Miracle-dz/UniFAR-FTUs huggingface dataset:
Melanin-concentrating hormone: a functional melanocortin antagonist in the hypothalamus.

Melanin-concentrating hormone (MCH) and α-melanocyte-stimulating hormone (α-MSH) demonstrate opposite actions on skin coloration in teleost fish. Both peptides are present in the mammalian brain, although their specific physiological roles remain largely unknown. In this study, we examined the interactions between MCH and α-MSH after intracerebroventricular administration in rats. MCH increased food intake in a dose-dependent manner and lowered plasma glucocorticoid levels through a mechanism involving ACTH. In contrast, α-MSH decreased food intake and increased glucocorticoid levels. MCH, at a twofold molar excess, antagonized both actions of α-MSH. α-MSH, at a threefold molar excess, blocked the orexigenic properties of MCH. MCH did not block α-MSH binding or the ability of α-MSH to induce cAMP in cells expressing either the MC3 or MC4 receptor, the principal brain α-MSH receptor subtypes. These data suggest that MCH and α-MSH exert opposing and antagonistic influences on feeding behavior and the stress response and may function in a coordinate manner to regulate metabolism through a novel mechanism mediated in part by an MCH receptor.
Consensus opinion on diagnosis and management of thrombotic microangiopathy in Australia and New Zealand

Thrombotic microangiopathy (TMA) arises in a variety of clinical circumstances with the potential to cause significant dysfunction of the kidneys, brain, gastrointestinal tract and heart. TMA should be considered in all patients with thrombocytopenia and anaemia, with an immediate request to the haematology laboratory to look for red cell fragments on a blood film. Although TMA of any aetiology generally demands prompt treatment, this is especially so in thrombotic thrombocytopenic purpura (TTP) and atypical haemolytic uraemic syndrome (aHUS), where organ failure may be precipitous, irreversible and fatal. In all adults, urgent, empirical plasma exchange (PE) should be started within 4–8 h of presentation for a possible diagnosis of TTP, pending a result for ADAMTS13 (a disintegrin and metalloprotease thrombospondin, number 13) activity. A sodium citrate plasma sample should be collected for ADAMTS13 testing prior to any plasma therapy. In children, Shiga toxin‐associated haemolytic uraemic syndrome due to infection with Escherichia coli (STEC‐HUS) is the commonest cause of TMA, and is managed supportively. If TTP and STEC‐HUS have been excluded, a diagnosis of aHUS should be considered, for which treatment is with the monoclonal complement C5 inhibitor, eculizumab. Although early confirmation of aHUS is often not possible, except in the minority of patients in whom auto‐antibodies against factor H are identified, genetic testing ultimately reveals a complement‐related mutation in a significant proportion of aHUS cases. The presence of other TMA‐associated conditions (e.g. infection, pregnancy/postpartum and malignant hypertension) does not exclude TTP or aHUS as the underlying cause of TMA.
Toxicity of carbon nanotubes: A review

Carbon nanotubes (CNTs) are widely used in the aerospace, automotive, and electronics industries because of their stability, enhanced metallic, and electrical properties. CNTs are also being investigated for biomedical applications such as drug delivery systems and biosensors. However, the toxic potential of CNTs was reported in various cell lines and animal models. The toxicity depends on diverse properties of the CNTs, such as length, aspect ratio, surface area, degree of aggregation, purity, concentration, and dose. In addition, CNTs and/or associated contaminants were well known for oxidative stress, inflammation, apoptosis, pulmonary inflammation, fibrosis, and granuloma in lungs. The increased production of CNTs likely enhanced the possibility of its exposure in people. Studies on the toxicity of CNTs are mainly focused on the pulmonary effects after intratracheal administration, and only a few studies are reported about the toxicity of CNTs via other routes of exposure. So, it is essential to consider the chronic toxicity of CNTs before using them for various biomedical applications. This review focuses on the potential toxicities of CNTs.
Drug treatment of hypertension in older patients with diabetes mellitus

ABSTRACT Introduction: Hypertension is more prevalent in the elderly (age>65 years) diabetic population than in the general population and shows an increasing prevalence with advancing age. Both diabetes mellitus (DM) and hypertension are independent risk factors for cardiovascular (CV) related morbidity and mortality. Optimal BP targets were not identified in elderly patients with DM and hypertension. Areas covered: In this review article, the authors briefly discuss the pathophysiology of hypertension in elderly diabetics, present evidence with various antihypertensive drug classes supporting the treatment of hypertension to reduce CV events in older diabetics, and then discuss the optimal target BP goals in these patients. Expert opinion: Clinicians should have a BP goal of less than 130/80 mm in all elderly patients with hypertension and DM, especially in those with high CV-risk. When medications are required for optimal BP control in addition to lifestyle measures, either thiazide diuretics, angiotensin-converting-enzyme inhibitors, angiotensin receptor blockers, or calcium channel blockers should be considered as initial therapy. Combinations of medications are usually required in these patients because BP control is more difficult to achieve in diabetics than those without DM.
Phenotypic plasticity in the intercalated cell : the hensin pathway

Al-Awqati, Qais, S. Vijayakumar, C. Hikita, J. Chen, and J. Takito. Phenotypic plasticity in the intercalated cell: the hensin pathway. Am. J. Physiol. 275 (Renal Physiol. 44): F183–F190, 1998. —The collecting duct of the renal tubule contains two cell types, one of which, the intercalated cell, is responsible for acidification and alkalinization of urine. These cells exist in a multiplicity of morphological forms, with two extreme types, a and b. The former acidifies the urine by an apical proton-translocating ATPase and a basolateral Cl/HCO3 exchanger, which is an alternately spliced form of band 3. This kidney form of band 3, kAE1, is present in the apical membrane of the b-cell, which has the H1-ATPase on the basolateral membrane. We had suggested previously that metabolic acidosis leads to conversion of b-types to a-types. To study the biochemical basis of this plasticity, we used an immortalized cell line of the b-cell and showed that these cells convert to the a-phenotype when plated at superconfluent density. At high density these cells localize a new protein, which we term ‘‘hensin,’’ to the extracellular matrix, and hensin acts as a molecular switch capable of changing the phenotype of these cells in vitro. Hensin induces new cytoskeletal proteins, makes the cells assume a more columnar shape and retargets kAE1 and the H1-ATPase. These recent studies suggest that the conversion of bto a-cells, at least in vitro, bears many of the hallmarks of terminal differentiation.
Evaluating drugged driving: Effects of exemplar pain and anxiety medications

ABSTRACT Objective: Distracted and drug-influenced driving presents a major risk for traffic safety morbidity and mortality. As part of an ongoing research program, we examined the effects of a commonly prescribed combination of medications for pain relief: alprazolam, a benzodiazepine, and a hydrocodone preparation, a combination opiate and acetaminophen, on a simulated driving protocol. Methods: Utilizing a within-subjects design, we recruited 8 healthy experienced drivers without major physical and psychological histories. Using a double-blind, placebo-controlled crossover design, we administered placebo, alprazolam alone, hydrocodone/acetaminophen, and the combination of the 2 drugs in a standardized simulated driving protocol. Measures of lateral and longitudinal control were collected and the data were reduced and statically analyzed. Results: The study observed clear detrimental effects of alprazolam on driving measures of lateral control and longitudinal control. Driving appeared to more aberrant at higher speeds and in rural scenarios. There were no statistical differences between hydrocodone and placebo. A measure of sedation showed that subjects rated alprazolam as more sedating than both hydrocodone and placebo. Conclusions: The findings suggest that impairing effects of this commonly prescribed combination of pharmacologic agents impact simulated driving performance. Negative changes in driving performance included measures of lateral and longitudinal control, although the deleterious effects on lateral control measures such as standard deviation of lane position (SDLP) were larger and more robust. Although the number of subjects was small, thus making it more difficult to draw conclusions on the narcotic effects, these results suggest that in this combination of central nervous system (CNS)-active drugs the benzodiazepine alprazolam accounted for the majority of impairing drug effects. The effect sizes associated with the hydrocodone preparation ranged from very small to medium. These results have potential implications for prescribing physicians and dispensing pharmacists, traffic safety experts, law enforcement officers, and patients themselves.
Management of side effects of immune checkpoint blockade by anti‐CTLA‐4 and anti‐PD‐1 antibodies in metastatic melanoma

CTLA‐4 and PD‐1 are potential targets for tumor‐induced downregulation of lymphocytic immune responses. Immune checkpoint‐modifying monoclonal antibodies oppose these effects, inducing T cell‐mediated immune responses to various tumors including melanoma. Both anti‐CTLA‐4 and anti‐PD‐1 antibodies modify the interaction between tumor, antigen‐presenting cells, and T lymphocytes. With respect to overall survival, clinical studies have shown a major benefit for the anti‐CTLA‐4 antibody ipilimumab as well as the two anti‐PD‐1 antibodies nivolumab and pembrolizumab. Following approval of ipilimumab in 2011, the latter two achieved market authorization in the summer of 2015.
In Vivo Relationship Between Hypoxia and Angiogenesis in Human Glioblastoma: A Multimodal Imaging Study

Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. This aggressiveness is in part attributed to the closely interrelated phenomena tumor hypoxia and angiogenesis, although few in vivo data exist in human brain tumors. This work aimed to study hypoxia and angiogenesis, in vivo and in situ, in patients admitted with GBM using multimodal imaging. Methods: Twenty-three GBM patients were assessed by 18F-fluoromisonidazole (18F-FMISO) PET and conventional and perfusion MRI before surgery. The level and location of hypoxia (18F-FMISO uptake, evaluated by tumor-to-blood [T/B] ratio), vascularization (cerebral blood volume [CBV]), and vascular permeability (contrast enhancement after gadolinium injection) were analyzed. The spatial relationship between tumor hypoxia and angiogenesis was assessed by an overlap analysis of the volume of 18F-FMISO uptake and the volumes of the high CBV regions and the contrast-enhancement regions. Results: A significant correlation was found between hypoxia and hypervascularization, especially for their maximum values (volume of maximal tumor hypoxia vs. relative CBV: r = 0.61, P = 0.002) and their volumes (hypoxia vs. hypervascularization: r = 0.91, P < 0.001). A large proportion of the high CBVs collocated with hypoxia (81.3%) and with contrast enhancement (46.5%). Conclusion: These results support the hypothesis of a tight association between hypoxia and angiogenesis. Our results suggest that there is insufficient tumor oxygenation in human GBM, despite increased tumor vascularization.
Caveat emptor: Folate in unipolar depressive illness, a systematic review and meta-analysis

Background: International guideline recommendations for the use of folate and its derivatives in the treatment of unipolar depressive disorders are confused and contradictory, perhaps reflecting wide variations in the underpinning evidence base. Introduction: We discuss differing methods of evidence synthesis in the formulation of international guideline recommendations. As an example we evaluated the efficacy of folate and its derivatives in unipolar depression via systematic review and meta-analysis. Methods: We searched Medline, EMBASE, PsychInfo and CENTRAL from database inception until 1 May 2017 for randomised controlled trials. We included trials that evaluated folate or its derivatives as monotherapy or to augment antidepressant therapy compared with placebo in patients with unipolar depressive illness. Standardised mean differences were used and studies were introduced as subgroups to explain the heterogeneity. Quality was assessed using the Grading of Recommendations Assessment, Development and Evaluation. Results: No trials report on folate or methylfolate versus placebo as a monotherapeutic option. Only when the evidence was restricted to folate at a dose of <5 mg/day or methylfolate at a dose of 15 mg once daily as an adjunct to selective serotonin reuptake inhibitor therapy was there a significant benefit compared with placebo. All evidence was graded as low or very low quality for each outcome. Discussion: Whilst previous guidelines on the treatment of unipolar depression have either avoided this topic entirely, or made recommendations on the basis of cherry-picked evidence, this review is the first to attempt to provide clinically useful recommendations based on comprehensive, current randomised placebo-controlled data. We invite discussion of the review and its recommendations, which are based on the limited evidence regarding folate formulation delivered and appropriate dosage.
Endoscopic Endonasal Skull Base Surgery: Advantages, Limitations, and Our Techniques to Overcome Cerebrospinal Fluid Leakage: Technical Note

In recent years, resections of midline skull base tumors have been conducted using endoscopic endonasal skull base (EESB) approaches. Nevertheless, many surgeons reported that cerebrospinal fluid (CSF) leakage is still a major complication of these approaches. Here, we report the results of our 42 EESB surgeries and discuss the advantages and limits of this approach for resecting various types of tumors, and also report our technique to overcome CSF leakage. All 42 cases involved midline skull base tumors resected using the EESB technique. Dural incisions were closed using nasoseptal flaps and fascia patch inlay sutures. Total removal of the tumor was accomplished in seven pituitary adenomas (33.3%), five craniopharyngiomas (62.5%), five tuberculum sellae meningiomas (83.3%), three clival chordomas (100%), and one suprasellar ependymoma. Residual regions included the cavernous sinus, the outside of the intracranial part of the internal carotid artery, the lower lateral part of the posterior clivus, and the posterior pituitary stalk. Overall incidence of CSF leakage was 7.1%. Even though the versatility of the approach is limited, EESB surgery has many advantages compared to the transcranial approach for managing mid-line skull base lesions. To avoid CSF leakage, surgeons should have skills and techniques for complete closure, including use of the nasoseptal flap and fascia patch inlay techniques.
Permeation of the luminal capillary glycocalyx is determined by hyaluronan.

The endothelial cell glycocalyx influences blood flow and presents a selective barrier to movement of macromolecules from plasma to the endothelial surface. In the hamster cremaster microcirculation, FITC-labeled Dextran 70 and larger molecules are excluded from a region extending almost 0.5 μm from the endothelial surface into the lumen. Red blood cells under normal flow conditions are excluded from a region extending even farther into the lumen. Examination of cultured endothelial cells has shown that the glycocalyx contains hyaluronan, a glycosaminoglycan which is known to create matrices with molecular sieving properties. To test the hypothesis that hyaluronan might be involved in establishing the permeation properties of the apical surface glycocalyx in vivo, hamster microvessels in the cremaster muscle were visualized using video microscopy. After infusion of one of several FITC-dextrans (70, 145, 580, and 2,000 kDa) via a femoral cannula, microvessels were observed with bright-field and fluorescence microscopy to obtain estimates of the anatomic diameters and the widths of fluorescent dextran columns and of red blood cell columns (means ± SE). The widths of the red blood cell and dextran exclusion zones were calculated as one-half the difference between the bright-field anatomic diameter and the width of the red blood cell column or dextran column. After 1 h of treatment with active Streptomyces hyaluronidase, there was a significant increase in access of 70- and 145-kDa FITC-dextrans to the space bounded by the apical glycocalyx, but no increase in access of the red blood cells or in the anatomic diameter in capillaries, arterioles, and venules. Hyaluronidase had no effect on access of FITC-Dextrans 580 and 2,000. Infusion of a mixture of hyaluronan and chondroitin sulfate after enzyme treatment reconstituted the glycocalyx, although treatment with either molecule separately had no effect. These results suggest that cell surface hyaluronan plays a role in regulating or establishing permeation of the apical glycocalyx to macromolecules. This finding and our prior observations suggest that hyaluronan and other glycoconjugates are required for assembly of the matrix on the endothelial surface. We hypothesize that hyaluronidase creates a more open matrix, enabling smaller dextran molecules to penetrate deeper into the glycocalyx.
Human Na+- myo-inositol cotransporter gene: alternate splicing generates diverse transcripts.

Na+- myo-inositol cotransport activity generally maintains millimolar intracellular concentrations of myo-inositol and specifically promotes transepithelial myo-inositol transport in kidney, intestine, retina, and choroid plexus. Glucose-induced, tissue-specific myo-inositol depletion and impaired Na+- myo-inositol cotransport activity are implicated in the pathogenesis of diabetic complications, a process modeled in vitro in cultured human retinal pigment epithelium (RPE) cells. To explore this process at the molecular level, a human RPE cDNA library was screened with a canine Na+-dependent myo-inositol cotransporter (SMIT) cDNA. Overlapping cDNAs spanning 3569 nt were cloned. The resulting cDNA sequence contained a 2154-nt open reading frame, 97% identical to the canine SMIT amino acid sequence. Genomic clones containing SMIT exons suggested that the cDNA is derived from at least five exons. Hypertonic stress induced a time-dependent increase, initially in a 16-kb transcript and subsequently in 11.5-, 9.8-, 8.5-, 3.8-, and ∼1.2-kb SMIT transcripts, that was ascribed to alternate exon splicing using exon-specific probes and direct cDNA sequencing. The human SMIT gene is a complex multiexon transcriptional unit that by alternate exon splicing generates multiple SMIT transcripts that accumulate differentially in response to hypertonic stress.
Preparations for semantics-based XML mining

XML allows users to define elements using arbitrary words and organize them in a nested structure. These features of XML offer both challenges and opportunities in information retrieval, document management, and data mining. In this paper, we propose a new methodology for preparing XML documents for quantitative determination of similarity between XML documents by taking into account XML semantics (i.e., meanings of the elements and nested structures of XML documents). Accurate quantitative determination of similarity between XML documents provides an important basis for a variety of applications of XML document mining and processing. Experiments with XML documents show that our methodology provides a 50-100% improvement in determining similarity over the traditional vector-space model that considers only term-frequency and 100% accuracy in identifying the category of each document from an on-line bookstore.
Type 2 innate lymphoid cells treat and prevent acute gastrointestinal graft-versus-host disease

Acute graft-versus-host disease (aGVHD) is the most common complication for patients undergoing allogeneic stem cell transplantation. Despite extremely aggressive therapy targeting donor T cells, patients with grade III or greater aGVHD of the lower GI tract, who do not respond to therapy with corticosteroids, have a dismal prognosis. Thus, efforts to improve understanding of the function of local immune and non-immune cells in regulating the inflammatory process in the GI tract during aGVHD are needed. Here, we demonstrate, using murine models of allogeneic BMT, that type 2 innate lymphoid cells (ILC2s) in the lower GI tract are sensitive to conditioning therapy and show very limited ability to repopulate from donor bone marrow. Infusion of donor ILC2s was effective in reducing the lethality of aGVHD and in treating lower GI tract disease. ILC2 infusion was associated with reduced donor proinflammatory Th1 and Th17 cells, accumulation of donor myeloid-derived suppressor cells (MDSCs) mediated by ILC2 production of IL-13, improved GI tract barrier function, and a preserved graft-versus-leukemia (GVL) response. Collectively, these findings suggest that infusion of donor ILC2s to restore gastrointestinal tract homeostasis may improve treatment of severe lower GI tract aGVHD.
Strong converse bounds for high-dimensional estimation

In statistical inference problems, we wish to obtain lower bounds on the minimax risk, that is to bound the performance of any possible estimator. A standard technique to obtain risk lower bounds involves the use of Fano's inequality. In an information-theoretic setting, it is known that Fano's inequality typically does not give a sharp converse result (error lower bound) for channel coding problems. Moreover, recent work has shown that an argument based on binary hypothesis testing gives tighter results. We adapt this technique to the statistical setting, and argue that Fano's inequality can always be replaced by this approach to obtain tighter lower bounds that can be easily computed and are asymptotically sharp. We illustrate our technique in three applications: density estimation, active learning of a binary classifier, and compressed sensing, obtaining tighter risk lower bounds in each case.