Miracle-dz/UniFAR-FTUs huggingface dataset:
Flexible RSV Prefusogenic Fusion Glycoprotein Exposes Multiple Neutralizing Epitopes that May Collectively Contribute to Protective Immunity

Human respiratory syncytial virus (RSV) is a significant cause of lower respiratory tract infection in infants, young children, and older adults. There is no licensed vaccine and prophylactic treatment options are limited and not widely available in developing countries with the greatest disease burden. The RSV fusion (F) glycoprotein is a primary target of host immunity and thus a major focus for vaccine development. The native F glycoprotein structure is flexible and undergoes significant rearrangements from the metastable prefusion to a stable postfusion structure with neutralizing epitopes on intermediate structures. We hypothesize trimeric vaccine strategies that recapitulate the breathable F quaternary structure, and provide accessibility of B-cells to epitopes on intermediate conformations, may collectively contribute to protective immunity, while ridge prefusion F structures restrict access to key protective epitopes. To test this hypothesis, we used the near full-length native prefusogenic F as a backbone to construct three prefusion F variants with substitutions in the hydrophobic head cavity: 1) disulfide bond double mutant (DS), 2) space filling hydrophobic amino acid substitutions (Cav1), and 3) DS plus Cav1 substitutions (DS-Cav1). In this study, we compared the immunogenicity of prefusogenic F to the immunogenicity of the prefusion F variants in two animal models. Native prefusogenic F was significantly more immunogenic producing high titer antibodies to prefusogenic, prefusion, and postfusion F structures compared to animals immunized with prefusion F DS or DS-Cav1. Importantly, native prefusogenic F elicited antibodies that targeted neutralizing epitopes including prefusion-specific site zero (Ø) and V as well as conformation-independent neutralizing sites II and IV. Immunization with prefusion F DS or DS-Cav1 elicited antibodies primarily targeting antigenic sites Ø and V with little or no detectable antibodies to other key neutralizing sites. Animals immunized with native prefusogenic F also had significantly higher neutralizing antibodies that cross-neutralized RSV A and B subtypes while immunization with DS or DS-Cav1 elicited neutralizing antibodies primarily to the A subtype. We conclude that breathable trimeric vaccines that closely mimic the native F-structure, and incorporate strategies for B-cell accessibility to protective epitopes, are important considerations for vaccine design. F structures locked in a single conformation restrict B-cell access to neutralizing epitopes that may collectively contribute to destabilizing F-trimers important for broad protection. These results also have implications for vaccine strategies targeting other type 1 integral membrane proteins.
Bumble Bees (Hymenoptera: Apidae) Respond to Moth (Lepidoptera: Noctuidae) Pheromone Components, Leading to Bee Bycatch in Monitoring Traps Targeting Moth Pests

Semiochemical-baited traps are commonly used to monitor moth pests and inform management decisions. Unfortunately, bee pollinators can be unintentionally captured, which reduces monitoring system efficiency and may negatively impact pollinator biodiversity and pollination services. We assessed the abundance and diversity of wild bees captured in semiochemical-baited traps designed to capture cutworm and armyworm (Lepidoptera: Noctuidae) pests in North America. Green Unitraps were baited with semiochemicals including: (1) species-specific noctuid pheromone lures; (2) food bait lures consisting of fermentation by-products; or (3) floral volatiles. Traps were positioned in canola (Brassica napus L.) and wheat (Triticum aestivum L.) fields in Alberta, Canada. We also explored the mechanisms of bee detection of moth pheromone components using electroantennogram (EAG) assays to assess the antennal response of two Bombus species. We found that more bumble bees (Hymenoptera: Apidae), and especially Bombus rufocinctus Cresson, were captured in traps baited with moth pheromone lures than in unbaited control traps. Fermentation by-product lures captured a similar low number of bees as unbaited traps, whereas floral volatile-based food bait lures captured more bees, comparable to capture in pheromone-baited traps. In general, more Bombus spp. were captured in traps positioned at canola vs. wheat fields, but the community composition was similar among crops. EAG assays indicate that sensory receptors on the antennae of B. rufocinctus Cresson and B. impatiens Cresson detect noctuid moth pheromones. Perception of chemical signals of a different insect order may be explained by structural similarities in pheromone components produced by both moths and bumble bees.
Human INCL fibroblasts display abnormal mitochondrial and lysosomal networks and heightened susceptibility to ROS-induced cell death

Infantile Neuronal Ceroid Lipofuscinosis (INCL) is a pediatric neurodegenerative disorder characterized by progressive retinal and central nervous system deterioration during infancy. This lysosomal storage disorder results from a deficiency in the Palmitoyl Protein Thioesterase 1 (PPT1) enzyme - a lysosomal hydrolase which cleaves fatty acid chains such as palmitate from lipid-modified proteins. In the absence of PPT1 activity, these proteins fail to be degraded, leading to the accumulation of autofluorescence storage material in the lysosome. The underlying molecular mechanisms leading to INCL pathology remain poorly understood. A role for oxidative stress has been postulated, yet little evidence has been reported to support this possibility. Here we present a comprehensive cellular characterization of human PPT1-deficient fibroblast cells harboring Met1Ile and Tyr247His compound heterozygous mutations. We detected autofluorescence storage material and observed distinct organellar abnormalities of the lysosomal and mitochondrial structures, which supported previous postulations about the role of ER, mitochondria and oxidative stress in INCL. An increase in the number of lysosomal structures was found in INCL patient fibroblasts, which suggested an upregulation of lysosomal biogenesis, and an association with endoplasmic reticulum stress response. The mitochondrial network also displayed abnormal spherical punctate morphology instead of normal elongated tubules with extensive branching, supporting the involvement of mitochondrial and oxidative stress in INCL cell death. Autofluorescence accumulation and lysosomal pathologies can be mitigated in the presence of conditioned wild type media suggesting that a partial restoration via passive introduction of the enzyme into the cellular environment may be possible. We also demonstrated, for the first time, that human INCL fibroblasts have a heightened susceptibility to exogenous reactive oxygen species (ROS)-induced cell death, which suggested an elevated basal level of endogenous ROS in the mutant cell. Collectively, these findings support the role of intracellular organellar networks in INCL pathology, possibly due to oxidative stress.
Stress and Tinnitus; Transcutaneous Auricular Vagal Nerve Stimulation Attenuates Tinnitus-Triggered Stress Reaction

Introduction Tinnitus can become a strong stressor for some individuals, leading to imbalance of the autonomous nervous system with reduction of parasympathetic activity. It can manifest itself as sleep disturbances, anxiety and even depression. This condition can be reversed by bioelectrical vagal nerve stimulation (VNS). Conventional invasive VNS is an approved treatment for epilepsy and depression. Transcutaneous VNS (taVNS) stimulating the auricular branch of the vagus nerve has been shown to activate the vagal pathways similarly as an implanted VNS. Therefore, taVNS might also be a therapeutic alternative in health conditions such as tinnitus-related mental stress (TRMS). This retrospective study in 171 TRMS patients reports the clinical features, psychophysiological characteristics, and results of the heart rate variability (HRV) tests before and after test-taVNS. This study also reports the therapy outcomes of 113 TRMS patients treated with taVNS, in combination with standard tinnitus therapy. Methods Diagnostic tinnitus and hearing profiles were defined. To detect possible cardiac adverse effects, test-taVNS with heart rate monitoring as well as pre- and post-stimulation HRV tests were performed. Daily taVNS home therapy was prescribed thereafter. To assess therapeutic usefulness of taVNS, 1-year follow-up outcome was studied. Results of HRV tests were retrospectively analyzed and correlated to diagnostic data. Results The large majority of patients with TRMS suffer from associated symptoms such as sleep disturbances and anxiety. Baseline HRV data showed that more than three quarters of the 171 patients had increased sympathetic activity before test-taVNS. Test-taVNS shifted mean values of different HRV parameters toward increased parasympathetic activity in about 80% of patients. Test-taVNS did not cause any cardiac or other side effects. No significant adverse effects were reported in follow-up questionnaires. Conclusion TRMS is an example of a stress condition in which patients may benefit from taVNS. As revealed by HRV, test-taVNS improved parasympathetic function, most efficiently in patients with a low starting HRV level. Our tinnitus treatment program, including taVNS, effectively alleviated tinnitus stress and handicap. For wider clinical use, there is a great need for more knowledge about the optimal methodology and parameters of taVNS.
Microscale Self-Assembly of Upconversion Nanoparticles Driven by Block Copolymer

Lanthanide-based upconversion nanoparticles can convert low-energy excitation to high-energy emission. The self-assembled upconversion nanoparticles with unique structures have considerable promise in sensors and optical devices due to intriguing properties. However, the assembly of isotropic nanocrystals into anisotropic structures is a fundamental challenge caused by the difficulty in controlling interparticle interactions. Herein, we report a novel approach for the preparation of the chain-like assemblies of upconversion nanoparticles at different scales from nano-scale to micro-scale. The dimension of chain-like assembly can be fine-tuned using various incubation times. Our study observed Y-junction aggregate morphology due to the flexible nature of amphiphilic block copolymer. Furthermore, the prepared nanoparticle assemblies of upconversion nanoparticles with lengths up to several micrometers can serve as novel luminescent nanostructure and offer great opportunities in the fields of optical applications.
Rapid Development of an Effective Newcastle Disease Virus Vaccine Candidate by Attenuation of a Genotype VII Velogenic Isolate Using a Simple Infectious Cloning System

Genotype-matched vaccines provide ideal protection against infection caused by new Newcastle disease virus (NDV) genotypes or variants even in the vaccinated chickens. In this study, we report a protocol for attenuation and rapid development of a velogenic NDV isolate as an effective vaccine candidate, using a simple and reliable infectious cloning platform. Based on DHN3, a genotype VII velogenic NDV isolate, recombinant rDHN3 was rescued by co-transfection of plasmids expressing the genomic RNA, NDV proteins NP, P and L, and the T7 polymerase without using a helper virus. Subsequently, an attenuated strain rDHN3-mF was produced by substitution of residues from amino acids 112 to 117 in the DHN3 F protein with the corresponding sequence from the LaSota strain. Both rDHN3 and rDHN3-mF are genetically stable during propagation in cell culture and chicken embryos. Further characterization through determination of EID50, MDT and clinical assessments confirmed that rDHN3 is velogenic and rDHN3-mF lentogenic. Vaccination of one-week-old SPF chicks with inactivated rDHN3-mF produced much higher anti-DHN3 antibody response and better protection against live DHN3 challenge than did the commercial LaSota vaccine, providing 100% protection and much earlier viral clearance. This attenuated NDV isolate would merit further development into a vaccine product.
A Systematic Review of the Pharmacology, Toxicology and Pharmacokinetics of Matrine

Matrine (MT) is a naturally occurring alkaloid and an bioactive component of Chinese herbs, such as Sophora flavescens and Radix Sophorae tonkinensis. Emerging evidence suggests that MT possesses anti-cancer, anti-inflammatory, anti-oxidant, antiviral, antimicrobial, anti-fibrotic, anti-allergic, antinociceptive, hepatoprotective, cardioprotective, and neuroprotective properties. These pharmacological properties form the foundation for its application in the treatment of various diseases, such as multiple types of cancers, hepatitis, skin diseases, allergic asthma, diabetic cardiomyopathy, pain, Alzheimer’s disease (AD), Parkinson’s disease (PD), and central nervous system (CNS) inflammation. However, an increasing number of published studies indicate that MT has serious adverse effects, the most obvious being liver toxicity and neurotoxicity, which are major factors limiting its clinical use. Pharmacokinetic studies have shown that MT has low oral bioavailability and short half-life in vivo. This review summarizes the latest advances in research on the pharmacology, toxicology, and pharmacokinetics of MT, with a focus on its biological properties and mechanism of action. The review provides insight into the future of research on traditional Chinese medicine.
Autophagy Induced Accumulation of Lipids in pgrl1 and pgr5 of Chlamydomonas reinhardtii Under High Light

Chlamydomonas (C) reinhardtii cells (wild-type CC125 and 137AH, and cyclic electron transport dependant mutants pgrl1 and pgr5) were grown in high light 500 µmol photons m−2 s−1 where the growth was significantly enhanced after three days. The starch and lipid contents were also increased; however, starch content was decreased in pgr5. Further, the Nile Red fluorescence shows that a significant amount of lipid bodies were observed in pgr5 cells under high light. Similarly, the electron micrographs show that large vacuoles were formed in high light stress despite the change in stacks of grana structure. We also observed increased production of reactive oxygen species (ROS) that could lead to autophagy. Inline, a significant increase of ATG8 protein was noticed in pgr5, which is a hallmark characteristic for autophagy formation. Consequently, the triacylglycerol (TAG) content was increased due to DGAT and PDAT enzymes’ expression, especially in pgr5. Here, the TAG synthesis would have been obtained from degraded membrane lipids in pgr5. Additionally, mono, polyunsaturated, and saturated fatty acids were identified more in the high light condition. Our study shows that the high light induces ROS, leads to autophagy and TAGs accumulation, which is stored as an energy source to acclimatize the algae.
Subject identification using edge-centric functional connectivity

Group-level studies do not capture individual differences in network organization, an important prerequisite for understanding neural substrates shaping behavior and for developing interventions in clinical conditions. Recent studies have employed “fingerprinting” analyses on functional connectivity to identify subjects’ idiosyncratic features. Here, we develop a complementary approach based on an edge-centric model of functional connectivity, which focuses on the co-fluctuations of edges. We first show whole-brain edge functional connectivity (eFC) to be a robust substrate that improves identifiability over nodal FC (nFC) across different datasets and parcellations. Next, we characterized subjects’ identifiability at different spatial scales, from single nodes to the level of functional systems and clusters using k-means clustering. Across spatial scales, we find that heteromodal brain regions exhibit consistently greater identifiability than unimodal, sensorimotor, and limbic regions. Lastly, we show that identifiability can be further improved by reconstructing eFC using specific subsets of its principal components. In summary, our results highlight the utility of the edge-centric network model for capturing meaningful subject-specific features and sets the stage for future investigations into individual differences using edge-centric models.
Regulation of Carbohydrate Metabolism by Trehalose-6-Phosphate Synthase 3 in the Brown Planthopper, Nilaparvata lugens

Nilaparvata lugens (Stål) (Hemiptera: Delphacidae) is one of the pests that harm rice. In this paper, a new trehalose-6-phosphate synthase gene, TPS3, was identified by transcriptome sequencing and gene cloning. To explore its role in the energy metabolism of N. lugens we examined the carbohydrate contents at different stages of development, the tissue expression of TPS, and some physiological and biochemical indicators by injecting dsTPS3 and dsTPSs (a proportional mixture of dsTPS1, dsTPS2, and dsTPS3). The glucose content at the fifth instar was significantly higher than that in the fourth instar and the adult stages. The trehalose and glycogen contents before molting were higher than those after molting. TPS1, TPS2, and TPS3 were expressed in the head, leg, wing bud, and cuticle, with the highest expression in the wing bud. In addition, compared with the control group, the glucose content increased significantly at 48 h after RNA interference, and the trehalose content decreased significantly after 72 h. qRT-PCR showed that the expression level of UGPase decreased significantly at 48 h after injection, whereas GS expression increased significantly at 48 h after injecting dsTPS3. After dsTPS injection, the expression levels of PPGM2, UGPase, GP, and GS increased significantly at 72 h. After interfering with the expression of TPS3 gene alone, UGPase expression decreased significantly at 48 h, and GS expression increased significantly at 72 h. Finally, combined with the digital gene expression and pathway analysis, 1439 and 1346 genes were upregulated, and 2127 and 1927 genes were downregulated in the dsTPS3 and dsTPSs groups, respectively. The function of most differential genes was concentrated in sugar metabolism, lipid metabolism, and amino acid metabolism. The results indicated that TPS3 plays a key role in the energy metabolism of N. lugens and confirmed that TPS3 is a feasible target gene for RNA interference in N. lugens. Simultaneously, they provide a theoretical basis for the development and utilization of TPS3 to control pests.
Throat Colonization and Antibiotic Susceptibility of Group a β-Hemolytic Streptococci Among Rheumatic Heart Disease Patients Attending a Cardiac Referral Hospital in Tanzania, a Descriptive Cross-Sectional Study

Background: Secondary prophylaxis against repeated attacks of acute rheumatic fever is an important intervention in patients with rheumatic heart disease (RHD), and it aims to prevent throat infection by group A β-hemolytic streptococcus (GAS); however, its implementation faces many challenges. This study aimed to assess throat colonization, antibiotic susceptibility, and factors associated with GAS colonization among patients with RHD attending care at Jakaya Kikwete Cardiac Institute in Dar-es-Salaam, Tanzania. Methods: A descriptive cross-sectional study of RHD patients attending the Jakaya Kikwete Cardiac Institute was conducted from March to May 2018, where we consecutively enrolled all patients known to have RHD and coming for their regular clinic follow-up. A structured questionnaire was used to obtain patients' sociodemographic information, factors associated with GAS colonization, and status of secondary prophylaxis use and adherence. Throat swabs were taken and cultured to determine the presence of GAS, and isolates of GAS were tested for antibiotic susceptibility using Kirby–Bauer disk diffusion method according to the Clinical and Laboratory Standards Institute version 2015. Antibiotics of interest were chosen according to the Tanzanian Treatment Guidelines. Results: In total, 194 patients with RHD were enrolled, their mean age was 28.4 ± 16.5 years, and 58.2% were females. Only 58 (29.9%) patients were on regular prophylaxis, 39 (20.1%) had stopped taking prophylaxis, whereas 97 (50.0%) had never been on prophylaxis. Throat cultures were positive for GAS in 25 (12.9%) patients. Patients who stopped prophylaxis were 3.26 times more likely to be colonized by GAS when compared to patients on regular prophylaxis. Majority (96%) of GAS isolates were susceptible to penicillin, ceftriaxone, and ciprofloxacin, whereas the highest resistance (20%) was observed with vancomycin. No GAS resistance was observed against penicillin. Conclusion: The prevalence of GAS throat colonization is high among this population and is associated with stopping prophylaxis. The proportion of patients on regular secondary prophylaxis is unacceptably low, and interventions should target both patients' and physicians' barriers to effective secondary prophylaxis.
Reward-associated configural cues elicit theta oscillations of rat retrosplenial neurons phase-locked to LFP theta cycles

Previous behavioral studies implicated the retrosplenial cortex (RSC) in stimulus-stimulus associations, and also in retrieval of remote associative memory based on EEG theta oscillations. To investigate the neural mechanisms underlying these processes, RSC neurons and local field potentials (LFPs) were simultaneously recorded from well-trained rats performing a cue-reward association task. In the task, simultaneous presentation of two multimodal conditioned stimuli (configural CSs) predicted a reward outcome opposite to that associated with individual presentation of each elemental CS. Here, we show neurophysiological evidence that the RSC is involved in stimulus-stimulus association where configural CSs are discriminated from each elementary CS that is a constituent of the configural CSs, and that memory retrieval of rewarding CSs is associated with theta oscillation of RSC neurons during CS presentation, which is phase-locked to LFP theta cycles.
Impaired Cortical Cytoarchitecture and Reduced Excitability of Deep-Layer Neurons in the Offspring of Diabetic Rats

Maternal diabetes has been related to low verbal task scores, impaired fine and gross motor skills, and poor performance in graphic and visuospatial tasks during childhood. The primary motor cortex is important for controlling motor functions, and embryos exposed to high glucose show changes in cell proliferation, migration, and differentiation during corticogenesis. However, the existing studies do not discriminate between embryos with or without neural tube defects, making it difficult to conclude whether the reported changes are related to neural tube defects or other anomalies. Furthermore, postnatal effects on central nervous system cytoarchitecture and function have been scarcely addressed. Through molecular, biochemical, morphological, and electrophysiological approaches, we provide evidence of impaired primary motor cerebral cortex lamination and neuronal function in pups from diabetic rats, showing an altered distribution of SATB2, FOXP2, and TBR1, impaired cell migration and polarity, and decreased excitability of deep-layer cortical neurons, suggesting abnormalities in cortico-cortical and extra-cortical innervation. Furthermore, phase-plot analysis of action potentials suggests changes in the activity of potassium channels. These results indicate that high-glucose insult during development promotes complex changes in migration, neurogenesis, cell polarity establishment, and dendritic arborization, which in turn lead to reduced excitability of deep-layer cortical neurons.