Reversible and irreversible inhibitors of coronavirus Nsp15 endoribonuclease.

The emergence of severe acute respiratory syndrome coronavirus 2, the causative agent of coronavirus disease 2019, has resulted in the largest pandemic in recent history. Current therapeutic strategies to mitigate this disease have focused on the development of vaccines and on drugs that inhibit the viral 3CL protease or RNA-dependent RNA polymerase enzymes. A less-explored and potentially complementary drug target is Nsp15, a uracil-specific RNA endonuclease that shields coronaviruses and other nidoviruses from mammalian innate immune defenses. Here, we perform a high-throughput screen of over 100,000 small molecules to identify Nsp15 inhibitors. We characterize the potency, mechanism, selectivity, and predicted binding mode of five lead compounds. We show that one of these, IPA-3, is an irreversible inhibitor that might act via covalent modification of Cys residues within Nsp15. Moreover, we demonstrate that three of these inhibitors (hexachlorophene, IPA-3, and CID5675221) block severe acute respiratory syndrome coronavirus 2 replication in cells at subtoxic doses. This study provides a pipeline for the identification of Nsp15 inhibitors and pinpoints lead compounds for further development against coronavirus disease 2019 and related coronavirus infections.

Risk factors for invasive pulmonary aspergillosis in patients with severe fever with thrombocytopenia syndrome: A multicenter retrospective study.

Invasive pulmonary aspergillosis (IPA) is a life-threatening complication in patients with severe fever with thrombocytopenia syndrome (SFTS), yet SFTS-associated IPA (SAPA)'s risk factors remain undefined. A multicenter retrospective cohort study across Hubei and Anhui provinces (May 2013-September 2022) utilized least absolute shrinkage and selection operator (LASSO) regression for variable selection. Multivariable logistic regression identified independent predictors of SAPA, Cox regression highlighted mortality-related risk factors. Of the 1775 screened SFTS patients, 1650 were included, with 169 developing IPA, leading to a 42-day mortality rate of 26.6% among SAPA patients. Multivariable logistic regression revealed SAPA risk factors including advanced age, petechia, hemoptysis, tremor, low albumin levels, elongated activated partial thromboplastin time (APTT), intensive care unit (ICU) admission, glucocorticoid usage, intravenous immunoglobulin (IVIG) and prolonged hospital stays. Cox regression identified predictors of 42-day mortality, including ecchymosis at venipuncture sites, absence of ICU admission, elongated prothrombin time (PT), vasopressor and glucocorticoid use, non-antifungals. Nomograms constructed on these predictors registered concordance indexes of 0.855 (95% CI: 0.826-0.884) and 0.778 (95% CI: 0.702-0.854) for SAPA onset and 42-day mortality, respectively. Lower survival rates for SAPA patients treated with glucocorticoids (p < 0.001) and improved 14-day survival with antifungal therapy (p = 0.036). Improving IPA management in SFTS-endemic areas is crucial, with effective predictive tool.

Decreased circulating IPA levels identify subjects with metabolic comorbidities: A multi-omics study.

In recent years several experimental observations demonstrated that the gut microbiome plays a role in regulating positively or negatively metabolic homeostasis. Indole-3-propionic acid (IPA), a Tryptophan catabolic product mainly produced by C. Sporogenes, has been recently shown to exert either favorable or unfavorable effects in the context of metabolic and cardiovascular diseases. We performed a study to delineate clinical and multiomics characteristics of human subjects characterized by low and high IPA levels. Subjects with low IPA blood levels showed insulin resistance, overweight, low-grade inflammation, and features of metabolic syndrome compared to those with high IPA. Metabolomics analysis revealed that IPA was negatively correlated with leucine, isoleucine, and valine metabolism. Transcriptomics analysis in colon tissue revealed the enrichment of several signaling, regulatory, and metabolic processes. Metagenomics revealed several OTU of ruminococcus, alistipes, blautia, butyrivibrio and akkermansia were significantly enriched in highIPA group while in lowIPA group Escherichia-Shigella, megasphera, and Desulfovibrio genus were more abundant. Next, we tested the hypothesis that treatment with IPA in a mouse model may recapitulate the observations of human subjects, at least in part. We found that a short treatment with IPA (4 days at 20/mg/kg) improved glucose tolerance and Akt phosphorylation in the skeletal muscle level, while regulating blood BCAA levels and gene expression in colon tissue, all consistent with results observed in human subjects stratified for IPA levels. Our results suggest that treatment with IPA may be considered a potential strategy to improve insulin resistance in subjects with dysbiosis.

The therapeutic potential of dietary intervention: based on the mechanism of a tryptophan derivative-indole propionic acid on metabolic disorders.

Tryptophan (TRP) contributes to individual immune homeostasis and good condition via three complex metabolism pathways (5-hydroxytryptamine (5-HT), kynurenine (KP), and gut microbiota pathway). Indole propionic acid (IPA), one of the TRP derivatives of the microbiota pathway, has raised more attention because of its impact on metabolic disorders. Here, we retrospect increasing evidence that TRP metabolites/IPA derived from its proteolysis impact host health and disease. IPA can activate the immune system through aryl hydrocarbon receptor (AHR) and/or Pregnane X receptor (PXR) as a vital mediator among diet-caused host and microbe cross-talk. Different levels of IPA in systemic circulation can predict the risk of NAFLD, T2DM, and CVD. IPA is suggested to alleviate cognitive impairment from oxidative damage, reduce gut inflammation, inhibit lipid accumulation and attenuate the symptoms of NAFLD, putatively enhance the intestinal epithelial barrier, and maintain intestinal homeostasis. Now, we provide a general description of the relationships between IPA and various physiological and pathological processes, which support an opportunity for diet intervention for metabolic diseases.

Reduction and prevention of agitation in persons with neurocognitive disorders: an international psychogeriatric association consensus algorithm.

OBJECTIVES: To develop an agitation reduction and prevention algorithm is intended to guide implementation of the definition of agitation developed by the International Psychogeriatric Association (IPA). DESIGN: Review of literature on treatment guidelines and recommended algorithms; algorithm development through reiterative integration of research information and expert opinion. SETTING: IPA Agitation Workgroup. PARTICIPANTS: IPA panel of international experts on agitation. INTERVENTION: Integration of available information into a comprehensive algorithm. MEASUREMENTS: None. RESULTS: The IPA Agitation Work Group recommends the Investigate, Plan, and Act (IPA) approach to agitation reduction and prevention. A thorough investigation of the behavior is followed by planning and acting with an emphasis on shared decision-making; the success of the plan is evaluated and adjusted as needed. The process is repeated until agitation is reduced to an acceptable level and prevention of recurrence is optimized. Psychosocial interventions are part of every plan and are continued throughout the process. Pharmacologic interventions are organized into panels of choices for nocturnal/circadian agitation; mild-moderate agitation or agitation with prominent mood features; moderate-severe agitation; and severe agitation with threatened harm to the patient or others. Therapeutic alternatives are presented for each panel. The occurrence of agitation in a variety of venues-home, nursing home, emergency department, hospice-and adjustments to the therapeutic approach are presented. CONCLUSIONS: The IPA definition of agitation is operationalized into an agitation management algorithm that emphasizes the integration of psychosocial and pharmacologic interventions, reiterative assessment of response to treatment, adjustment of therapeutic approaches to reflect the clinical situation, and shared decision-making.

Clinic, CT radiomics, and deep learning combined model for the prediction of invasive pulmonary aspergillosis.

BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a serious fungal infection. However, current diagnostic methods have limitations. The purpose of this study was to use artificial intelligence to achieve a more accurate diagnosis of IPA. METHODS: Totally 263 patients (148 cases of IPA, 115 cases of non-IPA) were retrospectively enrolled from a single institution and randomly divided into training and test sets at a ratio of 7:3. Clinic-radiological independent risk factors for IPA were screened using univariate analysis and multivariate logistic regression analysis, after which a clinic-radiological model was constructed. The optimal radiomics features were extracted and screened based on CT images to construct the radiomics label score (Rad-score) and radiomics model. The optimal DL features were extracted and screened using four pre-trained convolutional neural networks, respectively, followed by the construction of the DL label score (DL-score) and DL model. Then, the radiomics-DL model was constructed. Finally, the combined model was constructed based on clinic-radiological independent risk factors, the Rad-score, and the DL-score. LR was adopted as the classifier. Receiver operating characteristic (ROC) curves were drawn, and the areas under the curve (AUC) were calculated to evaluate the efficacy of each model in predicting IPA. Additionally, based on the best-performing model on the LR classifier, four other machine learning (ML) classifiers were constructed to evaluate the predictive value for IPA. RESULTS: The AUC of the clinic-radiological model for predicting IPA in the training and test sets was 0.845 and 0.765, respectively. The AUC of the radiomics-DL and combined models in the training set was 0.871 and 0.932, while in the test set was 0.851 and 0.881, respectively. The combined model showed better predictive performance than all other models. DCA showed that taking 0.00-1.00 as the threshold, the clinical benefit of the combined model was higher than that of all other models. Then, the combined model was trained on four other machine learning classifiers, all of which achieved AUC values above 0.80 in the test set, showing good performance in predicting IPA. CONCLUSION: Clinic, CT radiomics, and DL combined model could be used to predict IPA effectively.

The agreement of phonetic transcriptions between paediatric speech and language therapists transcribing a disordered speech sample.

BACKGROUND: Speech and language therapists (SLTs) regularly use phonetic transcription to record and analyse typical and disordered speech. Phonetic transcription is highly demanding of auditory perceptual skills so researchers are sceptical about its accuracy and reliability. The literature describes how phonetic transcription is prone to auditory illusions and biases, such as a preference to transcribe speech sounds from the transcriber's own language. Few empirical research studies have calculated agreement amongst transcribers where a range of agreement scores have been reported (51%-97%). There is a consensus that agreement rates decrease as phonetic detail increases. Vowels and consonants are characterised by different perceptual features within the International Phonetic Alphabet (IPA) so they may differ in agreement rates, and thus far there is contradictory evidence as to whether vowels or consonants are more agreed upon. Transcription agreement studies to date have most commonly recruited phoneticians rather than SLTs so further research is warranted to determine transcription agreement amongst SLTs and its impact on clinical practice. AIMS: The study's primary aim was to calculate agreement scores from a group of English-speaking SLTs who transcribed disordered speech samples in an ecologically valid setting. The study also sought to contribute to the pre-existing contradictory evidence base regarding whether vowels or consonants may be more agreed upon by comparing their agreement scores. The researcher aimed to comment on SLTs' use of diacritics and non-native speech symbols (symbols not included in the English phonetic inventory) in terms of their frequency and agreement of use. By analysing transcriptions, the study aimed to discuss the impact transcription variability has on speech sound error patterns and thus its impact on clinical decision-making such as diagnosis, choice of intervention and therapy targets. METHODS: Twelve paediatric SLTs were recruited via a convenience sample at two National Health Service trusts, two of whom were specialists in Speech Sound Disorders (SSDs). Participants transcribed 16 words from a video of a boy with disordered speech completing the Diagnostic Evaluation of Articulation and Phonology (DEAP, Dodd et al., 2006) from a telehealth appointment. The use of diacritics and non-English IPA symbols were manually analysed. A classic agreement score was calculated for each target word using a Python script, and then for vowels and consonants in isolation. Datasets were manually analysed to determine whether differences in transcription resulted in the identification of different speech sound error patterns. The researcher considered the implications this had within clinical practice. RESULTS: The average classic agreement score was 56.3%. Consonants were more agreed upon than vowels with agreement scores of 62.8% and 48.6%, respectively. Nine participants (75%) used diacritics (most commonly length marks) and eight participants (67%) transcribed non-native IPA symbols at least once in their datasets, but generally with low frequencies and agreements amongst their use. Transcriptions captured the occurrence of typical and atypical error patterns but only three error patterns, out of the 20 identified, were present in all 12 participants' transcriptions. CONCLUSIONS: The agreement score of 56.3% questions the accuracy and reliability of transcription amongst SLTs which is an essential skill of the profession. The findings highlight SLTs should be more cautious of interpreting vowels than consonants given lower agreement rates. The frequency of use of non-native symbols and diacritics was relatively low which could reflect a low accuracy of their use or reduced confidence in transcribing these. The study discussed how variations in transcriptions can impact phonological and phonetic analysis, which in turn can influence clinical decision-making such as diagnosing SSDs, selecting further diagnostic assessments and choosing therapy targets and interventions. The Royal College of Speech and Language Therapists-endorsed transcription guidelines (Child Speech Disorder Research Network, 2017) could be revised to convey realistic expectations of SLTs' transcription skills, or SLTs should be offered more training to improve transcription skills to meet current expectations. Other suggestions to improve transcription accuracy are discussed such as via instrumental methods, yet these come with their own limitations such as practicality, costs and need for specialist training. WHAT THIS PAPER ADDS: What is already known on this subject Phonetic transcription is highly demanding of human perceptual skills, and researchers are sceptical about its reliability. There are few empirical research studies calculating agreement amongst transcribers, and a range of agreement scores have been reported (51%-97%) dependent on the research conditions. Research mostly involves experienced transcribers (e.g., phoneticians) rather than speech and language therapists (SLTs), a profession expected to regularly use phonetic transcription to record and analyse typical and disordered speech. What this study adds to existing knowledge A range of transcription agreement scores have been reported in previous studies, mainly comparing pairs or small groups of specialist transcribers rather than SLTs. This study provides an agreement score of 56.3% when a group of 12 SLTs transcribed a disordered speech sample in an ecologically valid setting (where speech samples were taken from a real-life speech sound assessment over a telehealth appointment using the Diagnostic Evaluation of Articulation and Phonology). The study found consonants are more agreed upon than vowels, adding to the contradictory evidence base. Unlike other studies, the researcher analysed transcriptions to identify error patterns to examine the impact that transcription variation has on clinical decision-making. What are the potential or actual clinical implications of this work? The researcher questions whether SLTs are meeting the expectations of 'accurate transcription' as listed by the Royal College of Speech and Language Therapists (RCSLT) endorsed transcription guidelines (Child Speech Disorder Research Network, 2017) given the relatively low agreement score of 56.3%. The study also questions the reliability of the use of diacritics and non-English International Phonetic Alphabet (IPA) symbols and whether SLTs should be expected to use these due to perceptual limitations. Twenty phonological processes emerged from the datasets, only three of which were agreed upon across all 12 participants. The researcher therefore discusses how transcription variations could result in different diagnoses, therapy targets and interventions choices. The paper suggests more training is required to enhance transcription accuracy, and also considers the appropriateness of utilising instrumental methods whilst recognising its limitations such as feasibility, costs and specialist training needs.

Optimizing Antifungal Treatment Strategies to Prevent Invasive Pulmonary Aspergillosis Infection-Related Deaths in Intensive Care Unit Patients: The Need for Standardization of Research Definitions.

The clinical spectrum of invasive pulmonary aspergillosis (IPA) has expanded in recent decades. A large group of patients admitted to intensive care units (ICU) is indeed susceptible to the development of IPA. Although timely diagnosis and antifungal therapy of IPA in this expanding population is crucial to prevent IPA-related deaths, the magnitude of the favorable prognostic impact of antifungal therapy is difficult to measure precisely. In our opinion, the development of standardized research definitions could have favorable implications for further improving our ability both to measure the favorable effect of antifungal treatment and to prevent IPA-related death in ICU patients.

FABP5 Is a Possible Factor for the Maintenance of Functions of Human Non-Pigmented Ciliary Epithelium Cells.

To elucidate the possible biological roles of fatty acid-binding protein 5 (FABP5) in the intraocular environment, the cells from which FABP5 originates were determined by using four different intraocular tissue-derived cell types including human non-pigmented ciliary epithelium (HNPCE) cells, retinoblastoma (RB) cells, adult retinal pigment epithelial19 (ARPE19) cells and human ocular choroidal fibroblast (HOCF) cell lines, and the effects of FABP ligand 6, a specific inhibitor for FABP5 and FABP7 were analyzed by RNA sequencing and seahorse cellular metabolic measurements. Among these four different cell types, qPCR analysis showed that FABP5 was most prominently expressed in HNPCE cells, in which no mRNA expression of FABP7 was detected. In RNA sequencing analysis, 166 markedly up-regulated and 198 markedly down-regulated differentially expressed genes (DEGs) were detected between non-treated cells and cells treated with FABP ligand 6. IPA analysis of these DEGs suggested that FABP5 may be involved in essential roles required for cell development, cell survival and cell homeostasis. In support of this possibility, both mitochondrial and glycolytic functions of HNPCE cells, in which mRNA expression of FABP5, but not that of FABP7, was detected, were shown by using a Seahorse XFe96 Bioanalyzer to be dramatically suppressed by FABP ligand 6-induced inhibition of the activity of FABP5. Furthermore, in IPA upstream analysis, various unfolded protein response (UPR)-related factors were identified as upstream and causal network master regulators. Analysis by qPCR analysis showed significant upregulation of the mRNA expression of most of UPR-related factors and aquaporin1 (AQP1). The findings in this study suggest that HNPCE is one of intraocular cells producing FABP5 and may be involved in the maintenance of UPR and AQP1-related functions of HNPCE.

"He is changing, but I'm changing too": An interpretative phenomenological analysis of spouse caregivers' identity in the context of dementia.

OBJECTIVE: This study explores the process through which informal caregivers, particularly spouses, construct their identity within the context of caregiving for individuals with dementia. Despite extensive research in psychology aimed at defining caregiving (e.g. tasks, consequences), few informal caregivers identify themselves as such. For instance, the affective bond shared between caregivers and care-recipients often imbues caregiving responsibilities with a sense of "naturalness," especially if the care-recipient is a spouse. METHODS: To investigate the nature of caregiver identity construction, eight semi-structured interviews were conducted with spouse caregivers of dementia patients. The collected data underwent interpretative phenomenological analysis (IPA). RESULTS: Three interconnected themes emerged from the analysis: (1) Perceiving changes in my partner, which involves recognising alterations in the care-receiver's characteristics due to dementia; (2) Processing changes, encompassing the experience of grieving losses and reminiscing about the past; and (3) Perceiving changes in myself, referring to the acknowledgement of personal changes due to caregiving. CONCLUSION: The study emphasises the dynamic and ongoing nature of caregiver identity construction, which begins with the early recognition of changes in the care-receiver. Interestingly, spouse caregivers oscillate between their identity as a spouse and caregiver, influenced by how they process changes undergone by their partner. Contrasting with previous theories on caregivers' identity, our results focus of caregivers' perceptions rather than their relationship with the care-recipient or caregiving tasks.

Moderate India Pale Ale beer consumption promotes antigenotoxic and non-mutagenic effects in ex vivo and in vivo mice models.

BACKGROUND: Discussion of the benefits of moderate alcohol consumption is ongoing. Broadly, research focusing on ethanol consumption tends to report no benefits. However, studies that distinguish between different types of alcoholic beverages, particularly beers, often reveal positive effects. The present study evaluated the genotoxic and mutagenic effects of moderate chronic consumption of India Pale Ale (IPA) craft beer. Sixty-four adult male Swiss mice were used and divided into control and treatment groups receiving water, IPA beer with 55.23 g of ethanol per liter of beer, aqueous solution with 55.23 g of ethanol per liter, and hop infusion ad libitum for 30 days. After this period, the animals were genetically evaluated with a comet assay. For the ex vivo comet assay, blood was collected and exposed to hydrogen peroxide (H2O2). For the in vivo assay, the alkylating agent cyclophosphamide (CP) was administered to the groups after blood collection and sacrificed after 24 h. Brain, liver, and heart tissues were analyzed. Bone marrow was collected and submitted to the micronucleus test. RESULTS: The groups treated with IPA beer, ethanol, and hops did not show genotoxic and mutagenic action in the blood, brain, heart, or liver. The antigenotoxic action of IPA beer and hops was observed in both in vivo and ex vivo models, showing a similar reduction in DNA damage caused by CP. There was no significant difference between the groups with regard to the formation of micronuclei by CP. CONCLUSION: Moderate chronic consumption of IPA beer and hops infusion showed antigenotoxic effects in mice but no antimutagenic action. © 2024 Society of Chemical Industry.

Improve the satisfaction of medical staff on the use of home nursing mobile APP by using a hybrid multi-standard decision model.

OBJECTIVE: To identify critical satisfaction gaps in a home nursing mobile application (APP) using a systematic decision-making model. METHODS: Initially, the decision-making trial and evaluation laboratory method was used to analyze the relationship structure and corresponding weights among the indicators. The Importance-Performance Analysis (IPA) method was used to identify the categories of all indicators and their corresponding strategic directions. Twenty-six home nursing specialists currently providing home nursing services were recruited for this study. RESULTS: The IPA results revealed that "Assurance," "Reliability," and "Personal security protection" are critical satisfaction gaps. From the influence network and weight results, "information quality" and "system quality" were the critical quality factors in the home nursing mobile APP. The influence of the network relationship structure and weight demonstrated a 98.12% significance level, indicating good stability. CONCLUSION: Continuous improvement in information and system quality is recommended to optimize the overall quality of the home nursing mobile APP. Additionally, user demands should be considered, and personal safety guarantee functions should be developed and integrated into the system to ensure the safety of home nursing workers.

In search of the 'like-minded' people: pregnant women's sense-making of their physical activity-related social experiences.

AIMS/BACKGROUND: Social factors are increasingly recognised as influential on antenatal physical activity. While pregnant women describe the people and support they require to remain physically active, little is known about how pregnant women select and make sense of their social experiences throughout pregnancy. This study followed pregnant women's sense-making of their physical activity-related social experiences as pregnancy progressed, and physical activity declined. DESIGN/METHODS: This study used a qualitative design. Four pregnant women were recruited in their second trimester, participated in three individual semi-structured interviews and submitted diary entries throughout trimesters two and three. Data were analysed using longitudinal interpretative phenomenological analysis. RESULTS: To facilitate physical activity, pregnant women were 'searching for the "like-minded" people who motivate, share and understand', namely pregnant women and prenatally trained exercise professionals. When making sense of social experiences, pregnant women were 'grading and critiquing the quality and paucity of "active pregnancy" information', and'cherry-picking social experiences necessary for "nesting", obtaining support and protecting self-esteem as physical activity declined'. This involved disengaging from social experiences, and consequently, some pregnant women found themselves 'lamenting interactions with the "like-minded" people, contending with grief and inner conflict'. CONCLUSION: Pregnant women proactively seek and make sense of social experiences to facilitate physical activity. In an increasingly digitalised society, interventions should support pregnant women to utilise social media constructively and safely to access 'like-minded' people, provide in-person and virtual networks to meet individual support needs throughout pregnancy and encourage health professionals to demonstrate interest in the 'active pregnancy' to maximise influence.

"No Medication Means No HIV Diagnosis": A Qualitative Study Based on Dual-System Theory on HIV Antiretroviral Therapy Initiation Decision-Making.

At least 30% of newly diagnosed people living with HIV (PLHIV) have delayed antiretroviral therapy (ART) initiation globally, resulting in irreversible impaired immune function and increased risk of HIV transmission. This study aimed to explore the decision-making process of ART initiation in China. A phenomenological research design was used and semi-structured, in-depth interviews based on dual-system theory were conducted. Participants were selected using purposive sampling between December 11, 2021 and June 25, 2022. Interpretative phenomenological analysis (IPA) was performed utilizing the software NVivo 12. A total of 34 PLHIV were interviewed. The heuristic system and the analytic system were involved in the complex decision-making process for ART initiation. Acceptability, negative emotion, and stigma were all parts of the heuristic system. The analytic system included the perception of ART benefits, positive support, and misconception. Two systems interacted with each other in the decision-making of ART initiation. PLHIV's initiation decision was determined by the components of the dominant system. This theory-driven qualitative study provided valuable insights on the decision-making process of ART initiation among newly diagnosed PLHIV.

Facilitating transformative endings: Therapists' experience of ending therapy with people with intellectual disabilities-An interpretative phenomenological analysis.

BACKGROUND: Endings in therapy are discussed widely in mainstream literature, however, there is only a small amount of research that considers endings in therapy for people with intellectual disabilities. METHODS: Eight therapists were interviewed about their experience of ending therapy with people with intellectual disabilities. Interviews were analysed using Interpretative Phenomenological Analysis (IPA). RESULTS: Four superordinate themes associated with endings that go well were identified: 'recognising', 'readying', 'reframing' and reflecting', with a fifth theme reflecting endings that were less successful. Participants worked hard to offer transformative experiences of endings and an overarching 'super-superordinate' theme of 'facilitating transformative endings' encompassed the findings. CONCLUSIONS: Endings are a multi-faceted component of psychological therapy with people with intellectual disabilities and are significant for both client and therapist. We discuss implications for therapy adaptations and future research.

The HCV-Melanoma Paradox: First Multi-Cohort and Molecular Net-Work Analysis Reveals Lower Incidence but Worse Outcomes-Integrating Clinical, Real-World, and In Silico Data.

Background and Objectives: The relationship between hepatitis C virus (HCV) infection and melanoma remains poorly understood. This study aimed to investigate the association between HCV and melanoma, assess outcomes in patients with both conditions, and explore potential molecular mechanisms connecting the two diseases. Materials and Methods: We conducted a retrospective cohort study of 142 melanoma patients, including 29 with HCV-related cirrhosis, and analyzed their clinical outcomes. For external validation, we used the TriNetX Global Collaborative Network database, comprising 219,960 propensity-matched patients per group. An in silico analysis was performed to identify the molecular pathways linking HCV and melanoma. Results: In the retrospective cohort, HCV-positive melanoma patients showed an increased risk of early relapse (41.4% vs. 18.6%, p = 0.014), recurrence (65.5% vs. 39.8%, p = 0.020), and mortality (65.5% vs. 23.0%, p < 0.001) compared to HCV-negative patients. TriNetX data analysis revealed that HCV-positive patients had a 53% lower risk of developing melanoma (RR = 0.470, 95% CI: 0.443-0.498, p < 0.001). However, HCV-positive melanoma patients had higher all-cause mortality (HR = 1.360, 95% CI: 1.189-1.556, p < 0.001). An in silico analysis identified key molecular players, including IL-6 and CTLA4, in the HCV-melanoma network. Conclusions: While HCV infection may be associated with a lower risk of melanoma development, HCV-positive patients who develop melanoma have poorer outcomes. The identified molecular pathways provide potential targets for future research and therapeutic interventions.

IPA1 improves drought tolerance by activating SNAC1 in rice.

Drought is a major abiotic stress to rice (Oryza sativa) during growth. Ideal Plant Architecture (IPA1), the first cloned gene controlling the ideal plant type in rice, has been reported to function in both ideal rice plant architecture and biotic resistance. Here, we report that the IPA1/OsSPL14, encoding a transcriptional factor, positively regulates drought tolerance in rice. The IPA1 is constitutively expressed and regulated by H2O2, abscisic acid, NaCl and polyethylene glycol 6000 treatments in rice. Furthermore, the IPA1-knockout plants showed much greater accumulation of H2O2 as measured by 3,3'-diaminobenzidine staining in leaves compared with WT plants. Yeast one-hybrid, dual-luciferase and electrophoretic mobility shift assays indicated that the IPA1 directly activates the promoter of SNAC1. Expression of SNAC1 is significantly down-regulated in IPA1 knockout plants. Further investigation indicated that the IPA1 plays a positive role in drought-stress tolerance by inducing reactive oxygen species scavenging in rice. Together, these findings indicated that the IPA1 played important roles in drought tolerance by regulating SNAC1, thus activating the antioxidant system in rice.

PLPP/CIN-mediated NF2 S10 dephosphorylation distinctly regulates kainate-induced seizure susceptibility and neuronal death through PAK1-NF-κB-COX-2-PTGES2 signaling pathway.

BACKGROUND: Pyridoxal-5'-phosphate phosphatase/chronophin (PLPP/CIN) selectively dephosphorylates serine (S) 10 site on neurofibromin 2 (NF2, also known as merlin (moesin-ezrin-radixin-like protein) or schwannomin). p21-activated kinase 1 (PAK1) is a serine/threonine protein kinase, which is involved in synaptic activity and plasticity in neurons. NF2 and PAK1 reciprocally regulate each other in a positive feedback manner. Thus, the aim of the present study is to investigate the effects of PLPP/CIN-mediated NF2 S10 dephosphorylation on PAK1-related signaling pathways under physiological and neuroinflammatory conditions, which are largely unknown. METHODS: After kainate (KA) injection in wild-type, PLPP/CIN-/- and PLPP/CINTg mice, seizure susceptibility, PAK1 S204 autophosphorylation, nuclear factor-κB (NF-κB) p65 S276 phosphorylation, cyclooxygenase-2 (COX-2) upregulation, prostaglandin E synthase 2 (PTGES2) induction and neuronal damage were measured. The effects of 1,1'-dithiodi-2-naphthtol (IPA-3, a selective inhibitor of PAK1) pretreatment on these responses to KA were also validated. RESULTS: PLPP/CIN overexpression increased PAK1 S204 autophosphorylation concomitant with the enhanced NF2 S10 dephosphorylation in hippocampal neurons under physiological condition. Following KA treatment, PLPP/CIN overexpression delayed the seizure on-set and accelerated PAK1 S204 phosphorylation, NF-κB p65 S276 phosphorylation, COX-2 upregulation and PTGES2 induction, which were ameliorated by PLPP/CIN deletion or IPA-3. Furthermore, IPA-3 pretreatment shortened the latency of seizure on-set without affecting seizure severity (intensity) and ameliorated CA3 neuronal death induced by KA. CONCLUSIONS: These findings indicate that PLPP/CIN may regulate seizure susceptibility (the latency of seizure on-set) and CA3 neuronal death in response to KA through NF2-PAK1-NF-κB-COX-2-PTGES2 signaling pathway.

The DnaJ domain-containing heat-shock protein NAL11 determines plant architecture by mediating gibberellin homeostasis in rice (Oryza sativa).

Ideal Plant Architecture 1 (IPA1) is a key regulator of plant architecture. However, knowledge of downstream genes applicable for improving rice plant architecture is very limited. We identified the plant architecture regulatory gene NARROW LEAF 11 (NAL11), which encodes a heat-shock protein (HSP) containing a DnaJ domain. A promising rare allele of NAL11 (NAL11-923del-1552 ) positively selected in Aus cultivars was identified; this allele exhibited increased expression and generated relatively few tillers, thick stems, and large panicles, components of the ideal plant architecture (IPA). NAL11 is involved in regulating the cell cycle and cell proliferation. NAL11 loss-of-function mutants present impaired chloroplast development and gibberellin (GA) defects. Biochemical analyses show that IPA1 directly binds to elements in the missing fragment of the NAL11-923del-1552 promoter and negatively regulates NAL11 expression. Genetic analyses support the hypothesis that NAL11 acts downstream of IPA1 to regulate IPA by modulating GA homeostasis, and NAL11 may be an essential complement for IPA1. Our work revealed that avoidance of the inhibition of NAL11-923del-1552 caused by IPA1 represents a positive strategy for rescuing GA defects accompanied by the upregulation of IPA1 in breeding high-yield rice.

Inhibition of cGAS aggravated the host inflammatory response to Aspergillus fumigatus.

Backgroud: Aspergillus fumigatus (A. fumigatus) is a clinically important fungal pathogen. Invasive pulmonary aspergillosis (IPA) is the main fungal infection with increased morbidity and mortality in immunocompromised populations, although treatments are available. An innate DNA sensor known as cyclic GMP-AMP Synthase (cGAS) has recently been discovered that senses invading pathogens and has a significant impact on innate immunity. It can activate the cGAS-STING signaling pathway to stimulate downstream signals. But it is still unclear what role it plays in IPA's pathogenesis.Methods: An investigation into the infection of A. fumigatus was conducted by inhibiting cGAS activity in vivo and in vitro using siRNA and RU.521(an inhibitor of cGAS).Results: We discovered that suppressing cGAS increased the host's susceptibility to A. fumigatus and harmed those with infections by enhancing pulmonary tissue damage and edema, as well as decreasing fungal clearance. Furthermore, our findings show that inhibiting or silencing cGAS can exacerbate the inflammatory response in IPA mouse models and human bronchi epithelial cells (HBECs) treated with A. fumigatus by upregulating the production of inflammatory genes with non-type 1 interferon.Conclusion: Based on our analysis, we conclude that activating cGAS might increase host resistance to A. fumigatus, protect against pulmonary illnesses brought on by A. fumigatus and that exploring the cGAS-STING signaling pathway is beneficial not only for the immunological investigation of IPA but also may be a potential therapeutic objective.