Miracle-dz/UniFAR-FTUs huggingface dataset:
Unraveling the dynamics of hepatitis C virus adaptive mutations and their impact on antiviral responses in primary human hepatocytes

ABSTRACT Hepatitis C virus (HCV) infection progresses to chronicity in the majority of infected individuals. Its high intra-host genetic variability enables HCV to evade the continuous selection pressure exerted by the host, contributing to persistent infection. Utilizing a cell culture-adapted HCV population (p100pop) which exhibits increased replicative capacity in various liver cell lines, this study investigated virus and host determinants that underlie enhanced viral fitness. Characterization of a panel of molecular p100 clones revealed that cell culture adaptive mutations optimize a range of virus-host interactions, resulting in expanded cell tropism, altered dependence on the cellular co-factor micro-RNA 122 and increased rates of virus spread. On the host side, comparative transcriptional profiling of hepatoma cells infected either with p100pop or its progenitor virus revealed that enhanced replicative fitness correlated with activation of endoplasmic reticulum stress signaling and the unfolded protein response. In contrast, infection of primary human hepatocytes with p100pop led to a mild attenuation of virion production which correlated with a greater induction of cell-intrinsic antiviral defense responses. In summary, long-term passage experiments in cells where selective pressure from innate immunity is lacking improves multiple virus-host interactions, enhancing HCV replicative fitness. However, this study further indicates that HCV has evolved to replicate at low levels in primary human hepatocytes to minimize innate immune activation, highlighting that an optimal balance between replicative fitness and innate immune induction is key to establish persistence. IMPORTANCE Hepatitis C virus (HCV) infection remains a global health burden with 58 million people currently chronically infected. However, the detailed molecular mechanisms that underly persistence are incompletely defined. We utilized a long-term cell culture-adapted HCV, exhibiting enhanced replicative fitness in different human liver cell lines, in order to identify molecular principles by which HCV optimizes its replication fitness. Our experimental data revealed that cell culture adaptive mutations confer changes in the host response and usage of various host factors. The latter allows functional flexibility at different stages of the viral replication cycle. However, increased replicative fitness resulted in an increased activation of the innate immune system, which likely poses boundary for functional variation in authentic hepatocytes, explaining the observed attenuation of the adapted virus population in primary hepatocytes.
Co-occurrence network analysis reveals the alterations of the skin microbiome and metabolome in adults with mild to moderate atopic dermatitis

ABSTRACT Skin microbiome can be altered in patients with atopic dermatitis (AD). An understanding of the changes from healthy to atopic skin can help develop new targets for treatment by identifying microbial and molecular biomarkers. This study investigates the skin microbiome and metabolome of healthy adult subjects and lesion (ADL) and non-lesion (ADNL) of AD patients by 16S rRNA gene sequencing and mass spectrometry, respectively. Samples from AD patients showed alterations in the diversity and composition of the skin microbiome, with ADL skin having the greatest divergence. Staphylococcus species, especially S. aureus, were significantly increased in AD patients. Metabolomic profiles were also different between the groups. Dipeptide derivatives are more abundant in ADL, which may be related to skin inflammation. Co-occurrence network analysis of the microbiome and metabolomics data revealed higher co-occurrence of metabolites and bacteria in healthy ADNL compared to ADL. S. aureus co-occurred with dipeptide derivatives in ADL, while phytosphingosine-derived compounds showed co-occurrences with commensal bacteria, for example, Paracoccus sp. , Pseudomonas sp. , Prevotella bivia, Lactobacillus iners, Anaerococcus sp. , Micrococcus sp. , Corynebacterium ureicelerivorans, Corynebacterium massiliense, Streptococcus thermophilus, and Roseomonas mucosa, in healthy and ADNL groups. Therefore, these findings provide valuable insights into how AD affects the human skin metabolome and microbiome. IMPORTANCE This study provides valuable insight into changes in the skin microbiome and associated metabolomic profiles in an adult population with mild to moderate atopic dermatitis. It also identifies new therapeutic targets that may be useful for developing personalized treatments for individuals with atopic dermatitis based on their unique skin microbiome and metabolic profiles.
Human saliva modifies growth, biofilm architecture, and competitive behaviors of oral streptococci

ABSTRACT The bacteria within supragingival biofilms participate in complex exchanges with other microbes inhabiting the same niche. One example is the mutans group streptococci (Streptococcus mutans), implicated in the development of tooth decay, and other health-associated commensal streptococci species. Previously, our group transcriptomically characterized intermicrobial interactions between S. mutans and several species of oral bacteria. However, these experiments were carried out in a medium without human saliva. To better mimic their natural environment, we first evaluated how inclusion of saliva affected growth and biofilm formation of eight Streptococcus species individually and found saliva to positively benefit growth rates while negatively influencing biofilm biomass accumulation and altering spatial arrangement. These results carried over during evaluation of 29 saliva-derived isolates of various species. Surprisingly, we also found that addition of saliva increased the competitive behaviors of S. mutans in coculture competitions against commensal streptococci that led to increases in biofilm microcolony volumes. Through transcriptomically characterizing mono- and cocultures of S. mutans and Streptococcus oralis with and without saliva, we determined that each species developed a nutritional niche under mixed-species growth, with S. mutans upregulating carbohydrate uptake and utilization pathways while S. oralis upregulated genome features related to peptide uptake and glycan foraging. S. mutans also upregulated genes involved in oxidative stress tolerance, particularly manganese uptake, which we could artificially manipulate by supplementing in manganese leading to an advantage over its opponent. Our report highlights observable changes in microbial behaviors through leveraging environmental- and host-supplied resources over their competitors. IMPORTANCE Dental caries (tooth decay) is the most prevalent disease for both children and adults nationwide. Caries are initiated from demineralization of the enamel due to organic acid production through the metabolic activity of oral bacteria growing in biofilm communities attached to the tooth’s surface. Mutans group streptococci are closely associated with caries development and initiation of the cariogenic cycle, which decreases the amount of acid-sensitive, health-associated commensal bacteria while selecting for aciduric and acidogenic species that then further drives the disease process. Defining the exchanges that occur between mutans group streptococci and oral commensals in a condition that closely mimics their natural environment is of critical need toward identifying factors that can influence odontopathogen establishment, persistence, and outgrowth. The goal of our research is to develop strategies, potentially through manipulation of microbial interactions characterized here, that prevent the emergence of mutans group streptococci while keeping the protective flora intact.
Pneumococcal population genomics changes during the early time period of conjugate vaccine uptake in southern India

Streptococcus pneumoniae is a major cause of invasive disease of young children in low- and middle-income countries. In southern India, pneumococcal conjugate vaccines (PCVs) that can prevent invasive pneumococcal disease began to be used more frequently after 2015. To characterize pneumococcal evolution during the early time period of PCV uptake in southern India, genomes were sequenced and selected characteristics were determined for 402 invasive isolates collected from children <5 years of age during routine surveillance from 1991 to 2020. Overall, the prevalence and diversity of vaccine type (VT) and non-vaccine type (NVT) isolates did not significantly change post-uptake of PCV. Individually, serotype 1 and global pneumococcal sequence cluster (GPSC or strain lineage) 2 significantly decreased, whereas serotypes 6B, 9V and 19A and GPSCs 1, 6, 10 and 23 significantly increased in proportion post-uptake of PCV. Resistance determinants to penicillin, erythromycin, co-trimoxazole, fluoroquinolones and tetracycline, and multidrug resistance significantly increased in proportion post-uptake of PCV and especially among VT isolates. Co-trimoxazole resistance determinants were common pre- and post-uptake of PCV (85 and 93 %, respectively) and experienced the highest rates of recombination in the genome. Accessory gene frequencies were seen to be changing by small amounts across the frequency spectrum specifically among VT isolates, with the largest changes linked to antimicrobial resistance determinants. In summary, these results indicate that as of 2020 this pneumococcal population was not yet approaching a PCV-induced equilibrium and they highlight changes related to antimicrobial resistance. Augmenting PCV coverage and prudent use of antimicrobials are needed to counter invasive pneumococcal disease in this region.
The salamander limb: a perfect model to understand imperfect integration during skeletal regeneration

ABSTRACT Limb regeneration in salamanders is achieved by a complex coordination of various biological processes and requires the proper integration of new tissue with old. Among the tissues found inside the limb, the skeleton is the most prominent component, which serves as a scaffold and provides support for locomotion in the animal. Throughout the years, researchers have studied the regeneration of the appendicular skeleton in salamanders both after limb amputation and as a result of fracture healing. The final outcome has been widely seen as a faithful re-establishment of the skeletal elements, characterised by a seamless integration into the mature tissue. The process of skeletal integration, however, is not well understood, and several works have recently provided evidence of commonly occurring flawed regenerates. In this Review, we take the reader on a journey through the course of bone formation and regeneration in salamanders, laying down a foundation for critically examining the mechanisms behind skeletal integration. Integration is a phenomenon that could be influenced at various steps of regeneration, and hence, we assess the current knowledge in the field and discuss how early events, such as tissue histolysis and patterning, influence the faithful regeneration of the appendicular skeleton.
Distribution of five toxic heavy metals in biotic and abiotic constituents of the Negombo Lagoon, Sri Lanka

The presence of toxic metals in water has become a matter of national concern. This situation is potentially more dangerous when it occurs in lagoons and estuaries which are both highly productive and sensitive in comparison to other natural habitats. In this study, the levels of five toxic heavy metals, As, Cd, Cr, Pb and Hg, present in several abiotic and biotic constituents of the Negombo lagoon, Sri Lanka, were investigated with the objective of assessing the potential risks of accumulation. Sampling, in five locations, was conducted from December 2014 to April 2015. Water, sediment, soil, bark and leaves of the mangrove Bruguiera gymnorhiza, and fauna of selected taxa were collected and heavy metals were analyzed using ICP – OES following microwave digestion. Apart from Cr which was detected at low levels, none of the other metals were detected in the water. Nevertheless, the five heavy metals were present in relatively large amounts in one or more of the other tested constituents, indicating lagoon pollution, depicting an overall trend water
Spectral probabilistic seismic hazard assessment for Italy

During the last decade the Italian Gruppo Nazionale per la Difesa dai Terremoti has undertaken a project for assessing seismic hazard on probabilistic bases in the national territory, to be used as scientific background for the revision of the current seismic zonation: the seismic hazard was expressed there in terms of peak ground acceleration and macroseismic intensity. A more detailed analysis is now performed. Probabilistic spectral seismic hazard maps at different frequencies of engineering interest demonstrate that the soil condition is a first order factor influencing the level of the expected shaking, with an average increase of about 0.2 g for the prediction related to a 475-year return period, when passing from rock to soft soil. The attenuation model similarly conditions the results, hut in a more magnitude-dependent fashion. Here, the two relationships selected account for the effects of strong rare seismicity and moderate frequent earthquakes differently: differences going from 20% to 80% of the predicted spectral accelerations are, therefore, model-dependent. The uniform hazard response spectra for some major Italian towns are then compared to the elastic response spectra of the present Italian seismic zonation, indicating that two important towns such as Rome and Naples are not adequately represented by the present code. The effective peak acceleration is considered, finally, a good synthetic parameter for representing seismic hazard in most engineering applications.
Efficacy of dupilumab and risk factors for dupilumab-induced hypereosinophilia in severe asthma: a preliminary study from China

Abstract Objective Dupilumab has been approved for the treatment of severe asthma with type 2 inflammation by inhibiting interleukin (IL)-4 and IL-13 signaling. However, dupilumab-induced hypereosinophilia (HE) has been reported and should not be ignored. The aim of this study was to investigate the efficacy of dupilumab in Chinese patients with severe asthma, whether HE affects its efficacy, and the possible risk factors for HE. Methods 20 patients with severe asthma who received dupilumab treatment for at least 12 months in the First Affiliated Hospital of Guangzhou Medical University from 2019 to 2022 were included. We compared clinical data and laboratory tests results before dupilumab treatment and at 4 and 12 months after treatment. Based on whether dupilumab treatment triggers HE defined as blood eosinophil count (BEC) ≥ 1.5 × 109 cells/L, the patients were allocated into non-HE and HE groups. Results The patients showed a significant increase in asthma control test (ACT) scores, a decrease in the number of exacerbations, a decrease in the proportion of patients taking an oral corticosteroid (OCS) and in the dose, and a significant improvement in the pulmonary function parameters FEV1/FVC (%) and FEV1 (% predicted) after 4 and 12 months of treatment with dupilumab. For type 2 inflammatory biomarkers, the levels of fractional concentration of exhaled nitric oxide (FeNO), sputum eosinophil count percentage (SEC%) and total immunoglobulin E (TIgE) decreased significantly, whereas BEC were higher after 4 months of treatment, but returned to baseline levels after 12 months. 8 patients (40%) developed asymptomatic HE after dupilumab, and the efficacy was not significantly different between the HE and non-HE groups. The earliest BEC elevation appeared at 1 month after treatment, but most of them declined after 6 months, and basically returned to the baseline level around 12 months of treatment. In addition, we further found that when patients had FeNO ≥ 60 ppb, food allergens positive and combined eosinophilic otitis media (EOM), their BEC increased significantly more than that of the control group after 4 months as well as 12 months of treatment. Conclusions This study demonstrated that dupilumab was efficacious in Chinese patients with severe asthma, and some patients developed asymptomatic, self-limited HE, which did not affect its efficacy. Additionally, FeNO ≥60 ppb, food allergens positive, and co-morbidities with EOM may be the risk factors for developing HE.
MicroRNA-124 negatively regulates STAT3 to alleviate hypoxic-ischemic brain damage by inhibiting oxidative stress

MicroRNA-124 (miR-124) is implicated in various neurological diseases; however, its significance in hypoxic-ischaemic brain damage (HIBD) remains unclear. This study aimed to elucidate the underlying pathophysiological mechanisms of miR-124 in HIBD. In our study performed on oxygen-glucose deprivation followed by reperfusion (OGD)/R-induced primary cortical neurons, a substantial reduction in miR-124 was observed. Furthermore, the upregulation of miR-124 significantly mitigated oxidative stress, apoptosis, and mitochondrial impairment. We demonstrated that miR-124 interacts with the signal transducer and activator of transcription 3 (STAT3) to exert its biological function using the dual-luciferase reporter gene assay. As the duration of OGD increased, miR-124 exhibited a negative correlation with STAT3. STAT3 overexpression notably attenuated the protective effects of miR-124 mimics, while knockdown of STAT3 reversed the adverse effects of the miR-124 inhibitor. Subsequently, we conducted an HIBD model in rats. In vivo experiments, miR-124 overexpression attenuated cerebral infarction volume, cerebral edema, apoptosis, oxidative stress, and improved neurological function recovery in HIBD rats. In summary, the neuroprotective effects of the miR-124/STAT3 axis were confirmed in the HIBD model. MiR-124 may serve as a potential biomarker with significant therapeutic implications for HIBD.
Bilateral pheochromocytomas: clinical presentation and morbidity rate related to surgery technique and genetic status

Background Pheochromocytomas (PHEOs) are rare catecholamine-secreting adrenal tumors. Approximately 60–90% of bilateral PHEOs are hereditary. We retrospectively analyzed the clinical characteristics of patients with bilateral PHEOs and the morbidity rate (malignancy, tumor recurrence and adrenal insufficiency (AI) rate) related to surgery technique and genetic status of the patients. Results Fourteen patients (12.5%, nine women, five men) had synchronous or metachronous bilateral PHEOs (out of 112 PHEO patients who underwent surgery between 1976 and 2021). The median age at diagnosis was 32 years (9–76) (three were children). Nine patients (64.2%) presented synchronous bilateral tumors, five (35.7%) contralateral metachronous tumors, 2–12 years after the first surgical intervention; three (21.4%) were metastatic. Median follow-up: 5 years (1–41), IQR 19 months. A total of 78.5% had a germline mutation (eight RET gene with MEN2A syndrome, three VHL syndrome, three not tested). Post-surgery recurrence was noted in 16.6% of patients (one with MEN2A syndrome and metastatic PHEOs, one with VHL syndrome), with similar rates after total adrenalectomy or cortical-sparing adrenal surgery. AI was avoided in 40% after cortical-sparing surgery. Conclusion Bilateral PHEOs are usually associated with genetic syndromes. The surgical technique for patients with hereditary bilateral PHEOs should be chosen based on a personalized approach, as they are at higher risk for developing new adrenal tumors requiring additional surgeries.
Nucleosome conformation dictates the histone code

Histone post-translational modifications (PTMs) play a critical role in chromatin regulation. It has been proposed that these PTMs form localized ‘codes’ that are read by specialized regions (reader domains) in chromatin-associated proteins (CAPs) to regulate downstream function. Substantial effort has been made to define [CAP: histone PTM] specificities, and thus decipher the histone code and guide epigenetic therapies. However, this has largely been done using the reductive approach of isolated reader domains and histone peptides, which cannot account for any higher-order factors. Here, we show that the [BPTF PHD finger and bromodomain: histone PTM] interaction is dependent on nucleosome context. The tandem reader selectively associates with nucleosomal H3K4me3 and H3K14ac or H3K18ac, a combinatorial engagement that despite being in cis is not predicted by peptides. This in vitro specificity of the BPTF tandem reader for PTM-defined nucleosomes is recapitulated in a cellular context. We propose that regulatable histone tail accessibility and its impact on the binding potential of reader domains necessitates we refine the ‘histone code’ concept and interrogate it at the nucleosome level.
Impact of tillage and herbicides on weed density and some physiological traits of wheat under rice-wheat cropping system.

To evaluate the impact of various tillage systems in combination with herbicides on weed density and some physiological traits under rice-wheat cropping system, an experiment using a winter wheat (Triticum aestivum L.) cultivar “Nasir 2000” was conducted in arid region of Khyber Pakhtunkhwa, Pakistan during 2007–2009 growing seasons. The experiment was laid out in randomized complete block design with split plot arrangements replicated four times. The treatments comprised of 3 tillage treatments, including conventional tillage with deep ploughing through disk plough (CT), reduced tillage with shallow ploughing through rotavator (RT), and zero tillage with stubble direct drilling (ZT) as main plots while five weed control treatments viz. 2,4-D ester @ 1.25 L ha, Puma super 75 EW @1.25 L ha, 2,4-D + Puma super @1.25 L ha each, Affinity 50 WDG @ 2 kg ha and weedy check as subplots. Herbicides had significant effect on weed density, fresh and dry weed biomass (FWB & DWB), leaf area tiller (LAT), leaf area index (LAI), plant height, grains spike, and grain yield. Tillage x herbicides interaction was significant for weed density and grain yield only. Maximum LAT (141 cm), LAI (3.4), plant height (88.2 cm), grains spike (72.4) and grain yield (6906.9 kg ha) were recorded with Affinity. Maximum weed density m (75.5), FWB (845.3 g m) and DWB (220.4 g m) were recorded in weedy check. Maximum grain yield (5583.8 kg ha) was obtained from RT being statistically similar to grain yield (5575.1 kg ha) in ZT. The lower grain yield (5479.3 kg ha) in CT was due to maximum weed density m (48.3), FWB (536.6 g m) and DWB (136.5 g m). Affinity was the most effective herbicide against grasses as well as broad-leaved weeds in combination with either ZT or RT and resulted in higher grain yield. ZT and RT in conjunction with affinity are recommended for significantly reducing weeds population and enhancing wheat yield under rice-based cropping system.