Influence Disease Severity Research Articles

The role of the co-chaperone DNAJB11 in polycystic kidney disease: Molecular mechanisms and cellular origin of cyst formation.

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1 and PKD2, encoding polycystin-1 (PC1) and polycystin-2 (PC2), which are required for the regulation of the renal tubular diameter. Loss of polycystin function results in cyst formation. Atypical forms of ADPKD are caused by mutations in genes encoding endoplasmic reticulum (ER)-resident proteins through mechanisms that are not well understood. Here, we investigate the function of DNAJB11, an ER co-chaperone associated with atypical ADPKD. We generated mouse models with constitutive and conditional Dnajb11 inactivation and Dnajb11-deficient renal epithelial cells to investigate the mechanism underlying autosomal dominant inheritance, the specific cell types driving cyst formation, and molecular mechanisms underlying DNAJB11-dependent polycystic kidney disease. We show that biallelic loss of Dnajb11 causes cystic kidney disease and fibrosis, mirroring human disease characteristics. In contrast to classical ADPKD, cysts predominantly originate from proximal tubules. Cyst formation begins in utero and the timing of Dnajb11 inactivation strongly influences disease severity. Furthermore, we identify impaired PC1 cleavage as a potential mechanism underlying DNAJB11-dependent cyst formation. Proteomic analysis of Dnajb11- and Pkd1-deficient cells reveals common and distinct pathways and dysregulated proteins, providing a foundation to better understand phenotypic differences between different forms of ADPKD.

Is There a Correlation Between the Location of the Clot in the Pulmonary Arterial Tree with the Location of the Mucus Plug in the Pulmonary Bronchial Tree in Patients with chronic obstructive pulmonary disease Experiencing Pulmonary Embolism? Novel Findings.

The study aimed to investigate the impact of mucus plugs on the localization of clots in pulmonary embolisms among chronic obstructive pulmonary disease (COPD) patients. The retrospective study examined 200 participants diagnosed with both COPD and pulmonary embolism. Of these, 100 patients exhibited mucus plugs in the segmental and subsegmental branches of the pulmonary bronchial tree, while the remaining 100 did not, using computed tomography images for diagnosis. Data collection encompassed a comprehensive review of patient records, including medical history and imaging reports, to determine the presence of mucus plugs and the localization of clots in pulmonary embolism cases. Patients with mucus plugs exhibited a notably longer duration of COPD (P = .021) and a higher mean pulmonary arterial occlusion index (23 vs. 12, P = .001). Moreover, the prevalence of clots in major pulmonary arteries was significantly elevated in the mucus plug group compared to the non-mucus plug group (P < .05). Conversely, patients without mucus plugs displayed a higher incidence of clots in segmental and subsegmental arteries (P < .001). Strong positive correlations existed between mucus plugs in segmental branches and clots in major pulmonary arteries, with moderate to strong correlation coefficients (0.51 to 0.62, P < .05). Additionally, strong negative correlations were observed between mucus plugs in segmental branches and clots in segmental and subsegmental arteries, with correlation coefficients (CC) ranging from -0.74 to -0.76 (P < .05). Similarly, a significant negative correlation was noted between mucus plugs in subsegmental branches and clots in subsegmental arteries (CC: -0.68 and -0.71, P < .05). The results suggest that mucus plugs may be associated with increased severity of COPD, higher pulmonary arterial occlusion index, and altered clot distribution within the pulmonary artery tree. These findings emphasize the importance of recognizing mucus plugs as a key consideration in COPD assessment and management, potentially influencing disease severity, vascular remodeling, and thrombotic risk management.

Modeling the contribution of cardiac fibroblasts in dilated cardiomyopathy using induced pluripotent stem cells (iPSCs).

Fibrosis is implicated in nearly all forms of cardiomyopathy and significantly influences disease severity and outcomes. The primary cell responsible for fibrosis is the cardiac fibroblast, which remains understudied relative to cardiomyocytes in the context of cardiomyopathy. The development of induced pluripotent stem cell-derived cardiac fibroblasts (iPSC-CFs) allows for the modeling of patient-specific disease characteristics and provides a scalable source of fibroblasts. iPSC-CFs are invaluable for understanding molecular pathways that affect disease progression and outcomes. This review explores various aspects of cardiomyopathy, with a focus on dilated cardiomyopathy (DCM), that can be modeled using iPSC-CFs and their application in drug discovery, given the current lack of approved therapies for cardiac fibrosis. We examine how iPSC-CFs can be utilized to study heart development, fibroblast heterogeneity, and activation, with the ultimate goal of developing better therapies for patients with cardiomyopathies. Significance Statement Here, we explore how iPSC-CFs can be used to study the fibrotic component of DCM. Most research has focused on cardiomyocytes, despite the significant contribution of fibroblasts to disease outcomes. iPSC-CFs serve as a valuable tool to elucidate molecular pathways leading to fibrosis, and paracrine interactions with cardiomyocytes, which are not fully understood. Gaining insights into these events could aid in the development of new therapies and enable the use of patient-derived iPSC-CFs for precision medicine, ultimately improving patient outcomes.

The Chilean COVID-19 Genomics Network Biorepository: A Resource for Multi-Omics Studies of COVID-19 and Long COVID in a Latin American Population

Although a lack of diversity in genetic studies is an acknowledged obstacle for personalized medicine and precision public health, Latin American populations remain particularly understudied despite their heterogeneity and mixed ancestry. This gap extends to COVID-19 despite its variability in susceptibility and clinical course, where ethnic background appears to influence disease severity, with non-Europeans facing higher hospitalization rates. In addition, access to high-quality samples and data is a critical issue for personalized and precision medicine, and it has become clear that the solution lies in biobanks. The creation of the Chilean COVID-19 Biorepository reported here addresses these gaps, representing the first nationwide multicentric Chilean initiative. It operates under rigorous biobanking standards and serves as one of South America’s largest COVID cohorts. A centralized harmonization strategy was chosen and included unified standard operating procedures, a sampling coding system, and biobanking staff training. Adults with confirmed SARS-CoV-2 infection provided broad informed consent. Samples were collected to preserve blood, plasma, buffy coat, and DNA. Quality controls included adherence to the standard preanalytical code, incident reporting, and DNA concentration and absorbance ratio 260/280 assessments. Detailed sociodemographic, health, medication, and preexisting condition data were gathered. In five months, 2262 participants were enrolled, pseudonymized, and sorted by disease severity. The average Amerindian ancestry considering all participant was 44.0% [SD 15.5%], and this value increased to 61.2% [SD 19.5%] among those who self-identified as Native South Americans. Notably, 279 participants self-identified with one of 12 ethnic groups. High compliance (&gt;90%) in all assessed quality controls was achieved. Looking ahead, our team founded the COVID-19 Genomics Network (C19-GenoNet) focused on identifying genetic factors influencing SARS-CoV-2 outcomes. In conclusion, this bottom-up collaborative effort aims to promote the integration of Latin American populations into global genetic research and welcomes collaborations supporting this endeavor. Interested parties are invited to explore collaboration opportunities through our catalog, accessible online.

Investigate the association between genetic polymorphisms of ACE and ACE-2 with some biomarkers in Iraqi patients with COVID-19.

BackgroundThe angiotensin-converting enzyme 2 (ACE2) receptor plays a critical role in mediating SARS-CoV-2 infection. Understanding the genetic factors influencing COVID-19 severity is crucial for developing effective treatment strategies. This study aimed to investigate the association between genetic polymorphism of the ACE gene, specifically the insertion/deletion (I/D) polymorphism in the promoter region, and clinical parameters in COVID-19 patients. MethodsA case-control study was conducted with 225 participants from an Iraqi population. Blood samples were collected for hematological analysis and ACE genotyping. The association between ACE genotypes (DD, ID, II), demographic factors, and clinical parameters, including D-dimer, ferritin, lactate dehydrogenase (LDH), C-reactive protein (CRP), white blood cell (WBC) count, lymphocyte count, packed cell volume (PCV), red blood cell (RBC) count, hemoglobin (HB), and platelet count, was assessed. ResultsCOVID-19 patients exhibited significant differences compared to controls regarding D-dimer, ferritin, LDH, CRP, WBC, lymphocytes, PCV, and RBC (P < 0.05), while no significant differences were found for HB and platelet counts. The DD genotype was predominant (43.11 %), followed by ID (39.56 %) and II (17.33 %). Notably, a significant association was observed between D-dimer levels and ACE genotype (P < 0.0001), with higher levels observed in individuals with the DD genotype. Additionally, a significant correlation was found between ACE genotype and sex (P = 0.0163). No significant association was observed between genotype and ICU admission or lung CT severity. ConclusionOur findings suggest a potential link between the ACE D/D genotype and elevated D-dimer levels in COVID-19 patients, indicating a potential role for ACE gene polymorphism in influencing disease severity. Further research is warranted to elucidate the underlying mechanisms and explore the potential for personalized treatment approaches based on ACE genotype.

THE ROLE OF INFLAMMATORY PARAMETERS AND SCORING SYSTEMS IN PREDICTING COMPLICATED ACUTE APPENDICITIS

Aim: To assess the complications associated with acute appendicitis (AA) and to evaluate how specific routine patient parameters influence disease severity. Materials and Methods: A retrospective study was carried out on patients diagnosed with AA who presented to the emergency department (ED) between January 1, 2019, and December 31, 2020. Data collected included demographic details, blood test results, and specific scoring systems utilized in the ED. Results: Of the 223 patients studied, 63.7% were male with a mean age of 37.5 ± 16.8 years. Patients with complicated appendicitis (CA) showed significantly elevated hematological parameters such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), C-reactive protein (CRP), systemic immune inflammation index (SII), white blood cell count (WBC), and neutrophil levels. Conversely, decreased lymphocyte/C-reactive protein ratio (LCRP) and lymphocyte levels were noted. Furthermore, CA cases exhibited significantly greater Appendicitis Inflammatory Response (AIR) and Alvarado scores. In the context of diagnosing CA, the AIR score had a sensitivity of 85.9% and a specificity of 47.9% with a cut-off value of ≥6 (95% CI 0.675-0.821, Area Under the Curve (AUC): 0.748; p

The Prognosis in Children With Pneumonia of Respiratory Syncytial Virus Co-detection With Airway Dominant Flora.

Airway bacterial microbiota influences the prognosis in children with respiratory syncytial virus infection. The study aimed to investigate the effect of the airway-dominant bacterial microbiota on disease severity in children with pneumonia of respiratory syncytial virus infection. A retrospective study was conducted in the Children's Hospital of Chongqing Medical University, which involved a cohort of patients with respiratory syncytial virus (RSV)-infected pneumonia from January 2012 to December 2021. Patients were assigned to a normal flora group or to a dominant flora group (with the top 5 individual bacteria) based on the nasopharyngeal aspirates culture and matched using propensity-score matching. Univariate analysis and multivariate analysis were performed to estimate the risk factors of poor prognosis in dominant flora. Five thousand five hundred and twelve patients in the normal flora and 4556 in the dominant flora were included ( Escherichia coli 514, Streptococcus pneumoniae 1516, Staphylococcus aureus 506, Moraxella catarrhalis 509 and Haemophilus influenzae 1516, respectively). The dominant flora had more patients developing severe pneumonia, needing mechanical ventilation/tracheal intubation (up to 15.8% in the S. aureus ) and admission to the intensive care unit (up to 4.5% in the E. coli ) than in the normal flora (28.5% vs. 25.9%; P = 0.001; 9.8% vs. 5.4%; P < 0.001; 2.0% vs. 1.2%; P <0.001). And the hospitalization was longer in the dominant flora than in the normal flora [8 (6-9) vs. 8 (7-9) days; P < 0.001], the E. coli and S. aureus had the longest hospitalization [8 (7-10) days]. Several factors were associated with critical illness in Dominant flora according to multivariate analysis ( P < 0.001), including age (OR: 0.965; CI: 0.954-0.976; P < 0.001), anhelation (OR: 0.530; CI: 0.446-0.631; P < 0.001), disorders of consciousness (OR: 0.055; CI: 0.016-0.185; P < 0.001) as well as assisted respiration (OR: 0.115; CI: 0.097-0.138; P < 0.001), C-reactive protein >10 mg/L (OR: 0.686; CI: 0.560-0.839; P < 0.001), SpO 2 <90% (OR: 0.366; CI: 0.214-0.628; P < 0.001), pulmonary consolidation (OR: 0.511; CI: 0.364-0.717; P < 0.001) and pulmonary atelectasis (OR: 0.362; CI: 0.236-0.555; P < 0.001). The airway-dominant bacterial microbiota influenced disease severity and comorbidities in children with RSV-infected pneumonia. Clinicians should pay attention to the nasopharyngeal aspirate culture, especially after detecting S. aureus and E. coli in RSV-infected children with pneumonia, closely observe the disease progression and take timely measures to avoid adverse outcomes.

Genetic Variants in RANK and OPG Could Influence Disease Severity and Bone Remodeling in Patients with Early Arthritis.

The aim of this study was to identify single-nucleotide polymorphisms (SNPs) in bone remodeling-related genes associated with disease severity and bone mineral density (BMD) in early arthritis (EA) patients. For this purpose, the genotyping of 552 SNPs located in gene regions of semaphorins 4b, 4d, 4f, DKK1, 2 and 3, sclerostin, OPG, RANK and RANKL was performed using Immunochip from Illumina Inc. in 268 patients from the Princesa Early Arthritis Register Longitudinal (PEARL) study. Measurements of BMD and disease activity were chosen as outcome variables to select SNPs of interest. The relationships of SNPs with the BMD of the forearm, lumbar spine and hip (Hologic-4500 QDR) were analyzed by linear regression adjusted for age, sex, body mass index and presence of anti-citrullinated peptide antibodies (ACPAs). The association of each SNP with activity variables was analyzed by linear regression, logistic regression or ordered logistic regression according to the variable, and multivariate models were adjusted for potentially confounding variables, such as age, sex and presence of ACPAs. These analyses showed that four SNPs located in the genes coding for RANK (TNFRSF11A) and OPG (TNFRSF11B) were significantly associated with clinical variables of severity. SNP rs1805034 located in exon 6 of TNFRSF11A, which causes a non-synonymous (A/V) mutation, showed significant association with BMD and therefore may be considered as a possible biomarker of severity in RA patients. SNPs in the OPG gene showed an association with serum OPG levels and predicted disease activity after two years of follow-up.

Investigation of the Relationship between Vitamin D Deficiency and Vitamin D-Binding Protein Polymorphisms in Severe COVID-19 Patients.

This study explores the association of vitamin D-binding protein (VDBP) gene polymorphisms, vitamin D levels, and the severity of COVID-19, including the need for intensive care unit (ICU) hospitalization. We analyzed a cohort of 56 consecutive age- and gender-matched adult COVID-19-positive patients and categorized them into three groups: outpatients with mild illness, inpatients with moderate disease, and ICU patients. We measured levels of free, total, and bioavailable 25-hydroxyvitamin D [25(OH)D], VDBP, and albumin. VDBP polymorphisms rs5488 and rs7041 were identified using real-time PCR. A significant proportion of ICU patients were vitamin D-deficient (56.25%) compared to outpatients (10%) and inpatients (5%) (p = 0.0003). ICU patients also had notably lower levels of VDBP (median: 222 mg/L) and total 25(OH)D (median: 18.8 ng/mL). Most patients carried heterozygous rs7041 (60.7%) and wild-type rs4588 (58.9%) genotypes. The distribution of rs7041 SNP varied significantly among groups (p = 0.0301), while rs4588 SNP distribution did not (p = 0.424). Heterozygous rs4588 patients had significantly lower VDBP levels (p = 0.029) and reduced bioavailable 25(OH)D compared to those with wild-type rs4588 (p = 0.020). Our findings indicate that VDBP gene polymorphisms, particularly rs7041 and rs4588, are associated with vitamin D status and the severity of COVID-19. The lower VDBP levels and bioavailable vitamin D in ICU patients suggest that these genetic variants may influence disease severity and hospitalization needs. These results highlight the potential role of VDBP polymorphisms in COVID-19 severity, suggesting that genetic screening could be valuable in assessing the risk of severe outcomes and guiding personalized treatment strategies.

Cardiovascular Risk Estimation and Stratification Among Individuals with Hypercholesterolemia.

This review aims to assess the variability in considering hypercholesterolemia for cardiovascular risk stratification in the general population. Recent literature on the integration of hypercholesterolemia into clinical risk scores and its interaction with other risk factors will be explored. The impact of hypercholesterolemia on risk estimation varies among different cardiovascular risk calculators. Elevated lipid levels during early life stages contribute to atherosclerotic plaque development, influencing disease severity despite later treatment initiation. The interplay between low-density lipoprotein cholesterol (LDLc), inflammatory markers and non-LDL lipid parameters enhances cardiovascular risk stratification. Studies have also examined the role of coronary artery calcium (CAC) score as a negative risk marker in populations with severe hypercholesterolemia. Furthermore, polygenic risk scores (PRS) may aid in diagnosing non-monogenic hypercholesterolemia, refining cardiovascular risk stratification and guiding lipid-lowering therapy strategies. Understanding the heterogeneity in risk estimation and the role of emerging biomarkers and imaging techniques is crucial for optimizing cardiovascular risk prediction and guiding personalized treatment strategies in individuals with hypercholesterolemia.

Asthma as a risk factor and allergic rhinitis as a protective factor for COVID-19 severity: a case-control study.

The COVID-19 pandemic has resulted in significant global morbidity and mortality. The disease presents a broad clinical spectrum, significantly influenced by underlying comorbidities. While certain conditions are known to exacerbate COVID-19 outcomes, the role of chronic inflammatory airway diseases such as asthma and rhinitis in influencing disease severity remains controversial. This study investigates the association between asthma and allergic rhinitis and the severity of COVID-19 outcomes in a specific geographical region prior to widespread vaccine deployment. We conducted a case-control study with unvaccinated adult patients who had laboratory-confirmed COVID-19 by polymerase chain reaction (PCR). Cases were defined as severe or critical COVID-19 patients requiring intensive care unit (ICU) admission, and controls were non-severe patients without signs of viral pneumonia or hypoxia. We utilized the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire to assess the presence of asthma and allergic rhinitis. The association between these chronic inflammatory airway diseases and the severity of COVID-19 was evaluated using multivariate logistic regression analysis. A total of 122 patients were analyzed, with 61 in each group. The presence of asthma (9 patients) was associated with an increased likelihood of severe COVID-19 (OR = 13.0; 95% CI 1.27-133.74), while rhinitis (39 patients) was associated with a protective effect against severe outcomes (OR = 0.36; 95% CI 0.13-0.99). No significant association was found between the frequency of asthmatic episodes or the severity of rhinitis and the severity of COVID-19 outcomes. This study underscores the divergent effects of chronic inflammatory airway diseases on COVID-19 severity, with asthma associated with a higher likelihood of severe outcomes and rhinitis potentially offering protective effects. These findings enhance our understanding of the complex interactions between respiratory allergies and COVID-19, emphasizing the importance of targeted clinical management and public health strategies.

Fluoxetine accelerates epileptogenesis and magnifies disease severity in a rat model of acquired epilepsy.

Many people with epilepsy experience comorbid anxiety and depression, and antidepressants remain a primary treatment for this. Emerging evidence suggests that these agents may modulate epileptogenesis to influence disease severity. Here, we assessed how treatment with the selective serotonin reuptake inhibitor (SSRI) antidepressant fluoxetine impacts epileptogenic, behavioral, and pathological sequelae following status epilepticus. Male Wistar rats received kainic acid to induce status epilepticus (SE) or vehicle (sham). Animals then received either fluoxetine (10 mg/kg/day) or vehicle for 8 weeks via subcutaneous osmotic pump. Video-electroencephalography was recorded continuously until behavioral testing at day 56, including assessments of anxiety- and depression-like behavior and spatial cognition. Postmortem immunocytochemistry studies examined mossy fiber sprouting. Fluoxetine treatment significantly accelerated epileptogenesis following SE, reducing the average period to the first spontaneous seizure (from 32 days [vehicle] to 6 days [fluoxetine], p < .01). Also, fluoxetine exposure magnified the severity of the resultant epilepsy, increasing seizure frequency compared to vehicle (p < .01). Exposure to fluoxetine was associated with improved anxiety- and depression-like behaviors but significantly worsened cognition. Mossy fiber sprouting was more pronounced in fluoxetine-treated rats compared to vehicle (p < .0001). Our studies demonstrate that, using a model exhibiting spontaneous seizures, epileptogenesis is accelerated and magnified by fluoxetine, an effect that may be related to more severe pathological neuroplasticity. The differential influence of fluoxetine on behavior indicates that different circuitry and mechanisms are responsible for these comorbidities. These findings suggest that caution should be exercised when prescribing SSRI antidepressants to people at risk of developing epilepsy.

Expression patterns of inflammatory and oxidative stress-related genes in the uterine and ovarian tissues of dogs diagnosed with pyometra based on cervical patency status

This study aimed to investigate the expression patterns of genes associated with inflammation and oxidative stress in ovarian and uterine tissues of dogs with pyometra, categorized by cervical status (open cervix or closed cervix), which influences disease severity. The control group comprised healthy animals undergoing elective ovariohysterectomy. Tissue inflammatory gene expression and Malondialdehyde (MDA) levels were determined while microbial and histopathological examinations were conducted, along with immunohistochemical evaluations. In the closed-cervix group, uterine TNF and IL6 were upregulated approximately 10-fold while IL10 was upregulated nearly 5-fold. TNF expression differed remarkably between the pyometra groups. In the closed-cervix group, PTGS2 and HMOX1 were upregulated approximately 5-fold whereas NFE2L2 expression was downregulated. The closed-cervix group also had the highest uterine MDA levels. Regarding ovarian tissue, MDA levels were higher in the closed-cervix group than in the open-cervix group while IL10 expression was lower in the closed-cervix group than the open-cervix group. In the closed-cervix group, NFE2L2 was downregulated whereas HMOX1 was upregulated. Uterine TNF levels were positively correlated with IL6, IL10, PTGS2, and HMOX1, but negatively correlated with NFE2L2. IL6 was positively correlated with IL10, PTGS2, and HMOX1. NFE2L2 was negatively correlated with IL6 and HMOX1. IL10 was positively correlated with PTGS2 and HMOX1. MDA was positively correlated with TNF, IL6, IL10, PTGS2, NFE2L2, and HMOX1. TNF levels were positively correlated with ovarian PTGS2, and with IL6 and NFE2L2. MDA was positively correlated with PTGS2 and HMOX1. MDA could be an important biomarker for understanding the severity of pyometra. Moreover, TNF expression and its relationships with various studied parameters such as IL10 may contribute to treatment and prognostic biomarker studies in closed-cervix pyometra pathology.

Prevalence of Fibromyalgia and Widespread Pain in Psoriatic Arthritis: Association With Disease Severity Assessment in a Large US Registry.

The classic conception of pain etiology in rheumatologic disease is nociceptive pain-tissue injury and inflammation signaling through peripheral and central nerve fibers. But this can be mixed with other pain etiologies, including nociplastic, which is augmented pain experience due to central sensitization. The pain of fibromyalgia (FM) is nociplastic, occurs in 10% to 30% of patients with rheumatologic disease, and its presence can influence disease severity assessment. The objective of our study was to (1) ascertain the prevalence of FM and widespread pain (WP) in the CorEvitas psoriatic arthritis (PsA) registry as assessed by the Widespread Pain Index (WPI) and Symptom Severity Scale (SSS) questionnaires; (2) characterize the demographic and clinical factors associated with FM and WP; and (3) ascertain the association of FM and WP on the Clinical Disease Activity in Psoriatic Arthritis (cDAPSA) score and other disease activity measures. PsA registry patients completing the WPI/SSS questionnaires since May 2020, at their most recent visit recorded in the registry, were analyzed. The analysis included 1,823 patients with PsA; 11.1% fulfilled the FM definition and 20.6% fulfilled the WP definition. Several factors were associated with the FM definition, including female sex, depression and/or anxiety, impaired function, increased body mass index, and increased number of comorbidities. cDAPSA, patient pain and global assessment, and tender joint count were twice as severe in patients with FM compared to those without. FM prevalence is elevated in PsA and is associated with elevated disease measures, confounding reliable disease assessment for treat-to-target goals. Identification of FM as an influential contextual factor in disease assessment is recommended.

Female sex hormones exacerbate retinal neurodegeneration.

Neurodegenerative disorders such as Alzheimer's disease and macular degeneration represent major sources of human suffering, yet the factors influencing disease severity remain poorly understood. Sex has been implicated as one potential modifying factor. Here, we show that female sex is a risk factor for worsened outcomes in a model of retinal degeneration. Further, we show that this susceptibility is caused by the presence of female-specific circulating sex hormones. The adverse effect of female sex hormones was specific to diseased retinal neurons, and depletion of these hormones ameliorated this phenotypic effect. These findings provide novel insights into the pathogenesis of neurogenerative diseases and how sex hormones can impact the severity of disease. These findings have far-reaching implications for clinical trial design and the use of hormonal therapy in females with certain neurogenerative disorders.

Unveiling epithelial plasticity regulation in lung cancer: Exploring the cross-talk among Tks4 scaffold protein partners.

The epithelial-to-mesenchymal transition (EMT) represents a hallmark event in the evolution of lung cancer. This work aims to study a recently described EMT-regulating protein, Tks4, and to explore its potential as a prognostic biomarker in non-small cell lung cancer. In this study, we used CRISPR/Cas9 method to knockout (KO) Tks4 to study its functional roles in invadopodia formation, migration, and regulation of EMT marker expressions and we identified Tks4-interacting proteins. Tks4-KO A549 cells exhibited an EMT-like phenotype characterized by elongated morphology and increased expression of EMT markers. Furthermore, analyses of a large-scale lung cancer database and a patient-derived tissue array data revealed that the Tks4 mRNA level was decreased in more aggressive lung cancer stages. To understand the regulatory role of Tks4 in lung cancer, we performed a Tks4-interactome analysis via Tks4 immunoprecipitation-mass spectrometry on five different cell lines and identified CAPZA1 as a novel Tks4 partner protein. Thus, we propose that the absence of Tks4 leads to disruption of a connectome of multiple proteins and that the resulting undocking and likely mislocalization of signaling molecules impairs actin cytoskeleton rearrangement and activates EMT-like cell fate switches, both of which likely influence disease severity.

Fine mapping and candidate gene analysis of Dravet syndrome modifier loci on mouse chromosomes 7 and 8

Dravet syndrome is a developmental and epileptic encephalopathy (DEE) characterized by intractable seizures, comorbidities related to developmental, cognitive, and motor delays, and a high mortality burden due to sudden unexpected death in epilepsy (SUDEP). Most Dravet syndrome cases are attributed to SCN1A haploinsufficiency, with genetic modifiers and environmental factors influencing disease severity. Mouse models with heterozygous deletion of Scn1a recapitulate key features of Dravet syndrome, including seizures and premature mortality; however, severity varies depending on genetic background. Here, we refined two Dravet survival modifier (Dsm) loci, Dsm2 on chromosome 7 and Dsm3 on chromosome 8, using interval-specific congenic (ISC) mapping. Dsm2 was complex and encompassed at least two separate loci, while Dsm3 was refined to a single locus. Candidate modifier genes within these refined loci were prioritized based on brain expression, strain-dependent differences, and biological relevance to seizures or epilepsy. High priority candidate genes for Dsm2 include Nav2, Ptpn5, Ldha, Dbx1, Prmt3 and Slc6a5, while Dsm3 has a single high priority candidate, Psd3. This study underscores the complex genetic architecture underlying Dravet syndrome and provides insights into potential modifier genes that could influence disease severity and serve as novel therapeutic targets.

African swine fever: analysing its epidemiology, pathogenesis and control strategies: a review

African Swine Fever Virus (ASFV) poses a significant threat to global swine populations, with devastating economic and agricultural implications. This review article provides a comprehensive examination of various facets of ASFV, encompassing its structure, entry mechanism, transmission dynamics, clinical signs, pathogenesis, diagnosis and control strategies. The complex virion architecture, including the multilayered core and distinctive outer envelope, is explored, shedding light on key elements influencing the virus’s stability and infectivity. The intricate mechanisms governing ASFV entry into host cells are discussed, emphasizing the interplay between viral proteins and cellular receptors. Insight into the virus-host interaction provides a foundation for understanding the initial stages of infection, influencing subsequent pathogenesis. Transmission dynamics, a critical aspect of ASFV epidemiology, are examined, encompassing both direct and indirect modes of spread. Factors influencing the persistence of ASFV in diverse environments and the role of vectors in disease dissemination are explored to elucidate the complex transmission pathways. Clinical signs and pathogenesis of ASFV infection are thoroughly reviewed, outlining the diverse manifestations in swine species. The immunopathological responses and host factors influencing disease severity are discussed, enhancing our understanding of ASFV pathobiology. A comprehensive understanding of diagnostic tools is pivotal for timely and accurate disease detection, enabling swift intervention measures. In conclusion, this review provides a nuanced and integrative overview of ASFV, offering valuable insights for researchers, veterinarians and policymakers engaged in combatting this significant threat to the swine industry.

Neutrophil-mediated hypoxia drives pathogenic CD8+ T cell responses in cutaneous leishmaniasis.

Cutaneous leishmaniasis caused by Leishmania parasites exhibits a wide range of clinical manifestations. Although parasites influence disease severity, cytolytic CD8+ T cell responses mediate disease. Although these responses originate in the lymph node, we found that expression of the cytolytic effector molecule granzyme B was restricted to lesional CD8+ T cells in Leishmania-infected mice, suggesting that local cues within inflamed skin induced cytolytic function. Expression of Blimp-1 (Prdm1), a transcription factor necessary for cytolytic CD8+ T cell differentiation, was driven by hypoxia within the inflamed skin. Hypoxia was further enhanced by the recruitment of neutrophils that consumed oxygen to produce ROS and ultimately increased the hypoxic state and granzyme B expression in CD8+ T cells. Importantly, lesions from patients with cutaneous leishmaniasis exhibited hypoxia transcription signatures that correlated with the presence of neutrophils. Thus, targeting hypoxia-driven signals that support local differentiation of cytolytic CD8+ T cells may improve the prognosis for patients with cutaneous leishmaniasis, as well as for other inflammatory skin diseases in which cytolytic CD8+ T cells contribute to pathogenesis.

Reduced protein-coding transcript diversity in severe dengue emphasises the role of alternative splicing.

Dengue fever, a neglected tropical arboviral disease, has emerged as a global health concern in the past decade. Necessitating a nuanced comprehension of the intricate dynamics of host-virus interactions influencing disease severity, we analysed transcriptomic patterns using bulk RNA-seq from 112 age- and gender-matched NS1 antigen-confirmed hospital-admitted dengue patients with varying severity. Severe cases exhibited reduced platelet count, increased lymphocytosis, and neutropenia, indicating a dysregulated immune response. Using bulk RNA-seq, our analysis revealed a minimal overlap between the differentially expressed gene and transcript isoform, with a distinct expression pattern across the disease severity. Severe patients showed enrichment in retained intron and nonsense-mediated decay transcript biotypes, suggesting altered splicing efficiency. Furthermore, an up-regulated programmed cell death, a haemolytic response, and an impaired interferon and antiviral response at the transcript level were observed. We also identified the potential involvement of the RBM39 gene among others in the innate immune response during dengue viral pathogenesis, warranting further investigation. These findings provide valuable insights into potential therapeutic targets, underscoring the importance of exploring transcriptomic landscapes between different disease sub-phenotypes in infectious diseases.