bluuebunny/crossref_metadata_2025 huggingface dataset:
Do Peer Navigators Improve Initiation and Retention in HIV/VH/STI Treatment Programs for People From Key Populations? A Systematic Review of Effectiveness, Values and Preferences, and Cost
Authors: Kennedy Caitlin E. , Yeh Ping T. , Verster Annette , Luhmann Niklas , Nguyen Van T. T. , de Mello Maeve B. , Baggaley Rachel , Macdonald Virginia
Published: February 2024

Background:

Key populations are disproportionately affected by HIV, viral hepatitis (VH), and sexually transmitted infections (STIs) and face barriers to care. Peer navigation programs are widely used, but evidence supporting their use has not been synthesized.

Setting:

Peer navigation programs for sex workers, men who have sex with men, people who inject drugs, prisoners, and trans and gender diverse people globally.

Methods:

To inform World Health Organization guidelines, we conducted a systematic review of effectiveness, values and preferences, and cost studies published between January 2010 and May 2021. We searched CINAHL, PsycINFO, PubMed, and EMBASE; screened abstracts; and extracted data in duplicate. The effectiveness review included randomized controlled trials and comparative observational studies evaluating time to diagnosis or linkage to care, treatment initiation, treatment retention/completion, viral load, cure, or mortality. We assessed risk of bias and summarized findings in GRADE evidence profiles. Values and preferences and cost data were summarized descriptively.

Results:

Four studies evaluated the effectiveness of peer navigators for key populations. All were focused on HIV; none were designed for VH or STIs. These studies showed mixed effects on linkage to care, treatment retention/completion, and viral load; no studies measured treatment initiation, cure, or mortality. Two values and preferences studies with community-based organization staff and health workers suggested peer navigators for key populations were acceptable and valued, although continued challenges remained. No cost studies were identified.

Conclusions:

Although limited, available studies provide moderate certainty evidence for benefits of HIV/VH/STI peer navigation programs for key populations. Further evaluations are needed.
Using Electronic Health Records to Improve HIV Preexposure Prophylaxis Care: A Randomized Trial
Authors: Volk Jonathan E. , Leyden Wendy A. , Lea Alexandra N. , Lee Catherine , Donnelly Michelle C. , Krakower Douglas S. , Lee Kristine , Liu Vincent X. , Marcus Julia L. , Silverberg Michael J.
Published: February 2024

Background:

Preexposure prophylaxis (PrEP) use remains limited and inequitable, and strategies are needed to improve PrEP provision in primary care.

Methods:

We conducted a cluster randomized trial at Kaiser Permanente, San Francisco, to evaluate the effectiveness of a clinical decision support intervention guided by an electronic health record (EHR)–based HIV risk prediction model to improve PrEP provision. Primary care providers (PCPs) were randomized to usual care or intervention, with PCPs who provide care to people with HIV balanced between arms. PCPs in the intervention arm received an EHR-based staff message with prompts to discuss HIV prevention and PrEP before upcoming in-person or video visits with patients whose predicted 3-year HIV risk was above a prespecified threshold. The main study outcome was initiation of PrEP care within 90 days, defined as PrEP discussions, referrals, or prescription fills.

Results:

One hundred twenty-one PCPs had 5051 appointments with eligible patients (2580 usual care; 2471 intervention). There was a nonsignificant increase in initiation of PrEP care in the intervention arm (6.0% vs 4.5%, HR 1.32, 95% CI: 0.84 to 2.1). There was a significant interaction by HIV provider status, with an intervention HR of 2.59 (95% CI: 1.30 to 5.16) for HIV providers and 0.89 (95% CI: 0.59 to 1.35) for non-HIV providers (P-interaction <0.001).

Conclusion:

An EHR-based intervention guided by an HIV risk prediction model substantially increased initiation of PrEP care among patients of PCPs who also care for people with HIV. Higher-intensity interventions may be needed to improve PrEP provision among PCPs less familiar with PrEP and HIV care.
Cutaneous Metastasis From Prostate Cancer on Posttherapeutic 177Lu–Prostate-Specific Membrane Antigen Scan
Authors: Taghavi Mohammad , Ahmadi Reyhane , Qutbi Mohsen
Published: February 2024

In this note, we aim to present a patient with a known case of prostate cancer with widespread metastasis to the skeleton and liver who has undergone several cycles of chemoradiotherapy. The patient received 2 doses of 177Lu–prostate-specific membrane antigen therapy, in which several zones of uptake were detected on the thoracic wall compatible with cutaneous metastatic lesions of prostate cancer.
To Draw a Detailed Map for Maxillofacial Fast-Flow Vascular Diseases With the Combination of Color Doppler Ultrasound and Three-Dimensional Computed Tomography Angiography
Authors: Yin Qiang , Chen Zhongping , Wang Haodong , Rong Li
Published: February 2024

Vascular diseases, such as vascular malformations and hemangiomas, are often classified into “fast-flow” and “slow-flow” based on their internal blood velocity. Fast-flow vascular diseases of maxillofacial regions are a kind of complicated and dangerous pathological changes originating from or containing arteries, their treatment is often complex and different from disease to disease, and large amounts of intraoperative blood loss and poor operation field may cause side injury or other problems without a detailed map of the lesion. The authors use the combination of color Doppler ultrasound and three-dimensional computed tomography angiography to diagnose and classify 36 cases of maxillofacial fast-flow vascular diseases, from January 2018 to December 2022 presented in the authors’ department. Three-dimensional computed tomography angiography can display the location, type, and blood supply of lesions, whereas color Doppler ultrasound has unique advantages in identifying some special lesions (such as the colorful images of orificium fistulaes and the “Yin-yang sign” of pseudoaneurysms), then projecting and marking them on the body surface, which greatly facilitate the surgical procedure. This cost-effective and noninvasive combination shows significant clinical application value.
Nutritional Support for the Trauma and Emergency General Surgery Patient: What You Need to Know
Authors: Hartwell Jennifer L. , Evans David C. , Martin Matthew J.
Published: February 2024

Decades of research have provided insight into the benefits of nutritional optimization in the elective surgical patient. Patients who are nutritionally prepared for surgery enjoy reduced length of hospital and intensive care unit stays and suffer fewer complications. In the Trauma and Emergency General Surgery (EGS) patient populations, we are not afforded the pre-operative period of optimization and patients often suffer longer lengths of hospital stay, discharge to nonhome destinations, and higher infectious and mortality rates. Nonetheless, ongoing research in this vulnerable and time critical diagnosis population has revealed significant outcomes benefits with the meticulous nutritional support of these patients. However, it is important to note that optimal nutritional support in this challenging patient population is not simply a matter of “feeding more and feeding earlier”. In this review, we will address assessing nutritional needs, the provision of optimal nutrition, the timing and route of nutrition, monitoring outcomes, and discuss the management of nutrition in the complex trauma and EGS patient.

LEVEL OF EVIDENCE

Level V, literature synthesis and expert opinion
Chemical genetics inC. elegansidentifies anticancer mycotoxins chaetocin and chetomin as potent inducers of a nuclear metal homeostasis response
Authors: Abraham Elijah , Athapaththu A. M. Gihan K. , Atanasova Kalina R. , Chen Qi-Yin , Corcoran Taylor J. , Piloto Juan , Wu Cheng-Wei , Ratnayake Ranjala , Luesch Hendrik , Choe Keith P.
Published: February 2024

C. elegans numr-1/2(nuclear-localizedmetal-responsive) is an identical gene pair encoding a nuclear protein previously shown to be activated by cadmium and disruption of the integrator RNA metabolism complex. We took a chemical genetic approach to further characterize regulation of this novel metal response by screening 41,716 compounds and extracts fornumr-1p::GFPactivation. The most potent activator was chaetocin, a fungal 3,6-epidithiodiketopiperazine (ETP) with promising anticancer activity. Chaetocin activatesnumr-1/2strongly in the alimentary canal but is distinct from metal exposure because it represses canonical cadmium-responsive metallothionine genes. Chaetocin has diverse targets in cancer cells including thioredoxin reductase, histone lysine methyltransferase, and acetyltransferase p300/CBP; further work is needed to identify the mechanism inC. elegansas genetic disruption and RNAi screening of homologs did not inducenumr-1/2in the alimentary canal and chaetocin did not affect markers of integrator dysfunction. We demonstrate that disulfides in chaetocin and chetomin, a dimeric ETP analog, are required to inducenumr-1/2.ETP monomer gliotoxin, despite possessing a disulfide linkage, had almost no effect onnumr-1/2, suggesting a dimer requirement. Chetomin inhibitsC. elegansgrowth at low micromolar levels and loss ofnumr-1/2increases sensitivity;C. elegansand Chaetomiaceae fungi inhabit similar environments raising the possibility thatnumr-1/2functions as a defense mechanism. There is no direct ortholog ofnumr-1/2in humans, but RNAseq suggests that chaetocin affects expression of cellular processes linked to stress response and metal homeostasis in colorectal cancer cells. Our results reveal interactions between metal response gene regulation and ETPs and identify a potential mechanism of resistance to this versatile class of preclinical compounds.
Neurovascular mitochondrial susceptibility impacts blood-brain barrier function and behavior
Authors: Crockett A. M. , Kebir H. , Vélez Colόn M. C. , Iascone D. M. , Cielieski B. , Rossano A. , Sehgal A. , Anderson S. A. , Alvarez J. I.
Published: February 2024

Maintenance of blood-brain barrier (BBB) integrity is critical to optimal brain function, and its impairment has been linked to multiple neurological disorders. A notable feature of the BBB is its elevated mitochondrial content compared to peripheral endothelial cells, although the functional implications of this phenomenon remain unknown. Here we studied BBB mitochondrial function in the context of the 22q11.2 deletion syndrome (22qDS), a condition associated with a highly increased risk for neuropsychiatric disease. As the 22q11.2 deletion includes 6 mitochondrial genes, and because we have previously identified BBB impairment in 22qDS, we addressed the hypothesis that mitochondrial deficits contribute to BBB dysfunction and impact behavior in this condition. We report mitochondrial impairment in human induced pluripotent stem cell (iPSC)-derived BBB endothelial cells from 22qDS patients, and in BBB endothelial cells from a mouse model of 22qDS. Remarkably, treatment to improve mitochondrial function attenuates mitochondrial deficits and enhances BBB function in both the iPSC and mouse 22qDS models. This treatment also corrected social memory in the mouse model, a deficit previously associated with BBB dysfunction. As BBB integrity correlated with social memory performance, together our findings suggest that mitochondrial dysfunction in the BBB influences barrier integrity and behavior in 22qDS.
A tale of too many trees: a conundrum for phylogenetic regression
Authors: Adams Richard , Lozano Jenniffer Roa , Duncan Mataya , Green Jack , Assis Raquel , DeGiorgio Michael
Published: February 2024

Abstract

Just exactly which tree(s) should we assume when testing evolutionary hypotheses? This question has plagued comparative biologists for decades. Given a perfectly estimated tree (if this is even possible in practice), we seldom know with certainty whether such a tree is truly best (or even adequate) to represent the evolutionary history of our studied traits. Regardless of our certainty, choosing a tree is required for all phylogenetic comparative methods. Yet, phylogenetic conflict and error are ubiquitous in modern comparative biology, and we are still learning about their dangers when testing evolutionary hypotheses. Here we investigated the consequences of gene tree-species tree mismatch for phylogenetic regression in the presence of incomplete lineage sorting. Our simulation experiments reveal excessively high false positive rates for mismatched phylogenetic regression with both small and large trees, simple and complex traits, and known and estimated phylogenies. In some cases, we find evidence of a directionality of error: incorrectly assuming a species tree for traits that evolved according to a gene tree sometimes fares worse than the opposite. To explore difficult yet realistic regression scenarios, we also used estimated rather than known trees to conduct case studies, as well as an expansive gene expression dataset to investigate an arguably best-case scenario in which one may have a better chance to match tree with trait. Though never meant to be a panacea for all that may ail phylogenetic comparative methods, we found promise in the application of a robust estimator as a potential, albeit imperfect, solution to some issues raised by tree mismatch, perhaps offering a path forward. Collectively, our results emphasize the importance of careful study design for comparative methods, highlighting the need to fully appreciate the role of adequate phylogenetic modeling for testing evolutionary hypotheses.
Alveolar macrophages play a key role in tolerance to ozone
Authors: Smith Gregory J. , Nalesnik Morgan , Immormino Robert M. , Simon Jeremy M. , Harkema Jack R. , Mock Jason R. , Moran Timothy P. , Kelada Samir N. P.
Published: February 2024

Acute exposure to ozone (O3) causes pulmonary inflammation and injury in humans and animal models. In rodents, acute O3-induced inflammation and injury can be mitigated by pre-exposure to relatively low concentration O3, a phenomenon referred to as tolerance. While tolerance was described long ago, the underlying mechanisms are not known, though upregulation of antioxidants has been proposed. To identify new mechanisms for O3tolerance, we generated a mouse model in which female C57BL6/NJ mice were pre-exposed to filtered air (FA) or 0.8 ppm O3for four days (4 hours/day), then challenged with 2 ppm O3(3 hours) 2 days later, and phenotyped for airway inflammation and injury 6 or 24 hours thereafter. As expected, pre-exposure to O3resulted in significantly reduced airway inflammation and injury at 24 hours, as well as reduced induction of antioxidant genes. Like previous studies in rats, tolerance was associated with changes in the frequency and proliferation of alveolar epithelial cells, but was not associated with upregulation of antioxidants, CCSP (SCGB1A1), or mucus. We found that alveolar macrophages (AMs) play a critical role in tolerance, as depletion of AMs using clodronate in mice pre-exposed to O3restored many responses to acute O3challenge. Further, AMs of O3tolerized mice exhibited decreased expression of genes involved in cellular signaling via Toll-like receptors, MYD88, and NF-kB, and proinflammatory cytokine production. We conclude that O3tolerance is highly, but not exclusively, dependent on AMs, and that further studies investigating how repeated O3exposure induces hypo-responsiveness in AMs are warranted.
Alterations in genes associated with cytosolic RNA sensing in whole blood are associated with coronary microvascular disease in SLE
Authors: Huo Lihong , Montano Erica , Tumurkhuu Gantseg , Bose Moumita , Berman Daniel S. , Wallace Daniel , Wei Janet , Ishimori Mariko , Merz C. Noel Bairey , Jefferies Caroline
Published: February 2024

Objective

To investigate whether gene signatures discriminate systemic lupus erythematosus (SLE) patients with coronary microvascular dysfunction (CMD) from those without and whether any signaling pathway is linked to the underlying pathobiology of SLE CMD.

Methods

This study collected whole blood RNA samples from female subjects aged 37 to 57, comprising 11 SLE patients (4 SLE-CMD, 7 SLE-non-CMD) and 10 HC. Total RNA was then used for library preparation and sequencing. Differential gene expression analysis was performed to identify gene signatures associated with CMD in SLE patients using DEseq2 v1.42.0. Gene Set Enrichment Analysis were performed by ClusterProfiler v4.10.0 and pathfindR v2.3.1.

Results

RNA-seq analysis revealed 143 differentially expressed (DE) genes between the SLE and HC groups. GO analysis indicated associations with virus defense and interferon signaling in SLE. 14 DE genes were identified from comparison between SLE-CMD and SLE-non-CMD with adjusted parameters (padj < 0.1). Notably, SLE-CMD exhibited elevated levels of genes associated with RNA sensing, while downregulated genes in SLE-non-CMD were associated with blood coagulation and cell-cell junction. Further investigation highlighted differences in IFN signaling and ADP-ribosylation pathways between SLE-CMD and SLE-non-CMD, suggesting distinct molecular mechanisms underlying vascular changes in CMD and reduced left ventricular function in non-CMD.

Conclusion

Our study identified a unique gene signature in SLE-CMD compared to the HC group, highlighting the significant involvement of type 1 interferon, RIG-I family proteins, and chronic inflammation in the progression of SLE-CMD. The intricate relationship between SLE-CMD and these factors underscores their probable role in initiating and advancing SLE-CMD.
A Mathematical Framework for Comparison of Intermittent versus Continuous Adaptive Chemotherapy Dosing in Cancer
Authors: McGehee Cordelia , Mori Yoichiro
Published: February 2024

Chemotherapy resistance in cancer remains a barrier to curative therapy in advanced disease. Dosing of chemotherapy is often chosen based on the maximum tolerated dosing principle; drugs that are more toxic to normal tissue are typically given in on-off cycles, whereas those with little toxicity are dosed daily. When intra-tumoral cell-cell competition between sensitive and resistant cells drives chemotherapy resistance development, it has been proposed that adaptive chemotherapy dosing regimens, whereby a drug is given intermittently at a fixed dose or continuously at a variable dose based on tumor size, may lengthen progression free survival over traditional dosing [1]. Indeed, in mathematical models using modified Lotka Volterra systems to study dose timing, rapid competitive release of the resistant population and tumor outgrowth is apparent when cytotoxic chemotherapy is maximally dosed [2]. This effect is ameliorated with continuous (dose modulation) or intermittent (dose skipping) adaptive therapy in mathematical models and experimentally, however, direct comparison between these two modalities has been limited. Here, we develop a mathematical framework to formally analyze intermittent adaptive therapy in the context of bang-bang control theory. We prove that continuous adaptive therapy is superior to intermittent adaptive therapy in its robustness to uncertainty in initial conditions, time to disease progression, and cumulative toxicity. We additionally show that under certain conditions, resistant population extinction is possible under adaptive therapy or fixed-dose continuous therapy. Here, continuous fixed-dose therapy is more robust to uncertainty in initial conditions than adaptive therapy, suggesting an advantage of traditional dosing paradigms.

Significance Statement

Intra-tumoral cell-cell competition between drug resistant and drug sensitive cancer cells is hypothesized to drive resistance development after chemotherapy administration in certain cancers. Optimization of chemotherapy delivery through dose or schedule adaptation based on tumor parameters (adaptive therapy) has been hypothesized to utilize chemotherapy sensitive cells to compete with chemotherapy resistant cells and delay tumor outgrowth. Here, we develop an analytical framework to compare two alternative adaptive therapy approaches: dose modulation (continuous) and schedule modulation (intermittent). Through direct analytical comparison, we demonstrate that continuous adaptive therapy is superior to intermittent adaptive therapy across physiologically relevant metrics. Furthermore, in parameters spaces where resistant population extinction is feasible, traditional fixed-dose therapy at a low dose may carry additional benefits over adaptive therapy.
Tetrameric INTS6-SOSS1 complex facilitates DNA:RNA hybrid autoregulation at double-strand breaks
Authors: Long Qilin , Ajit Kamal , Sedova Katerina , Haluza Vojtech , Stefl Richard , Dokaneheifard Sadat , Beckedorff Felipe , Valencia Monica G , Sebesta Marek , Shiekhattar Ramin , Gullerova Monika
Published: February 2024

DNA double strand breaks (DSBs) represent a lethal form of DNA damage that can trigger cell death and initiate oncogenesis. The activity of RNA polymerase II (RNAPII) at the break site is required for efficient DSB repair. However, the regulatory mechanisms governing the transcription cycle at DSBs are not well understood. Here, we show that Integrator complex subunit 6 (INTS6) associates with the trimeric SOSS1 (comprising INTS3, INIP, and hSSB1) to form a tetrameric SOSS1 complex following DNA damage. INTS6 binds to DNA:RNA hybrids and plays a crucial role in Protein Phosphatase 2 (PP2A) recruitment to DSBs, facilitating the dephosphorylation of RNAPII. Furthermore, INTS6 prevents the accumulation of damage-induced RNA transcripts (DARTs) and the stabilization of DNA:RNA hybrids at DSB sites. INTS6 interacts with, and promotes the recruitment of Senataxin (SETX) to DSBs, facilitating the resolution of DNA:RNA hybrids/R-loops. Our results underscore the significance of the SOSS1 complex in the autoregulation of DNA:RNA dynamics and the promotion of efficient DNA repair.
Estimating Propulsion Kinetics in Absence of a Direct Measurement of the Anterior Component of Ground Reaction Force
Authors: Cohen Hannah N. , Vasquez Miguel , Sergi Fabrizio
Published: February 2024

Anterior ground reaction force (AGRF) is a common measurement of walking function in post-stroke individuals. It is typically measured using multi-axis force-plates which are not always found in robotic research labs. Here we present a comparison of models using kinematic and kinetic metrics of propulsion to estimate AGRF.

Nine models using measurements of maximum vertical ground reaction force (maxVGRF), vertical ground reaction force at peak AGRF (aVGRF), maximum trailing limb angle (maxTLA), trailing limb angle at peak AGRF (aTLA) and stride length (SL) were used to predict different metrics of propulsion kinetics, including maximum AGRF (maxAGRF), propulsive impulse (PI), maximum AGRF normalized by body-weight (maxAGRFnorm), and normalized PI (PInorm) from participants at speeds [0.6 1.4] m/s. R2and AICc scores were recorded for each model, and the individual participant R2values for the best single and two-factor models for each outcome were examined.

Of the single-factor models, kinematic measurements were the best predictors of the outcome measurements. More specifically, maxAGRF/norm were best predicted by SL (R2= 0.91, 0.82, respectively), and PI/norm were best predicted by maxTLA (R2= 0.84, 0.43, respectively). For the two-factor models, maxAGRFnorm and PInorm were both best predicted by SL and aVGRFnorm, and maxVGRF yeilded the best predictions for maxAGRF and PI. Models predicting maxAGRF/norm better fit individual participants than those predicting PI/norm. These results indicate that maxAGRF can be estimated with reasonable accuracy (R2= 0.92, RMSE of residuals: 1.5% bodyweight, equivalent to a 0.09 m/s increase in velocity) in the absence of a direct measurement of AGRF using both kinematic and kinetic measurements of propulsion.
Human like severe hypertriglyceridemia in a high fat fed chicken model
Authors: Saranya K. , Beniha JG , Deepshikha TK , Shankar Kriti , Vishnu R , Kadiyala Gopi , Saxena Uday
Published: February 2024

Cardiovascular disease (CVD) is the biggest cause of mortality globally. Controlling the risk factors for CVD such as blood cholesterol and triglycerides is the hallmark of primary prevention of CVD. There are several drugs to control cholesterol that are available but not many approaches to reducing triglycerides safely are available.

High blood triglycerides or hypertriglyceridemia in humans is classified as moderate (200-400 mg/dl plasma levels) severe (400-800 mg/dl) and very severe (>800 mg/dl). There are not many appropriate in vivo models to study human like severe hypertriglyceridemia. We show here that high fat fed chickens rapidly and in a sustained manner respond by demonstrating triglyceride levels reminiscent of severe hypertriglyceridemia in humans. Such a model could be useful in better understanding this human disease as well as serve to test new therapies.
STING contributes to pulmonary hypertension by targeting the interferon and BMPR2 signaling through targeting F2RL3
Authors: Deng Lin , Cao Chengrui , Cai Zongye , Wang Ziping , Leng Bin , Chen Zhen , Kong Fanhao , Zhou Zhiyue , He Jun , Nie Xiaowei , Bian Jin-Song
Published: February 2024

Rational/Objectives

Pulmonary hypertension (PH) is an incurable disease characterized by pulmonary arterial remodeling. Endothelial injury and inflammation are the key triggers of the disease initiation. Recent findings suggest that STING (stimulator of interferon genes) activation plays a critical role in the endothelial dysfunction and interferon signaling. Here, we investigated the involvement of STING in the pathogenesis of PH.

Methods

PH patients and rodent PH model samples, Sugen5416/hypoxia (SuHx) PH model, and pulmonary artery endothelial cells (PAECs) were used to evaluate the hypothesis.

Measurement and Main Results

The cyclic GMP-AMP (cGAS)-STING signaling pathway was activated in the lung tissues from rodent PH models and PH patients, and the TNF-α induced PAECsin vitro. In particular, STING significantly elevated in the endothelial cell in PH disease settings. In SuHx mouse model, genetic knockout or pharmacological inhibition of STING prevented the progression of PH. Functionally, knockdown of STING reduced the proliferation and migration in PAECs. Mechanistically, STING transcriptional regulates its binding partner F2RL3 through STING-NF-κB axis, which activated the interferon signaling and repressed the BMPR2 signaling bothin vitroandin vivo. Further analysis revealed that F2RL3 expression was increased in PH settings and identified negative feedback regulation of F2RL3/BMPR2 signaling. Accordingly, a positive correlation of expression levels between STING and F2RL3/ interferon-stimulated genes (ISGs) was observedin vivo.

Conclusions

Our findings suggest that STING activation in PAECs plays a critical role in the pathobiology of PH. Targeting STING may be a promising therapeutic strategy for preventing the development of PH.
Superoxide enters neurons via LRRC8A – containing volume-regulated anion channels
Authors: Harris Kate , Uruk Gokhan , Won Seok Joon , Mai Nguyen , Baxter Paul , Everaerts Katharina , Sah Rajan , Swanson Raymond A.
Published: February 2024

Superoxide (O2-) is both an intercellular signaling molecule and a cause of neuronal oxidative stress. Superoxide entry into neurons is thought to be indirect, requiring its dismutation to nonpolar hydrogen peroxide. Here we show instead that superoxide enters neurons directly, via LRRC8A-containing volume-sensitive organic anion channels. In primary cultures, neuronal oxidative stress induced either by NMDA receptor stimulation or exposure to authentic superoxide was blocked by the anion channel blockers DIDS and DCPIB and by LRRC8A gene disruption. In mouse cortex, neuronal oxidative stress induced by either NMDA injection or transient ischemia was likewise blocked by both DCPIB and LRRC8A gene disruption. These findings identify a role for LRRC8A-containing volume-sensitive organic anion channels in neuronal oxidative signaling, stress, and glutamate excitotoxicity.
Environmental and Historical Determinants of African Horse Sickness: Insights from Predictive Modeling
Authors: Kim KwangHyok , Xu TianGang , Villalan Arivizhivendhan Kannan , Chi TianYing , Yu XiaoJing , Jin MyongIl , Wu RenNa , Ni GuanYing , Sui ShiFeng , Wang ZhiLiang , Wang XiaoLong
Published: February 2024

This study marks a pioneering effort in analyzing the global epidemiological patterns of African Horse Sickness (AHS) across different regions. By employing predictive modeling with a comprehensive set of environmental variables, we uncovered overarching global patterns in AHS dynamics, a first in this field. Our analysis revealed significant regional differences influenced by specific climatic conditions, highlighting the disease’s complexity. The study also identifies new high-risk areas for AHS, underscoring the necessity for regionally tailored disease management strategies. Despite some limitations, such as the exclusion of wild equine data, this research offers critical insights for global AHS intervention and prevention, setting a path for future research incorporating broader datasets and socio-economic factors.

Author Summary

AHS presents a significant challenge to the global equine industry, impacting both health and economic aspects. Our study highlights the profound effect of climate change, particularly the frequency of extreme climatic events including temperature and humidity variations, on the transmission dynamics of diseases like AHS. In our research, we focused on overcoming the challenges associated with identifying key environmental factors and determining the appropriate geographic scale for a comprehensive global understanding of AHS. Our aim was to bridge existing knowledge gaps and elucidate the fundamental principles governing AHS transmission. This study establishes a solid foundation for understanding the intricate dynamics of AHS and offers practical pathways for conservation efforts. It emphasizes the urgent need for environmentally conscious strategies to protect horse populations and the industries dependent on them. By highlighting the relationship between environmental factors, vector presence, and AHS transmission, our research underscores the importance of a holistic approach to disease mitigation. In conclusion, the findings of our study not only contribute to the scientific understanding of AHS but also serve as a guide for policymakers and practitioners in developing effective strategies for disease management and prevention, tailored to the specific environmental conditions and challenges faced in different regions around the world.
Bycatch mitigation of endangered marine life
Authors: García Mireia Villafáfila , Carpio Antonio , Rivas Marga L
Published: February 2024

The fishing gear deployed by fishermen in seas and oceans throughout the world not only captures target species but also unintentionally ensnares non-target species, a phenomenon known as “by-catch”. This unintended capture of marine life can represent significant challenges for the fishing industry, with adverse impacts on both the environment and species such as sea turtles, marine mammals, seabirds and elasmobranchs, which may be injured or even killed. To address this problem, the fishing industry has implemented regulations and mitigation measures. In this literature review, we have examined 389 articles published between 2010 and 2022 that assess the effectiveness of these measures. It has been demonstrated that the most effective measures are ‘pingers’ for marine mammals, ‘TEDs’ (Turtle Excluder Devices) for sea turtles, and ‘BSLs’ (Bird Scaring Lines), more commonly known as ‘tori lines’, for seabirds. The most complex case is that of elasmobranchs, and the most effective measure has yet to be discovered. This complexity arises from the ongoing targeted fishing of these species, resulting in less monitoring of their catches and, therefore, fewer surveys. Overall, we encourage the global implementation of these measures by the fishing industry in order to reduce by-catch in an attempt to ensure the future of many endangered species.
Transient DREADD manipulation of the dorsal Dentate Gyrus in rats impairs disambiguation of similar place-outcome associations
Authors: Lim Judith , Souiki A. , Ahmad P. , Oomen Charlotte A. , Huis in ’t Veld Gerjan , Lansink Carien S. , Pennartz Cyriel M.A. , Olcese Umberto
Published: February 2024

The dentate gyrus subfield of the hippocampus is thought to be critically involved in the disambiguation of similar episodic experiences and places in a context-dependent manner. However, most empirical evidence has come from lesion and gene knock-out studies in rodents, in which the dentate gyrus function is permanently perturbed and compensation of affected functions via other areas within the memory circuit could take place. The acute and causal role of the dentate gyrus herein remains therefore elusive. The present study aimed to investigate the acute role of the dorsal dentate gyrus in disambiguation learning using reversible inhibitory DREADDs.

Rats were trained on a location discrimination task and learnt to discriminate between a rewarded and unrewarded location with either small (similar condition) or large (dissimilar condition) separation. Reward contingencies switched after a reversal rule, allowing us to track the temporal engagement of the dentate gyrus during the task. Bilateral but not unilateral DREADD modulation of the dentate gyrus impaired the initial acquisition learning of place-reward associations, but performance rapidly recovered to control levels within the same session. Modelling of the behavioural patterns revealed that reward learning and reward sensitivity were not associated with the DREADD-dependent impairment during acquisition learning, suggesting that either the ability to encode place-reward associations, or the fine-grained coding of place were instead affected. Our study thus provides novel evidence that the dorsal dentate gyrus is acutely and bilaterally engaged during the initial acquisition learning of ambiguous place-reward associations, although the exact neural mechanisms supporting this function still need to be fully understood.
RNA-MobiSeq: Deep mutational scanning and mobility-based selection for RNA structure inference
Authors: Tang Jinle , Shi Yazhou , Zhang Zhe , Luo Dailin , Zhan Jian , Zhou Yaoqi
Published: February 2024

Tertiary structures of RNAs are increasingly found to be essential for their functions and yet are notoriously challenging to be determined by experimental techniques or predicted by energy-based and AlphaFold2-like deep-learning-based computational methods. Here, we coupled deep mutational scanning with mobility-based selection to separate structurally stable from nonstable RNA variants. The subsequent high-throughput sequencing allows the detection of the covariational signals of key secondary and tertiary base pairs with significantly improved, RNA-specific, unsupervised analysis of covariation-induced deviation of activity (CODA2) and amplification of these signals by Monte-Carlo simulated annealing. The resulting base-pairing structures can serve as the restraints for final energy-based structure predictions. This MobiSeq technique was tested on four structurally different RNAs. The results show that the detection of tertiary base pairs by MobiSeq allows reasonably accurate prediction of RNA tertiary structures. The proposed method should be useful for structural inference and improved mechanistic understanding of all RNAs with detectable changes in mobility due to deleterious mutations.
Improved BOLD Detection with Sliced Inverse Regression
Authors: Lizarraga Andrew , Li Katherine
Published: February 2024

Abstract

Functional magnetic resonance imaging (fMRI) has been effective in linking task-related brain responses to changes in blood oxygen level density (BOLD). However, its reliance on BOLD measurements makes it vulnerable to artifacts and false-positive signals. Commonly, researchers use many regressors in a General Linear Model to filter true signals, but this adds noise and complicates interpretation. In this paper we suggest using Sliced Inverse Regression (SIR) to simplify covariate dimensionality and identify relevant regressors. We compare a general linear model applied to both original and SIR-adjusted data, demonstrating that SIR improves signal detection, reduces noise, and yields statistically significant results even with conservative measures.
Female GluA3-KO mice show early onset hearing loss and afferent swellings in ambient sound levels
Authors: Pal Indra , Bhattacharyya Atri , V-Ghaffari Babak , Williams Essence D. , Xiao Maolei , Rutherford Mark A. , Rubio María Eulalia
Published: February 2024

AMPA-type glutamate receptors (AMPAR) mediate excitatory cochlear transmission. However, the unique roles of AMPAR subunits are unresolved. Lack of subunit GluA3 (Gria3KO) in male mice reduced cochlear output by 8-weeks of age. SinceGria3is X-linked and considering sex differences in hearing vulnerability, we hypothesized accelerated presbycusis inGria3KOfemales. Here, auditory brainstem responses (ABR) were similar in 3-week-old femaleGria3WTandGria3KOmice. However, when raised in ambient sound, ABR thresholds were elevated and wave-1 amplitudes were diminished at 5-weeks and older inGria3KO. In contrast, these metrics were similar between genotypes when raised in quiet. Paired synapses were similar in number, but lone ribbons and ribbonless synapses were increased in femaleGria3KOmice in ambient sound compared toGria3WTor to either genotype raised in quiet. Synaptic GluA4:GluA2 ratios increased relative toGria3WT, particularly in ambient sound, suggesting an activity-dependent increase in calcium-permeable AMPARs inGria3KO. Swollen afferent terminals were observed by 5-weeks only inGria3KOfemales reared in ambient sound. We propose that lack of GluA3 induces sex-dependent vulnerability to AMPAR-mediated excitotoxicity.
WITHDRAWN: Assessment of Remediation Through Measuring Nuclear Respiratory Factor 1 (nrf1) Environmental Stressor Transcriptomic Gene Signatures
Authors: Morales Juan , Deoraj Alok , Felty Quentin , Lagos Leonel , Yoo Changwon , Roy Deodutta
Published: February 2024

Withdrawal Statement

This manuscript has been withdrawn by the authors as it was submitted and made public without the full consent of all the authors. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
A specific phosphorylation-dependent conformational switch of SARS-CoV-2 nucleoprotein inhibits RNA binding
Authors: Botova Maiia , Camacho-Zarco Aldo R. , Tognetti Jacqueline , Bessa Luiza Mamigonian , Guseva Serafima , Mikkola Emmi , Salvi Nicola , Maurin Damien , Herrmann Torsten , Blackledge Martin
Published: February 2024

The nucleoprotein (N) of SARS-CoV-2 encapsidates the viral genome and is essential for viral function. The central disordered domain comprises a serine-arginine-rich domain (SR) that is hyperphosphorylated in infected cells. This modification is thought to regulate function of N, although mechanistic details remain unknown. We use time-resolved NMR to follow local and long-range structural changes occurring during hyperphosphorylation by the kinases SRPK1/GSK-3/CK1, thereby identifying a conformational switch that abolishes interaction with RNA. When 8 approximately uniformly-distributed sites are phosphorylated, the SR domain competitively binds the same interface as single-stranded RNA, resulting in RNA binding inhibition. Phosphorylation by PKA does not prevent RNA binding, indicating that the pattern resulting from the physiologically-relevant kinases is specific for inhibition. Long-range contacts between the RNA-binding, linker and dimerization domains are also abrogated, phenomena possibly related to genome packaging and unpackaging. This study provides insight into recruitment of specific host kinases to regulate viral function.
The maternal microbiome modifies adverse effects of protein undernutrition on offspring neurobehavioral impairment in mice
Authors: Coley-O’Rourke Elena J. , Lum Gregory R. , Pronovost Geoffrey N. , Özcan Ezgi , Yu Kristie B. , McDermott Janet , Chakhoyan Anna , Goldman Eliza , Vuong Helen E. , Paramo Jorge , Chu Alison , Calkins Kara L. , Hsiao Elaine Y.
Published: February 2024

Protein undernutrition is a global risk factor for impaired growth and neurobehavioral development in children. However, the critical periods, environmental interactions, and maternal versus neonatal influences on programming lasting behavioral abnormalities are poorly understood. In a mouse model of fetal growth restriction, limiting maternal protein intake particularly during pregnancy leads to cognitive and anxiety-like behavioral abnormalities in adult offspring, indicating a critical role for the gestational period. By cross-fostering newborn mice to dams previously exposed to either low protein or standard diet, we find that the adult behavioral impairments require diet-induced conditioning of both fetal development and maternal peripartum physiology, rather than either alone. This suggests that protein undernutrition during pregnancy directly disrupts fetal neurodevelopment and indirectly alters maternal state in ways that interact postnatally to precipitate behavioral deficits. Consistent with this, maternal protein restriction during pregnancy reduces the diversity of the maternal gut microbiome, modulates maternal serum metabolomic profiles, and yields widespread alterations in fetal brain transcriptomic and metabolomic profiles, including subsets of microbiome-dependent metabolites. Depletion of the maternal microbiome in protein-restricted dams further alters fetal brain gene expression and exacerbates neurocognitive behavior in adult offspring, suggesting that the maternal microbiome modifies the impact of gestational protein undernutrition on risk for neurobehavioral impairment in the offspring. To explore the potential for microbiome-targeted interventions, we find that maternal treatment with short chain fatty acids or a cocktail of 10 diet- and microbiome-dependent metabolites each yield differential effects on fetal development and/or postnatal behavior. Results from this study highlight impactful prenatal influences of maternal protein undernutrition on fetal neurodevelopment and adverse neurobehavioral trajectories in offspring, which are mitigated by microbiome-targeted interventions during pregnancy.
ProT-Diff: A Modularized and Efficient Approach to De Novo Generation of Antimicrobial Peptide Sequences through Integration of Protein Language Model and Diffusion Model
Authors: Wang Xue-Fei , Tang Jing-Ya , Liang Han , Sun Jing , Dorje Sonam , Peng Bo , Ji Xu-Wo , Li Zhe , Zhang Xian-En , Wang Dian-Bing
Published: February 2024

Antimicrobial Peptides (AMPs) represent a promising class of antimicrobial agents crucial for combating antibiotic-resistant pathogens. Despite the emergence of deep learning approaches for AMP discovery, there remains a gap in efficiently generating novel AMPs across various amino acid lengths without prior knowledge of peptide structures or sequence alignments. Here we introduce ProT-Diff, a modularized and efficient deep generative approach that ingeniously combines a pre-trained protein language model with a diffusion model to de novo generate candidate AMP sequences. ProT-Diff enabled the rapid generation of thousands of AMPs with diverse lengths within hours. Following in silico screening based on physicochemical properties and predicted antimicrobial activities, we selected 35 peptides for experimental validation. Remarkably, 34 of these peptides demonstrated antimicrobial activity against Gram-positive or Gram-negative bacteria, with 6 exhibiting broad-spectrum efficacy. Of particular interest, AMP_2, one of the broad-spectrum peptides, displayed potent antimicrobial activity, low hemolysis, and minimal cytotoxicity. Further in vivo assessment revealed its high effectiveness against a clinically relevant drug-resistantE. colistrain in a mouse model of acute peritonitis. This study not only presents a viable generative strategy for novel AMP design but also underscores its potential for generating other functional peptides, thereby broadening the horizon for new drug development.
Deciphering the impact of cancer cell’s secretome and its derived-peptide VGF on breast cancer brain metastasis
Authors: Carvalho Rita , Santos Liliana , Conde Inês , Leitão Ricardo , Ferreira Hugo R. S. , Gomes Célia , Silva Ana Paula , Schmitt Fernando , Carvalho-Maia Carina , Lobo João , Jerónimo Carmen , Paredes Joana , Ribeiro Ana Sofia
Published: February 2024

Brain metastases (BM) are one of the most serious clinical problems in breast cancer (BC) progression, associated with lower survival rates and a lack of effective therapies. Thus, to dissect the early stages of the brain metastatic process, we have searched for a brain-tropic metastatic signature on BC cells’ secretome, as a promising source for the discovery of new biomarkers involved in brain metastatic progression.

Therefore, six specifically deregulated peptides were found to be enriched in the secretome of brain organotropic BC cells. Importantly, these secretomes caused significant blood-brain barrier (BBB) disruption, as well as microglial activation,in vitroandin vivo. We identified the VGF nerve growth factor inducible as a brain-specific peptide, promoting BBB dysfunction similar to the secretome of brain organotropic BC cells. Concerning microglial activation, a slight increase was also observed upon VGF treatment.

In a series of human breast tumors, VGF was found to be expressed in both cancer cells and in the adjacent stroma. VGF-positive tumors showed a significant worse prognosis and were associated with HER2 overexpression and triple-negative molecular signatures. Finally, in a cohort including primary breast tumors and their corresponding metastatic locations to the lung, bone, and brain, we found that VGF significantly correlates with the brain metastatic site.

In conclusion, we found a specific BC brain metastatic signature, where VGF was identified as a key mediator in this process. Importantly, its expression was associated with poor prognosis for BC patients, probably due to its associated increased risk of developing BM.
Dynamic representation of appetitive and aversive stimuli in nucleus accumbens shell D1- and D2-medium spiny neurons
Authors: Domingues Ana Verónica , Carvalho Tawan T. A. , Martins Gabriela J. , Correia Raquel , Coimbra Bárbara , Gonçalves Ricardo , Wezik Marcelina , Gaspar Rita , Pinto Luísa , Sousa Nuno , Costa Rui M. , Soares-Cunha Carina , Rodrigues Ana João
Published: February 2024

The nucleus accumbens (NAc) is a key brain region for motivated behaviors, yet how distinct neuronal populations encode appetitive or aversive stimuli remains undetermined. Using microendoscopic calcium imaging, we tracked NAc shell D1- or D2-medium spiny neurons’ (MSNs) activity during exposure to stimuli of opposing valence and associative learning. Despite drift in individual neurons’ coding, both D1- and D2-population activity was sufficient to discriminate opposing valence unconditioned stimuli, but not predictive cues. Notably, D1- and D2-MSNs were similarly co-recruited during appetitive and aversive conditioning, supporting a concurrent role in associative learning. Conversely, when contingencies changed, there was an asymmetric response in the NAc, with more pronounced changes in the activity of D2-MSNs. Optogenetic manipulation of D2-MSNs provided causal evidence of the necessity of this population in the extinction of aversive associations.

Our results reveal how NAc shell neurons encode valence, Pavlovian associations and their extinction, and unveil new mechanisms underlying motivated behaviors.