Miracle-dz/UniFAR-FTUs huggingface dataset:
Axonal Degeneration in Retinal Ganglion Cells Is Associated with a Membrane Polarity-Sensitive Redox Process

Axonal degeneration is a pathophysiological mechanism common to several neurodegenerative diseases. The slow Wallerian degeneration (WldS) mutation, which results in reduced axonal degeneration in the central and peripheral nervous systems, has provided insight into a redox-dependent mechanism by which axons undergo self-destruction. We studied early molecular events in axonal degeneration with single-axon laser axotomy and time-lapse imaging, monitoring the initial changes in transected axons of purified retinal ganglion cells (RGCs) from wild-type and WldS rat retinas using a polarity-sensitive annexin-based biosensor (annexin B12-Cys101,Cys260-N,N′-dimethyl-N-(iodoacetyl)-N′-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) ethylenediamine). Transected axons demonstrated a rapid and progressive change in membrane phospholipid polarity, manifested as phosphatidylserine externalization, which was significantly delayed and propagated more slowly in axotomized WldS RGCs compared with wild-type axons. Delivery of bis(3-propionic acid methyl ester)phenylphosphine borane complex, a cell-permeable intracellular disulfide-reducing drug, slowed the onset and velocity of phosphatidylserine externalization in wild-type axons significantly, replicating the WldS phenotype, whereas extracellular redox modulation reversed the WldS phenotype. These findings are consistent with an intra-axonal redox mechanism for axonal degeneration associated with the initiation and propagation of phosphatidylserine externalization after axotomy. SIGNIFICANCE STATEMENT Axonal degeneration is a neuronal process independent of somal apoptosis, the propagation of which is unclear. We combined single-cell laser axotomy with time-lapse imaging to study the dynamics of phosphatidylserine externalization immediately after axonal injury in purified retinal ganglion cells. The extension of phosphatidylserine externalization was slowed and delayed in Wallerian degeneration slow (WldS) axons and this phenotype could be reproduced by intra-axonal disulfide reduction in wild-type axons and reversed by extra-axonal reduction in WldS axons. These results are consistent with a redox mechanism for propagation of membrane polarity asymmetry in axonal degeneration.
Selective Increase of Intention-Based Economic Decisions by Noninvasive Brain Stimulation to the Dorsolateral Prefrontal Cortex

The intention behind another's action and the impact of the outcome are major determinants of human economic behavior. It is poorly understood, however, whether the two systems share a core neural computation. Here, we investigated whether the two systems are causally dissociable in the brain by integrating computational modeling, functional magnetic resonance imaging, and transcranial direct current stimulation experiments in a newly developed trust game task. We show not only that right dorsolateral prefrontal cortex (DLPFC) activity is correlated with intention-based economic decisions and that ventral striatum and amygdala activity are correlated with outcome-based decisions, but also that stimulation to the DLPFC selectively enhances intention-based decisions. These findings suggest that the right DLPFC is involved in the implementation of intention-based decisions in the processing of cooperative decisions. This causal dissociation of cortical and subcortical backgrounds may indicate evolutionary and developmental differences in the two decision systems.
Cortical Regulation of Nociception of the Trigeminal Nucleus Caudalis

Pain perception is strongly influenced by descending pathways from “higher” brain centers that regulate the activity of spinal circuits. In addition to the extensively studied descending system originating from the medulla, the neocortex provides dense anatomical projections that directly target neurons in the spinal cord and the spinal trigeminal nucleus caudalis (SpVc). Evidence exists that these corticotrigeminal pathways may modulate the processing of nociceptive inputs by SpVc, and regulate pain perception. We demonstrate here, with anatomical and optogenetic methods, and using both rats and mice (of both sexes), that corticotrigeminal axons densely innervate SpVc, where they target and directly activate inhibitory and excitatory neurons. Electrophysiological recordings reveal that stimulation of primary somatosensory cortex potently suppresses SpVc responses to noxious stimuli and produces behavioral hypoalgesia. These findings demonstrate that the corticotrigeminal pathway is a potent modulator of nociception and a potential target for interventions to alleviate chronic pain. SIGNIFICANCE STATEMENT Many chronic pain conditions are resistant to conventional therapy. Promising new approaches to pain management capitalize on the brain's own mechanisms for controlling pain perception. Here we demonstrate that cortical neurons directly innervate the brainstem to drive feedforward inhibition of nociceptive neurons. This corticotrigeminal pathway suppresses the activity of these neurons and produces analgesia. This corticotrigeminal pathway may constitute a therapeutic target for chronic pain.
An Adenosine-Mediated Glial-Neuronal Circuit for Homeostatic Sleep

Sleep homeostasis reflects a centrally mediated drive for sleep, which increases during waking and resolves during subsequent sleep. Here we demonstrate that mice deficient for glial adenosine kinase (AdK), the primary metabolizing enzyme for adenosine (Ado), exhibit enhanced expression of this homeostatic drive by three independent measures: (1) increased rebound of slow-wave activity; (2) increased consolidation of slow-wave sleep; and (3) increased time constant of slow-wave activity decay during an average slow-wave sleep episode, proposed and validated here as a new index for homeostatic sleep drive. Conversely, mice deficient for the neuronal adenosine A1 receptor exhibit significantly decreased sleep drive as judged by these same indices. Neuronal knock-out of AdK did not influence homeostatic sleep need. Together, these findings implicate a glial-neuronal circuit mediated by intercellular Ado, controlling expression of homeostatic sleep drive. Because AdK is tightly regulated by glial metabolic state, our findings suggest a functional link between cellular metabolism and sleep homeostasis. SIGNIFICANCE STATEMENT The work presented here provides evidence for an adenosine-mediated regulation of sleep in response to waking (i.e., homeostatic sleep need), requiring activation of neuronal adenosine A1 receptors and controlled by glial adenosine kinase. Adenosine kinase acts as a highly sensitive and important metabolic sensor of the glial ATP/ADP and AMP ratio directly controlling intracellular adenosine concentration. Glial equilibrative adenosine transporters reflect the intracellular concentration to the extracellular milieu to activate neuronal adenosine receptors. Thus, adenosine mediates a glial-neuronal circuit linking glial metabolic state to neural-expressed sleep homeostasis. This indicates a metabolically related function(s) for this glial-neuronal circuit in the buildup and resolution of our need to sleep and suggests potential therapeutic targets more directly related to sleep function.
TALE nucleases and next generation GM crops

Site-specific and adaptable DNA binding domains are essential modules to develop genome engineering technologies for crop improvement. Transcription activator-like effectors (TALEs) proteins are used to provide a highly specific and adaptable DNA binding modules. TALE chimeric nucleases (TALENs) were used to generate site-specific double strand breaks (DSBs) in vitro and in yeast, Caenorhabditis elegans, mammalian and plant cells. The genomic DSBs can be generated at predefined and user-selected loci and repaired by either the non-homologous end joining (NHEJ) or homology dependent repair (HDR). Thus, TALENs can be used to achieve site-specific gene addition, stacking, deletion or inactivation. TALE-based genome engineering tools should be powerful to develop new agricultural biotechnology approaches for crop improvement. Here, we discuss the recent research and the potential applications of TALENs to accelerate the generation of genomic variants through targeted mutagenesis and to produce a non-transgenic GM crops with the desired phenotype.
Versican V2 Assembles the Extracellular Matrix Surrounding the Nodes of Ranvier in the CNS

The CNS-restricted versican splice-variant V2 is a large chondroitin sulfate proteoglycan incorporated in the extracellular matrix surrounding myelinated fibers and particularly accumulating at nodes of Ranvier. In vitro, it is a potent inhibitor of axonal growth and therefore considered to participate in the reduction of structural plasticity connected to myelination. To study the role of versican V2 during postnatal development, we designed a novel isoform-specific gene inactivation approach circumventing early embryonic lethality of the complete knock-out and preventing compensation by the remaining versican splice variants. These mice are viable and fertile; however, they display major molecular alterations at the nodes of Ranvier. While the clustering of nodal sodium channels and paranodal structures appear in versican V2-deficient mice unaffected, the formation of the extracellular matrix surrounding the nodes is largely impaired. The conjoint loss of tenascin-R and phosphacan from the perinodal matrix provide strong evidence that versican V2, possibly controlled by a nodal receptor, organizes the extracellular matrix assembly in vivo.
Shank Modulates Postsynaptic Wnt Signaling to Regulate Synaptic Development

Prosap/Shank scaffolding proteins regulate the formation, organization, and plasticity of excitatory synapses. Mutations in SHANK family genes are implicated in autism spectrum disorder and other neuropsychiatric conditions. However, the molecular mechanisms underlying Shank function are not fully understood, and no study to date has examined the consequences of complete loss of all Shank proteins in vivo. Here we characterize the single Drosophila Prosap/Shank family homolog. Shank is enriched at the postsynaptic membrane of glutamatergic neuromuscular junctions and controls multiple parameters of synapse biology in a dose-dependent manner. Both loss and overexpression of Shank result in defects in synaptic bouton number and maturation. We find that Shank regulates a noncanonical Wnt signaling pathway in the postsynaptic cell by modulating the internalization of the Wnt receptor Fz2. This study identifies Shank as a key component of synaptic Wnt signaling, defining a novel mechanism for how Shank contributes to synapse maturation during neuronal development. SIGNIFICANCE STATEMENT Haploinsufficiency for SHANK3 is one of the most prevalent monogenic causes of autism spectrum disorder, making it imperative to understand how the Shank family regulates neurodevelopment and synapse function. We created the first animal model lacking all Shank proteins and used the Drosophila neuromuscular junction, a model glutamatergic synapse, to characterize the role of Shank at synapses. We identified a novel function of Shank in synapse maturation via regulation of Wnt signaling in the postsynaptic cell.
Signature tagged mutagenesis in the functional genetic analysis of gastrointestinal pathogens

Signature tagged mutagenesis is a genetic approach that was developed to identify novel bacterial virulence factors. It is a negative selection method in which unique identification tags allow analysis of pools of mutants in mixed populations. The approach is particularly well suited to functional genetic analysis of the gastrointestinal phase of infection in foodborne pathogens and has the capacity to guide the development of novel vaccines and therapeutics. In this review we outline the technical principles underpinning signature-tagged mutagenesis as well as novel sequencing-based approaches for transposon mutant identification such as TraDIS (transposon directed insertion-site sequencing). We also provide an analysis of screens that have been performed in gastrointestinal pathogens which are a global health concern (Escherichia coli, Listeria monocytogenes, Helicobacter pylori, Vibrio cholerae and Salmonella enterica). The identification of key virulence loci through the use of signature tagged mutagenesis in mice and relevant larger animal models is discussed.
Associations of Plasma Homocysteine Levels with Arterial Stiffness in Prehypertensive Individuals

Prehypertension is associated with oxidative stress and increased arterial stiffness. While plasma homocysteine levels are associated with increased pulse wave velocity in hypertensive individuals, there is no report regarding this relationship in prehypertensives. Homocysteine levels and brachial-ankle pulse wave velocity (baPWV) were investigated in 4177 prehypertensives (3178 men, mean age 53 ± 11 years) with ankle-brachial indexes (ABIs) greater than 0.95 who had visited the Kangbuk Samsung Health Promotion Center. The subjects were subdivided into two groups according to baPWV; group I (1720 subjects) was defined as subjects with a baPWV of 1366cm/sec or lower, while group II (2457 subjects) included subjects with a baPWV greater than 1366cm/sec. Subjects were also divided into four quartile groups depending on homocysteine level. Homocysteine levels in group II were found to be significantly higher than those in group I. There were significant differences in baPWV value among the four quartile groups (quartile I, 1411 ± 213.9 cm/sec; quartile II, 1436 ± 223.3 cm/sec; quartile III, 1460 ± 220.4 cm/sec; quartile IV, 1494 ± 251.3 cm/sec; p-value <0.001). In multivariate regression models, the increasing quartile groups of homocysteine had higher odds ratios (ORs) for increased baPWV compared to that of the lowest quartile group (OR [95% confidence interval (CI)] in the second, third, and highest quartiles: 1.41 [1.12–1.77], 1.65 [1.30–2.10], and 1.82 [1.42–2.33], respectively, p < 0.001), irrespective of confounding factors. This study indicates an independent relationship between circulating homocysteine level and arterial stiffness in prehypertensives, suggesting that circulating homocysteine level could be a useful biomarker of subclinical target organ damage in prehypertensives.
The gut microbiota and mucosal homeostasis

The intimate interplay between the gut microbiota and the host may contribute to health and disease in the host. Experiments using conventionalized and conventionally raised animal models have illustrated the role of the intestinal microbiota in shaping and maintaining the host immune system. However, it is still unclear whether colonization at birth or at adulthood induces different host responses. Here, we perform comparative transcriptome analyses to elucidate the impact of the gut microbiota on the development and maintenance of the immune system in adult conventionalized (after 16 and 30 days of colonization) and conventionally raised mice, which were obtained in two independent laboratories. Transcriptional profiles of jejunum, ileum and colon were compared between germfree, conventionally raised mice and conventionalized mice. Germfree mice from the two different facilities clustered together, establishing the validity of the comparative analysis. Nevertheless, significant spatial differences were detected along the gut; the jejunum and colon exhibited a transient response (conventionalized mice) that eventually returned to a homeostatic level (conventionally raised). In contrast, the ileal response to microbiota was similar in conventionalized and conventionally raised mice. Overall, this comparative analysis supports the hypothesis that co-development of the gut microbiota and its host initiates at early stage of development and indicates that despite the achieved homeostasis, immune development is substantially different in mice conventionalized in adulthood. These findings imply that colonization during development is required to meet the window of opportunity where the gut microbiota can imprint the host’s mucosal immune-homeostasis in a way that cannot be achieved at later stages in life.
Reduced Bone Mineral Density in Hypertensive Patients Is Associated with Left Ventricular Diastolic Dysfunction, Not Left Ventricular Hypertrophy

Left ventricular (LV) hypertrophy and diastolic dysfunction are commonly observed in hypertensive patients, and have been demonstrated to be risk factors of chronic heart failure due to LV diastolic dysfunction. Recently, reduced bone mineral density has been found in hypertensive patients compared with healthy controls. However, relationships between bone mineral density and LV hypertrophy and diastolic dysfunction have not been fully assessed. We examined relationships between bone mineral density and both LV hypertrophy and diastolic dysfunction in 38 hypertensive patients (23 males, 15 females; mean age 71 ± 8 y) who had been treated with antihypertensive drugs for at least 1 year. The bone mineral density of the calcaneus was measured with a quantitative ultrasound measurement device (A-1000 EXPRESS/InSight, GE Healthcare, Horten, Norway), and the stiffness index was determined as a parameter of bone mineral density. Echocardiography was performed to measure the left ventricular mass index as a parameter of LV hypertrophy. Left ventricular diastolic dysfunction was also assessed by early diastolic mitral annular velocity (e′), and the ratio of early transmitral flow velocity (E) to e′ (E/e′). The bone mineral density did not correlate with left ventricular mass index, but did correlate with e′ (r = 0.453, P < .01) and E/e′ (r = −0.359, P < .05). Thus, reduced bone mineral density in hypertensive patients is not associated with LV hypertrophy but with LV diastolic dysfunction. Hypertensive patients with reduced bone mineral density may have a high risk of chronic heart failure due to LV diastolic dysfunction as well as bone fractures due to osteoporosis.
Crossmodal Adaptation in Right Posterior Superior Temporal Sulcus during Face–Voice Emotional Integration

The integration of emotional information from the face and voice of other persons is known to be mediated by a number of “multisensory” cerebral regions, such as the right posterior superior temporal sulcus (pSTS). However, whether multimodal integration in these regions is attributable to interleaved populations of unisensory neurons responding to face or voice or rather by multimodal neurons receiving input from the two modalities is not fully clear. Here, we examine this question using functional magnetic resonance adaptation and dynamic audiovisual stimuli in which emotional information was manipulated parametrically and independently in the face and voice via morphing between angry and happy expressions. Healthy human adult subjects were scanned while performing a happy/angry emotion categorization task on a series of such stimuli included in a fast event-related, continuous carryover design. Subjects integrated both face and voice information when categorizing emotion—although there was a greater weighting of face information—and showed behavioral adaptation effects both within and across modality. Adaptation also occurred at the neural level: in addition to modality-specific adaptation in visual and auditory cortices, we observed for the first time a crossmodal adaptation effect. Specifically, fMRI signal in the right pSTS was reduced in response to a stimulus in which facial emotion was similar to the vocal emotion of the preceding stimulus. These results suggest that the integration of emotional information from face and voice in the pSTS involves a detectable proportion of bimodal neurons that combine inputs from visual and auditory cortices.
Super Tb: Another manmade disaster

Resistant tuberculosis is aman made disaster due to negligence of patients, physicians, and policy makers. It has been fuelled by inadequate use of sputum smear microscopy, excessive dependence on chest radiography, illogical manufacture and irrational prescription of improper combinations of medicines, inadequate dose,duration and noncompliance to the prescribed treatment. The resultant gift is the dreaded Totally Drug Resistant Tuberculosis (TDR-TB). Culture and drug sensitivity testing (DST) should not blindly direct the management of TDR-TB, but has the importance in individualising the drug therapy in TDR-TB patients.The DST which is a crucial part of Directly Observed Treatment Short course (DOTS) plus has been introduced in a phased manner in India. However measuring resistance to second line anti-tubercular drugs (SLDs) with DST is complex and lacks standardization. The WHO has categorized the SLDs based on their efficacy. Most of the DST methods have a turnaround time of several months and empirical regimen should be switched to individual regimen depending on DST results. Newer assays like microscopic observation drug susceptibility assay,line-probe assay and bacteriophage assay can be used for rapid detection of drug resistance. Pharmacovigilanceis urgently needed for resistant tuberculosis as SLDs are less efficacious and more toxic. Presently, the treatment of TDR-TB is not consolidated. Precaution in the treatment, prevention of spread of the infected cases and use of newer vaccines are some of the strategies which have to be used to contain the new mighty variant of microbe mycobacterium tuberculosis.
Evaluation of Nutritional Status of Rural Bengalee Primary School Boys (6-9 Years) in Comparison to Indian Children

A cross sectional study was undertaken to determine nutritional status and growth pattern of 410 rural primary school boys (6-9 years of age) belong from lower socioeconomic status according Kuppuswamy's socioeconomic scale (2012) in West Midnapore District of West Bengal. The daily nutritional intake of the children was measured by weighing raw and cooked foods and also by 24 hrs recall method. The body mass indexes (BMI), body composition, protein/calory adequacy status, protein-energy ratio of the primary school boys were measured to assess the nutritional status. The food and nutrient intake of the subjects were compared with their respective Indian values (NNMB, 2002). The diet of rural school boys was found to be imbalanced with plenty intake of milk and lower in intake of cereals, pulses but higher in intake of vegetables than that of their Indian counterpart. It was observed that the diets are predominantly more deficient in calories than protein. Most of the boys had normal body weight and only a little number of boys was overweight or underweight and the protein energy ratio is lower than ICMR recommended value except the age group of 7 years and the maximum percentage (about 20%) of underweight boys is found in the age group of 9 years. It was further observed that there was a significant correlation between body composition and BMI (p<0.001).