bluuebunny/crossref_metadata_2025 huggingface dataset:
Using a Quality Improvement Approach to improve reporting of malaria deaths in Namutumba District, Eastern Uganda, 2022–2023
Authors: Zalwango Marie Gorreti , Migisha Richard , Kwesiga Benon , Bulage Lilian , Kadobera Daniel , Ario Alex Riolexus
Published: May 2024

Background

Reporting malaria deaths is critical for assessing prevention and case management interventions. In Uganda, malaria mortality is recorded in inpatient registers and reported through weekly and monthly surveillance reports. During a data quality assessment in Namutumba District in October 2022, we found more malaria deaths in health facility registers than were reported. We conducted a continuous quality improvement initiative to improve the accuracy of reported malaria deaths in Namutumba District.

Methods

We purposively selected 2 high-level health centers (HC) in Namutumba District that reported malaria deaths during September 2021–October 2022. We formed quality improvement teams (QIT) comprising clinical and statistical staff at the HC. We held focus group discussions with QITs to identify challenges with reporting malaria deaths, prioritized areas for improvement, and conducted root cause analysis. Using the plan, do, study, act (PDSA) cycle, we identified change ideas to address root causes.

Interventions

Challenges included knowledge gaps on malaria death definitions, lack of consequences for failing to document deaths, and unclear guidance on how to document deaths. Sustainable interventions identified included continuous medical education on malaria death definition, one-on-one mentorship of staff on documentation in inpatient registers, and weekly verification of inpatient register data, all implemented during November 2022–February 2023.

Results

Of the 36 malaria deaths that occurred during the baseline period (September 2021– October 2022), 25 (69%) were included in the weekly report, and four (11%) in the monthly report. Following the intervention implementation, all 7 malaria deaths recorded at the 2 health facilities during November 2022–February 2023 were reported in the weekly and monthly reports.

Conclusion

Continuous medical education, supervision and mentoring of HC staff, and clear and comprehensive guidance on documenting malaria deaths could facilitate improved malaria death reporting from HC in Uganda, enabling more accurate resource allocation for malaria control.
Gut microbiome alterations precede graft rejection in kidney transplantation patients
Authors: Holle Johannes , Reitmeir Rosa , Behrens Felix , Singh Dharmesh , Schindler Daniela , Potapenko Olena , McParland Victoria , Anandakumar Harithaa , Kanzelmeyer Nele , Sommerer Claudia , Hartleif Steffen , Andassy Joachim , Heemann Uwe , Neuenhahn Michael , Forslund-Startceva Sofia K. , Gerhard Markus , Oh Jun , Wilck Nicola , Löber Ulrike , Bartolomaeus Hendrik ,   members of the German Center of Infection Research Transplant Cohort
Published: May 2024

Background

Kidney transplantation (KT) is the optimal treatment for end-stage kidney disease, with graft survival critically affected by the recipient’s immune response. The role of the gut microbiome in modulating this immune response remains underexplored. Our study investigates how microbiome alterations might associate with allograft rejection.

Methods

We analyzed existing biomaterials of a multicenter prospective study involving 217 KT recipients and 28 kidney donors from the German Center for Infection Research. Changes in the gut microbiome were analyzed using 16S rRNA gene amplicon sequencing and functional predictions (PICRUSt2) and quantitative PCRs for the production potential of propionate and butyrate. Propensity score matching was utilized to compare patients who experienced graft rejection with those who did not.

Results

The gut microbiome showed gradual recovery post-KT, marked by an increase of Shannon diversity and SCFA-producing bacterial taxa. However, prior to graft rejection, significant alterations were noted in microbiome composition, characterized by a decrease in microbial diversity and SCFA-producing taxa. Post-rejection analysis revealed normalization of these microbiome features. Functional analysis highlighted a decreased potential for SCFA production in patients prior to rejection. Comparison to published microbiome signatures from chronic kidney disease (CKD) patients demonstrated a partial overlap of the microbiome alterations preceding graft rejection with the alterations typically found in CKD.

Conclusions

Our findings suggest that alterations in the gut microbiome composition and function may precede and influence KT rejection, suggesting potential for use as biomarker and early therapeutic microbiome-targeting interventions to improve transplant outcomes.

Key points

– CKD-related microbiome alterations recover over time after transplantation mirroring CKD-to-health transition

– Microbiome alterations with lowered production potential of short-chain fatty acids precede graft rejection, likely influencing graft immunity

– The persistence of CKD-associated microbiome characteristics in rejection patients opens avenues for innovative treatment strategies.
STRchive: a dynamic resource detailing population-level and locus-specific insights at tandem repeat disease loci
Authors: Hiatt Laurel , Weisburd Ben , Dolzhenko Egor , VanNoy Grace E. , Kurtas Edibe Nehir , Rehm Heidi L. , Quinlan Aaron , Dashnow Harriet
Published: May 2024

Approximately 3% of the human genome consists of repetitive elements called tandem repeats (TRs), which include short tandem repeats (STRs) of 1–6bp motifs and variable number tandem repeats (VNTRs) of 7+bp motifs. TR variants contribute to several dozen mono- and polygenic diseases but remain understudied and “enigmatic,” particularly relative to single nucleotide variants. It remains comparatively challenging to interpret the clinical significance of TR variants. Although existing resources provide portions of necessary data for interpretation at disease-associated loci, it is currently difficult or impossible to efficiently invoke the additional details critical to proper interpretation, such as motif pathogenicity, disease penetrance, and age of onset distributions. It is also often unclear how to apply population information to analyses.

We present STRchive (S-T-archive,http://strchive.org/), a dynamic resource consolidating information on TR disease loci in humans from research literature, up-to-date clinical resources, and large-scale genomic databases, with the goal of streamlining TR variant interpretation at disease-associated loci. We apply STRchive —including pathogenic thresholds, motif classification, and clinical phenotypes—to a gnomAD cohort of ∼18.5k individuals genotyped at 60 disease-associated loci.

Through detailed literature curation, we demonstrate that the majority of TR diseases affect children despite being thought of as adult diseases. Additionally, we show that pathogenic genotypes can be found within gnomAD which do not necessarily overlap with known disease prevalence, and leverage STRchive to interpret locus-specific findings therein. We apply a diagnostic blueprint empowered by STRchive to relevant clinical vignettes, highlighting possible pitfalls in TR variant interpretation. As a living resource, STRchive is maintained by experts, takes community contributions, and will evolve as understanding of TR diseases progresses.
Deep Learning Enhances Detection of Extracapsular Extension in Prostate Cancer from mpMRI of 1001 Patients
Authors: Khosravi Pegah , Saikali Shady , Alipour Abolfazl , Mohammadi Saber , Boger Max , Diallo Dalanda M. , Smith Christopher , Moschovas Marcio Covas , Hajirasouliha Iman , Hung Andrew J. , Venkataraman Srirama S. , Patel Vipul
Published: May 2024

Extracapsular extension (ECE) is detected in approximately one-third of newly diagnosed prostate cancer (PCa) cases at stage T3a or higher and is associated with increased rates of positive surgical margins and early biochemical recurrence following radical prostatectomy (RP). This study presents the development of AutoRadAI, an end-to-end, user-friendly artificial intelligence (AI) pipeline designed for the identification of ECE in PCa through the analysis of multiparametric MRI (mpMRI) fused with prostate histopathology. The dataset consists of 1001 patients, including 510 pathology-confirmed positive ECE cases and 491 negative ECE cases. AutoRadAI integrates comprehensive preprocessing followed by a sequence of two novel deep learning (DL) algorithms within a multi-convolutional neural network (multi-CNN) strategy. The pipeline exhibited strong performance during its evaluation. In the blind testing phase, AutoRadAI achieved an area under the curve (AUC) of 0.92 for assessing image quality and 0.88 for detecting the presence of ECE in individual patients. Additionally, AutoRadAI is implemented as a user-friendly web application, making it ideally suited for clinical applications. Its data-driven accuracy offers significant promise as a diagnostic and treatment planning tool. Detailed instructions and the full pipeline are available athttps://autoradai.anvil.appand on our GitHub page athttps://github.com/PKhosravi-CityTech/AutoRadAI.
Prevalence of Obesity According to Body Mass Index, Waist Circumference, and Waist-to-Height Ratio in Peru: A Systematic Review and Meta-Analysis
Authors: Vásquez-Romero Luisa Erika Milagros , Zuzunaga-Montoya Fiorella E. , Loayza-Castro Joan A. , Vigil-Ventura Enrique , Ramos Willy , Vera-Ponce Víctor Juan
Published: May 2024

Introduction

Obesity is a global public health issue with significant health implications. However, studies on the prevalence of obesity in Peru have yielded varied results, highlighting the need for updated data to inform effective public health policies.

Objective

The primary objective of this study is to determine the prevalence of obesity in Peru using three anthropometric measures: body mass index (BMI), waist circumference (WC), and waist-to-height ratio (WHtR).

Methods

Between March and April 2024, a systematic review of published studies reporting the prevalence of obesity in Peru was conducted. The databases Scopus, Web of Science, Embase, PubMed, LILACS, and Scielo were Searched.

Results

Overall, the prevalence of obesity was 23.23%, 38.90%, and 81.53% according to BMI, WC, and WHtR, respectively. However, these figures show wide variability, ranging from 13.10% to 37.4% according to BMI and from 19.4% to 51.6% according to WC. The highest reported prevalence of obesity by WHtR was 85.4%. Nonetheless, only a fraction of these studies were published in the last five years, and few specifically focused on obesity as the primary objective.

Conclusions

The prevalence of obesity in Peru varies significantly depending on the anthropometric measure used. To improve the collection and frequency of data on obesity in Peru, it is recommended that cut-off points be standardized to be suitable for the country and that annual national surveys specifically designed for this purpose be implemented.
Effect of antibacterial mouthwash on NO bioavailability and muscle contractile function in young healthy men and women
Authors: Gallardo Edgar J , Zoughaib William S , Singhal Ahaan , Hoffman Richard L , Coggan Andrew R
Published: May 2024

The use of antiseptic mouthwash is widespread due to its oral health benefits. However, its impact on systemic physiological processes, particularly nitric oxide (NO) bioavailability and muscle contractility, is not fully understood. PURPOSE: To determine the effects of cetylpyridinium-based (antibacterial) versus sodium chloride (NaCl) -based (control) mouthwashes on salivary and breath NO markers and muscle contractile function in healthy young adults. METHODS: Twenty-six participants (n=13/group) completed a randomized, parallel-arm, blinded trial, comparing the effects of the two mouthwashes before and after 7 d of treatment. NO bioavailability was assessed via measurement of nitrate (NO3-), nitrite (NO2-), and cyclic guanyl monophosphate (cGMP) concentrations in saliva and the level of NO in breath. The contractile function of the knee extensor muscles was determined via isokinetic dynamometry. RESULTS: No significant changes in salivary NO3-, NO2-, or cGMP or in breath NO were observed in response to either treatment. However, cetylpyridinium-based mouthwash reduced the percentage of NO2- in saliva (16. 9± 10.5% vs. 24.9 ± 13.4%; p=0.0036), supporting compliance with the intervention. Peak torque at velocities of 0-6.28 rad/s was unaffected by mouthwash use. Calculated maximal knee extensor velocity (Vmax) and power (Pmax) were therefore also unchanged. CONCLUSION: Cetylpyridinium-containing mouthwash inhibits reduction of NO3- to NO2- in the oral cavity but does not significantly diminish overall NO bioavailability or impair muscle contractile function in healthy young men and women.
Epigenetic Biomarkers of Socioeconomic Status are Associated with Age-Related Chronic Diseases and Mortality in Older Adults
Authors: Schmitz Lauren L. , Opsasnick Lauren A. , Ratliff Scott M. , Faul Jessica D. , Zhao Wei , Hughes Timothy M. , Ding Jingzhong , Liu Yongmei , Smith Jennifer A.
Published: May 2024

Later-life health is patterned by socioeconomic influences across the lifecourse. However, the pathways underlying the biological embedding of socioeconomic status (SES) and its consequences on downstream morbidity and mortality are not fully understood. Epigenetic markers like DNA methylation (DNAm) may be promising surrogates of underlying biological processes that can enhance our understanding of how SES shapes population health. Studies have shown that SES is associated with epigenetic aging measures, but few have examined relationships between early and later-life SES and DNAm sites across the epigenome. In this study, we trained and tested DNAm-based surrogates, or “biomarkers,” of childhood and adult SES in two large, multi-racial/ethnic samples of older adults—the Health and Retirement Study (HRS) (N=3,527) and the Multi-Ethnic Study of Atherosclerosis (MESA) (N=1,182). Both biomarkers were associated with downstream morbidity and mortality, and these associations persisted after controlling for measured SES, and in some cases, epigenetic aging clocks. Both childhood and adult SES biomarker CpG sites were enriched for genomic features that regulate gene expression (e.g., DNAse hypersensitivity sites and enhancers) and were implicated in prior epigenome-wide studies of inflammation, aging, and chronic disease. Distinct patterns also emerged between childhood CpGs and immune system dysregulation and adult CpGs and metabolic functioning, health behaviors, and cancer. Results suggest DNAm-based surrogate biomarkers of SES may be useful proxies for unmeasured social exposures that can augment our understanding of the biological mechanisms between social disadvantage and downstream health.

Significance Statement

Information on DNA methylation (DNAm)—an epigenetic modification that plays a central role in regulating gene expression—is increasingly available in large epidemiological studies. Since DNAm is relatively stable but responsive to environmental influences, genome-wide signatures are promising surrogates or biomarkers of exposure that may both shed light on biological mechanisms between adverse environments and downstream health and/or act as proxies for unmeasured exposures. To better understand the biological embedding of social disadvantage, this study trained and tested DNAm-based surrogates of childhood and adult socioeconomic status (SES) in two US-based cohorts of older adults. Findings reveal distinct DNAm signatures of SES that connect social adversity across the lifecourse with dysregulated immune system responses, inflammatory pathways, poorer metabolic functioning, chronic diseases, and cancer.
An International Longitudinal Natural History Study of Danon Disease Patients: Unique Cardiac Trajectories Identified Based on Sex and Heart Failure Outcomes
Authors: Hong Kimberly N. , Eshraghian Emily , Khedro Tarek , Argirò Alessia , Attias Jennifer , Storm Garrett , Tsotras Melina , Bloks Tanner , Jackson Isaiah , Ahmad Elijah , Graw Sharon , Mestroni Luisa , Bui Quan M. , Schwartz Jonathan , Turner Stuart , Adler Eric D. , Taylor Matthew
Published: May 2024

Introduction

Danon disease (DD) is a rare X-linked dominant cardioskeletal myopathy caused by mutations in the lysosome-associated membrane protein-2 gene. Though the severe morbidity of disease in males is well established, longitudinal studies describing the trajectory of cardiovascular disease in both sexes have not been performed. Herein we performed an analysis using the International Danon Disease Registry, a retrospective dataset that includes longitudinal data from a cohort of males and females with DD.

Methods

Data were from the International Danon Disease Registry and includes patients from 2005 to 2022. Records were obtained from the first episode of care to the date of enrollment and included demographics, clinical characteristics, echocardiographic and laboratory values, and outcomes. The primary outcome in this study was a heart failure (HF) composite defined as either transplant (TXP), left ventricular assist device (LVAD) or death.

Results

The analysis included 116 DD patients: female (n=64, 55%) and male (n=52, 45%). Median age of diagnosis for the entire cohort was 15.2 years (10.0-25.2 years), and 21.9 years (15.0-34.9 years) and 12.4 years (7.1-15.6 years) for females and males respectively. The incidence of HF outcome was higher in males compared to females (p<0.001). Regarding trends in echocardiographic parameters over time, LVEF decreased and LVEDD increased regardless of sex and HF outcome, however, rate of change was increased in patients who experienced a HF outcome in both sexes. Increasing LV mass occurs in males but not females. Consistent with this, LV wall hypertrophy continues in males who have not yet experienced a HF outcome and stabilizes prior to HF outcome, while females have progressive LV thinning regardless of HF outcome. Analyses stratified by age of HF outcome in females found two distinct groups of females, one who experienced HF outcome prior to 26 years of age and another after.

Conclusions

In this largest longitudinal natural history study of DD to date, we confirmed that males present on average a decade earlier and demonstrate more progressive cardiac hypertrophy and heart failure than females. Of note, there may be a subset of females who are phenotypically similar to males with profound LV hypertrophy that appears to stabilize or regress prior to HF outcome. Correlations between structural changes including LV hypertrophy, dilation and dysfunction and disease progression may allow for risk stratification of Danon patients and refinement of treatment algorithms while also informing therapeutic trial design.
High-effect gene-coding variants impact cognition, mental well-being, and neighborhood safety substrates in brain morphology
Authors: Kopal Jakub , Huguet Guillaume , Marotta Justin , Aggarwal Shambhavi , Osayande Nicole , Kumar Kuldeep , Saci Zohra , Jean-Louis Martineau , Chai Xiaoqian J. , Ge Tian , Yeo B.T. Thomas , Thompson Paul M. , Bearden Carrie E. , Andreassen Ole A. , Jacquemont Sebastien , Bzdok Danilo
Published: May 2024

Our genetic makeup, together with environmental and social influences, shape our brain's development. Yet, the imaging genetics field has struggled to integrate all these modalities to investigate the interplay between genetic blueprint, environment, human health, daily living skills and outcomes. Hence, we interrogated the Adolescent Brain Cognitive Development (ABCD) cohort to outline the effects of rare high-effect genetic variants on brain architecture and corresponding implications on cognitive, behavioral, psychosocial, and socioeconomic traits. Specifically, we designed a holistic pattern-learning algorithm that quantitatively dissects the impacts of copy number variations (CNVs) on brain structure and 962 behavioral variables spanning 20 categories in 7,657 adolescents. Our results reveal associations between genetic alterations, higher-order brain networks, and specific parameters of the family well-being (increased parental and child stress, anxiety and depression) or neighborhood dynamics (decreased safety); effects extending beyond the impairment of cognitive ability or language capacity, dominantly reported in the CNV literature. Our investigation thus spotlights a far-reaching interplay between genetic variation and subjective life quality in adolescents and their families.
Temperature-Dependent Fold-Switching Mechanism of the Circadian Clock Protein KaiB
Authors: Zhang Ning , Sood Damini , Guo Spencer C. , Chen Nanhao , Antoszewski Adam , Marianchuk Tegan , Chavan Archana , Dey Supratim , Xiao Yunxian , Hong Lu , Peng Xiangda , Baxa Michael , Partch Carrie , Wang Lee-Ping , Sosnick Tobin R. , Dinner Aaron R. , LiWang Andy
Published: May 2024

The oscillator of the cyanobacterial circadian clock relies on the ability of the KaiB protein to switch reversibly between a stable ground-state fold (gsKaiB) and an unstable fold-switched fold (fsKaiB). Rare fold-switching events by KaiB provide a critical delay in the negative feedback loop of this post-translational oscillator. In this study, we experimentally and computationally investigate the temperature dependence of fold switching and its mechanism. We demonstrate that the stability of gsKaiB increases with temperature compared to fsKaiB and that the Q10 value for the gsKaiB → fsKaiB transition is nearly three times smaller than that for the reverse transition. Simulations and native-state hydrogen-deuterium exchange NMR experiments suggest that fold switching can involve both subglobally and near-globally unfolded intermediates. The simulations predict that the transition state for fold switching coincides with isomerization of conserved prolines in the most rapidly exchanging region, and we confirm experimentally that proline isomerization is a rate-limiting step for fold switching. We explore the implications of our results for temperature compensation, a hallmark of circadian clocks, through a kinetic model.
Evolutionary and functional connections between the typhoid toxins encoded byS.Typhi andS. bongori
Authors: Chemello Antonio J. , Fowler Casey C.
Published: May 2024

The virulence properties of numerous important bacterial pathogens have been shaped by the horizontal acquisition of an AB5-type toxin. A major obstacle to the fruitful horizontal transfer of an AB5-type toxin amongst bacteria that infect divergent host species is that these toxins bind specific glycan receptors on target host cells to mediate toxin uptake, and glycosylation patterns vary substantially between different host species. In this study, we explore the evolutionary and functional connections between the related typhoid toxins that are encoded byS. entericaserovar Typhi, a human-adapted pathogen, and byS. bongori, which infects cold-blooded animals. We uncover genetic fingerprints that indicateS. Typhi’s typhoid toxin islet evolved from a larger virulence islet similar toS. bongori’s, and show thatS. Typhi’s glycan-binding PltB subunit is more similar toS. bongoriPltB than it is to many diverse PltB sequence variants found inS. enterica. We further show that, surprisingly,S. Typhi strains that encode theS. bongorityphoid toxin islet intoxicate infected human epithelial cells with substantially greater potency than wild-typeS. Typhi. The results of this study therefore suggest that the unexpected potency of theS. bongorityphoid toxin toward mammalian cells paved the way for sequence variants derived from this species to be acquired by - and effectively integrated into the virulence program of - the human-adapted pathogenS. Typhi.
Norepinephrine Signals Through Astrocytes To Modulate Synapses
Authors: Lefton Katheryn B , Wu Yifan , Yen Allen , Okuda Takao , Zhang Yufen , Dai Yanchao , Walsh Sarah , Manno Rachel , Dougherty Joseph D , Samineni Vijay K , Simpson Paul C , Papouin Thomas
Published: May 2024

Abstract

Locus coeruleus (LC)-derived norepinephrine (NE) drives network and behavioral adaptations to environmental saliencies by reconfiguring circuit connectivity, but the underlying synapse-level mechanisms are elusive. Here, we show that NE remodeling of synaptic function is independent from its binding on neuronal receptors. Instead, astrocytic adrenergic receptors and Ca2+dynamics fully gate the effect of NE on synapses as the astrocyte-specific deletion of adrenergic receptors and three independent astrocyte-silencing approaches all render synapses insensitive to NE. Additionally, we find that NE suppression of synaptic strength results from an ATP-derived and adenosine A1 receptor-mediated control of presynaptic efficacy. An accompanying study from Chen et al. reveals the existence of an analogous pathway in the larval zebrafish and highlights its importance to behavioral state transitions. Together, these findings fuel a new model wherein astrocytes are a core component of neuromodulatory systems and the circuit effector through which norepinephrine produces network and behavioral adaptations, challenging an 80-year-old status quo.
Host-strain compatibility influences transcriptional responses inMycobacterium tuberculosisinfections
Authors: Ruiz-Rodriguez Paula , Caballer-Gual Marta , Santamaria Guillem , Hiza Hellen , Coscolla Mireia
Published: May 2024

Tuberculosis, caused byMycobacterium tuberculosis, is a leading cause of infectious mortality and affects humans and other mammals. Understanding the drivers of its host-specificity shapes the landscape of infectivity, which could potentially inform strategies for tuberculosis management. We hypothesise that host-strain compatibility influences infection outcome and we aim to reveal bacteria and host specific transcriptional responses duringin vitroinfections.

We infected human and bovine cell lines with two human-associatedM. tuberculosisstrains from lineages 5 and 6, as well as two animal-associated strains (Mycobacterium bovisand the Chimpanzee bacillus), and quantified infection ratios, cell death, and transcriptional responses. By integrating those data from different compatibility combinations, we identified global transcription profiles associated with strain-host compatibility.

Our results show that the most compatible host-strain combinations had higher infection rates, and different transcriptional patterns than low-compatibility infections. Both hosts had similar transcriptional responses to their most compatible strains, upregulating pathways related with increased cell proliferation. Host proliferation could potentially favour bacterial growth, explaining the success of the strain in its corresponding host. Conversely, both hosts responded to non-associated strains with defence related transcriptional patterns, among other pathways, supporting their lower success in the non-associated host. Finally, we revealed bacteria and host-specific expression patterns in molecules implicated in immune response and inflammation through the eicosanoid pathway.

In conclusion, we confirmed that bacteria-host compatibility determines common transcriptional responses, but also specific responses that depend on the infecting strain. This study enhances the understanding of host-specific adaptation mechanisms inM. tuberculosis.
Virus propagation linked to exceedingly rare gene-expression errors
Authors: Luzón-Hidalgo Raquel , d’Agostino Gianluca , Risso Valeria A. , Delgado Asuncion , Ibarra-Molero Beatriz , Campos Luis A. , Requejo-Isidro Jose , Sanchez-Ruiz Jose M.
Published: May 2024

Viruses are obligate parasites that establish extensive interactions with proteins and other biomolecules of their hosts. About 20% of protein molecules bear phenotypic mutations due to errors during gene expression. Phenotypic mutations are not inherited and are not purged/amplified by natural selection. Therefore, protein variants harboring phenotypic mutations remain at very low levels. Here, we show that proteins at exceedingly low levels may enable virus propagation. Bacteriophage T7 recruits the host thioredoxin as an essential processivity factor for its replisome. Thioredoxin constitutive expression yields 10000-20000 molecules perE. colicell. We inserted early stop codons in the thioredoxin gene and appended to its end the sequence encoding for a photoconvertible fluorescent protein. Virus propagation was not abolished, indicating that some thioredoxin molecules were produced through mistranscription or mistranslation. Single-molecule localization microscopy detected 12±5 molecules per cell when an ochre codon was inserted. This work demonstrates that crucial virus-host biomolecular interactions may need occur only a few times to trigger virus propagation and supports that viruses may exploit the wide diversity of host and viral protein variants arising from gene-expression errors to establish such interactions. Immediate implications of this notion for the mechanisms of cross-species transmission and antibody evasion are discussed.
Astrocytic RIPK3 exerts protective anti-inflammatory activity during viral encephalitis via induction of serpin protease inhibitors
Authors: Lindman Marissa , Estevez Irving , Marmut Eduard , DaPrano Evan M. , Chou Tsui-Wen , Newman Kimberly , Atkins Colm , O’Brown Natasha M. , Daniels Brian P.
Published: May 2024

Flaviviruses pose a significant threat to public health due to their ability to infect the central nervous system (CNS) and cause severe neurologic disease. Astrocytes play a crucial role in the pathogenesis of flavivirus encephalitis through their maintenance of blood-brain barrier (BBB) integrity and their modulation of immune cell recruitment and activation within the CNS. We have previously shown that receptor interacting protein kinase-3 (RIPK3) is a central coordinator of neuroinflammation during CNS viral infection, a function that occurs independently of its canonical function in inducing necroptotic cell death. To date, however, roles for necroptosis-independent RIPK3 signaling in astrocytes are poorly understood. Here, we use mouse genetic tools to induce astrocyte-specific deletion, overexpression, and chemogenetic activation of RIPK3 to demonstrate an unexpected anti-inflammatory function for astrocytic RIPK3. RIPK3 activation in astrocytes was required for host survival in multiple models of flavivirus encephalitis, where it restricted neuropathogenesis by limiting immune cell recruitment to the CNS. Transcriptomic analysis revealed that, despite inducing a traditional pro-inflammatory transcriptional program, astrocytic RIPK3 paradoxically promoted neuroprotection through the upregulation of serpins, endogenous protease inhibitors with broad immunomodulatory activity. Notably, intracerebroventricular administration of SerpinA3N in infected mice preserved BBB integrity, reduced leukocyte infiltration, and improved survival outcomes in mice lacking astrocytic RIPK3. These findings highlight a previously unappreciated role for astrocytic RIPK3 in suppressing pathologic neuroinflammation and suggests new therapeutic targets for the treatment of flavivirus encephalitis.
Rab6a enables BICD2/dynein-mediated trafficking of human papillomavirus from thetrans-Golgi network during virus entry
Authors: Choi Jeongjoon , Speckhart Kaitlyn , Tsai Billy , DiMaio Daniel
Published: May 2024

Rab GTPases control intracellular vesicular transport, including retrograde trafficking of human papillomavirus (HPV) during cell entry, guiding the virus from the endosome to thetrans-Golgi network (TGN), the Golgi apparatus, and eventually the nucleus. Rab proteins that act prior to the arrival of HPV to the TGN have been identified, but Rab proteins operating in later stages of entry remain elusive. Here, we report that knockdown of Rab6a impairs HPV entry by impeding intra-Golgi transport of the incoming virus, resulting in HPV accumulation in the TGN. Rab6a supports HPV trafficking by facilitating the association of HPV with dynein, a motor protein complex, and BICD2, a dynein adaptor. L2 can bind directly to GTP-Rab6ain vitro, and excess of either GTP-Rab6a or GDP-Rab6 inhibits HPV entry, suggesting that cycling between GDP- Rab6 and GTP-Rab6 is critical. Notably, Rab6a is crucial for HPV-BICD2 and HPV-dynein association in the TGN of infected cells, but the HPV-dynein association in the endosome does not require Rab6a. Our findings reveal an important feature of the molecular basis of intra-Golgi trafficking of HPV and identify potential targets for therapeutic approaches to inhibit HPV infection.
The major surface protein of malaria sporozoites is GPI-anchored to the plasma membrane
Authors: Nagar Rupa , Garcia Castillo Stefano S. , Pinzon-Ortiz Maria , Patray Sharon , Coppi Alida , Kanatani Sachie , Moritz Robert L. , Swearingen Kristian E. , Ferguson Michael A. J. , Sinnis Photini
Published: May 2024

Glycosylphosphatidylinositol (GPI) anchor protein modification inPlasmodiumspecies is well known and represents the principal form of glycosylation in these organisms. The structure and biosynthesis of GPI anchors ofPlasmodiumspp. has been primarily studied in the asexual blood stage ofP. falciparumand is known to contain the typical conserved GPI structure of EtN-P-Man3GlcN-PI. Here, we have investigated the circumsporozoite protein (CSP) for the presence of a GPI-anchor. CSP is the major surface protein ofPlasmodiumsporozoites, the infective stage of the malaria parasite. While it is widely assumed that CSP is a GPI-anchored cell surface protein, compelling biochemical evidence for this supposition is absent. Here, we employed metabolic labeling and mass-spectrometry based approaches to confirm the presence of a GPI anchor in CSP.

Biosynthetic radiolabeling of CSP with [3H]-palmitic acid and [3H]-ethanolamine, with the former being base-labile and therefore ester-linked, provided strong evidence for the presence of a GPI anchor on CSP, but these data alone were not definitive. To provide further evidence, immunoprecipitated CSP was analyzed for presence ofmyo-inositol (a characteristic component of GPI anchor) using strong acid hydrolysis and GC-MS for a highly sensitive and quantitative detection. The single ion monitoring (SIM) method for GC-MS analysis confirmed the presence of themyo-inositol component in CSP. Taken together, these data provide confidence that the long-assumed presence of a GPI anchor on this important parasite protein is correct.
Red Light Mediated Photo-Conversion of Silicon Rhodamines to Oxygen Rhodamines for Single-Molecule Microscopy
Authors: Ritz Jacob M. , Khakimzhan Aset , Dalluge Joseph J. , Noiraeux Vincent , Puchner Elias M.
Published: May 2024

The rhodamine motif has been modified in myriad ways to produce probes with specific fluorescent and chemical properties optimal for a variety of microscopy experiments. Recently, far-red emitting silicon rhodamines have become popular in single-molecule localization microscopy (SMLM), since these dyes are membrane-permeable and can be used alongside red fluorophores for two-color imaging. While this has expanded multi-color SMLM imaging capabilities, we demonstrate that silicon rhodamines can create previously unreported photoproducts with significantly blueshifted emissions, which appear as bright single-molecule crosstalk in the red emission channel. We show that this fluorescence is caused by the replacement of the central silicon group with oxygen after 640 nm illumination, turning far-red silicon rhodamines (JFX650, JF669, etc.) into their red oxygen rhodamine counterparts (JFX554, JF571, etc.). While this blueshifted population can cause artifacts in two-color SMLM data, we demonstrate up to 16-fold reduction in crosstalk using oxygen-scavenging systems. We also leverage this far-red photoconversion to demonstrate UV-free photoactivated localization microscopy (PALM) without the need for additives, and with 5-fold higher efficiency than the Cy5 to Cy3 conversion. Finally, we demonstrate multiplexed pseudo two-color PALM in a single emission channel by separating localizations by their photo-activation wavelengths instead of their emission wavelengths.

Abstract Figure
Single-cell spatial transcriptomics reveals a dystrophic trajectory following a developmental bifurcation of myoblast cell fates in facioscapulohumeral muscular dystrophy
Authors: Chen Lujia , Kong Xiangduo , Johnston Kevin G. , Mortazavi Ali , Holmes Todd C. , Tan Zhiqun , Yokomori Kyoko , Xu Xiangmin
Published: May 2024

Facioscapulohumeral muscular dystrophy (FSHD) is linked to abnormal derepression of the transcription activator DUX4. This effect is localized to a low percentage of cells, requiring single-cell analysis. However, single-cell/nucleus RNA-seq cannot fully capture the transcriptome of multinucleated large myotubes. To circumvent these issues, we use multiplexed error-robust fluorescent in situ hybridization (MERFISH) spatial transcriptomics that allows profiling of RNA transcripts at a subcellular resolution. We simultaneously examined spatial distributions of 140 genes, including 24 direct DUX4 targets, in in vitro differentiated myotubes and unfused mononuclear cells (MNCs) of control, isogenic D4Z4 contraction mutant and FSHD patient samples, as well as the individual nuclei within them. We find myocyte nuclei segregate into two clusters defined by the expression of DUX4 target genes, which is exclusively found in patient/mutant nuclei, whereas MNCs cluster based on developmental states. Patient/mutant myotubes are found in “FSHD-hi” and “FSHD-lo” states with the former signified by high DUX4 target expression and decreased muscle gene expression. Pseudotime analyses reveal a clear bifurcation of myoblast differentiation into control and FSHD-hi myotube branches, with variable numbers of DUX4 target-expressing nuclei found in multinucleated FSHD-hi myotubes. Gene coexpression modules related to extracellular matrix and stress gene ontologies are significantly altered in patient/mutant myotubes compared with the control. We also identify distinct subpathways within the DUX4 gene network that may differentially contribute to the disease transcriptomic phenotype. Taken together, our MERFISH-based study provides effective gene network profiling of multinucleated cells and identifies FSHD-induced transcriptomic alterations during myoblast differentiation.
Generic quartic solitons in optical media
Authors: Tsoy Eduard N. , Suyunov Laziz A.
Published: May 2024

Our analysis suggests strongly that stationary pulses exist in nonlinear media with second-, third-, and fourth-order dispersion. A theory, based on the variational approach, is developed for finding approximate parameters of such solitons. It is obtained that the soliton velocity in the retarded reference frame can be different from the inverse of the group velocity of linear waves. It is shown that the interaction of the pulse spectrum with that of linear waves can affect the existence of stationary solitons. These theoretical results are supported by numerical simulations. Transformations between solitons of different systems are derived. A generalization for solitons in media with the highest even-order dispersion is suggested.

Published by the American Physical Society
2024
Controlled refraction and focusing of spin waves determined by the Aharonov-Casher effect
Authors: Krivoruchko V. N. , Savchenko A. S.
Published: May 2024

The influence of an external static electric field on spin wave (SW) dynamics leads to an additional topological phase called the Aharonov-Casher (AC) phase. It is manifested as a shift in dispersion and the group velocity direction of the spin wave under the electric field. Within a linear approximation, the AC effect can be considered by including the Dzyaloshinskii-Moriya-like interaction between neighboring spins, which is proportional to the applied electric field. In this paper, we use these findings to examine the possibility of the electric field control of the refraction of coherently propagating SWs. This is done by studying the propagation SWs across the boundary between two regions of a homogeneous ferromagnetic film under the influence of different external electric fields. We have derived an analytical expression for a magnetic Snell's law and performed micromagnetic simulations to demonstrate how the AC phase shift can control SW refraction. This effect enables us to quantify the topological AC phase action. It presents a promising approach for guiding and manipulating the phase and energy flow of SWs using an external electric field, opening a way to control magnonic devices.

Published by the American Physical Society
2024
Deconfinement transition within the Curci-Ferrari model: Renormalization scale and scheme dependences
Authors: Surkau Victor Tomas Mari , Reinosa Urko
Published: May 2024

We analyze the confinement/deconfinement transition of pure Yang-Mills theories within the framework of the center-symmetric Landau gauge supplemented by a Curci-Ferrari mass term that models the effect of the associated Gribov copies in the infrared. In addition to providing details for earlier one-loop calculations in that framework, we explore how the results depend on the renormalization scale and/or on the renormalization scheme. We find that the predicted values for the transition temperatures of SU(2) and SU(3) Yang-Mills theories are similar in both schemes and are little sensitive to the renormalization scale μ over a wide range of values including the standard range μ∈[πT,4πT]. These values are also close both to those obtained from a minimal sensitivity principle and to those of lattice simulations, especially in the SU(3) case. These results further confirm the good behavior of perturbative calculations within the Curci-Ferrari model and support the adequacy of the latter as an effective description of Yang-Mills theories in the infrared. We perform a similar analysis for the spinodal temperatures in the SU(3) case and for the Polyakov loop, the order parameter associated with the breaking of center symmetry.

Published by the American Physical Society
2024
Higgs boson off-shell measurements probe nonlinearities
Authors: Anisha  , Englert Christoph , Kogler Roman , Spannowsky Michael
Published: May 2024

The measurements of off-shell Higgs boson contributions in massive gauge boson pair production are known to probe its electroweak interactions across different energy scales. Often employed as an estimator of the Higgs boson width in restricted theories of beyond the Standard Model physics, we revisit this measurement and readvertise its potential to constrain aspects of Higgs boson nonlinearity. We show that this so-called off-shell measurement complements related analyses of multi-Higgs final states.

Published by the American Physical Society
2024
Unraveling the collisional energy loss of a heavy quark in a quark-gluon plasma
Authors: Peng Jiazhen , Yu Kewei , Li Shuang , Xiong Wei , Sun Fei , Xie Wei
Published: May 2024

At leading order in the QCD coupling constant, we compute the energy loss per traveling distance of a heavy quark dE/dz from elastic scattering off thermal quarks and gluons at a temperature T, including the thermal perturbative description of soft scatterings (−t<−t*) and a perturbative QCD-based calculation for hard collisions (−t>−t*). Within this soft-hard factorization model, we find that the full results of dE/dz behaves a mild sensitivity to the intermediate cutoff t*, supporting the validity of the soft-hard approach within the temperature region of interest. We rederive the analytic formula for dE/dz in the high-energy approximation, E1≫m12/T, where E1 is the injected heavy quark energy and m1 is its mass. It is realized that the soft logarithmic contribution, dE/dz∝ln(−t*/mD2), arises from the t-channel scattering off thermal partons, while the hard logarithmic term, dE/dz∝ln[E1T/(−t*)], stems from the t-channel scattering off thermal partons, and the one dE/dz∝ln(E1T/m12) comes from the s- and u-channel scattering off gluons. The sum of these contributions cancels the t*-dependence as observed in the full result. The mass hierarchy is observed dE/dz(charm)>dE/dz(bottom). Our full results are crucial for a better description of heavy quark transport in QCD medium, in particular at low and moderate energy. We also calculate the energy loss by imposing the Einstein’s relationship. The related results appear to be systematically larger than that without imposing the Einstein’s relationship.

Published by the American Physical Society
2024
Rheology of granular mixtures with varying size, density, particle friction, and flow geometry
Authors: Breard Eric C. P. , Fullard Luke , Dufek Josef
Published: May 2024

Employing the discrete element method, we study the rheology of dense granular media, varying in size, density, and frictional properties of particles, across a spectrum from quasistatic to inertial regimes. By accounting for the volumetric contribution of each solid phase, we find that the stress ratio, μ, and concentration, ϕ, scale with the inertial number when using volume averaging to calculate mean particle density, friction, and size. Moreover, the critical packing fraction correlates with skewness, polydispersity, and particle friction, irrespective of the size distribution. Notably, following the work of Kim and Kamrin , we introduce a rheological power-law scaling to collapse all our monodisperse and polydisperse data, reliant on concentration, dimensionless granular temperature, and the inertial number. This model seamlessly merges the μ(I)-rheology and kinetic theory, enabling the unification of all local and nonlocal rheology data onto a single master curve.

Published by the American Physical Society
2024