Intervention strategies targeting virus and host factors against porcine reproductive and respiratory syndrome virus: A systematic review.

Porcine reproductive and respiratory syndrome (PRRS) caused by porcine reproductive and respiratory syndrome virus (PRRSV) causes considerable economic losses to the global swine industry every year and seriously hinders the healthy development of this industry. Although tremendous efforts have been made over the past 30 years toward the development of prevention and control strategies against PRRSV infection, to date, treatments with proven efficacy have yet to be available due to our incomplete understanding of the molecular basis and complexity of the infection machinery. This review systematically discusses recent advances in the research and development of anti-PRRSV therapies targeting different stages of the viral life cycle. Furthermore, this review puts forward novel intervention targets and research approaches based on our in-depth exploration of virus-host interactions and the latest biological technologies, which have the potential to complement or transform current anti-PRRSV strategies and become breakthrough points for the control of PRRS in the future.

Podocyte senescence: from molecular mechanisms to therapeutics.

As an important component of the glomerular filtration membrane, the state of the podocytes is closely related to kidney function, they are also key cells involved in aging and play a central role in the damage caused by renal aging. Therefore, understanding the aging process of podocytes will allow us to understand their susceptibility to injury and identify targeted protective mechanisms. In fact, the process of physiological aging itself can induce podocyte senescence. Pathological stresses, such as oxidative stress, mitochondrial damage, secretion of senescence-associated secretory phenotype, reduced autophagy, oncogene activation, altered transcription factors, DNA damage response, and other factors, play a crucial role in inducing premature senescence and accelerating aging. Senescence-associated-ß-galactosidase (SA-ß-gal) is a marker of aging, and ß-hydroxybutyric acid treatment can reduce SA-ß-gal activity to alleviate cellular senescence and damage. In addition, CCAAT/enhancer-binding protein-α, transforming growth factor-ß signaling, glycogen synthase kinase-3ß, cycle-dependent kinase, programmed cell death protein 1, and plasminogen activator inhibitor-1 are closely related to aging. The absence or elevation of these factors can affect aging through different mechanisms. Podocyte injury is not an independent process, and injured podocytes interact with the surrounding epithelial cells or other kidney cells to mediate the injury or loss of podocytes. In this review, we discuss the manifestations, molecular mechanisms, biomarkers, and therapeutic drugs for podocyte senescence. We included elamipretide, lithium, calorie restriction, rapamycin; and emerging treatment strategies, such as gene and immune therapies. More importantly, we summarize how podocyte interact with other kidney cells.

Genome-wide RNA interference of the nhr gene family in barber's pole worm identified members crucial for larval viability in vitro.

Nuclear hormone receptors (NHRs) are emerging target candidates against nematode infection and resistance. However, there is a lack of comprehensive information on NHR-coding genes in parasitic nematodes. In this study, we curated the nhr gene family for 60 major parasitic nematodes from humans and animals. Compared with the free-living model organism Caenorhabditis elegans, a remarkable contraction of the nhr family was revealed in parasitic species, with genetic diversification and conservation unveiled among nematode Clades I (10-13), III (16-42), IV (33-35) and V (25-64). Using an in vitro biosystem, we demonstrated that 40 nhr genes in a blood-feeding nematode Haemonchus contortus (clade V; barber's pole worm) were responsive to host serum and one nhr gene (i.e., nhr-64) was consistently stimulated by anthelmintics (i.e., ivermectin, thiabendazole and levamisole); Using a high-throughput RNA interference platform, we knocked down 43 nhr genes of H. contortus and identified at least two genes that are required for the viability (i.e., nhr-105) and development (i.e., nhr-17) of the infective larvae of this parasitic nematode in vitro. Harnessing this preliminary functional atlas of nhr genes for H. contortus will prime the biological studies of this gene family in nematode genetics, infection, and anthelmintic metabolism within host animals, as well as the promising discovery of novel intervention targets.

Mental health services for German university students: acceptance of intervention targets and preference for delivery modes.

Introduction: Most university students with mental disorders remain untreated. Evaluating the acceptance of intervention targets in mental health treatment, promotion, and prevention, as well as mental health service delivery modes is crucial for reducing potential barriers, increasing healthcare utilization, and efficiently allocating resources in healthcare services. Aim: The study aimed to evaluate the acceptance of various intervention targets and delivery modes of mental health care services in German first-year university students. Methods: In total, 1,376 first-year students from two German universities from the 2017-2018 multi-center cross-sectional cohort of the StudiCare project, the German arm of the World Mental Health International College Student Survey initiative, completed a web-based survey assessing their mental health. Mental disorder status was based on self-reported data fulfilling the DSM-IV criteria. We report frequencies of accepted delivery modes [categories: group or in-person therapy with on or off campus services, self-help internet- or mobile-based intervention (IMI) with or without coaching, or a combination of a in-person and IMI (blended)]. In a multinomial logistic regression, we estimate correlates of the preference for in-person vs. IMI vs. a combination of both modes (blended) modalities. Additionally, we report frequencies of intervention targets (disorder specific: e.g., social phobia, depressive mood; study-related: test anxiety, procrastination; general well-being: sleep quality, resilience) their association with mental disorders and sex, and optimal combinations of treatment targets for each mental illness. Results: German university students' acceptance is high for in-person (71%-76%), moderate for internet- and mobile-based (45%-55%), and low for group delivery modes (31%-36%). In-person treatment (72%) was preferred over IMI (19%) and blended modalities (9%). Having a mental disorder [odds ratio (OR): 1.56], believing that digital treatments are effective (OR: 3.2), and showing no intention to use services (OR: 2.8) were associated with a preference for IMI compared to in-person modes. Students with prior treatment experience preferred in-person modes (OR: 0.46). In general, treatment targets acceptance was higher among female students and students with mental disorders. However, this was not true for targets with the highest (i.e., procrastination) and the lowest (i.e., substance-use disorder) acceptance. If only two intervention targets were offered, a combination of study-related targets (i.e., procrastination, stress, time management) would reach 85%-88% of the students. Conclusion: In-person services are preferred, yet half of the students consider using IMI, preferably aiming for a combination of at least two study-related intervention targets. Student mental health care services should offer a combination of accepted targets in different delivery modes to maximize service utilization.

[Mechanism of "Trichosanthis Fructus-Allii Macrostemonis Bulbus" in treating cardiovascular diseases with syndrome of combined phlegm and stasis based on serum metabolomics].

This study aimed at investigating the mechanism of Trichosanthis Fructus-Allii Macrostemonis Bulbus(GX) in treating cardiovascular diseases in rats with the syndrome of combined phlegm and stasis. The rat model was established by a high-fat diet, ice-water bath combined with subcutaneous injection of adrenalin hydrochloride, and the syndrome score was determined. The serum samples of rats in the control, model, and GX groups were collected. Ultra-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry(UPLC-Q-TOF-MS) was employed to analyze the metabolic profiles of the serum samples. The differential metabolites were screened and identified by partial least squares-discriminant analysis(PLS-DA) and orthogonal partial least squares-discriminant analysis(OPLS-DA). The intervention targets of GX-regulated metabolites and their metabolic pathways were searched against MetaboAnalyst. Gene Ontology enrichment was carried out to predict the biological pathways associated with the intervention targets of metabolic pathways. A total of 129 potential biomarkers were detected in the rat model with the syndrome of combined phlegm and stasis via metabolomics, and GX regulated 54 metabolites in several metabolic pathways such as linoleic acid metabolism, sphingolipid metabolism, and tricarboxylic acid cycle. The further screening against MetaboAnalyst showed that GX recovered the levels of nine metabolites associated with cardiovascular diseases with the syndrome of combined phlegm and stasis, which involved 69 targets in the pathways regarding cholesterol metabolism, fatty acid metabolism, inflammatory response, and glucose homeostasis and metabolism. The above-mentioned results suggested that GX can alleviate the symptoms of the rat model of cardiovascular diseases with the syndrome of combined phlegm and stasis by regulating the metabolism of linoleic acid, sphingosine, docosahexaenoic acid, rosemary acid, succinic acid, adenine, L-phenylalanine, L-valine and modulating the biological pathways such as cholesterol metabolism, fatty acid metabolism, inflammatory response, and glucose homeostasis and metabolism.

Exploring cuproptosis as a mechanism and potential intervention target in cardiovascular diseases.

Copper (Cu) is a vital trace element for maintaining human health. Current evidence suggests that genes responsible for regulating copper influx and detoxification help preserve its homeostasis. Adequate Cu levels sustain normal cardiac and blood vessel activity by maintaining mitochondrial function. Cuproptosis, unlike other forms of cell death, is characterized by alterations in mitochondrial enzymes. Therapeutics targeting cuproptosis in cardiovascular diseases (CVDs) mainly include copper chelators, inhibitors of copper chaperone proteins, and copper ionophores. In this review, we expound on the primary mechanisms, critical proteins, and signaling pathways involved in cuproptosis, along with its impact on CVDs and the role it plays in different types of cells. Additionally, we explored the influence of key regulatory proteins and signaling pathways associated with cuproptosis on CVDs and determined whether intervening in copper metabolism and cuproptosis can enhance the outcomes of CVDs. The insights from this review provide a fresh perspective on the pathogenesis of CVDs and new targets for intervention in these diseases.

Network Pharmacology-Based Approach for Investigating the Role of Xanthii Fructus in Treatment of Allergic Rhinitis.

Xanthii Fructus (XF) has been used for treatment of allergic rhinitis (AR), but its pharmacological mechanism of action remains unclear. We aimed to explore the potential mechanism of XF in treatment of AR by using a network pharmacology approach combined with in vivo verification experiments in this study. We identified 945 AR-related pathogenic genes, 11 active components in XF and 178 targets of those active components by corresponding databases. Finally, 54 targets of active components from XF in treatment of AR were identified by the Protein-protein interaction (PPI) network, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, among which Tumor Necrosis Factor (TNF), Mitogen-activated Protein Kinase 3 (MAPK3), Prostaglandin G/H Synthase 2 (PTGS2), Epidermal Growth Factor Receptor (EGFR) showed strongest interactions. The molecular docking analysis showed that moupinamide could bind to EGFR at LEU704 and LEU703, and PTGS2 at TRP387; 24-Ethylcholest-4-en-3-one was identified to bind to MAPK3 at THR347. The validation of quantitative real-time reverse transcription PCR (RT-PCR) showed that XF decreased the levels of MAPK3, PTGS2, and EGFR expression in the nasal mucosa from AR mice gavaged with an XF water decoction. Meanwhile, the levels of interleukin (IL)-4, IL-5 and IL-13were also decreased after the treatment of XF by Enzyme-linked immunosorbent assay (ELISA). Our results provide the pharmacological mechanism and possible intervention targets of XF in treatment of AR.

T helper 17 (Th17) cell responses to the gut microbiota in human diseases.

The gut microbiota colonizing the gastrointestinal tract, is an indispensable "invisible organ" that affects multiple aspects of human health. The gut microbial community has been assumed to be an important stimulus to the immune homeostasis and development, and increasing data support the role of the gut microbiota-immunity axis in autoimmune diseases. Host's immune system requires recognition tools to communicate with the gut microbial evolutionary partners. Among these microbial perceptions, T cells enable the widest spectrum of gut microbial recognition resolution. Specific gut microbiota direct the induction and differentiation of Th17 cells in intestine. However, the detailed links between the gut microbiota and Th17 cells have not been well established. In this review, we describe the generation and characterization of Th17 cells. Notably, we discuss the induction and differentiation of Th17 cells by the gut microbiota and their metabolites, as well as recent advances in our understanding of interactions between Th17 cells and the gut microbiota in human diseases. In addition, we provide the emerging evidences in support of interventions targeting the gut microbes/Th17 cells in human diseases.

Identification of dynamic driver sets controlling phenotypical landscapes.

Controlling phenotypical landscapes is of vital interest to modern biology. This task becomes highly demanding because cellular decisions involve complex networks engaging in crosstalk interactions. Previous work on control theory indicates that small sets of compounds can control single phenotypes. However, a dynamic approach is missing to determine the drivers of the whole network dynamics. By analyzing 35 biologically motivated Boolean networks, we developed a method to identify small sets of compounds sufficient to decide on the entire phenotypical landscape. These compounds do not strictly prefer highly related compounds and show a smaller impact on the stability of the attractor landscape. The dynamic driver sets include many intervention targets and cellular reprogramming drivers in human networks. Finally, by using a new comprehensive model of colorectal cancer, we provide a complete workflow on how to implement our approach to shift from in silico to in vitro guided experiments.

Prevalence and predictive factors for depressive symptoms among medical students in Germany - a cross-sectional study.

Background: Elevated levels of depressive symptoms among medical students have been the subject of international and national research before, yet associated risk factors and protective factors are to be determined. This study aims to show the burdens of depression at different stages of academic medical education with a special emphasis on correlated risk factors and protective factors. Methods: A total number of n=1103 medical students of a middle-sized German university were sampled and surveyed regarding depressive symptoms and correlating factors. The assessment of potential depressive symptoms was based on the BDI-II. Correlating factors were surveyed through a self-designed questionnaire consisting of possible cofactors for depressive symptoms based on established scientific literature. Results: Survey response rate was 90.2% (1103/1223). The prevalence of depressive symptoms was 11% for mild, 5.6% for moderate and 2.4% for severe symptoms. The sample's most prevalent risk factors were feeling unable to confide one's own worries to someone else (88%); and experiencing a lack of time for partner, friends and family (77%) or hobbies (76%). Significant predictors for depressive symptoms were neuroticism above all, insufficient emotional support, eating irregular meals, use of medication or drugs to calm down, and mental overload. Factors associated with less depressive symptoms could be identified as: spending time with partner, friends, family, hobbies and exercise; and confiding worries to classmates. Conclusions: Every fifth medical student surveyed reported at least mild depressive symptoms. The majority of the surveyed medical students felt unable to confide their worries to someone else and lamented not having enough time for social interaction with peers, family and hobbies. Certain personality traits - such as neuroticism - and insufficient emotional support showed to play important roles in making medical students more prone to developing depressive symptoms. Based on this research, control of the surveyed cofactors associated with depressive symptoms and possible intervention programs targeted to these are proposed to be a key subject of further research.

Cross-cultural comparison of symptom networks in late-life major depressive disorder: Yoruba Africans and the Spanish Population.

BACKGROUND: The concept of European psychologisation of depression versus somatisation in non-European populations has been the basis of several studies of cultural psychopathology in the general population. Little is currently known about cross-cultural differences and similarities in late-life depression symptom reporting. We cross-culturally compared symptom reporting in the context of Major Depressive Disorder (MDD) among community-dwelling older adults from Spain and Nigeria. METHODS: We relied on data from two household multistage probability samples comprising 3,715 persons aged 65 years or older in the Spanish and Nigerian populations. All participants underwent assessments for MDD using the World Mental Health Survey version of the Composite International Diagnostic Interview. Cross-cultural comparison of broad somatic and psychological categories as well as relationship and influence of individual symptoms were analysed using the Symptom Network Analysis approach. RESULTS: Current MDD was diagnosed in 232 and 195 older persons from Spain and Nigeria, respectively. The symptom network of the two samples were invariant in terms of global strength, S(GSPAIN , GNIGERIA ) = 7.56, P = .06, with psychological and somatic symptoms demonstrating centrality in both countries. However, country-specific relationships and influence of individual symptoms were found in the network structure of both samples, M(GSPAIN , GNIGERIA ) = 2.95, P < .01. CONCLUSION: Broad somatic and psychological symptoms categories contributed to the structural network of older Africans and their peers from the Spanish population. Variations in the relationship and influence of individual symptoms suggests that the functional and "communicative" role of individual symptoms may be differentiated by context specific imperatives. J Am Geriatr Soc 68:-, 2020.

Identifying key targets for interventions to improve psychological wellbeing: replicable results from four UK cohorts.

BACKGROUND: An increasing importance is being placed on mental health and wellbeing at individual and population levels. While there are several interventions that have been proposed to improve wellbeing, more evidence is needed to understand which aspects of wellbeing are most influential. This study aimed to identify key items that signal improvement of mental health and wellbeing. METHODS: Using network analysis, we identified the most central items in the graph network estimated from the well-established Warwick-Edinburgh Mental Well-being Scale (WEMWBS). Results were compared across four major UK cohorts comprising a total of 47,578 individuals: the Neuroscience in Psychiatry Network, the Scottish Schools Adolescent Lifestyle and Substance Use Survey, the Northern Ireland Health Survey, and the National Child Development Study. RESULTS: Regardless of gender, the three items most central in the network were related to positive self-perception and mood: 'I have been feeling good about myself'; 'I have been feeling confident'; and 'I have been feeling cheerful'. Results were consistent across all four cohorts. CONCLUSIONS: Positive self-perception and positive mood are central to psychological wellbeing. Psychotherapeutic and public mental health interventions might best promote psychological wellbeing by prioritising the improvement of self-esteem, self-confidence and cheerfulness. However, empirical testing of interventions using these key targets is needed.

Urinary Urgency in Working Women: What Factors Are Associated with Urinary Urgency Progression?

BACKGROUND: Urinary urgency is the primary symptom of overactive bladder (OAB). This study aimed to identify targets for effective intervention to delay progression of urinary urgency. MATERIAL AND METHODS: Secondary analyses of data from a study conducted with female employees of a large academic medical center were conducted. Women were ≥18 years and nonpregnant at the time of the survey. An online questionnaire obtained demographic information, presence of lower urinary tract symptoms, and toileting behaviors. Bivariate analyses and multivariate logistic regression were applied to explore factors related to different stages of urinary urgency. RESULTS: Four stages of urinary urgency were constructed: (1) Stage 1: no urinary symptoms (n = 20), (2) Stage 2: continent but urinary urgency reported (n = 19), (3) Stage 3: nonsevere urgency urinary incontinence (UUI) (incontinent but leakage ≤1/day, n = 74); and (4) Stage 4: severe UUI (leakage ≥1/day, n = 26). In multivariate analyses, older women were more likely to be in Stage 3 than in Stage 2 (aOR 1.053, 95% CI 1.012-1.096). Women who lost urine with defecation were more likely to be in Stage 4 than Stage 3 (aOR 3.828, 95% CI 1.921-7.629). Women who habitually strained to empty the bladder faster were more likely to be in Stage 4 than in Stage 3 (aOR 6.588, 95% CI 1.317-32.971). CONCLUSIONS: Losing urine with defecation and making the bladder empty faster by pushing down should be explored as intervention targets to prevent women from progressing from Stage 3 to Stage 4.

RNA-Seq analysis during the life cycle of Cryptosporidium parvum reveals significant differential gene expression between proliferating stages in the intestine and infectious sporozoites.

Cryptosporidium parvum is a major cause of diarrhoea in humans and animals. There are no vaccines and few drugs available to control C. parvum. In this study, we used RNA-Seq to compare gene expression in sporozoites and intracellular stages of C. parvum to identify genes likely to be important for successful completion of the parasite's life cycle and, thereby, possible targets for drugs or vaccines. We identified 3774 protein-encoding transcripts in C. parvum. Applying a stringent cut-off of eight fold for determination of differential expression, we identified 173 genes (26 coding for predicted secreted proteins) upregulated in sporozoites. On the other hand, expression of 1259 genes was upregulated in intestinal stages (merozoites/gamonts) with a gene ontology enrichment for 63 biological processes and upregulation of 117 genes in 23 metabolic pathways. There was no clear stage specificity of expression of AP2-domain containing transcription factors, although sporozoites had a relatively small repertoire of these important regulators. Our RNA-Seq analysis revealed a new calcium-dependent protein kinase, bringing the total number of known calcium-dependent protein kinases (CDPKs) in C. parvum to 11. One of these, CDPK1, was expressed in all stages, strengthening the notion that it is a valid drug target. By comparing parasites grown in vivo (which produce bona fide thick-walled oocysts) and in vitro (which are arrested in sexual development prior to oocyst generation) we were able to confirm that genes encoding oocyst wall proteins are expressed in gametocytes and that the proteins are stockpiled rather than generated de novo in zygotes. RNA-Seq analysis of C. parvum revealed genes expressed in a stage-specific manner and others whose expression is required at all stages of development. The functional significance of these can now be addressed through recent advances in transgenics for C. parvum, and may lead to the identification of viable drug and vaccine targets.

Neuroprotection or neurotoxicity? new insights into the effects of Acanthopanax senticosus harms on nervous system through cerebral metabolomics analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Acanthopanax senticosus harms (AS), also called "Ciwujia" in Chinese and "Siberian ginseng" in the Siberian Taiga region, is the herb used in traditional medicinal systems in China and Russia, which has been applied to the treatment of various nervous and cerebrovascular diseases, such as depression, mental fatigue, and transient global cerebral ischemia. The previous research works usually tended to focus on the neuroprotective effects of AS, but ignored its additional effects that are not entirely beneficial to the nervous system. Therefore, to discover the potential intervention targets of AS and evaluate their roles in the nervous system are the urgent problems. MATERIALS AND METHODS: Ultra-performance liquid chromatography-quadrupole time-of-flight-mass spectrometry (UPLC-QTOF-MS) coupled with pattern recognition methods were integrated to investigate the metabolic profiles of AS-treated rats. The analysis of possible pathways influenced by AS was performed by ingenuity pathway analysis (IPA) with MetPA. RESULTS: Treated with AS, 16 modulated metabolites were identified and considered as the potential intervention targets of AS, out of which 3 metabolites had protective effects on the nervous system, whereas 7 metabolites showed the neurotoxicity. CONCLUSION: These results may reveal that the effects of AS on nervous system had two sides, and it could not only exert the neuroprotection but also produce some potential neurotoxicity.

Depressive symptoms and compromised parenting in low-income mothers of infants and toddlers: distal and proximal risks.

Low-income mothers develop depressive symptoms at higher rates than the general population, adding to the existing risk that economic hardship places on their infants and toddlers. Emphasizing a few key intervention targets, an approach that is especially relevant to mothers when depressive symptoms compromise their energy and concentration, can improve interventions with populations facing adversity. The goal of this study was to identify contextual risk factors that significantly contributed to depressive symptoms and that, in combination with depressive symptoms, were associated with compromised parenting. Using baseline data from 251 ethnically diverse mothers from six Early Head Start programs in the Northeastern and Southeastern US, who were recruited for a clinical trial of an in-home intervention, Belsky's ecological framework of distal to proximal levels of influence was used to organize risk factors for depressive symptoms in hierarchical regression models. Under stress, mothers of toddlers reported more severe depressive symptoms than mothers of infants, supporting the need for depressive symptom screening and monitoring past the immediate postpartum period. Multivariate models revealed intervention targets that can focus depression prevention and intervention efforts, including helping mothers reduce chronic day-to-day stressors and conflicts with significant others, and to effectively handle challenging toddler behaviors, especially in the face of regional disciplinary norms. Presence of a live-in partner was linked to more effective parenting, regardless of participants' depressive symptom severity.

Insights into the immuno-molecular biology of Angiostrongylus vasorum through transcriptomics--prospects for new interventions.

Angiostrongylus vasorum is a metastrongyloid nematode of dogs and other canids of major clinical importance in many countries. In order to gain first insights into the molecular biology of this worm, we conducted the first large-scale exploration of its transcriptome, and predicted essential molecules linked to metabolic and biological processes as well as host immune responses. We also predicted and prioritized drug targets and drug candidates. Following Illumina sequencing (RNA-seq), 52.3 million sequence reads representing adult A. vasorum were assembled and annotated. The assembly yielded 20,033 contigs, which encoded proteins with 11,505 homologues in Caenorhabditis elegans, and additional 2252 homologues in various other parasitic helminths for which curated data sets were publicly available. Functional annotation was achieved for 11,752 (58.6%) proteins predicted for A. vasorum, including peptidases (4.5%) and peptidase inhibitors (1.6%), protein kinases (1.7%), G protein-coupled receptors (GPCRs) (1.5%) and phosphatases (1.2%). Contigs encoding excretory/secretory and immuno-modulatory proteins represented some of the most highly transcribed molecules, and encoded enzymes that digest haemoglobin were conserved between A. vasorum and other blood-feeding nematodes. Using an essentiality-based approach, drug targets, including neurotransmitter receptors, an important chemosensory ion channel and cysteine proteinase-3 were predicted in A. vasorum, as were associated small molecular inhibitors/activators. Future transcriptomic analyses of all developmental stages of A. vasorum should facilitate deep explorations of the molecular biology of this important parasitic nematode and support the sequencing of its genome. These advances will provide a foundation for exploring immuno-molecular aspects of angiostrongylosis and have the potential to underpin the discovery of new methods of intervention.