Miracle-dz/UniFAR-FTUs huggingface dataset:
Noise analysis to study unitary properties of transporter-associated ion channels

Excitatory amino acid transporters (EAATs) do not only mediate secondary-active glutamate uptake but also function as anion channels. We recently used macroscopic current recordings and noise analysis to determine unitary current amplitudes of anion channels associated with a neuronal EAAT isoform, EAAT4. We found that, at symmetrical NO3-, EAAT4 anion channels exhibit a single channel conductance of ~1 pS in the absence as well as in the presence of glutamate. These results indicate that glutamate increases EAAT4 anion currents by modifying exclusively open probabilities, however, leaves unitary current amplitudes unaffected. Noise analysis has been developed for ion channels with a single conductance state and limitations might ensue when using this approach for transporter-associated ion channels. We here performed stochastic simulations of EAAT transporter-associated anion channels and noise analysis of simulated currents to assess the reliability and possible limitations of this technique in studying this special class of ion channels.
Plasmodium falciparum RuvB proteins

The urgent requirement of next generation antimalarials has been of recent interest due to the emergence of drug-resistant parasite. The genome-wide analysis of Plasmodium falciparum helicases revealed three RuvB proteins. Due to the presence of helicase motif I and II in PfRuvBs, there is a high probability that they contain ATPase and possibly helicase activity. The Plasmodium database has homologs of several key proteins that interact with RuvBs and are most likely involved in the cell cycle progression, chromatin remodeling, and other cellular activities. Phylogenetically PfRuvBs are closely related to Saccharomyces cerevisiae RuvB, which is essential for cell cycle progression and survival of yeast. Thus PfRuvBs can serve as potential drug target if they show an essential role in the survival of parasite.
Modulation of Illusory Reversal in Tactile Temporal Order by the Phase of Posterior α Rhythm

The subjective temporal order of tactile stimuli, delivered sequentially to each hand with an interval of 100–300 ms, is often inverted when the arms are crossed. Based on data from behavioral and neuroimaging studies, it has been proposed that the reversal is due to a conflict between anatomical and spatial representations of the tactile signal or to the production of an inverted apparent motion signal. Because the α rhythms, which consist of a few distinct components, reportedly modulate tactile perception and apparent motion and serve as a 10 Hz timer, we hypothesized that the illusory reversal would be regulated by some of the α rhythms. To test this hypothesis, we conducted magnetoencephalographic recordings in both male and female participants during the tactile temporal order judgment task. We decomposed the α rhythms into five independent components and discovered that the illusory reversal was modulated by the phase of one independent component with strong current sources near the parieto-occipital (PO) sulcus (peri-PO component). As expected, the estimated current sources distributed over the human MST implicated to represent tactile apparent motion, in addition to the intraparietal region implicated in mapping tactile signals in space. However, the strongest source was located in the precuneus that occupies a central hub region in the cortical networks and receives tactile inputs through a tecto-thalamic pathway. These results suggest that the peri-PO component plays an essential role in regulating tactile temporal perception by modulating the thalamic nuclei that interconnect the superior colliculus with the cortical networks. SIGNIFICANCE STATEMENT Despite a long-held hypothesis that the posterior α rhythm serves as a 10 Hz timer that regulates human temporal perception, the contribution of the α rhythms in temporal perception is still unclear. We examined how the α rhythms influence tactile temporal order judgment. Judgment reversal depended on the phase of one particular α rhythm with its source near the parieto-occipital sulcus. The peri-parieto-occipital α rhythm may play a crucial role in organizing tactile temporal perception.
Amiloride-Insensitive Salt Taste Is Mediated by Two Populations of Type III Taste Cells with Distinct Transduction Mechanisms

Responses in the amiloride-insensitive (AI) pathway, one of the two pathways mediating salty taste in mammals, are modulated by the size of the anion of a salt. This “anion effect” has been hypothesized to result from inhibitory transepithelial potentials (TPs) generated across the lingual epithelium as cations permeate through tight junctions and leave their larger and less permeable anions behind (Ye et al., 1991). We tested directly the necessity of TPs for the anion effect by measuring responses to NaCl and Na-gluconate (small and large anion sodium salts, respectively) in isolated taste cells from mouse circumvallate papillae. Using calcium imaging, we identified AI salt-responsive type III taste cells and demonstrated that they compose a subpopulation of acid-responsive taste cells. Even in the absence of TPs, many (66%) AI salt-responsive type III taste cells still exhibited the anion effect, demonstrating that some component of the transduction machinery for salty taste in type III cells is sensitive to anion size. We hypothesized that osmotic responses could explain why a minority of type III cells (34%) had AI salt responses but lacked anion sensitivity. All AI type III cells had osmotic responses to cellobiose, which were significantly modulated by extracellular sodium concentration, suggesting the presence of a sodium-conducting osmotically sensitive ion channel. However, these responses were significantly larger in AI type III cells that did not exhibit the anion effect. These findings indicate that multiple mechanisms could underlie AI salt responses in type III taste cells, one of which may contribute to the anion effect. SIGNIFICANCE STATEMENT Understanding the mechanisms underlying salty taste will help inform strategies to combat the health problems associated with NaCl overconsumption by humans. Of the two pathways underlying salty taste in mammals, the amiloride-insensitive (AI) pathway is the least understood. Using calcium imaging of isolated mouse taste cells, we identify two separate populations of AI salt-responsive type III taste cells distinguished by their sensitivity to anion size and show that these cells compose subpopulations of acid-responsive taste cells. We also find evidence that a sodium-conducting osmotically sensitive mechanism contributes to salt responses in type III taste cells. Our data not only provide new insights into the transduction mechanisms of AI salt taste but also have important implications for general theories of taste encoding.
Possible eosinophilic pneumonia from Alternaria

We reported a 15-year-old Japanese girl with possible eosinophilic pneumonia (EP) from inhaled Alternaria. She presented with a fever, cough and general fatigue and with a moderate infiltrate in the right lower to middle lung fields on a chest roentgenogram one week previously. On admission, the above infiltrate had disappeared, while a left upper infiltrate had appeared. Eosinophilic pneumonia (EP) was diagnosed by a cytological study of bronchoalveolar lavage fluid and histology of a transbronchial lung biopsy. Skin test to and specific serum IgE antibody against Alternaria were both positive. An inhaled Alternaria challenge test showed both immediate and late phase allergic reactions as evidenced by %FEV1. In addition, Alternaria was significantly detected in all places of the patient’s house. Alternaria could be a causative organism of EP and should always be considered one of its etiologic agents.
Calcium signaling components in the human pathogen Cryptococcus neoformans

Calcium signaling through calmodulin and the phosphatase calcineurin are required for key events of the biology of the human pathogen Cryptococcus neoformans, including mating, morphogenesis, growth at 37°C and virulence. In a recent work we described the functional characterization of a new component of this calcium signaling network: the vacuolar calcium exchanger Vcx1. This transporter is involved in calcium tolerance and virulence in C. neoformans. Two other uncharacterized calcium transporters which are putative orthologs of Saccharomyces cerevisiae PMC1 (a vacuolar calcium ATPase) and PMR1 (a Golgi calcium ATPase) are also functional in C. neoformans. No ortholog of CRZ1, the target of calcineurin in other fungi, has been identified in C. neoformans, indicating a high complexity in cryptococcal calcium-related pathways. Future studies are necessary for the complete understanding of calcium signaling regulation in C. neoformans.
Evolution of glycosaminoglycans

Glycosaminoglycans, a major component of the extracellular matrix molecules in animal tissues, play important roles in various physiological events. Glycosaminoglycans are found in not only vertebrates but also many invertebrates, implying a conserved function in the animal kingdom. Here, we discuss the analysis of glycosaminoglycans in 11 invertebrate phyla focusing on structure as well as physiological functions elucidated in model organisms. Various sulfated structures of heparan sulfate are widely distributed from very primitive organisms to humans, indicating an involvement in fundamental biological processes. By contrast, chondroitin/dermatan sulfate from lower organisms is limited in its structural complexity and often associated with a particular function. The presence of hyaluronic acid outside of vertebrates has been reported only in a mollusk.
KCNQ Channels Determine Serotonergic Modulation of Ventral Surface Chemoreceptors and Respiratory Drive

Chemosensitive neurons in the retrotrapezoid nucleus (RTN) regulate breathing in response to CO2/H+ changes. Their activity is also sensitive to neuromodulatory inputs from multiple respiratory centers, and thus they serve as a key nexus of respiratory control. However, molecular mechanisms that control their activity and susceptibility to neuromodulation are unknown. Here, we show in vitro and in vivo that KCNQ channels are critical determinants of RTN neural activity. In particular, we find that pharmacological block of KCNQ channels (XE991, 10 μm) increased basal activity and CO2 responsiveness of RTN neurons in rat brain slices, whereas KCNQ channel activation (retigabine, 2–40 μm) silenced these neurons. Interestingly, we also find that KCNQ and apamin-sensitive SK channels act synergistically to regulate firing rate of RTN chemoreceptors; simultaneous blockade of both channels led to a increase in CO2 responsiveness. Furthermore, we also show that KCNQ channels but not SK channels are downstream effectors of serotonin modulation of RTN activity in vitro. In contrast, inhibition of KCNQ channel did not prevent modulation of RTN activity by Substance P or thyrotropin-releasing hormone, previously identified neuromodulators of RTN chemoreception. Importantly, we also show that KCNQ channels are critical for RTN activity in vivo. Inhibition of KCNQ channels lowered the CO2 threshold for phrenic nerve discharge in anesthetized rats and decreased the ventilatory response to serotonin in awake and anesthetized animals. Given that serotonergic dysfunction may contribute to respiratory failure, our findings suggest KCNQ channels as a new therapeutic avenue for respiratory complications associated with multiple neurological disorders.
Integrating biological invasions, climate change and phenotypic plasticity

Invasive species frequently change the ecosystems where they are introduced, e.g., by affecting species interactions and population densities of native species. We outline the connectedness of biological invasions, climate change, and the phenomenon of phenotypic plasticity. Integrating these hot topics is important for understanding the biology of many species, their information transfer and general interactions with other organisms. One example where this is particularly true is the zooplankton species Daphnia lumholtzi which has successfully invaded North America. The combination of a high thermal tolerance and a phenotypically plastic defence in D. lumholtzi might be responsible for its invasion success. Its morphological defence consists of rigid spines and is formed after sensory detecting the presence of native fish predators. The integration of biological invasions, climate change, and phenotypic plasticity is an important goal for integrative biology.
ROLE OF ORAL ZINC SULPHATE IN WARTS-A PLACEBO CONTROLLED, SINGLE-BLINDED STUDY

Verrucae (synonym: warts) are one of the most common viral infections of humans in which the most frequently used modalities of treatment involve destruction of the affected area, which does not prevent recurrences and often results in scarring. In the present study oral zinc sulphate, an immunomodulator was evaluated as a treatment modality for warts. A placebo-controlled, single-blinded study was conducted on one hundred OPD patients with various types of verrucae. Fifty patients were put on oral zinc sulphate at dose of 5mg/kg for six weeks, while an equal number of patients received placebo for the same duration. In the patients who received oral zinc sulphate, 60.97% showed complete response at the end of six weeks in comparison to 6.45% partial response in the placebo group. The resolution of the lesions occurred with restoration of normal epidermal texture with transient alteration in pigmentation.
Neuronal P2X7 Receptor: Involvement in Neuronal Physiology and Pathology

The proposed presence of P2X7 receptor (P2X7R) in neurons has been the source of some contention. Initial studies suggested an absence of P2X7R mRNA in neurons, and the apparent nonspecificity of the antibodies used to identify P2X7R raised further doubts. However, subsequent studies using new pharmacological and biomolecular tools provided conclusive evidence supporting the existence of functional P2X7Rs in neurons. The P2X7 receptor has since been shown to play a leading role in multiple aspects of neuronal physiology, including axonal elongation and branching and neurotransmitter release. P2X7R has also been implicated in neuronal pathologies, in which it may influence neuronal survival. Together, this body of research suggests that P2X7R may constitute an important therapeutic target for a variety of neurological disorders.
Activity-Induced Synaptic Structural Modifications by an Activator of Integrin Signaling at the Drosophila Neuromuscular Junction

Activity-induced synaptic structural modification is crucial for neural development and synaptic plasticity, but the molecular players involved in this process are not well defined. Here, we report that a protein named Shriveled (Shv) regulates synaptic growth and activity-dependent synaptic remodeling at the Drosophila neuromuscular junction. Depletion of Shv causes synaptic overgrowth and an accumulation of immature boutons. We find that Shv physically and genetically interacts with βPS integrin. Furthermore, Shv is secreted during intense, but not mild, neuronal activity to acutely activate integrin signaling, induce synaptic bouton enlargement, and increase postsynaptic glutamate receptor abundance. Consequently, loss of Shv prevents activity-induced synapse maturation and abolishes post-tetanic potentiation, a form of synaptic plasticity. Our data identify Shv as a novel trans-synaptic signal secreted upon intense neuronal activity to promote synapse remodeling through integrin receptor signaling. SIGNIFICANCE STATEMENT The ability of neurons to rapidly modify synaptic structure in response to neuronal activity, a process called activity-induced structural remodeling, is crucial for neuronal development and complex brain functions. The molecular players that are important for this fundamental biological process are not well understood. Here we show that the Shriveled (Shv) protein is required during development to maintain normal synaptic growth. We further demonstrate that Shv is selectively released during intense neuronal activity, but not mild neuronal activity, to acutely activate integrin signaling and trigger structural modifications at the Drosophila neuromuscular junction. This work identifies Shv as a key modulator of activity-induced structural remodeling and suggests that neurons use distinct molecular cues to differentially modulate synaptic growth and remodeling to meet synaptic demand.
Bestrophin-1 Encodes for the Ca2+-Activated Anion Channel in Hippocampal Astrocytes

In mammalian brain, neurons and astrocytes are reported to express various chloride and anion channels, but the evidence for functional expression of Ca2+-activated anion channel (CAAC) and its molecular identity have been lacking. Here we report electrophysiological evidence for the CAAC expression and its molecular identity by mouse Bestrophin 1 (mBest1) in astrocytes of the mouse brain. Using Ca2+ imaging and perforated-patch-clamp analysis, we demonstrate that astrocytes displayed an inward current at holding potential of −70 mV that was dependent on an increase in intracellular Ca2+ after Gαq-coupled receptor activation. This current was mediated mostly by anions and was sensitive to well known anion channel blockers such as niflumic acid, 5-nitro-2(3-phenylpropylamino)-benzoic acid, and flufenamic acid. To find the molecular identity of the anion channel responsible for the CAAC current, we analyzed the expression of candidate genes and found that the mRNA for mouse mBest1 is predominantly expressed in acutely dissociated or cultured astrocytes. Whole-cell patch-clamp analysis using HEK293T cells heterologously expressing full-length mBest1 showed a Ca2+-dependent current mediated by mBest1, with a complete impairment of the current by a putative pore mutation, W93C. Furthermore, mBest1-mediated CAAC from cultured astrocytes was significantly reduced by expression of mBest1-specific short hairpin RNA (shRNA), suggesting that the CAAC is mediated by a channel encoded by mBest1. Finally, hippocampal CA1 astrocytes in hippocampal slice also showed mBest1-mediated CAAC because it was inhibited by mBest1-specific shRNA. Collectively, these data provide molecular evidence that the mBest1 channel is responsible for CAAC function in astrocytes.
Correlation between BRAF mutation and promoter methylation of TIMP3, RARβ2 and RASSF1A in thyroid cancer

Our aim was to comprehensively analyze promoter hypermethylation of a panel of novel and known methylation markers for thyroid neoplasms and to establish their relationship with BRAF mutation and clinicopathologic parameters of thyroid cancer. A cohort of thyroid tumors, consisting of 44 cancers and 44 benign thyroid lesions, as well as 15 samples of adjacent normal thyroid tissue, was evaluated for BRAF mutation and promoter hypermethylation. Genes for quantitative methylation specific PCR (QMSP) were selected by a candidate gene approach. Twenty-two genes were tested: TSHR, RASSF1A, RARβ2, DAPK, hMLH1, ATM, S100, p16, CTNNB1, GSTP1, CALCA, TIMP3, TGFßR2, THBS1, MINT1, CTNNB1, MT1G, PAK3, NISCH, DCC, AIM1 and KIF1A. The PCR-based “mutector assay” was used to detect BRAF mutation. All p values reported are two sided. Considerable overlap was seen in the methylation markers among the different tissue groups. Significantly higher methylation frequency and level were observed for KIF1A and RARß2 in cancer samples compared with benign tumors. A negative correlation between BRAF mutation and RASSF1A methylation, and a positive correlation with RARß2 methylation were observed in accordance with previous results. In addition, positive correlation with TIMP3 and a marginal correlation with DCC methylation were observed. The present study constitutes a comprehensive promoter methylation profile of thyroid neoplasia and shows that results must be analyzed in a tissue-specific manner to identify clinically useful methylation markers. Integration of genetic and epigenetic changes in thyroid cancer will help identify relevant biologic pathways that drive its development.
Patterned, But Not Tonic, Optogenetic Stimulation in Motor Thalamus Improves Reaching in Acute Drug-Induced Parkinsonian Rats

High-frequency deep brain stimulation (DBS) in motor thalamus (Mthal) ameliorates tremor but not akinesia in Parkinson's disease. The aim of this study was to investigate whether there are effective methods of Mthal stimulation to treat akinesia. Glutamatergic Mthal neurons, transduced with channelrhodopsin-2 by injection of lentiviral vector (Lenti.CaMKII.hChR2(H134R). mCherry), were selectively stimulated with blue light (473 nm) via a chronically implanted fiber-optic probe. Rats performed a reach-to-grasp task in either acute drug-induced parkinsonian akinesia (0.03–0.07 mg/kg haloperidol, s.c.) or control (vehicle injection) conditions, and the number of reaches was recorded for 5 min before, during, and after stimulation. We compared the effect of DBS using complex physiological patterns previously recorded in the Mthal of a control rat during reaching or exploring behavior, with tonic DBS delivering the same number of stimuli per second (rate-control 6.2 or 1.8 Hz, respectively) and with stimulation patterns commonly used in other brain regions to treat neurological conditions (tonic 130 Hz, theta burst (TBS), and tonic 15 Hz rate-control for TBS). Control rats typically executed >150 reaches per 5 min, which was unaffected by any of the stimulation patterns. Acute parkinsonian rats executed <20 reaches, displaying marked akinesia, which was significantly improved by stimulating with the physiological reaching pattern or TBS (both p < 0.05), whereas the exploring and all tonic patterns failed to improve reaching. Data indicate that the Mthal may be an effective site to treat akinesia, but the pattern of stimulation is critical for improving reaching in parkinsonian rats.
Angiopoietin-like proteins 3, 4 and 8: regulating lipid metabolism and providing new hope for metabolic syndrome

Abstract Angiopoietin-like proteins (ANGPTLs) are a group of eight proteins that share structural similarity to the members of the angiopoietin protein family. ANGPTL3 plays a vital role in the regulation of the plasma levels of triglyceride and cholesterol, mainly via reversible inhibition of the lipoprotein lipase activity. ANGPTL4, which functions as a homo-oligomer different from ANGPTL3 and ANGPTL8, not only regulates the plasma levels of triglyceride and prevents the uptake of dietary lipids into adipose tissues but also inhibits intravascular lipolysis. ANGPTL8 (also called betatrophin) has been identified as an important factor in regulating the triglyceride levels and adipose tissue mass as well as in replenishing the adipose tissue triglyceride store. ANGPTL8 acts together with ANGPTL3 to regulate the lipid metabolism, and ANGPTL8 promotes cleavage of ANGPTL3 to augment the activity of ANGPTL3. In addition, ANGPTL8 promotes proliferation of pancreatic β-cells and enhances insulin secretion. The properties of ANGPTLs in regulating the lipid metabolism suggest their application in the target therapy for metabolic syndrome. As ANGPTLs are regulated by several factors and may be involved in certain specific pathways of lipid metabolism, designing drugs that target ANGPTLs or factors regulating ANGPTLs may be an efficient approach to treat metabolic syndrome.