bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of PCSK9 Inhibitors on Lipoprotein(a): A Meta-analysis and Meta-regression of Randomized Controlled Trials
Authors: Rivera Frederick Berro , Cha Sung Whoy , Magalong John Vincent , Tang Vincent Anthony , Enriquez Mary Grace , Gulati Martha , Enkhmaa Byambaa , Pagidipati Neha , Shah Nishant P. 
Published: July 2024

ABSTRACTBackgroundLipoprotein(a) [Lp(a)] has been independently associated with increased cardiovascular risk. We examined the effect of monoclonal antibody proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) on plasma Lp(a) levels across multiple clinical trials.MethodsStudies were retrieved comparing the effect of PCSK9i vs. placebo on Lp(a) levels. The primary outcome was percent change in Lp(a) levels. Secondary outcomes included percent change in additional cholesterol markers. Factors associated with the treatment effect were determined by meta-regression analysis. Subgroup analyses were done to explore potential treatment effect differences based on comparator, PCSK9i type, treatment duration, and presence of familial hypercholesterolemia (FH).Results47 studies with 67,057 patients were analyzed. PCSK9i reduced Lp(a) levels on average of -27% (95% CI: -29.8 to -24.1, p<0.001). Concurrent reduction in LDL-C, non-HDL-C, total cholesterol, triglycerides ApoB, ApoA-1, and increased HDL-C were also observed with PCSK9i use. Factors associated with the treatment effect included mean percent change in LDL-C (p=0.02, tau2=177.1, R2=0.00) and Apo-B (p<0.00, tau2=114.20, R2=1.42). Subgroup analyses revealed consistent treatment effect amongst comparators (vs. placebo: -27.69% (95% CI: - 30.85 to -24.54, p<0.00), vs. ezetimibe: -24.0% (95% CI: -29.95% to -18.01, p<0.00), type of PCSK9i, evolocumab: -29.35% (95% CI: -33.56 to -25.14, p<0.00) vs. alirocumab: -24.50% (95% CI: -27.96 to -21.04, p<0.00), and presence of FH: -25.63% (95% CI: -31.96% to -19.30, p<0.00 vs. no FH: -27.22% (95% CI: -30.34. to -24.09, p<0.00). Varying treatment effects were noted in the duration of treatment (12 weeks or shorter: -32.43% (95% CI: -36.63 to -28.23 vs. >12 weeks: -22.31% (95% CI: -25.13 to -19.49, p<0.00), p interaction <0.01.ConclusionPCSK9 inhibitors reduce Lp(a) levels by an average of 27%. Mean percent change in LDL-C and Apo-B were associated with treatment effect. PCSK9i also significantly reduced other atherogenic lipoproteins. Across multiple clinical trials, PCSK9i has a consistent effect of significantly lowering Lp(a) levels.
Global siRNA Screen Reveals Critical Human Host Factors of SARS-CoV-2 Multicycle Replication
Authors: Yin Xin , Pu Yuan , Yuan Shuofeng , Pache Lars , Churas Christopher , Weston Stuart , Riva Laura , Simons Lacy M , Cisneros William , Clausen Thomas , de Jesus Paul , Kim Ha Na , Fuentes Daniel , Whitelock John , Esko Jeffrey , Lord Megan , Mena Ignacio , Garcia-Sastre Adolfo , Hultquist Judd , Frieman Matthew , Ideker Trey , Pratt Dexter , Martin-Sancho Laura , Chanda Sumit 
Published: July 2024

Defining the subset of cellular factors governing SARS-CoV-2 replication can provide critical insights into viral pathogenesis and identify targets for host-directed antiviral therapies. While a number of genetic screens have previously reported SARS-CoV-2 host dependency factors, these approaches relied on utilizing pooled genome-scale CRISPR libraries, which are biased towards the discovery of host proteins impacting early stages of viral replication. To identify host factors involved throughout the SARS-CoV-2 infectious cycle, we conducted an arrayed genome-scale siRNA screen. Resulting data were integrated with published datasets to reveal pathways supported by orthogonal datasets, including transcriptional regulation, epigenetic modifications, and MAPK signalling. The identified proviral host factors were mapped into the SARS-CoV-2 infectious cycle, including 27 proteins that were determined to impact assembly and release. Additionally, a subset of proteins were tested across other coronaviruses revealing 17 potential pan-coronavirus targets. Further studies illuminated a role for the heparan sulfate proteoglycan perlecan in SARS-CoV-2 viral entry, and found that inhibition of the non-canonical NF-kB pathway through targeting of BIRC2 restricts SARS-CoV-2 replication both in vitro and in vivo. These studies provide critical insight into the landscape of virus-host interactions driving SARS-CoV-2 replication as well as valuable targets for host-directed antivirals.
A porcine chronic hepatitis E virus (HEV) infection model exhibits HEV replication in male accessory reproductive glands and immune-mediated reproductive damage
Authors: Yadav Kush K. , Boley Patricia A , Laocharoensuk Thamonpan , Khatiwada Saroj , Lee Carolyn M , Bhandari Menuka , Hanson Juliette , Kenney Scott P. 
Published: July 2024

AbstractHepatitis E virus (HEV) is an expanding zoonotic viral disease threat. Although HEV causes acute viral hepatitis, it is increasingly being recognized as a systemic pathogen with detection and damage in extrahepatic tissues. The presence of HEV RNA in the semen of chronically infected human patients in the absence of viremia and fecal shedding and presence of HEV in the sperm head underscores the need to understand the interaction of HEV within the male reproduction system. Male accessory glands secrete biofluids necessary for sperm nourishment and to neutralize the acidity of the vagina. The role of male accessory glands in the dissemination and persistence of HEV infection have not been studied. Using an immunosuppressed pig model for chronic HEV infection, we demonstrate infectious HEV in mature sperm cells altering the sperm motility and morphology. HEV isolated from sperm cells remained infectious in human hepatoma cells. Spermatic fluid contained lower virus titers than the sperm cells from chronically infected pigs highlighting that the sperm cells themselves can associate with the virus. Evaluation of the male accessory glands demonstrated viral replication, infiltration of CD45 leukocytes, and apoptosis associated with HEV infection. A decrease in serum testosterone levels was evident in the HEV infected pigs. Even though a lower viral RNA titer was seen in serum and feces of chronically infected, immunosuppressed and ribavirin treated pigs, high viral RNA and infectious particles in sperm is a concern. Our findings necessitate further studies defining the mechanism of sperm cell invasion by HEV, length of HEV survival in sperm cells during chronic HEV infection, and risk of sexual transmission of HEV during both acute and chronic phases of infection.Author SummaryHepatitis E virus, a leading cause of acute viral hepatitis, causes both acute and chronic infection in humans. Recent advances within the HEV field have demonstrated extrahepatic diseases associated with HEV. More recent findings have revealed infectious HEV in the vagina, Sertoli cells, and ejaculate of humans, and sperm cells of pigs. We demonstrate that the male accessory sex glands may have a role in the persistence of HEV infection during chronic infections. We utilized an established immunosuppressed pig model and treated pigs with ribavirin to study the presence of virus in the sperm cells. We demonstrated high viral RNA loads and infectious particles associated with sperm cells. Our study further highlights the importance of the testis, as an immune privileged site, in the maintenance of chronic HEV infection. New studies to evaluate the mechanisms by which HEV associates with sperm cells, the length of HEV survival in sperm cell fractions, and consideration of the testes as a potential HEV reservoir are necessary.
Polysaccharide quantification using microbial enzyme cocktails
Authors: Pontrelli Sammy , Sauer Uwe 
Published: July 2024

AbstractPolysaccharide quantification plays a vital role in understanding ecological and nutritional processes in microbes, plants, and animals. Traditional methods hydrolyze these large molecules into monomers, but these approaches are restricted to chemically hydrolysable polysaccharides. Enzymatic degradation is a promising alternative but typically requires the use of characterized recombinant enzymes or microbial isolates that secrete enzymes. In this study, we introduce a versatile method that employs undefined enzyme cocktails secreted by individual microbes or complex environmental microbial communities for the hydrolysis of polysaccharides. We focus on colloidal chitin and laminarin as representative polysaccharides of ecological relevance. Our results demonstrate that colloidal chitin can be effectively digested with an enzyme cocktail derived from a chitin-degradingPsychromonas sp.isolate. Utilizing a 3,5-dinitrosalicylic acid reducing sugar assay or liquid chromatography–mass spectrometry for mono- and oligomers detection, we successfully determined chitin concentrations as low as 62 mg/L and 15 mg/L, respectively. This allows for effective monitoring of microbial chitin degradation. To extend the applicability of our method, we also leveraged complex, undefined microbial communities as sources of enzyme cocktails capable of degrading laminarin. With this approach, we achieved a detection limit of 30 mg/L laminarin through the reducing sugar assay. Our findings highlight the potential of utilizing enzyme cocktails from both individual microbes and, notably, from undefined microbial communities for polysaccharide quantification. This advancement addresses limitations associated with traditional chemical hydrolysis methods.
The structural and biophysical basis of substrate binding to the hydrophobic groove in Ubiquilin Sti1 domains
Authors: Onwunma Joan , Binsabaan Saeed , Allen Shawn P. , Sankaran Banumathi , Wohlever Matthew L. 
Published: July 2024

AbstractUbiquilins are a family of cytosolic proteins that ferry ubiquitinated substrates to the proteasome for degradation. Recent work has demonstrated that Ubiquilins can also act as molecular chaperones, utilizing internal Sti1 domains to directly bind to hydrophobic sequences. Ubiquilins are associated with several neurodegenerative diseases with point mutations in UBQLN2 causing dominant, X-linked Amyotrophic Lateral Sclerosis (ALS). The molecular basis of Ubiquilin chaperone activity and how ALS mutations in the Sti1 domains affect Ubiquilin activity are poorly understood. This study presents the first crystal structure of the Sti1 domain from a fungal Ubiquilin homolog bound to a transmembrane domain (TMD). The structure reveals that two Sti1 domains form a head-to-head dimer, creating a hydrophobic cavity that accommodates two TMDs. Mapping the UBQLN2 sequence onto the structure shows that several ALS mutations are predicted to disrupt the hydrophobic groove. Using a newly developed competitive binding assay, we show that Ubiquilins preferentially bind to hydrophobic substrates with low helical propensity, motifs that are enriched in both substrates and in Ubiquilins. This study provides insights into the molecular and structural basis for Ubiquilin substrate binding, with broad implications for the role of the Sti1 domain in phase separation and ALS.
Developmental dynamics of the prefrontal cortical SST and PV interneuron networks: Insights from the monkey highlight human-specific features
Authors: Hosseini Fin Nafiseh S. , Yip Adrian , Teo Leon , Homman-Ludiye Jihane , Bourne James A. 
Published: July 2024

AbstractThe primate prefrontal cortex (PFC) is a quintessential hub of cognitive functions. Amidst its intricate neural architecture, the interplay of distinct neuronal subtypes, notably parvalbumin (PV) and somatostatin (SST) interneurons (INs), emerge as a cornerstone in sculpting cortical circuitry and governing cognitive processes. While considerable strides have been made in elucidating the developmental trajectory of these neurons in rodent models, our understanding of their postmigration developmental dynamics in primates still needs to be studied. Disruptions to this developmental trajectory can compromise IN function, impairing signal gating and circuit modulation within cortical networks. This study examined the expression patterns of PV and SST, ion transporter KCC2, and ion channel subtypes Kv3.1b, and Nav1.1 -associated with morphophysiological stages of development in the postnatal marmoset monkey in different frontal cortical regions (granular areas 8aD, 8aV, 9, 46; agranular areas 11, 47L). Our results demonstrate that the maturation of PV+ INs extends into adolescence, characterized by discrete epochs associated with specific expression dynamics of ion channel subtypes. Interestingly, we observed a postnatal decrease in SST interneurons, contrasting with studies in rodents. This endeavor broadens our comprehension of primate cortical development and furnishes invaluable insights into the etiology and pathophysiology of neurodevelopmental disorders characterized by perturbations in PV and SST IN function.Summary Statement:The prefrontal cortex (PFC) in primates is crucial for cognitive functions, with parvalbumin (PV) and somatostatin (SST) interneurons playing key roles. This study in marmoset monkeys explores their developmental dynamics, revealing prolonged maturation of PV interneurons and contrasting SST patterns from rodents, enhancing understanding of primate cortical development.
Star-polymers as potent broad-spectrum extracellular virucidal antivirals
Authors: Super Elana H. , Lai Si Min , Cytlak-Chaudhuri Urszula , Coppola Francesco , Saouaf Olivia , Song Ye Eun , Casey Kerriann M. , Batt Lauren J. , Macleod Shannan-Leigh , Bagley Robert H.T. , Walsh-Korb Zarah , Král Petr , Appel Eric A. , Travis Mark A. , Jones Samuel T. 
Published: July 2024

ABSTRACTViruses pose a significant threat to both global health and the global economy. It is clear that novel antiviral strategies are urgently needed, with a broad-spectrum approach being most desired. We have discovered a broad-spectrum, non-toxic polymer virucide that can tackle the viral threat. This polymeric virucide is effective at nanomolar concentrations, against a broad-spectrum of viruses and, demonstrated using an intranasal respiratory syncytial virus (RSV) murine model, has excellent efficacy, low anti-coagulant properties and low toxicityin vivo. Molecular dynamic simulations show that this polymer achieves its virucidal antiviral effectviaself-assembly of viral-receptors leading to increased envelope forces and viral disassembly. The discovery of this cheap and readily produced polymer marks the start of a new type of receptor-crosslinking broad-spectrum antiviral that has significant potential to combat the global threat posed by viruses.
Transcriptome signatures of the medial prefrontal cortex underlying GABAergic control of resilience to chronic stress exposure
Authors: Shao Meiyu , Botvinov Julia , Banerjee Deepro , Girirajan Santhosh , Lüscher Bernhard 
Published: July 2024

ABSTRACTAnalyses of postmortem human brains and preclinical studies of rodents have identified somatostatin (SST)-positive interneurons as key elements that regulate the vulnerability to stress-related psychiatric disorders. Conversely, genetically induced disinhibition of SST neurons or brain region-specific chemogenetic activation of SST neurons in mice results in stress resilience. Here, we used RNA sequencing of mice with disinhibited SST neurons to characterize the transcriptome changes underlying GABAergic control of stress resilience. We found that stress resilience of male but not female mice with disinhibited SST neurons is characterized by resilience to chronic stress-induced transcriptome changes in the medial prefrontal cortex. Interestingly, the transcriptome of non-stressed stress-resilient male mice resembled the transcriptome of chronic stress-exposed stress-vulnerable mice. However, the behavior and the serum corticosterone levels of non-stressed stress-resilient mice showed no signs of physiological stress. Most strikingly, chronic stress exposure of stress-resilient mice was associated with an almost complete reversal of their chronic stress-like transcriptome signature, along with pathway changes indicating stress-induced enhancement of mRNA translation. Behaviorally, the mice with disinhibited SST neurons were not only resilient to chronic stress-induced anhedonia — they also showed an inversed anxiolytic-like response to chronic stress exposure that mirrored the chronic stress-induced reversal of the chronic stress-like transcriptome signature. We conclude that GABAergic dendritic inhibition by SST neurons exerts bidirectional control over behavioral vulnerability and resilience to chronic stress exposure that is mirrored in bidirectional changes in expression of putative stress resilience genes, through a sex-specific brain substrate.
Dysregulations in Cardiogenic Mechanisms by TGF-beta and Angiotensin II in Cardiac Remodeling Post-Ischemic Injury: a systematic review
Authors: Shafi Ovais , Zahra Kashaf , Shah Haider Hussain 
Published: July 2024

AbstractObjectiveThe objective of this study is to look into how TGF-beta and Angiotensin II disrupt cardiogenic regulators (Isl1, Brg1/Baf60-Smarcd3 complex, Nkx2-5, GATA4, Tbx5, Mef2c, HAND1/2, MYOCD, MSX2, HOPX, Wnt-signaling pathway, Notch, FGF, BMPs) during cardiac remodeling post-ischemic injury.BackgroundCardiac remodeling post-ischemic injury, influenced by TGF-beta and Angiotensin II, disrupts critical cardiogenic regulators essential for heart function. Understanding these disruptions is crucial for developing targeted therapies and biomarkers to assess disease severity. This research addresses a crucial gap in cardiovascular treatment by focusing on mechanisms underlying remodeling processes, aiming to improve therapeutic strategies and outcomes for ischemic heart disease patients.MethodsDatabases, including PubMed, MEDLINE, Google Scholar, and open access/ subscription-based journals were searched for published articles without any date restrictions, to look into how TGF beta and Angiotensin II disrupt cardiogenic regulators in cardiac remodeling post-ischemic. Based on the criteria mentioned in the methods section, studies were systematically reviewed with focus on objectives of the study. This study adheres to relevant PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses).ResultsCardiac remodeling post-ischemic injury involves complex disruptions of cardiogenic regulators, prominently influenced by TGF-beta and Angiotensin II. Our study reveals these factors significantly alter critical regulators like Isl1, Nkx2–5, and GATA4, impacting myocardial repair mechanisms. TGF-beta induces fibrosis and inflammatory responses, while Angiotensin II exacerbates hypertrophic pathways and oxidative stress. Interactions between these pathways amplify remodeling through Smad, MAPK, and other signaling cascades. These findings point to the crucial roles of TGF-beta and Angiotensin II in pathological cardiac remodeling, highlighting potential targets for therapeutic interventions.ConclusionCardiac remodeling post-ischemic injury, influenced by TGF-beta and Angiotensin II, disrupts vital cardiogenic regulators like Isl1, Brg1/Baf60 – Smarcd3 complex, Nkx2–5, GATA4, Tbx5, Mef2c, HAND1/2, MYOCD, MSX2, HOPX, Wnt-signaling pathway, Notch, FGF, and BMPs. These disruptions, involving altered receptor expression, signaling pathway interference, hypertrophic responses, and fibrosis promotion, compromise cardiac development and repair mechanisms. Targeting these pathways could enhance therapeutic strategies for ischemic heart disease by restoring normal regulator function and promoting effective cardiac repair and regeneration, thereby improving clinical outcomes.
A Longitudinal and Reproducible Anti-coactivation Pattern Between the Cerebellum and the Ventral Tegmental Area Relates to Apathy in Schizophrenia
Authors: Delavari Farnaz , Awada Jade , Bolton Thomas A. W. , Alouf Fares , Carruzzo Fabien , Kuenzi Noemie , Kaliuzhna Mariia , Geffen Tal , Katthagen Teresa , Schlagenhauf Florian , Van De Ville Dimitri , Eliez Stephan , Kaiser Stefan , Bègue Indrit 
Published: July 2024

ABSTRACTBackgroundNegative symptoms of schizophrenia lack effective treatments. Anomalies in the reward system and cerebellum have been linked to negative symptom The cerebellum modulates reward circuitry via the ventral tegmental area (VTA). The “cognitive dysmetria theory” posits that reduced cerebellar inhibition in schizophrenia may underlie striatal hyperdopaminergia. However, cerebellum-VTA connectivity and its impact on negative symptoms in schizophrenia remains unclear.MethodsFrom 427 individuals screened, 146 participants were recruited: 90 with schizophrenia (SZ) and 56 healthy controls (HC). At 3 months (T2), 65 individuals (36 SZ, 29 HC) completed follow-up. SZ participants were invited for clinical interviews at 9 months (T3; 33 SZ). After quality check, 105 participants were retained at T1, 41 at T2, and 21 at T3. The validation cohort consisted of 53 individuals (28 SZ, 25 HC). The Brief Negative Symptom Scale was used to quantify negative symptoms. Dynamic functional connectivity of the cerebellum and VTA was analyzed using state-of-the-art coactivation patterns analysis.ResultsA reproducible cerebellum-VTA anti-coactivation pattern was found across T1 and T2 (r = 0.98) in bilateral paravermal Crus I/II. Lower anti-coactivation emergence at T1 correlated with worse apathy, particularly asociality and avolition. At T2, lower anti-coactivation persistence related to worse apathy, especially anhedonia, and correlated with worse anhedonia at T3. Similarly, reduced anti-coactivation emergence at T2 linked to worse asociality at T3. In the validation cohort, we replicated the anti-coactivation pattern (r = 0.93) and the correlation of its emergence with apathy, in particular, asociality.ConclusionReduced cerebellum-VTA anti-coactivation is a reproducible neural marker of apathy in schizophrenia, highlighting its potential as a target for therapeutic intervention.
Time-Dependent Variation in Immunoparalysis Biomarkers Among Patients with Sepsis and Critical Illness
Authors: Samuelsen Abigail , Lehman Erik , Burrows Parker , Bonavia Anthony S 
Published: July 2024

AbstractImmunoparalysis is a significant concern in patients with sepsis and critical illness, potentially leading to increased risk of secondary infections. This study aimed to perform a longitudinal assessment of immune function over the initial two weeks following the onset of sepsis and critical illness. We compared ex vivo stimulated cytokine release to traditional markers of immunoparalysis, including monocyte Human Leukocyte Antigen (mHLA)-DR expression and absolute lymphocyte count (ALC). A total of 64 critically ill patients were recruited in a tertiary care academic medical setting, including 31 septic and 33 non-septic patients. Results showed that while mHLA-DR expression significantly increased over time, this was primarily driven by the non-septic subset of critically ill patients. ALC recovery was more prominent in septic patients. Ex vivo stimulation revealed significant increases in TNF and IL-6 production over time in septic patients. However, IFNγ production varied with the stimulant used and did not show significant recovery when normalized to cell count. No significant correlation was found between mHLA-DR expression and other immunoparalysis biomarkers. These findings suggest the need for more nuanced immune monitoring approaches beyond the traditional ‘sepsis’ versus ‘non-sepsis’ classifications in critically ill patients. It also provided further evidence of a potential window for targeted immunotherapeutic interventions in the first week of critical illness.