bluuebunny/crossref_metadata_2025 huggingface dataset:
Changes in Auditory Performance Following a Virtual Reality Music Concert
Authors: Grinn Sarah K. , Notaro Dana E. , Shokar Jatinder K. , Cheng Chin-I
Published: October 2024

Objectives:

The purpose of this study was to evaluate threshold and suprathreshold auditory risk from a newly popular platform of music concert entertainment; virtual reality (VR) headsets. Recreational noise exposure to music is the primary source of hearing hazard in young-adults, with noise doses of in-person concert venues and music festivals well in excess of the recommended daily exposure recommendation from the National Institute for Occupational Safety and Health. While research on the relationship between personal music players and noise-induced hearing loss risk is abundant, no study has yet evaluated noise-induced hearing loss risk from VR headsets, which are newest to the commercial market at this time.

Design:

Thirty-one young-adult participants (18 to 25 years) with normal-hearing sensitivity (0 to 16 dB HL) experienced a VR music concert and participated in three data collection timepoints: Session A preexposure, Session A post-exposure, and Session B post-exposure. Participants underwent baseline testing for audiometry (0.25 to 20 kHz), distortion product otoacoustic emission testing (1 to 10 kHz), and Words-in-Noise testing. Participants then wore a commercially available VR headset (Meta Quest 2) and experienced a freely available online VR music concert (via the video-sharing website “YouTube”). The VR music concert duration was 90 min set to maximum volume, which yielded an average sound level equivalent of 78.7 dBA, max sound level of 88.2 dBA, and LC peak sound level of 98.6 dBA. Post-exposure testing was conducted immediately at the conclusion of the VR concert, and again within 24 hr to 1 week after the exposure. Participants also answered a questionnaire that estimated noise exposure history (National Acoustics Laboratory “Noise Calculator”).

Results:

Post-exposure deficit was not observed in DPOAEs or Words-in-Noise score (p’s > 0.05). However, statistically significant temporary post-exposure deficit was observed in audiometry at 4, 8, and 12.5 kHz (p’s < 0.05) (mean differences: 2 to 3 dB HL). Twenty-four hours and 1-week post-exposure measurements revealed no permanent changes from baseline measurements (p’s > 0.05) aside from one spurious difference at 12.5 kHz. Males tended to exhibit a significantly higher noise history score on average than females. The primary, secondary, and tertiary sources of noise hazard history in this young-adult cohort included amplified music.

Conclusions:

These preliminary data suggest that VR music concerts—which are likely to produce a substantially lower noise dose than in-person music concerts—may still be capable of producing at least slight, temporary threshold shifts on the order of 2 to 3 dB HL. Future research should include VR headsets in personal music player risk assessment, as the VR music concert platform is increasing rapidly in popularity among young-adults.
EUS–guided therapies for primary and secondary prophylaxis in gastric varices—An updated systematic review and meta-analysis
Authors: Chandan Saurabh , Nguyen Andrew Khoi , Mohan Babu P. , Deliwala Smit , Ramai Daryl , Kassab Lena L. , Muthusamy Arunkumar , Facciorusso Antonio , Kamal Faisal , Bilal Mohammad , Samanta Jayanta , Adler Douglas G.
Published: October 2024

Background and Objectives

Gastric varices (GVs) are associated with a higher risk of uncontrolled bleeding and death when compared with esophageal varices. While endoscopic glue injection therapy has been traditionally used for secondary prophylaxis in GV, data regarding primary prophylaxis continue to emerge. Recently, EUS–guided therapies have been used in GV bleeding.

Methods

We conducted a comprehensive search of several major databases from inception to June 2022. Our primary goals were to estimate the pooled rates of treatment efficacy, GV obliteration, GV recurrence, and rebleeding with EUS-guided therapy in primary and secondary prophylaxis. Overall adverse events and technical failures were assessed. Random-effects model was used for our meta-analysis, and heterogeneity was assessed using the I
2 % statistics.

Results

Eighteen studies with 604 patients were included. In primary prophylaxis, pooled rate of GV obliteration was 90.2% (confidence interval [CI], 81.1–95.2; I
2 = 0). With combination EUS–glue and coil therapy, the rate was 95.4% (CI, 86.7%–98.5%; I
2 = 0). Pooled rate of posttherapy GV bleeding was 4.9% (CI, 1.8%–12.4%; I
2 = 0). In secondary prophylaxis, pooled rate of treatment efficacy was 91.9% (CI, 86.8%–95.2%; I
2 = 12). With EUS-glue, EUS-coil, and combination EUS–glue and coil, the rates were 94.3% (CI, 88.9%–97.1%; I
2 = 0), 95.5% (CI, 80.3%–99.1%; I
2 = 0), and 88.7% (CI, 76%–95.1%; I
2 = 14), respectively. Pooled rate of GV obliteration was 83.6% (CI, 71.5%–91.2%; I
2 = 74). With EUS-glue, EUS-coil, and combination EUS–glue and coil, the rates were 84.6% (CI, 75.9%–90.6%; I
2 = 31), 92.3% (CI, 81.1%–97.1%; I
2 = 0), and 84.5% (CI, 50.8%–96.7%; I
2 = 75), respectively. Pooled rates of GV rebleeding and recurrence were 18.1% (CI, 13.1%–24.3%; I
2 = 16) and 20.6% (CI, 9.3%–39.5%; I
2 = 66), respectively.

Conclusion

Our analysis shows that EUS-guided therapy for GVs is technically feasible and clinically successful in both primary and secondary prophylaxis of GV.
HeartMate 3 Ventricular Assist Device in a Single-Ventricle and Single-Lung Patient Palliated With a Bidirectional Glenn
Authors: Caneo Luiz Fernando , Campos Carolina Vieira de , Jatene Marcelo Biscegli , Mello João Gabriel Guedes da Cunha , Barreto Isabela Guersoni Menna , Jatene Fabio Biscegli
Published: October 2024

We describe a 15 year old patient with failing second-stage single-ventricle palliation and left pulmonary artery thrombosis successfully supported with HeartMate 3 ventricular assist device and a Fontan completion as destination therapy.
Implementation of a Standardized Tool for Root Cause Analysis Selection
Authors: Wahlstedt Eric , Levy Brittany E. , Scott Emma , Stephens Wesley , Fletcher Kristen E. , Harris Andrew
Published: October 2024

Objectives:

This study sought to determine if a standardized root cause analysis (RCA2) selection algorithm, developed by the Veterans Affairs, would select high-risk events for RCA.

Methods:

Physician-entered incident reports for all surgical service admissions and perioperative visits were queried over 12 months in the DATIX Clinical Incident Management System. Independent reviewers assigned potential harm and event frequency scores using an institutional scoring system and then calculated and rounded average scores. These were classified using RCA2 terminology (catastrophic, major, moderate, minor for harm; frequent, occasional, uncommon, remote for frequency). The scores were then evaluated with the standardized Safety Assessment Code Matrix (SAC) algorithm from the National Patient Safety Foundation’s RCA2 guidelines to determine Potential Harm Scores. The SAC combines severity and probability to determine the necessity of conducting an RCA. Catastrophic and major high-frequency events (matrix score = 3) were classified as “RCA recommended.” The study then compared cases selected for RCAs using the updated RCA2 algorithm against cases selected using a current, institutional-specific RCA selection process.

Results:

One hundred four cases were reviewed, comprising 20 catastrophic, 48 major harm, 26 moderate harm, and 10 minor harm events. After removing 9 high-variance cases, our institution’s current selection process selected 18 cases for RCAs, including 6/20 catastrophic, 8/39 major harm, and 4/36 moderate/minor harm events. Only 17.3% of cases had an RCA completed, while the standardized RCA2 algorithm recommended investigation for 56.7% of patient safety events, based on SAC Matrix scoring. Current RCA selection processes rendered 4 RCAs on low potential harm or low-frequency events, while 45 potential high-frequency, high potential harm events did not complete RCAs.

Conclusions:

Standardizing the selection of patient safety incidents for RCA using the RCA2 algorithm improves case identification based on the event frequency and potential harm score. Thus, this algorithm has the potential to advance patient safety.
The Effect of Hospital-to-Home Discharge Interventions on Reducing Unplanned Hospital Readmissions: A Systematic Review and Meta-analysis
Authors: Demir Avcı Yasemin , Gözüm Sebahat , Karadag Engin
Published: October 2024

Background and Objectives:

Unplanned hospital readmissions (UHRs) constitute a persistent health concern worldwide. A high level of UHRs imposes a burden on individuals, their families, and health care system budgets. This systematic review and meta-analysis aimed to evaluate the effectiveness of discharge interventions in the transition from hospital to home in the context of reducing UHRs.

Methods:

The study design was a meta-analysis of randomized and nonrandomized controlled trials. Eight databases were searched. The effect on UHR rates (odds ratio [OR]) of discharge interventions in the transition from hospital to home was calculated at a 95% confidence interval (95% CI) based on meta-regression and meta-analysis of random-effects models.

Results:

Results showed that discharge interventions were effective in reducing rehospitalizations (effectiveness/OR =1.39; 95% CI, 1.24-1.55). It was furthermore determined that the studies showed heterogeneous characteristics (P ≤ .001, Q = 50.083, I
2 = 44.093; df = 28). According to Duval and Tweedie's trim and fill results, there was no publication bias. Interventions in which telephone communications and hospital visits (OR = 1.64; 95% CI, 1.25-2.16; P < .001) were applied together were effective among patients with cardiovascular diseases (OR = 1.54; 95% CI, 1.28-2.09; P < .001), and it was found that UHRs were reduced within a period of 90 days (OR = 1.68; 95% CI, 1.16-2.42; P < .001). It was also found that discharge interventions applied to transitions from hospital to home had a diminishing effect on UHRs as the publication dates of the reviewed studies advanced from the past to the present (OR = 0.015; 95% CI, 0.002-0.003; P < .001).

Conclusion:

Supporting and facilitating cooperation between health care professionals and families should be a key focus of discharge interventions.
Patient Satisfaction and QoL in SUI: Results With Single-Incision or Full-Length Slings
Authors: Erickson Ty , Gheiler Edward , Hanson Craig E. , McCrery Rebecca , Parekh Mitesh , Parva Mohamad , Tu Le Mai
Published: October 2024

Importance

Understanding treatment impact on quality of life of patients with stress urinary incontinence (SUI) in the short- and long-term is vital to optimizing treatment success.

Objectives

This study aimed to report 36-month patient satisfaction and quality of life results from a 522 study of single-incision and full-length slings in SUI.

Study Design

This was a secondary analysis of the Altis 522 study, a prospective, multicenter, nonrandomized, noninferiority cohort study comparing the Altis single-incision sling to full-length slings for the treatment of SUI. The current study endpoints are patient-reported outcomes on quality of life related to continence status at 6, 12, 18, 24, and 36 months, measured through patient-reported, validated questionnaires: Urogenital Distress Inventory, Incontinence Impact Questionnaire, Patient Global Impression of Improvement, and Surgical Satisfaction Questionnaire.

Results

A total of 355 women underwent the sling procedure (184, Altis group; 171, comparator group). At 36 months, 140 (76.0%) of Altis and 101 (59.1%) of comparator group patients were assessed. Patient Global Impression of Improvement at 36 months indicated that 92.9% of Altis and 90.1% of comparator patients reported that their condition was “very much better” or “much better” (P = 0.444). Urogenital Distress Inventory at 36 months indicated improvement in quality of life in both groups with a mean change from baseline of 41.7 ± 19.3 (Altis group; n = 140) versus 44.4 ± 22.2 (comparator group; n = 101) (P = 0.305). The Incontinence Impact Questionnaire indicated average quality-of-life improvement of 50% in both groups from presurgery to 36 months, with a mean change from baseline of 51.8 ± 25.8 (Altis group) versus 50.2 ± 25.1 (comparator group) (P = 0.619).

Conclusions

This 36-month study demonstrated the lasting, positive effect that surgical intervention can have on patients with SUI.
Access to Waitlisting and Posttransplant Outcomes in Patients With Failed Kidney Allografts Secondary to Recurrent Glomerulonephritis
Authors: Gately Ryan , Wong Germaine , Teixeira-Pinto Armando , Pilmore Helen , Hawley Carmel , Campbell Scott , Mulley William , Lim Wai H.
Published: October 2024

Background.

Recurrent glomerulonephritis (GN) is an important cause of allograft loss after transplantation when GN is the primary cause of kidney failure. Retransplantation after allograft loss from recurrent disease requires careful consideration. We aimed to determine the probability of relisting and the risk of allograft loss after retransplantation in recipients with prior allograft loss from recurrent GN.

Methods.

Using data from the Australia and New Zealand Dialysis and Transplant Registry and multivariable Cox modeling, we compared the probability of waitlisting and allograft loss after second transplantation between those with and without prior allograft loss from recurrent disease.

Results.

Of 3276 patients who received a second kidney transplant, 179 (5%) lost their first allograft from recurrent GN. Between 2006 and 2021, 1524 patients with failed first allografts (6% with recurrent GN, 45% with primary GN but no disease recurrence) were relisted for transplantation. Compared with patients without primary GN, the adjusted hazard ratios (95% confidence intervals) for relisting in patients with primary GN, with and without disease recurrence, were 1.09 (0.88-1.34) and 1.16 (1.05-1.29), respectively. The respective adjusted hazard ratios for allograft loss after repeat transplantation were 0.77 (0.59-1) and 1.02 (0.9-1.16). Of the 81 patients who received a second allograft after losing their first allograft to GN recurrence, 18 patients (22%) also lost their second allograft because of recurrent GN.

Conclusions.

Patients with prior allograft loss from GN recurrence were not disadvantaged, with comparable waitlist potential and allograft outcome after repeat transplantation. However, >20% of those with prior allograft loss from disease recurrence also lost their second allografts from recurrent disease.
Risk Factors for Early Post-transplant Weight Changes Among Simultaneous Pancreas-kidney Recipients and Impact on Outcomes
Authors: Parajuli Sandesh , Tamburrini Riccardo , Aziz Fahad , Dodin Ban , Astor Brad C. , Mandelbrot Didier , Kaufman Dixon , Odorico Jon
Published: October 2024

Background.

There are limited data about the risk factors for weight changes and the association of significant weight changes with graft and metabolic outcomes after simultaneous pancreas and kidney (SPK) transplantation.

Methods.

We included all SPK recipients with both allografts functioning for at least 6 mo post-transplant and categorized them based on the weight changes from baseline to 6 mo post-transplant. We analyzed risk factors for significant weight gain (SWG) and significant weight loss (SWL) over 6 mo post-transplant, as well as outcomes including pancreas uncensored graft failure, pancreas death-censored graft failure (DCGF), composite pancreas graft outcomes of DCGF, use of an antidiabetic agent, or hemoglobin A1C >6.5%, and kidney DCGF.

Results.

Of 280 SPK recipients, 153 (55%) experienced no significant weight change, 57 (20%) SWG, and 70 (25%) SWL. At 6 mo post-transplant, mean weight changes were 1.2% gain in the no significant weight change group, 13.4% gain in SWG, and 9.6% loss in the SWL groups. In multivariate analysis, the only factor associated with decreased risk for weight gain was older recipient age (aOR, 0.97; 95% confidence intervals, 0.95-0.99). Importantly, SWG or SWL were not associated with pancreas graft failure, P-DCGF, or K-DCGF. Interestingly in the adjusted model, SWG at 6 mo was associated with a lower risk for composite outcomes (HR, 0.35; 95% confidence intervals, 0.14-0.85).

Conclusions.

Forty-five percent of SPK recipients had significant weight changes by 6 mo post-transplant, but only 20% exhibited SWG. Likely because of proper management, weight changes were not associated with poor outcomes post-SPK transplant.
Sodium valproate ablates ferroptosis in kainic acid-induced epileptic seizure via suppressing lysyl oxidase
Authors: Li Qin , Huang Yu-Han , Li Qiu-Qi , Jia Ji-Ning , Liu Zhao-Qian , Zhou Hong-Hao , Zhou Xin-Yu , Jin Wei-Lin , Mao Xiao-Yuan
Published: October 2024

The objective of this study is to explore whether sodium valproate (VPA) alleviates epileptic seizures via suppressing lysyl oxidase (Lox)-mediated ferroptosis. Epileptic seizure mouse model was prepared via intrahippocampal injection of kainic acid (250 ng/μl). After treatment with kainic acid, VPA was injected intraperitoneally by the dose of 250 mg/kg twice daily for 4 days. Ferroptosis-associated indices including lipid peroxides (LPO) level and Ptgs2 mRNA in hippocampal tissue samples were detected. Additionally, effects of VPA on Lox mRNA and enzymatic activity were assessed by quantitative real-time PCR and a commercial kit, respectively. Neuronal survival was assessed by Nissl staining. In kainic acid-induced epileptic seizure mouse model, VPA significantly suppressed LPO level and Ptgs2 mRNA and the suppression of ferroptosis was positively correlated with its anti-seizure effect. Lox mRNA and enzymatic activity were also found to decrease in hippocampus of epileptic seizure mice after VPA treatment. Furthermore, overexpression of Lox via adeno-associated virus infection remarkably abrogated the inhibitory effect of VPA on ferroptosis and neuronal impairment together with its anti-seizure effect. VPA suppresses Lox-mediated ferroptosis process, which can provide the explanation for its anti-seizure property.
Environmental sampling for the detection of capripox viruses and peste des petits ruminants virus in households and livestock markets in Plateau State, Nigeria
Authors: Brown Emma , Ehizibolo David , Dogonyaro Banenat B. , Wungak Yiltawe , Oyekan Olumuyiwa , Adedeji Adeyinka , Ijeoma Sandra , Atai Rebecca , Oguche Moses , Samson Mark , Rosso Fabrizio , Ludi Anna B. , Limon Georgina , Shaw Andrew E. , Colenutt Claire , Gubbins Simon
Published: October 2024

Multiple transboundary animal diseases (TADs) circulate in Plateau State, Nigeria, where livestock keeping is common and contributes to both the physical and socio-economic well-being of a large proportion of the population. In this study, we explored the potential for environmental sampling to detect viruses causing TADs circulating in the region. Electrostatic dust cloths were used to swab areas of the environment likely to have contact with secretions and excretions from infected animals. Samples were collected monthly from five households, one transhumance site and one livestock market in two local government areas in Plateau State between March and October 2021. These were tested for the presence of peste des petits ruminants virus (PPRV) and capripox viruses using real-time PCR. Of the 458 samples collected, 2.4% (n = 11) were positive for PPRV RNA and 1.3 % (n = 6) were positive for capripox virus DNA. A capripox differentiation assay showed that these samples were positive for sheep pox virus (n = 2), goat pox virus (n = 2) and lumpy skin disease virus (n = 2). Our results demonstrate that environmental sampling could be used as part of TAD surveillance in the area. Environmental swabs require little technical knowledge to collect and can be used to detect multiple viruses from a single sample.
Outdoor Air Pollution Relates to Amygdala Subregion Volume and Apportionment in Early Adolescents
Authors: Morrel Jessica , Overholtzer L. Nate , Sukumaran Kirthana , Cotter Devyn L. , Cardenas-Iniguez Carlos , Tyszka J. Michael , Schwartz Joel , Hackman Daniel A. , Chen Jiu-Chiuan , Herting Megan M.
Published: October 2024

Background

Outdoor air pollution is associated with an increased risk for psychopathology. Although the neural mechanisms remain unclear, air pollutants may impact mental health by altering limbic brain regions, such as the amygdala. Here, we examine the association between ambient air pollution exposure and amygdala subregion volumes in 9–10-year-olds.

Methods

Cross-sectional Adolescent Brain Cognitive DevelopmentSM(ABCD) Study®data from 4,473 participants (55.4% male) were leveraged. Air pollution was estimated for each participant’s primary residential address. Using the probabilistic CIT168 atlas, we quantified total amygdala and 9 distinct subregion volumes from T1- and T2-weighted images. First, we examined how criteria pollutants (i.e., fine particulate matter [PM2.5], nitrogen dioxide, ground-level ozone) and 15 PM2.5components related with total amygdala volumes using linear mixed-effect (LME) regression. Next, partial least squares correlation (PLSC) analyses were implemented to identify relationships between co-exposure to criteria pollutants as well as PM2.5components and amygdala subregion volumes. We also conducted complementary analyses to assess subregion apportionment using amygdala relative volume fractions (RVFs).

Results

No significant associations were detected between pollutants and total amygdala volumes. Using PLSC, one latent dimension (LD) (52% variance explained) captured a positive association between calcium and several basolateral subregions. LDs were also identified for amygdala RVFs (ranging from 30% to 82% variance explained), with PM2.5and component co-exposure associated with increases in lateral, but decreases in medial and central, RVFs.

Conclusions

Fine particulate and its components are linked with distinct amygdala differences, potentially playing a role in risk for adolescent mental health problems.

Graphical Abstract
Mechanistic Studies of Small Molecule Ligands Selective to RNA Single G Bulges
Authors: Hegde Shalakha , Akhter Sana , Tang Zhichao , Qi Chang , Yu Chenguang , Lewicka Anna , Liu Yu , Koirala Kushal , Reibarkh Mikhail , Battaile Kevin P. , Cooper Anne , Lovell Scott , Holmstrom Erik D. , Wang Xiao , Piccirilli Joseph A. , Gao Qi , Miao Yinglong , Wang Jingxin
Published: October 2024

Small-molecule RNA binders have emerged as an important pharmacological modality. A profound understanding of the ligand selectivity, binding mode, and influential factors governing ligand engagement with RNA targets is the foundation for rational ligand design. Here, we report a novel class of coumarin derivatives exhibiting selective binding affinity towards single G RNA bulges. Harnessing the computational power of all-atom Gaussian accelerated Molecular Dynamics (GaMD) simulations, we unveiled a rare minor groove binding mode of the ligand with a key interaction between the coumarin moiety and the G bulge. This predicted binding mode is consistent with results obtained from structure-activity-relationship (SAR) studies and transverse relaxation measurements by NMR spectroscopy. We further generated 444 molecular descriptors from 69 coumarin derivatives and identified key contributors to the binding events, such as charge state and planarity, by lasso (least absolute shrinkage and selection operator) regression. Strikingly, small structure perturbations on these key contributors, such as the addition of a methyl group that disrupts the planarity of the ligand resulted in > 100-fold reduction in the binding affinity. Our work deepened the understanding of RNA-small molecule interactions and integrated a new generalizable platform for the rational design of selective small-molecule RNA binders.
Annotating full-scan MS data using tandem MS libraries
Authors: Xing Shipei , Charron-Lamoureux Vincent , El Abiead Yasin , Dorrestein Pieter C.
Published: October 2024

Full-scan mass spectrometry (MS) data from both liquid chromatography (LC) and MS imaging capture multiple ion forms, including their in-source fragments. Here we leverage such fragments to structurally annotate full-scan data from LC-MS or MS imaging by matching against peak intensity scaled tandem MS spectral libraries using precursor-tolerant reverse match scoring. Applied to inflammatory bowel disease and imaging datasets, we show the approach facilitates re-analyses of data in public repositories.
REPORTH: Determining orthologous locations of repetitive sequences between genomes
Authors: Bharadwaj Prajwal , van Dijk Bram , Bertels Frederic
Published: October 2024

Repetitive sequences are a common feature of bacterial genomes. Some repetitive sequences such as REPINs are mobile within the genome but inherited only vertically from mother to daughter across bacterial genomes. Selfish elements in contrast are mobile within the genome but also travel horizontally from genome to genome. Yet, no matter the nature of the association between the repetitive elements and the host, it is difficult to study the evolutionary dynamics of repetitive sequences across genomes. If it is unclear whether two sequences in two different genomes are in orthologous positions, it is difficult to infer parameters like the replication rate, horizontal transfer rate and rate of loss. Here we present a tool to facilitate these analyses called REPORTH. REPORTH determines whether repetitive sequences in different but closely related bacterial genomes occur in orthologous genomic positions. Whether a position is orthologous or not depends on the orthology of flanking sequences. Flanking sequences are deemed orthologous if they are bidirectional best hits. All repetitive sequences that are found in orthologous positions across different genomes are grouped together. Analyses of these groups can be used to study the evolutionary dynamics of selfish repetitive elements such as insertion sequences, but also for mutualistic repetitive elements such as REPINs.
Bacteria-phage (co)evolution is constrained in a synthetic community across multiple bacteria-phage pairs
Authors: Castledine Meaghan , Padfield Daniel , Schoeman Marli , Berry Amy , Buckling Angus
Published: October 2024

Bacteriophages can be important drivers of bacterial densities, and therefore microbial community composition and function. These ecological interactions are likely to be greatly affected by evolutionary dynamics, because bacteria can rapidly evolve resistance to phage while phage can reciprocally evolve to increase infectivity. Most studies to date have explored eco-evolutionary dynamics using isolated pairs of bacteria-phage but in nature, multiple bacteria and phages coexist and (co)evolve simultaneously. How coevolution plays out in this context is poorly understood. Here, we examine how three coexisting soil bacteria (Ochrobactrumsp.,Pseudomonassp., andVariovoraxsp.) interact and evolve with three species-specific bacteriophages over eight weeks of experimental evolution, both as host-parasite pairs in isolation and as a mixed community. Across all species phage resistance evolution was inhibited in polyculture, with the most pronounced effect onOchrobactrum. Between bacteria-phage pairs there were also substantial differences in the effect of phage on host densities, and evolutionary dynamics including whether pairs coevolved. These contrasts emphasise the difficulty in generalising from monoculture to polyculture, and between bacteria-phage pairs to wider systems. Future studies should consider how multiple bacteria and phage pairs interact simultaneously to better understand how coevolutionary dynamics happen in natural communities.

Importance

This project is unique in examining evolutionary dynamics among coexisting bacteria and their phages, rather than focus on single focal species – this makes our work more applicable to natural contexts while still working with controlled synthetic communities. While it is commonly assumed that bacteria will evolve phage resistance and coevolve with phage, this may be uncommon in more complex communities due to reduced contact rates and/or reduced mutation rates. Furthermore, the contrast in population dynamics and ability to coevolve between bacteria-phage pairs highlights the need for more pairs to be studied. Over-reliance on model systems that are known to coevolve means we lack an understanding of how wider bacteria-phage pairs interact, and to what extent results can be generalised beyond these pairs.
A genome-wide-level insight into the HSF gene family ofRhodomyrtus tomentosaand the functional divergence ofRtHSFA2aandRtHSFA2bin thermal adaption
Authors: Li Hui-Guang , Yang Ling , Fang Yujie , Wang Gui , Lyu Shanwu , Deng Shulin
Published: October 2024

Heat shock transcription factor (HSF) is one of the most important regulatory elements in plant development and stress response.Rhohomyrtus tomentosahas many advantages in adapting to high temperature and humidity climates, whereas the inherence has barely been elucidated. In this study, we aimed to characterize the HSF family and investigate the thermal adaption mechanisms ofR. tomentosa. We identified 25 HSF genes in theR. tomentosagenome. They could be classified into three classes: HSFA, HSFB, and HSFC. Gene duplication event is a major motivation for the expansion of theRtHSFgene family. Most of the genes in the same subclass share similar conserved motifs and gene structures. Thecis-actingelements of the promoter regions ofRtHSFgenes are related to development, phytohormone signaling, and stress responses, and they vary among the genes even in the same subclass, resulting in different expression patterns. Especially, there exists subfunctionalization in theRtHSFA2subfamily in responding to various abiotic stresses,viz. RtHSFA2ais sensitive to drought, salt, and cold stresses, whilstRtHSFA2bis mainly induced by heat stress. We further prove thatRtHSFA2bmight be of more importance inR. tomentosathermotolerance, forArabidopsiswith overexpressedRtHSFA2boutperformed those withRtHSFA2aunder heat stress, andRtHSFA2bhas much higher transcription activity thanRtHSFA2ain regulating certain heat shock response (HSR) genes.RtHSFA2aplays a role in transactivatingRtHSFA2b. All these results provide a general prospect of theRtHSFgene family and enclose a basal thermal adaption mechanism ofR. tomentosa.
Chromatin Buffers Torsional Stress During Transcription
Authors: Qian Jin , Lubkowska Lucyna , Zhang Shuming , Tan Chuang , Hong Yifeng , Fulbright Robert M. , Inman James T. , Kay Taryn M. , Jeong Joshua , Gotte Deanna , Berger James M. , Kashlev Mikhail , Wang Michelle D.
Published: October 2024

Transcription through chromatin under torsion represents a fundamental problem in biology. Pol II must overcome nucleosome obstacles and, because of the DNA helical structure, must also rotate relative to the DNA, generating torsional stress. However, there is a limited understanding of how Pol II transcribes through nucleosomes while supercoiling DNA. In this work, we developed methods to visualize Pol II rotation of DNA during transcription and determine how torsion slows down the transcription rate. We found that Pol II stalls at ± 9 pN·nm torque, nearly sufficient to melt DNA. The stalling is due to extensive backtracking, and the presence of TFIIS increases the stall torque to + 13 pN·nm, making Pol II a powerful rotary motor. This increased torsional capacity greatly enhances Pol II’s ability to transcribe through a nucleosome. Intriguingly, when Pol II encounters a nucleosome, nucleosome passage becomes more efficient on a chromatin substrate than on a single-nucleosome substrate, demonstrating that chromatin efficiently buffers torsional stress via its torsional mechanical properties. Furthermore, topoisomerase II relaxation of torsional stress significantly enhances transcription, allowing Pol II to elongate through multiple nucleosomes. Our results demonstrate that chromatin greatly reduces torsional stress on transcription, revealing a novel role of chromatin beyond the more conventional view of it being just a roadblock to transcription.
Glial cell derived pathway directs regenerating optic nerve axons toward the CNS midline
Authors: Harvey Beth M , Baxter Melissa , Garcia Alexis M , Granato Michael
Published: October 2024

Several RGC intrinsic signaling pathways have been shown to enhance RGC survival and RGC axonal growth after optic nerve injury. Yet an unresolved challenge for regenerating RGC axons is to properly navigate the optic chiasm located at the Central Nervous System midline. Here, we use live-cell imaging in larval zebrafish to show that regrowing RGC axons initiate growth toward the midline and extend along a trajectory similar to their original projection. From a candidate genetic screen, we identify the glycosyltransferase Lh3 to be required during the process of regeneration to direct regrowing RGC axons toward the midline. Moreover, we find that mutants in collagen 18a1 (col18a1), a putative Lh3 substrate, display RGC axonal misguidance phenotypes similar to those we observe in lh3 mutants, suggesting that lh3 may act through col18a1 during regeneration. Finally, we show that transgenic lh3 expression in sox10+ presumptive olig2+ oligodendrocytes located near the optic chiasm restores directed axonal growth. Combined these data identify lh3 and col18a1 as part of a glial derived molecular pathway critical for guiding in vivo regenerating RGC axons towards and across the optic chiasm.
Harnessing Global HLA Data for Enhanced Patient Matching in iPSC Haplobanks
Authors: Maiers Martin , Sullivan Stephen , McClain Christopher , Leonhard-Melief Christina , Turner Marc L. , Turner David
Published: October 2024

Several countries have either developed or are developing national induced pluripotent stem cell (iPSC) banks of cell lines derived from donors with HLA homozygous genotypes (two identical haplotypes) prevalent in their local populations to provide immune matched tissues and cells to support regenerative medicine therapies. This ‘haplobank’ approach relies on knowledge of the HLA genotypes of the population to identify the most beneficial haplotypes for patient coverage, and ultimately identify donors or cord blood units carrying two copies of the target haplotype. A potentially more efficient alternative to a national bank approach is to assess the haplotypes required to provide global patient coverage and to produce a single, global haplobank. Toward that end, we have developed an algorithm to prioritize HLA haplotypes that optimize coverage across the global population.

We analyzed data from eighteen countries participating in the Global Alliance for iPS Therapy (GAiT). A representative pool of HLA genotypes, reflecting the HLA of patients, was derived by sampling from each country’s WMDA hematopoietic stem cell donor registry, or surrogate population. An algorithm was created based on HLA-A, -B and -DRB1 haplotype homozygous types with population HLA matching coverage defined by the absence of Host versus Graft (HvG) mismatches at these loci. HLA matching coverage was determined by iteratively selecting HLA haplotypes that provide the largest coverage against patient HLA genotypes sampled from the same population, excluding genotypes compatible with previous iterations. The top 10 haplotypes for each of the 18 countries were identified with patient coverage ranging from 19.5% in Brazil to 63.8% in Japan, with a mean coverage of 33.3%. In a ‘global’ model, utilizing the 180 most frequent haplotypes across all 18 populations (equivalent to 10 lines pe country), the patient coverage ranged from 54.6% in India to 81.7% in Sweden, with a mean of 68.4%. Our findings demonstrate that global collaboration could more than double the potential for patient HLA matching coverage.

Interrogation of unrelated hematopoietic stem cell donor registry and cord blood bank HLA data demonstrated that HLA-A, -B, and -DRB1 homozygous donors for the top 180 global haplotypes are widely available. These results show that a globally coordinated strategy for haplobanking would reduce redundancy and allow more patients to be treated with the same investment.

Visual Abstract

Highlights

iPSC banks are being developed targeting HLA coverage to meet national needs

Global collaboration has the potential to substantially increase the efficiency of this effort
Heritable non-genetic phenotypes are enriched for stress responses as a form of bet hedging
Authors: Grissom Spencer , Dixon Zachary , Singh Abhyudai , Blenner Mark
Published: October 2024

During manufacturing batches, Chinese hamster ovary (CHO) cells encounter critical levels of environmental stressors such as ammonia, lactate, and osmolality accumulation that can significantly reduce cell health and productivity. It is therefore crucial that stress adaptation and resistance be factored into cell line development (CLD). In this study, we employee population-based transcriptomic and differential gene expression analysis on stress-induced CHO cells to identify biomarkers displaying both heritable and stress-responsive properties. Using this workflow, 199 genes displayed transcriptional variability characteristic of a bistable system that formed four network communities of co-fluctuating genes. These communities were enriched in genes related to the regulation of apoptotic processes and gene expression/metabolic pathways. Seven genes were identified as promising biomarkers for engineering a stress-resistant phenotype. Genetic engineering methods may be employed in the future to bias clonal populations for higher stress tolerance to manufacturing stress, therefore increasing cell health and productivity in at-scale bioreactors.
The ATP-dependent protease ClpYQ degrades cell division proteins DivIVA and Mbl inBacillus subtilis
Authors: Lanosky Taylor D. , Darnowski Michael G. , Brazeau-Henrie Jordan T. , Labana Puneet , Boddy Christopher N.
Published: October 2024

ATP-dependent proteases play key roles in bacterial protein quality control and regulation of cellular processes. ClpYQ and ClpXP are ATP-dependent proteases in the Gram-positive bacteriaBacillus subtilis. To date, no substrate proteins ofB. subtilisClpYQ have been characterized. The protease component encoded byclpQis synthetically lethal withclpPand the two genes are non-essential individually, suggesting potentially redundant roles for ClpYQ and ClpXP. Previous quantitative proteomic data predicted thatB. subtilisproteins DivIVA and Mbl, components of the divisome and elongasome respectively, are potential substrates of ClpYQ. The role of DivIVA and Mbl in cell division and elongation suggests a significant role of ClpYQ in regulating cell division through targeted degradation of key divisome and elongasome proteins. Here we confirm that DivIVA and Mbl are degraded by ClpYQ bothin vitroandin vivo, and thus identify the first two substrates of ClpYQ inB. subtilis.
Human Anti-Glycan Reactivity is Driven by the Selection of B cells Utilizing Private Antibody Gene Rearrangements that are Affinity Maturated in Germinal Centers
Authors: New J. Stewart , Fucile Christopher F. , Callahan Amanda R. , Burke Julia N. , Davis Randall S. , Duck Wayne L. , Rosenberg Alexander F. , Kearney John F. , King R. Glenn
Published: October 2024

The human antibody repertoire is broadly reactive with carbohydrate antigens represented in the universe of all living things, including both the host/self-as well as the commensal microflora-derived glycomes. Here we have used BCR receptor cloning and expression together with single-cell transcriptomics to analyze the B cell repertoire to the ubiquitous N-acetyl-D-glucosamine (GlcNAc) epitope in human cohorts and dissect the immune phylogeny of this predominant class of antibodies. We find that circulating anti-GlcNAc B cells exhibiting canonical BMem phenotypes emerge rapidly after birth and couple this observation with evidence for germinal center-dependent affinity maturation of carbohydrate-specific B cell receptorsin situduring early childhood. Direct analysis of individual B cell clonotypes reveals they exhibit strikingly distinct fine-specificity profiles for palettes of GlcNAc containing moieties. These results suggest that a generalized exposure to complex environmental glycans drives the steady state anti-glycan repertoire.
Multimodal learning of transcriptomes and text enables interactive single-cell RNA-seq data exploration with natural-language chats
Authors: Schaefer Moritz , Peneder Peter , Malzl Daniel , Peycheva Mihaela , Burton Jake , Hakobyan Anna , Sharma Varun , Krausgruber Thomas , Menche Jörg , Tomazou Eleni M. , Bock Christoph
Published: October 2024

Single-cell RNA-seq characterizes biological samples at unprecedented scale and detail, but data interpretation remains challenging. Here we introduce CellWhisperer, a multimodal machine learning model and software that connects transcriptomes and text for interactive single-cell RNA-seq data analysis. CellWhisperer enables the chat-based interrogation of transcriptome data in English language. To train our model, we created an AI-curated dataset with over a million pairs of RNA-seq profiles and matched textual annotations across a broad range of human biology, and we established a multimodal embedding of matched transcriptomes and text using contrastive learning. Our model enables free-text search and annotation of transcriptome datasets by cell types, states, and other properties in a zero-shot manner and without the need for reference datasets. Moreover, Cell-Whisperer answers questions about cells and genes in natural-language chats, using a biologically fluent large language model that we fine-tuned to analyze bulk and single-cell transcriptome data across various biological applications. We integrated CellWhisperer with the widely used CELLxGENE browser, allowing users to in-teractively explore RNA-seq data through an integrated graphical and chat interface. Our method demonstrates a new way of working with transcriptome data, leveraging the power of natural language for single-cell data analysis and establishing an important building block for future AI-based bioinformatics research assistants.
Mitochondria are absent from microglial processes performing surveillance, chemotaxis, and phagocytic engulfment
Authors: Pietramale Alicia N. , Bame Xhoela , Doty Megan E. , Hill Robert A.
Published: October 2024

Microglia continually surveil the brain allowing for rapid detection of tissue damage or infection. Microglial metabolism is linked to tissue homeostasis, yet how mitochondria are subcellularly partitioned in microglia and dynamically reorganize during surveillance, injury responses, and phagocytic engulfment in the intact brain are not known. Here, we performed intravital imaging of microglia mitochondria, revealing that microglial processes diverge, with some containing multiple mitochondria while others are completely void. Microglial processes that engage in minute-to-minute surveillance typically do not have mitochondria. Moreover, unlike process surveillance, mitochondrial motility does not change with animal anesthesia. Likewise, the processes that acutely chemoattract to a lesion site or initially engage with a neuron undergoing programmed cell death do not contain mitochondria. Rather, microglia mitochondria have a delayed arrival into the responding cell processes. Thus, there is subcellular heterogeneity of mitochondrial partitioning and asymmetry between mitochondrial localization and cell process motility or acute damage responses.
Citalopram exhibits immune-dependent anti-tumor effects by modulating C5aR1+TAMs and CD8+T cells
Authors: Dong Fangyuan , Zhang Shan , Song Kaiyuan , Jiang Luju , Hu Li-Peng , Li Qing , Zhang Xue-Li , Li Jun , Feng Mingxuan , Cai Zhi-Wei , Yao Hong-Fei , Li Rong-Kun , Li Hui , Chen Jie , Hu Xiaona , Wang Jiaofeng , Jiang Chongyi , Zhu Helen He , Wang Cun , Da Lin-Tai , Zhang Zhi-Gang , Bao Zhijun , Wang Xu , Jiang Shu-Heng
Published: October 2024

Administration of selective serotonin reuptake inhibitors (SSRIs) is associated with a reduced cancer risk and shows significant anti-tumor effects across multiple tumor types, suggesting the potential for repurposing SSRIs in cancer therapy. Nonetheless, the specific molecular target and mechanism of action of SSRIs remain to be fully elucidated. Here, we reveal that citalopram exerts an immune-dependent anti-tumor effects in hepatocellular carcinoma (HCC). Interestingly, the anti-HCC effects of citalopram are not reliant on its conventional target, the serotonin transporter. Through various drug repurposing approaches, including global reverse gene expression profiling, drug affinity responsive target stability assay, and molecular docking, the complement component 5a receptor 1 (C5aR1) is identified as a new target of citalopram. C5aR1 is predominantly expressed by tumor-associated macrophages (TAMs), and citalopram treatment enhances local macrophage phagocytosis and elicits CD8+T anti-tumor immunity. At a systemic level, citalopram treatment results in decreased serum 5-HT levels, which correlates with increased activation of CD8+T cells. Additionally, citalopram promotes αCD3/αCD28-stimulated CD8+T cell activation, expansion, and cytotoxicity. Depletion of CD8+T cells partially hinders the anti-HCC effects of citalopram. Collectively, our study reveals multiple immunomodulatory roles of citalopram in inducing anti-tumor immunity, and provides a basis for considering the repurposing of SSRIs as promising anticancer agents for HCC treatment.
Niclosamide Prodrug Enhances Oral Bioavailability and Targets Vasorin-TGFβ Signaling in Hepatocellular Carcinoma
Authors: Tan Mingdian , Ye Wei , Liu Yi , Chen Xiaowu , Huttad Lakshmi , Chua Mei-Sze , So Samuel
Published: October 2024

Background

Hepatocellular carcinoma (HCC) ranks third in cancer-related deaths worldwide, with limited therapeutic options. While niclosamide (NIC) has shown potential for repurposing in HCC, its poor water solubility and low bioavailability limit its efficacy, and its mechanisms of action are not yet fully elucidated.

Methods

We designed a water-soluble NIC prodrug (NIC-PS) and evaluated its efficacy throughin vitroandin vivostudies, including pharmacokinetic (PK) and pharmacodynamic (PD) assays, HCC patient-derived xenograft (PDX) models were applied in two independent experiments, vasorin (VASN) knockout models, and combination treatments with NIC-PS and sorafenib or anti-PD-L1 antibody. Bioinformatic analyses and western blotting were used to investigate NIC-PS’s target, VASN, and related signaling pathways.

Results

NIC-PS exhibited aten-fold increase in oral bioavailabilityand reduced tumor volume by over75%in HCC PDX models. NIC-PS directly binds and suppresses VASN, suppressing TGFβ signaling and reducing SMAD2/3 phosphorylation. VASN inhibition led to a50% tumor reduction, and NIC-PS enhanced responses to sorafenib and anti-PD-L1 therapy.

Conclusions

NIC-PS, equal to 36% of NIC in molecular weight, offers improved bioavailability, efficacy, and anovel mechanism of action in targeting VASN, showing promise for HCC treatment alone or in combination therapy.