 does not function as part of a native restriction enzyme system in PCC 7002, but rather may improve transformation efficiency via two complementary mechanisms: i) altering DNA binding/uptake/processing prior to homologous recombination, and ii) increasing the efficiency of homologous recombination in a manner reminiscent of a crossover hotspot instigator (Chi) site. Future studies are needed, however, to more clearly elucidate the specific role of HIP1 during natural transformation of cyanobacteria.
In vivoCRISPR screens identify GRA12 as a transcendent secreted virulence factor acrossToxoplasma gondiistrains and mouse subspecies
Authors: Torelli Francesca , Butterworth Simon , Lockyer Eloise , Song Ok-Ryul , Pearson-Farr Jennifer , Treeck Moritz
Published: September 2024

Toxoplasma gondiiparasites exhibit extraordinary host promiscuity owing to over 250 putative secreted proteins that disrupt host cell functions, enabling parasite persistence. However, most of the known effector proteins are specific toToxoplasmagenotypes or hosts. To identify virulence factors that function across different parasite isolates and mouse strains that differ in susceptibility to infection, we performed systematic pooledin vivoCRISPR-Cas9 screens targeting theToxoplasmasecretome. We identified several proteins required for infection across parasite strains and mouse species, of which the dense granule protein 12 (GRA12) emerged as the most important effector protein during acute infection. GRA12 deletion in IFNγ-activated macrophages results in collapsed parasitophorous vacuoles and increased host cell necrosis, which is partially rescued by inhibiting early parasite egress. GRA12 orthologues from related coccidian parasites, includingNeospora caninumandHammondia hammondi,complement TgΔGRA12in vitro, suggesting a common mechanism of protection from immune clearance by their hosts.
Natural selection acting on complex traits hampers the predictive accuracy of polygenic scores in ancient samples
Authors: Añorve-Garibay Valeria , Huerta-Sanchez Emilia , Sohail Mashaal , Ortega-Del Vecchyo Diego
Published: September 2024

The prediction of phenotypes from ancient humans has gained interest due to its potential to investigate the evolution of complex traits. These predictions are commonly performed using polygenic scores computed with DNA information from ancient humans along with genome-wide association studies (GWAS) data from present-day humans. However, numerous evolutionary processes could impact the prediction of phenotypes from ancient humans based on polygenic scores. In this work we investigate how natural selection impacts phenotypic predictions on ancient individuals using polygenic scores. We use simulations of an additive trait to analyze how natural selection impacts phenotypic predictions with polygenic scores. We simulate a trait evolving under neutrality, stabilizing selection and directional selection. We find that stabilizing and directional selection have contrasting effects on ancient phenotypic predictions. Stabilizing selection accelerates the loss of large-effect alleles contributing to trait variation. Conversely, directional selection accelerates the loss of small and large-effect alleles that drive individuals farther away from the optimal phenotypic value. These effects result in specific shared genetic variation patterns between ancient and modern populations which hamper the accuracy of polygenic scores to predict phenotypes. Furthermore, we conducted simulations that include realistic strengths of stabilizing selection and heritability estimates to show how natural selection could impact the predictive accuracy of ancient polygenic scores for two widely studied traits: height and body mass index. We emphasize the importance of considering how natural selection can decrease the reliability of ancient polygenic scores to perform phenotypic predictions on an ancient population.
Discovery of a new species of subterranean eel loach from southern India
Authors: Sreenath K.R. , Pradeep B. , Aju K. R. , Sukumaran Sandhya , Sebastian Wilson , Anto Alvin
Published: September 2024

Pangio juhuaesp nov, a new species of subterranean eel loach, is described from Kerala, India. It is distinguished from its subterranean congeners by the presence of a dorsal fin, four pectoral rays and five segmented anal fin rays. Genetic analyses suggest thatP. juhuaeis closely related toP. bhujiabut is distinct in morphology, particularly by the presence of a dorsal fin. The low genetic distance and significant morphological difference between these twoPangiospecies suggest that they have diverged from an immediate common ancestor and evolved distinct adaptations to subterranean niches.P. juhuaeexhibits less evolved troglobitic traits compared toP. bhujiaandP. pathala, suggesting it could be a connecting species in the evolutionary transition from terrestrial to subterranean loaches. This discovery provides evidence for possible subterranean speciation of fishes in underground habitats.
Kinetics of reformation of the S0state capable of progressing to the S1state after the O2release by Photosystem II
Authors: Boussac Alain , Sellés Julien , Sugiura Miwa
Published: September 2024

The active site for water oxidation in Photosystem II (PSII) comprises a Mn4CaO5cluster adjacent to a redox-active tyrosine residue (TyrZ). During the water-splitting process, the enzyme transitions through five sequential oxidation states (S0to S4), with O2evolution occurring during the S3TyrZ•to S0TyrZtransition. Chloride also plays a role in this mechanism. Using PSII fromThermosynechococcus vestitus, where Ca and Cl were replaced with Sr and Br to slow the S3TyrZ•to S0TyrZ+ O2transition (t1/2∼ 5 ms at room temperature), it was observed that the recovery of a S0state, defined as the state able to progress to S1, exhibits similar kinetics (t1/2∼ 5 ms). This suggests that in CaCl-PSII, the reformation of the functional S0state directly follows the S3TyrZ•to S0TyrZ+ O2transition, with no additional delay required for the insertion of a new substrate water molecule (O5) and associated protons.
A circular engineered sortase for interrogating histone H3 in chromatin
Authors: Whedon Samuel D. , Lee Kwangwoon , Wang Zhipeng A. , Zahn Emily , Lu Congcong , Yapa-Abeywardana Maheeshi , Fairall Louise , Nam Eunju , Dubois-Coyne Sarah , De Ioannes Pablo , Sheng Xinlei , Andrei Adelina , Lundberg Emily , Jiang Jennifer , Armache Karim-Jean , Zhao Yingming , Schwabe John W. R. , Wu Mingxuan , Garcia Benjamin A. , Cole Philip A.
Published: September 2024

Reversible modification of the histone H3 N-terminal tail is critical in regulating chromatin structure, gene expression, and cell states, while its dysregulation contributes to disease pathogenesis. Understanding the crosstalk between H3 tail modifications in nucleosomes constitutes a central challenge in epigenetics. Here we describe an engineered sortase transpeptidase, cW11, that displays highly favorable properties for introducing scarless H3 tails onto nucleosomes. This approach significantly accelerates the production of both symmetrically and asymmetrically modified nucleosomes. We demonstrate the utility of asymmetrically modified nucleosomes produced in this way in dissecting the impact of multiple modifications on eraser enzyme processing and molecular recognition by a reader protein. Moreover, we show that cW11 sortase is very effective at cutting and tagging histone H3 tails from endogenous histones, facilitating multiplex “cut-and-paste” middle down proteomics with tandem mass tags. This cut-and-paste proteomics approach permits the quantitative analysis of histone H3 modification crosstalk after treatment with different histone deacetylase inhibitors. We propose that these chemoenzymatic tail isolation and modification strategies made possible with cW11 sortase will broadly power epigenetics discovery and therapeutic development.
Ferrimagnetic structure in the high-pressure phase of
α−Mn
Authors: Araki Shingo , Iwamoto Kaisei , Akiba Kazuto , Kobayashi Tatsuo C. , Munakata Koji , Kaneko Koji , Osakabe Toyotaka
Published: September 2024

The α−Mn phase exhibits a large anomalous Hall effect (AHE) in its pressure-induced weak ferromagnetic (WFM) state, despite its relatively small spontaneous magnetization of ∼0.02μB/Mn. To understand the underlying mechanism behind this AHE, we performed single crystal neutron diffraction measurements at 2.0 GPa to determine the magnetic structure of the WFM phase. Our investigation reveals a ferrimagnetic structure characterized by nearly collinear magnetic moments aligned along the [001] direction at sites I, II, III-1, and IV-1. In contrast, the small moments at sites III-2 and IV-2 lie within the (001) plane. The calculated net magnetization of this magnetic structure, (−0.08±0.10)μB/Mn atom, is in agreement with the experimentally determined spontaneous magnetization. The observation of a magnetic reflection at q=(0,0,0) satisfies a key condition for the emergence of the AHE.

Published by the American Physical Society
2024
Meson mass and width: Deep learning approach
Authors: Malekhosseini M. , Rostami S. , Olamaei A. R. , Ostovar R. , Azizi K.
Published: September 2024

It is fascinating to predict the mass and width of the ordinary and exotic mesons solely based on their quark content and quantum numbers. Such prediction goes beyond conventional methodologies traditionally employed in hadron physics for calculating or estimating these quantities. The relation between the quantum numbers and the properties of the mesons, such as the mass and width, is complicated in the world of particle physics. However, the deep neural network (DNN) as a subfield of machine learning techniques provides a solution to this problem. By analyzing large datasets, deep learning algorithms can automatically identify complex patterns among the particles’ quantum numbers, and their mass and width, that would otherwise require complex calculations. In this study, we present two approaches using the DNNs to estimate the mass of some ordinary and exotic mesons. Also for the first time, the DNNs are trained to predict the width of ordinary and exotic mesons, whose widths have not been experimentally known. Our predictions obtained through the DNNs, will be useful for future experimental searches.

Published by the American Physical Society
2024
Dynamical Correlations and Order in Magic-Angle Twisted Bilayer Graphene
Authors: Rai Gautam , Crippa Lorenzo , Călugăru Dumitru , Hu Haoyu , Paoletti Francesca , de’ Medici Luca , Georges Antoine , Bernevig B. Andrei , Valentí Roser , Sangiovanni Giorgio , Wehling Tim
Published: September 2024

The interplay of dynamical correlations and electronic ordering is pivotal in shaping phase diagrams of correlated quantum materials. In magic-angle twisted bilayer graphene, transport, thermodynamic, and spectroscopic experiments pinpoint a competition between distinct low-energy states with and without electronic order, as well as between localized and delocalized charge carriers. In this study, we utilize dynamical mean-field theory on the topological heavy fermion model of twisted bilayer graphene to investigate the emergence of electronic correlations and long-range order in the absence of strain. We contrast moment formation, Kondo screening, and ordering on a temperature basis and explain the nature of emergent correlated states based on three central phenomena: (i) the formation of local spin and valley isospin moments around 100 K, (ii) the ordering of the local isospin moments around 10 K preempting Kondo screening, and (iii) a cascadic redistribution of charge between localized and delocalized electronic states upon doping. At integer fillings, we find that low-energy spectral weight is depleted in the symmetric phase, while we find insulating states with gaps enhanced by exchange coupling in the zero-strain ordered phases. Doping away from integer filling results in distinct metallic states: a “bad metal” above the ordering temperature, where scattering off the disordered local moments suppresses electronic coherence, and a “good metal” in the ordered states with coherence of quasiparticles facilitated by isospin order. This finding reveals coherence from order as the microscopic mechanism behind the Pomeranchuk effect observed experimentally by Rozen [] and by Saito []. Upon doping, there is a periodic charge reshuffling between localized and delocalized electronic orbitals leading to cascades of doping-induced Lifshitz transitions, local spectral weight redistributions, and periodic variations of the electronic compressibility ranging from nearly incompressible to negative. Our findings highlight the essential role of charge transfer, hybridization, and ordering in shaping the electronic excitations and thermodynamic properties in twisted bilayer graphene and provide a unified understanding of the most puzzling aspects of scanning tunneling spectroscopy, transport, and compressibility experiments.

Published by the American Physical Society
2024