Miracle-dz/UniFAR-FTUs huggingface dataset:
Development of Novel Solid Nanostructured Lipid Carriers for Bioavailability Enhancement Using a Quality by Design Approach

α, β-Arteether (ART) antimalarial drug is used to treat chloroquine-resistant malaria and cerebral malaria. The drug’s solubility in water is relatively low (17 μg/mL), and 40% of the drug degrades in the stomach, resulting in poor bioavailability. This article discusses the quality by design technique used for formulation development and optimization of nanostructured lipid carriers (NLCs). The ART-NLCs were made by solvent diffusion method. To develop solid NLCs, the NLCs were freeze-dried and encapsulated in enteric-coated capsule shells. The prepared NLCs showed particle size ranging between 156.8 ± 12 nm while zeta potential ranging between − 26.1 ± 0.22 mV. They also showed high encapsulation efficiency (> 85%) and an amorphous drug’s lipid matrix state. Pharmacokinetic parameters of optimized formulation enhance oral bioavailability to 18.45%. These investigations demonstrated the superiority of NLCs for improvement of solubility as well as oral bioavailability of poorly water-soluble drugs.
Effect of feeding raw potato starch on the composition dynamics of the piglet intestinal microbiome

Objective Raw potato starch (RPS) is resistant to digestion, escapes absorption, and is metabolized by intestinal microflora in the large intestine and acts as their energy source. In this study, we compared the effect of different concentrations of RPS on the intestinal bacterial community of weaned piglets. Methods Male weaned piglets (25-days-old, 7.03±0.49 kg) were either fed a corn/soybean-based control diet (CON, n = 6) or two treatment diets supplemented with 5% RPS (RPS5, n = 4) or 10% RPS (RPS10, n = 4) for 20 days and their fecal samples were collected. The day 0 and 20 samples were analyzed using a 16S rRNA gene sequencing technology, followed by total genomic DNA extraction, library construction, and high-throughput sequencing. After statistical analysis, five phyla and 45 genera accounting for over 0.5% of the reads in any of the three groups were further analyzed. Furthermore, short-chain fatty acids (SCFAs) in the day 20 fecal samples were analyzed using gas chromatography. Results Significant changes were not observed in the bacterial composition at the phylum level even after 20 d post feeding (dpf); however, the abundance of Intestinimonas and Barnesiella decreased in both RPS treatment groups compared to the CON group. Consumption of 5% RPS increased the abundance of Roseburia (p<0.05) and decreased the abundance of Clostridium (p<0.01) and Mediterraneibacter (p< 0.05). In contrast, consumption of 10% RPS increased the abundance of Olsenella (p<0.05) and decreased the abundance of Campylobacter (p<0.05), Kineothrix (p<0.05), Paraprevotella (p<0.05), and Vallitalea (p<0.05). Additionally, acetate (p<0.01), butyrate (p<0.05), valerate (p = 0.01), and total SCFAs (p = 0.01) were upregulated in the RPS5 treatment group Conclusion Feeding 5% RPS altered bacterial community composition and promoted gut health in weaned piglets. Thus, resistant starch as a feed additive may prevent diarrhea in piglets during weaning.
Evidence that genomic incompatibilities and other multilocus processes impact hybrid fitness in a rattlesnake hybrid zone

Hybrid zones provide valuable opportunities to understand the genomic mechanisms that promote speciation by providing insight into factors involved in intermediate stages of speciation. Here, we investigate introgression in a hybrid zone between two rattlesnake species (Crotalus viridis and Crotalus oreganus concolor) that have undergone historical allopatric divergence and recent range expansion and secondary contact. We use Bayesian genomic cline models to characterize genomic patterns of introgression between these lineages and identify loci potentially subject to selection in hybrids. We find evidence for a large number of genomic regions with biased ancestry that deviate from the genomic background in hybrids (i.e., excess ancestry loci), which tend to be associated with genomic regions with higher recombination rates. We also identify suites of excess ancestry loci that show highly correlated allele frequencies (including conspecific and heterospecific combinations) across physically unlinked genomic regions in hybrids. Our findings provide evidence for multiple multilocus evolutionary processes impacting hybrid fitness in this system.
Intracranial Hemorrhages in Neonates: Incidence, Risk Factors, and Treatment

Abstract Hemostasis is a dynamic process that starts in utero . Neonates, especially those who are born preterm, are at high risk of bleeding. The coagulation system evolves with age, and the decreased levels of coagulation factors along with hypo-reactive platelets are counterbalanced with increased activity of von Willebrand factor, high hematocrit and mean corpuscular volume as well as low levels of coagulation inhibitors that promote hemostasis. Neonates with congenital bleeding disorders such as hemophilia are at even higher risk of bleeding complications. This review will focus upon one of the most devastating complications associated with neonatal bleeding: intracranial hemorrhages (ICH). While etiology may be multifactorial and impacted by maternal as well as fetal risk factors, the mode of delivery certainly plays an important role in the pathogenesis of ICH. We will address prematurity and congenital bleeding disorders such as hemophilia A and B and other rare bleeding disorders as risk factors and present an updated approach for treatment and possible prevention.
Impact of spiritual healing on moderate depression in adults: a study protocol of a pilot randomised controlled trial (RCT)

Introduction Depression is a common mental disorder and the (global) leading cause of all non-fatal burden of disease worldwide. Currently, supported treatment for depression is antidepressant medication and different psychotherapeutic interventions. Many patients experience, however, adverse effects of antidepressant medication, while at the same time the access to psychotherapeutic interventions are limited. Many patients who suffer from depression turn to complementary medicine and among those modalities often spiritual healing. There is some evidence that consulting a spiritual healer can be beneficial for patients who suffer from depression, and that spiritual healing is associated with low risk. The aim of this protocol is to conduct a pilot randomised controlled trial (RCT) (spiritual healing as addition to usual care vs usual care alone) in preparation of a larger trial in adults with moderate depression, to examine feasibility and individuals’ experience of spiritual healing. Methods and analysis This study is a pilot RCT with two parallel groups. A total of 28 adult patients with moderate depression, diagnosed by the physician and according to the Montgomery and Åsberg Depression Rating Scale criteria will be randomised to spiritual healing in addition to usual care (n=14) or usual care alone (n=14). To determine if there is a statistical indication of an effect of healing warranting a full-scale study; the separation test will be used. To investigate participants’ experience with spiritual healing, a qualitative study will be included using semistructured interviews. The data will be analysed based on a direct content analysis. Ethics and dissemination This protocol was approved by regional committees for medical and health research ethics by the identifier (63692). The results will be disseminated through open-access, peer-reviewed publications, in addition to stakeholders’ reporting and presenting at conferences. Trial registration Norwegian Centre for Research Data (845302) and clinicaltrials.gov (ID: NCT04766242)
The associations of job strain and leisure-time physical activity with the risk of hypertension: the population-based Midlife in the United States cohort study

OBJECTIVES Job strain is positively associated with incident hypertension, while increasing leisure-time physical activity (LTPA) can reduce incident hypertension. However, the joint associations of job strain and LTPA with incident hypertension among United States workers have yet to be investigated. This study examined the independent and joint associations of job strain and LTPA with incident hypertension. METHODS This prospective cohort study (n=1,160) utilized data from the population-based Midlife in the United States study. The associations of job strain and LTPA at baseline with incident hypertension during follow-up were examined using Cox proportional hazards models. High job strain was derived from a combination of high job demands and low job control, and high LTPA was defined as engagement in moderate or vigorous LTPA at least once per week. RESULTS During 9,218 person-years of follow-up, the hypertension incidence rate was 30.6 (95% confidence interval [CI], 27.3 to 34.3) per 1,000 person-years. High job strain was associated with a higher risk for hypertension than low job strain (adjusted hazard ratio [aHR], 1.29; 95% CI, 1.00 to 1.67). High LTPA was associated with lower hypertension risk than low LTPA (aHR, 0.77; 95% CI, 0.60 to 0.98). Hypertension risk was higher among workers with high job strain and low LTPA than among those with low job strain and high LTPA (aHR, 1.70; 95% CI, 1.18 to 2.43). CONCLUSIONS Job strain and LTPA showed positive and inverse associations, respectively, with incident hypertension. The combination of high job strain and low LTPA was associated with the highest risk for hypertension.
MEX3A impairs DNA mismatch repair signaling and mediates acquired temozolomide resistance in glioblastoma.

MutS protein homolog 2 (MSH2) is a key element involved in the DNA mismatch repair system, which is responsible for recognizing and repairing mispaired bases. Simultaneously, MSH2 identifies DNA adducts induced by temozolomide (TMZ) and triggers apoptosis and autophagy in tumor cells. Previous work has revealed that reduced MSH2 expression is often observed in glioblastoma (GBM) patients who relapse after chemotherapy. Elucidation of the mechanism behind TMZ-mediated reduction of MSH2 could help improve GBM treatment. Here, we report significant upregulation of Mex-3 RNA binding family member A (MEX3A) in GBM tissues and cell lines following TMZ treatment. MEX3A bound to the MEX-3 recognition element (MRE) of MSH2 mRNA, which in turn recruited CCR4-NOT complexes to target MSH2 mRNA for deadenylation and degradation. In addition, ectopic expression of MEX3A significantly decreased cellular DNA mismatch repair activities and reduced the chemosensitivity of GBM cells via downregulation of MSH2, while depletion of MEX3A sensitized GBM cells to TMZ. In MGMT-deficient GBM patients, MEX3A expression correlated with MSH2 levels, and high MEX3A expression was associated with poor prognosis. Overall, these findings reveal a potential mechanism by which MSH2 expression is reduced in post-TMZ recurrent GBM.
Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients With Solid Tumor Cancer

Historically, professional society guidelines have recommended limited genetic testing for hereditary cancer syndromes (HCS) to patients with cancer thought to be at highest risk for carrying pathogenic/ likely pathogenic germline variants (PGVs) in a few selected genes. Reasons for this approach were largely based on the high costs of testing, perceptions that HCS were rare in the general population, and a paucity of clinical utility. Here, we discuss the current evidence that challenges these assumptions and supports the implementation of universal HCS testing among patients with solid tumors.
CBP Is Required for Establishing Adaptive Gene Programs in the Adult Mouse Brain

Environmental factors and life experiences impinge on brain circuits triggering adaptive changes. Epigenetic regulators contribute to this neuroadaptation by enhancing or suppressing specific gene programs. The paralogous transcriptional coactivators and lysine acetyltransferases CREB binding protein (CBP) and p300 are involved in brain plasticity and stimulus-dependent transcription, but their specific roles in neuroadaptation are not fully understood. Here we investigated the impact of eliminating either CBP or p300 in excitatory neurons of the adult forebrain of mice from both sexes using inducible and cell type-restricted knock-out strains. The elimination of CBP, but not p300, reduced the expression and chromatin acetylation of plasticity genes, dampened activity-driven transcription, and caused memory deficits. The defects became more prominent in elderly mice and in paradigms that involved enduring changes in transcription, such as kindling and environmental enrichment, in which CBP loss interfered with the establishment of activity-induced transcriptional and epigenetic changes in response to stimulus or experience. These findings further strengthen the link between CBP deficiency in excitatory neurons and etiopathology in the nervous system. SIGNIFICANCE STATEMENT How environmental conditions and life experiences impinge on mature brain circuits to elicit adaptive responses that favor the survival of the organism remains an outstanding question in neurosciences. Epigenetic regulators are thought to contribute to neuroadaptation by initiating or enhancing adaptive gene programs. In this article, we examined the role of CREB binding protein (CBP) and p300, two paralogous transcriptional coactivators and histone acetyltransferases involved in cognitive processes and intellectual disability, in neuroadaptation in adult hippocampal circuits. Our experiments demonstrate that CBP, but not its paralog p300, plays a highly specific role in the epigenetic regulation of neuronal plasticity gene programs in response to stimulus and provide unprecedented insight into the molecular mechanisms underlying neuroadaptation.
Experiencing Stress During COVID-19: A Computational Analysis of Stressors and Emotional Responses to Stress

This study aims to unveil how COVID-19 affected the experience of stress by focusing on the stressors. Using computational analysis based on a newly developed stressor identification model, we compared the experience of stress expressed by Korean Twitter users before and during the pandemic in terms of (1) the stressors as the source of stress and (2) emotion as the manifestation of stress. Both tweet-level (N = 202,556) and user-level (N = 24,803) analyses revealed that social factors are prevalent sources of stress both before and during the pandemic. Moreover, social stressors increased the most during the pandemic. While stress from social stressors was manifested mainly as sadness before the pandemic, anger became the predominant emotional manifestation during the pandemic. Public health policies and educators should consider social stressors as the predominant source of stress during the pandemic and seek ways to prepare the public better for such threats.
Good perceived sleep quality protects against the raised risk of respiratory infection during sleep restriction in young adults

Abstract Study Objectives Prospectively examine the association between sleep restriction, perceived sleep quality (PSQ) and upper respiratory tract infection (URTI). Methods In 1318 military recruits (68% males) self-reported sleep was assessed at the beginning and end of a 12-week training course. Sleep restriction was defined as an individualized reduction in sleep duration of ≥2 hours/night compared with civilian life. URTIs were retrieved from medical records. Results On commencing training, approximately half of recruits were sleep restricted (52%; 2.1 ± 1.6 h); despite the sleep debt, 58% of recruits with sleep restriction reported good PSQ. Regression adjusted for covariates showed that recruits commencing training with sleep restriction were more likely to suffer URTI during the course (OR = 2.93, 95% CI 1.29–6.69, p = .011). Moderation analysis showed this finding was driven by poor PSQ (B = −1.12, SE 0.50, p = .023), as no significant association between sleep restriction and URTI was observed in recruits reporting good PSQ, despite a similar magnitude of sleep restriction during training. Associations remained in the population completing training, accounting for loss to follow-up. Recruits reporting poor PSQ when healthy at the start and end of training were more susceptible to URTI (OR = 3.16, 95% CI 1.31–7.61, p = .010, vs good PSQ). Conclusion Good perceived sleep quality was associated with protection against the raised risk of respiratory infection during sleep restriction. Studies should determine whether improvements in sleep quality arising from behavioral sleep interventions translate to reduced respiratory infection during sleep restriction.
Vaccine clinical trials in low- and middle-income countries: a brief review of standard, newer and proposed approaches

ABSTRACT Introduction Vaccine clinical trials are necessary in low- and middle-income countries (LMICs) because new vaccine candidates are developed against diseases found mainly in these settings, the results of trials done in industrialized countries may not be generalizable to LMICs and more institutions in middle-income countries are producing vaccines for use in LMICs. Areas covered We searched PubMed and conducted a narrative review on standard, newer and proposed approaches toward obtaining data supportive for vaccine licensure, with a special focus in LMICs. Expert opinion Of the vaccine trials done worldwide, only a small proportion is conducted in LMICs, but this is likely to increase as more research experience and infrastructure is developed. At present, the majority of vaccine trials follows the standard paradigm of fixed phase 1 to 3 trials, the latter with clinical endpoints, or immunobridging studies when a valid immunocorrelate of vaccine protection exists. Other study designs may help facilitate the generation of data toward licensure of and recommendations for needed vaccines. Increased international collaboration is needed for local capacity building and regulatory oversight to ensure that all studies are conducted under good clinical practice.
CaMKII orchestrates endoplasmic reticulum stress and apoptosis in doxorubicin‐induced cardiotoxicity by regulating the IRE1α/XBP1s pathway

Doxorubicin (Dox), an anthracycline antibiotic with potent antitumor effects, has limited clinical applications due to cumulative cardiotoxicity. Ca2+/calmodulin‐dependent protein kinase II (CaMKII) is implicated in the pathological progression of Dox‐induced cardiotoxicity. This study examined the hypothesis that CaMKII exacerbates Dox‐induced cardiotoxicity by promoting endoplasmic reticulum stress and apoptosis through regulation of the inositol‐requiring enzyme 1α (IRE1α)/spliced X‐box binding protein 1 (XBP1s) pathway. Our results demonstrated that CaMKII activation and IRE1α/XBP1s pathway were involved in Dox‐treated hearts. CaMKII inhibition with KN‐93 ameliorated Dox‐induced cardiac dysfunction and pathological myocardial changes. In addition, CaMKII inhibition prevented Dox‐induced endoplasmic reticulum stress and apoptosis. Moreover, CaMKII inhibition increased the expression of IRE1α and XBP1s in Dox‐treated hearts. The IRE1α inhibitor 4μ8C blocked the protective effect of CaMKII inhibition against Dox‐induced cardiotoxicity. Mechanistically, 4μ8C prevented the effects of CaMKII inhibition on Dox‐induced endoplasmic reticulum stress and apoptosis by inhibiting the expression of IRE1α and XBP1s. Additionally, treatment with rhADAMTS13 decreased the protein level of thrombospondin 1 (TSP1) and the phosphorylation of CaMKII in Dox‐treated human AC16 cardiomyocytes. Taken together, these results demonstrate that the ADAMTS13‐TSP1 axis regulates CaMKII activation and exacerbates Dox‐induced cardiotoxicity by triggering endoplasmic reticulum stress and apoptosis by inhibiting the IRE1α/XBP1s pathway.
Evaluation of standardized ileal digestibility of amino acids in fermented soybean meal for nursery pigs using direct and difference procedures

Objective This study was to evaluate standardized ileal digestibility (SID) of amino acids (AA) in fermented soybean meal (FSBM) for nursery pigs using both direct procedure and difference procedure when FSBM was added at 20% in diets. Methods Forty-eight pigs at 9.2±0.9 kg body weight (BW) were individually housed and allotted to 4 treatments. Treatments included NFD (a semi-purified N free diet), FSD (a diet with 20% FSBM), CBD (corn basal diet), and CFD (corn basal diet:FSBM at 80:20). The FSD was used to measure AA digestibility in FSBM using the direct procedure, whereas CBD and CFD were used in the difference procedure. Pigs were fed for 10 days (0.09×BW0.75 kg per day) and euthanized to collect ileal digesta for TiO2 and AA. Results Total endogenous AA loss was 12.1 g/kg of dry matter intake. The apparent ileal digestibility (AID) Thr was greater (p<0.05) and AID His (p = 0.073) and Leu (p = 0.052) tended to be greater using the direct procedure compared with the difference procedure. The SID Thr were greater (p<0.05) in FSBM for nursery pigs calculated using a direct procedure compared with a difference procedure. In addition, SID Lys in FSBM was about 83% to 88% for nursery pigs higher than SID Lys described in National Research Council (2012). Conclusion The SID of AA in FSBM when included at practical levels using the direct procedure were similar to those from the difference procedure. Considering the SID of AA obtained using both direct and difference procedures, FSBM is an effective protein supplement providing highly digestible AA to nursery pigs. The SID of AA from this study was considerably higher than those previous reported. This study also indicates the importance of including the test feedstuffs at practical levels when evaluating digestibility.
Advanced oxidation protein products mediate human keratinocytes apoptosis by inducing cell autophagy through the mTOR–Beclin‐1 pathway

Excessive keratinocyte apoptosis leads to impaired wound healing. Recently, advanced oxidation protein products (AOPP) have been recognized as a marker of oxidative stress and a potent inducer of apoptosis. Previously, we have demonstrated that extracellular AOPP accumulation induced keratinocyte apoptosis, and we discovered that autophagy was involved. To further elucidate the role and mechanism of autophagy in AOPP‐induced‐apoptosis of keratinocytes, we treated HaCaT cells with increasing concentrations of AOPP‐human serum albumin or with AOPP‐human serum albumin for increasing durations. Cyto‐ID solution staining was used to assess cell autophagy using confocal laser scanning microscopy. Autophagy‐related protein interactions were investigated using western blot analysis. Exposure of HaCaT cells to AOPP decreased the expression of mammalian target of rapamycin (mTOR) and increased the expression of autophagy‐related proteins Beclin‐l and LC3, and eventually led to autophagy. Furthermore, an autophagy agonist significantly decreased the expression of apoptosis‐related proteins. Taken together, we showed that accumulation of extracellular AOPP induced autophagy in HaCaT cells via a reactive oxygen species‐dependent, mTOR–Beclin‐1‐mediated pathway, and that excessive autophagy‐mediated apoptosis, which resulted in delayed wound healing.