Miracle-dz/UniFAR-FTUs huggingface dataset:
DDX3 Modulates Neurite Development via Translationally Activating an RNA Regulon Involved in Rac1 Activation

The RNA helicase DDX3 is a component of neuronal granules, and its gene mutations are linked to intellectual disability (ID). Here we demonstrate that DDX3 depletion in neurons impairs neurite development by downregulating Rac1 level and activation. Moreover, DDX3 activates the translation of functionally coherent mRNAs involved in Rac1 activation including Rac1. Among the DDX3 regulon, Prkaca encodes the catalytic subunit of PKA, a potential activator of Rac1 in neurons. DDX3-modulated PKAcα and Rac1 expression tunes the strength of PKA–Rac1 signaling and thereby contributes to neurite outgrowth and dendritic spine formation. Inhibition of DDX3 activity or expression in neonatal mice impaired dendritic outgrowth and spine formation of hippocampal neurons, echoing neuronal deficits underling DDX3 mutation-associated ID. Finally, we provide evidence that DDX3 activates local protein synthesis through a 5′ UTR-dependent mechanism in neurons. The novel DDX3 regulon may conduct a spatial and temporal control of Rac1 signaling to regulate neurite development. SIGNIFICANCE STATEMENT DDX3X mutations are linked to intellectual disability (ID). We provide first evidence that DDX3 is required for neurite outgrowth and dendritic spine formation in vitro and in vivo. We identified a DDX3 regulon constituting functionally cohesive mRNAs involved in Rac1 signaling, which contributes to DDX3-modulated neurite development. Inhibition or ablation of DDX3 in vivo shortened neurite lengths and impaired dendritic spine formation in hippocampal neurons, reflecting the prevalence of ID-associated DDX3X mutations in the helicase domain. Mechanistically, DDX3 activates local protein synthesis of mRNAs sharing similar 5′ UTR structures and therefore controls Rac1 signaling strength in neurites.
The development of gut microbiota in critically ill extremely low birth weight infants assessed with 16S rRNA gene based sequencing

Objective: An increasing number of studies that are using high-throughput molecular methods are rapidly extending our knowledge of gut microbial colonization in preterm infants whose immaturity and requirement for extensive treatment may result in altered colonization process. We aimed to describe the profile of gut microbiota in 50 extremely low birth weight (<1200 g) critically ill infants at three different time points during the first two months of life by using 16S rRNA gene specific sequencing. Patients and Methods: Stool samples were collected at the age of one week, one month and two months. Bacterial community profiling was done using universal amplification of 16S rRNA gene and 454 pyrosequencing. Results: The diversity of gut microbiota in preterm neonates in the first week of life was low but increased significantly over two months. The gut microbiota was dominated by facultative anaerobic bacteria (Staphylococcus spp. and Enterobacteriaceae) and lacked colonization with bacteria known to provide resistance against pathogens (Bacteroides, Bifidobacterium, and Lactobacillus) throughout the study. Colonization of Escherichia coli and uncultured Veillionella was positively correlated with maturity. Infants born to mothers with chorioamnionitis had significantly higher bacterial diversity than those without. Conclusions: High prevalence and abundance of potentially pathogenic Enterobacteriaceae and Staphylococcaceae with low prevalence and abundance of colonization resistance providing taxa bifidobacteria, Bacteroides and lactobacilli may lead to high infection risk via microbial translocation from the gut. Additionally, our data suggest that maternal chorioamnionitis may have an effect on the diversity of infants’ gut microbiota; however, the mechanisms involved remain to be elucidated.
Association of Natriuretic Peptide Receptor-C Gene with Ischemic Stroke and Hypertension in Chinese Han Population

To investigate whether natriuretic peptide receptor-C (NPR3) gene polymorphisms were associated with ischemic stroke (IS) and hypertension (a conventional risk factor for stroke), we conducted a case–control study in Chinese Han population. We found that rs696831, located in intron 2, was associated with IS. In addition, we found that rs16890208 and rs700925, in linkage disequilibrium (LD) with each other in intron 3, were associated with hypertension. The A allele of the rs16890208, T allele of the rs700925, and the AT haplotype, derived from rs16890208 and rs700925, increased the risk of hypertension with odds ratios (ORs) of 1.74 (95% CI = 1.23–2.47), 1.72 (95% CI = 1.21–2.42), and 1.54 (95% CI = 1.14–2.08), respectively. Further, we found that rs11745562 and rs2270915, in LD with each other in intron 5 and exon 8, were associated with hypertension. The A allele of the rs11745562 and the G allele of the rs2270915 increased the risk of hypertension with ORs of 1.53 (95% CI = 1.07–2.19) and 1.55 (95% CI = 1.08–2.22), respectively. Therefore, we provided novel evidences that polymorphisms or haplotype in NPR3 gene may influence the risk of IS or hypertension independently in Chinese population.
Dynamics of the antibodies in cohorts of cured cases of visceral leishmaniasis: Its implication on the validity of serological test, value in prognosis and in post therapeutic assessment

The major disadvantage of a Serological test like Direct Agglutination Test (DAT) for Visceral Leishmaniasis (also called Kala-azar) is its inability to distinguish between recent and past infection. The objective of our study was to look at rate of decline of antibodies in fully cured cases of Kala-azar and length of time it takes for DAT to become negative. Cohort Study involving completely treated Kala-azar cases from Government Hospital during one calendar year of study. Cases were selected on the basis of treatment cohorts 0,3,6,9 &12 mo after completion of treatment. Phase I- The cases were traced and after obtaining the informed consent they were subjected to Direct Agglutination Test (DAT). Phase II-The five treatment cohorts, constituting 82 cured cases (average of 15 cured cases per each treatment cohort) were tested again with DAT three months after the first test. The titers of Phase-I and phase-II tests were analyzed for the dynamics of the antibodies for the period. Cutoff- Values of DAT below 1:800 are considered negative. Values of 1:800, 1:1200, 1:1600 and so on are considered positive. The mean titer [Geometric Mean Titer (GMT)] at the start of treatment was 1:1120, which showed steady decline up to six months, plummeting below the cutoff titer for the DAT (1:800) at the ninth month. Antibodies continue to linger for about one year in cured Kala-azar cases even after correct and complete treatment. Single DAT results may be misleading due to high false positivity up to one year after the cure. Paired test defined as two tests 3 mo apart on the same subject. Paired test is highly recommended for diagnosis and prognosis. DAT is still a very useful tool for diagnosis if used along with clinical correlation
Hypertension promotes islet morphological changes with vascular injury on pre-diabetic status in SHRsp rats

Abstract Hypertensive patients have a higher incidence of new-onset diabetic mellitus than normotensive subjects, and we hypothesized that hypertension induces morphological changes in islets via vascular injury. To test our hypothesis, we administrated hydralazine or irbesartan to spontaneously hypertensive stroke-prone (SHRsp) rats. A greater islet fibrosis was observed in SHRsp rats compared with controls, and irbesartan significantly ameliorated the fibrosis. High fat diet induced glucose intorelance in SHRsp rats and irbesartan but not hydralazine improved glucose torelance. We demonstrate islet morphological changes in hypertensive rats, and our data suggest that angiotensin receptor blockers have the potential to prevent islet injury.
Celiac in type 1 diabetes children and youth – prevalence, metabolic control and growth parameters.

Background & Aims : To assess the prevalence of biopsy-confirmed celiac disease (CD) among ch il dren and youth with type 1 diabetes mellitus, and the implications of CD on metabolic control, nutritional status, and physical growth in type 1 diabetes patients. Methods : A retrospective study of type 1 diabetes patients at Maccabi Juvenile Diabetes Center. Those diagnosed with CD based on positive intestinal biopsy were compared to a control group compromising two patients matched by sex, age, and duration of diabetes for each CD patient. Results : Of 316 type 1 diabetes patients, 294 (93%) were screened for CD, and eleven (3.7%) diagnosed. There was no statistically significant difference in mean HbA1c levels between the CD and control groups. However, CD patients with good adherence to gluten-free diet (GFD) (n=7), had better metabolic control than those with poor adherence (n=4), without statistical significance. For patients with both type 1 diabetes and CD, and not for the control group, mean final height was significantly lower than target height (p=0.01). Among those with poor adherence to GFD, growth impairment was severe. Conclusions : Patients with both type 1 diabetes and CD had significant growth impairment; more pronounced impairment was observed in ch il dren with poor adherence to GFD.
Comparison of subclinical left and right ventricular systolic dysfunction in non-dipper and dipper hypertensives: impact of isovolumic acceleration

Abstract Objectives: To evaluate subclinical left ventricular and right ventricular systolic impairment in dipper and non-dipper hypertensives by using isovolumic acceleration. Methods: About 45 normotensive healthy volunteers (20 men, mean age 43 ± 9 years), 45 dipper (27 men, mean age 45 ± 9 years) and 45 non-dipper (25 men, 47 ± 7 years) hypertensives were enrolled. Isovolumic acceleration was measured by dividing the peak myocardial isovolumic contraction velocity by isovolumic acceleration time. Results: Non-dippers indicated lower left ventricular (2.2 ± 0.4 m/s2 versus 2.8 ± 1.0 m/s2, p < 0.01) and right ventricular isovolumic acceleration values (2.8 ± 0.8 m/s2 versus 3.5 ± 1.0 m/s2, p = 0.012) compared with dippers. Left ventricular mass index (p = 0.001), interventricular septal thickness (p = 0.002) and myocardial performance index (p < 0.001) were negatively correlated with left ventricular isovolumic acceleration. Left ventricular septal thickness (p = 0.002), mass index (p = 0.001) and right ventricular myocardial performance index (p < 0.001) were negatively correlated with right ventricular isovolumic acceleration. Conclusion: The present study demonstrates that non-dipper hypertensives have increased left and right ventricular subclinical systolic dysfunction compared with dippers. Isovolumic acceleration is the only echocardiographic parameter in predicting this subtle impairment.
Alteration in bowel habit

An alteration or change in bowel habit is a common symptom.Colorectal cancer and Crohn's disease are common causes of this symptom that can be diagnosed radiologically.Barium enema is still a frequently performed investigation in the UK, but has been replaced, to an extent, by CT-based techniques. Alteration in bowel habit is a common symptom, and has many causes. Patients are frequently referred for imaging to exclude colorectal carcinoma, and the investigation of this diagnosis is thoroughly discussed in this review, together with other causes of alteration in bowel habit that can be diagnosed radiologically.
Spinogenesis and Pruning Scales across Functional Hierarchies

Spinogenesis and synaptic pruning during development are widely believed to subserve connectional specificity in the mature CNS via Hebbian-type reinforcement. Refinement of neuronal circuit through this “use it or lose it” principle is considered critical for brain development. Here we demonstrate that the magnitude of spinogenesis and pruning in the basal dendritic trees of pyramidal cells differ dramatically among sensory, association, and executive cortex. Moreover, somewhat counterintuitively, we demonstrate that the dendritic trees of pyramidal cells in the primary visual area actually lose more spines than they grow following the onset of visual experience. The present findings reveal that the process of synaptic refinement differs not only according to time, but also location.
Plant-derived virus-like particles as vaccines

Virus-like particles (VLPs) are self-assembled structures derived from viral antigens that mimic the native architecture of viruses but lack the viral genome. VLPs have emerged as a premier vaccine platform due to their advantages in safety, immunogenicity, and manufacturing. The particulate nature and high-density presentation of viral structure proteins on their surface also render VLPs as attractive carriers for displaying foreign epitopes. Consequently, several VLP-based vaccines have been licensed for human use and achieved significant clinical and economical success. The major challenge, however, is to develop novel production platforms that can deliver VLP-based vaccines while significantly reducing production times and costs. Therefore, this review focuses on the essential role of plants as a novel, speedy and economical production platform for VLP-based vaccines. The advantages of plant expression systems are discussed in light of their distinctive posttranslational modifications, cost-effectiveness, production speed, and scalability. Recent achievements in the expression and assembly of VLPs and their chimeric derivatives in plant systems as well as their immunogenicity in animal models are presented. Results of human clinical trials demonstrating the safety and efficacy of plant-derived VLPs are also detailed. Moreover, the promising implications of the recent creation of “humanized” glycosylation plant lines as well as the very recent approval of the first plant-made biologics by the U. S. Food and Drug Administration (FDA) for plant production and commercialization of VLP-based vaccines are discussed. It is speculated that the combined potential of plant expression systems and VLP technology will lead to the emergence of successful vaccines and novel applications of VLPs in the near future.
Vaccination with synthetic constructs expressing cytomegalovirus immunogens is highly T cell immunogenic in mice

There is no licensed vaccine or cure for human cytomegalovirus (CMV), a ubiquitous β-herpesvirus infecting 60–95% of adults worldwide. Infection can cause congenital abnormalities, result in severe disease in immunocompromised patients, and is a major impediment during successful organ transplantation. In addition, it has been associated with numerous inflammatory diseases and cancers, as well as being implicated in the development of essential hypertension, a major risk factor for heart disease. To date, limited data regarding the identification of immunogenic viral targets has frustrated CMV vaccine development. Based upon promising clinical data suggesting an important role for T cells in protecting against disease in the transplantation setting, we designed a novel panel of highly-optimized synthetic vaccines encoding major CMV proteins and evaluated their immune potential in murine studies. Vaccination induced robust CD8+ and CD4+ T cells of great epitopic breadth as extensively analyzed using a novel modified T cell assay described herein. Together with improved levels of CMV-specific T cells as driven by a vaccine, further immune evaluation of each target is warranted. The present model provides an important tool for guiding future immunization strategies against CMV.
Cellular Mechanisms Underlying Spatiotemporal Features of Cholinergic Retinal Waves

Before vision, a transient network of recurrently connected cholinergic interneurons, called starburst amacrine cells (SACs), generates spontaneous retinal waves. Despite an absence of robust inhibition, cholinergic retinal waves initiate infrequently and propagate within finite boundaries. Here, we combine a variety of electrophysiological and imaging techniques and computational modeling to elucidate the mechanisms underlying these spatial and temporal properties of waves in developing mouse retina. Waves initiate via rare spontaneous depolarizations of SACs. Waves propagate through recurrent cholinergic connections between SACs and volume release of ACh as demonstrated using paired recordings and a cell-based ACh optical sensor. Perforated-patch recordings and two-photon calcium imaging reveal that individual SACs have slow afterhyperpolarizations that induce SACs to have variable depolarizations during sequential waves. Using a computational model in which the properties of SACs are based on these physiological measurements, we reproduce the slow frequency, speed, and finite size of recorded waves. This study represents a detailed description of the circuit that mediates cholinergic retinal waves and indicates that variability of the interneurons that generate this network activity may be critical for the robustness of waves across different species and stages of development.
Brain Changes in Older Adults at Very Low Risk for Alzheimer's Disease

Alzheimer's disease (AD) has a slow onset, so it is challenging to distinguish brain changes in healthy elderly persons from incipient AD. One-year brain changes with a distinct frontotemporal pattern have been shown in older adults. However, it is not clear to what extent these changes may have been affected by undetected, early AD. To address this, we estimated 1-year atrophy by magnetic resonance imaging (MRI) in 132 healthy elderly persons who had remained free of diagnosed mild cognitive impairment or AD for at least 3 years. We found significant volumetric reductions throughout the brain. The sample was further divided into low-risk groups based on clinical, biomarker, genetic, or cognitive criteria. Although sample sizes varied, significant reductions were observed in all groups, with rates and topographical distribution of atrophy comparable to that of the full sample. Volume reductions were especially pronounced in the default mode network, closely matching the previously described frontotemporal pattern of changes in healthy aging. Atrophy in the hippocampus predicted change in memory, with no additional default mode network contributions. In conclusion, reductions in regional brain volumes can be detected over the course of 1 year even in older adults who are unlikely to be in a presymptomatic stage of AD.
Comparative immunogenicity in mice of rotavirus VP6 tubular structures and virus-like particles

Rotavirus (RV) is the most important cause of severe gastroenteritis in children worldwide. Current live RV vaccines are efficacious but show lower efficacy in developing countries, as well as a low risk of intussusception. This has led to the development of parenteral non-live candidate vaccines against RV. RV capsid VP6 protein is highly conserved and the most abundant RV protein forming highly immunogenic oligomeric structures with multivalent antigen expression. Both recombinant VP6 (rVP6) or double-layered (dl) 2/6-virus-like particles (VLPs), might be considered as the simplest RV subunit vaccine candidates. Human rVP6 protein and dl2/6-VLPs were produced in Sf9 insect cells by baculovirus expression system. Formation of rVP6 tubules and VLPs were confirmed by electron microscopy. BALB/c mice were immunized intramuscularly, and immune responses were analyzed. Both rVP6 and dl2/6-VLPs induced a balanced Th1-type and Th2-type response and high levels of serum IgG antibodies with cross-reactivity against different RV strains (Wa, SC2, BrB, 69M, L26, WC3, and RRV). In addition, mucosal VP6-specific IgG and IgA antibodies were detected in feces and vaginal washes (VW) of immunized animals. Importantly, VWs of immunized mice inhibited RV Wa and RRV infection in vitro. Immunization with either protein preparation induced a similar level of VP6-specific, interferon-γ secreting CD4+ T cells in response to different RVs or the 18-mer peptide (AA242–259), a VP6-specific CD4+ T cell epitope. RV rVP6 and dl2/6-VLPs induced equally strong humoral and cellular responses against RV in mice and therefore, may be considered as non-live vaccine candidates against RV.
Striatal D2 Receptors Regulate Dendritic Morphology of Medium Spiny Neurons via Kir2 Channels

Structural plasticity in the adult brain is essential for adaptive behaviors and is thought to contribute to a variety of neurological and psychiatric disorders. Medium spiny neurons of the striatum show a high degree of structural plasticity that is modulated by dopamine through unknown signaling mechanisms. Here, we demonstrate that overexpression of dopamine D2 receptors in medium spiny neurons increases their membrane excitability and decreases the complexity and length of their dendritic arbors. These changes can be reversed in the adult animal after restoring D2 receptors to wild-type levels, demonstrating a remarkable degree of structural plasticity in the adult striatum. Increased excitability and decreased dendritic arborization are associated with downregulation of inward rectifier potassium channels (Kir2.1/2.3). Downregulation of Kir2 function is critical for the neurophysiological and morphological changes in vivo because virally mediated expression of a dominant-negative Kir2 channel is sufficient to recapitulate the changes in D2 transgenic mice. These findings may have important implications for the understanding of basal ganglia disorders, and more specifically schizophrenia, in which excessive activation of striatal D2 receptors has long been hypothesized to be of pathophysiologic significance.
Physical modelling of HBTs for microwave power applications

This paper presents a one-dimensional HBT physical model which can accurately simulate the characteristics of microwave power transistors. The structure of the model is briefly discussed, and simulation results for a three layer device are presented and compared with analytical results. Measured and modelled DC characteristics for a power HBT are also presented, and these show good agreement over several decades of base and collector current.
Integration of H-2Z1, a Somatosensory Cortex-Expressed Transgene, Interferes with the Expression of the Satb1 and Tbc1d5 Flanking Genes and Affects the Differentiation of a Subset of Cortical Interneurons

H-2Z1 is an enhancer trap transgenic mouse line in which the lacZ reporter delineates the somatosensory area of the cerebral cortex where it is expressed in a subset of layer IV neurons. In the search of somatosensory specific genes or regulatory sequences, we mapped the H-2Z1 transgene insertion site to chromosome 17, 100 and 460 kb away from Tbc1d5 and Satb1 flanking genes. We show here that insertion of the H-2Z1 transgene results in three distinct outcomes. First, a genetic background-sensitive expression of lacZ in several brain and body structures. While four genes in a 1 Mb region around the insertion are expressed in the barrel cortex, H-2Z1 expression resembles more that of its two direct neighbors. Moreover, H-2Z1 closely reports most of the body and brain expression sites of the Satb1 chromatin remodeling gene including tooth buds, thymic epithelium, pontine nuclei, fastigial cerebellar nuclei, and cerebral cortex. Second, the H-2Z1 transgene causes insertional mutagenesis of Tbc1d5 and Satb1, leading to a strong decrease in their expressions. Finally, insertion of H-2Z1 affects the differentiation of a subset of cortical GABAergic interneurons, a possible consequence of downregulation of Satb1 expression. Thus, the H-2Z1 “somatosensory” transgene is inserted in the regulatory landscape of two genes highly expressed in the developing somatosensory cortex and reports for a subdomain of their expression profiles. Together, our data suggest that regulation of H-2Z1 expression results from local and remote genetic interactions.