Miracle-dz/UniFAR-FTUs huggingface dataset:
Alternate Splicing of Transcripts upon Mycobacterium tuberculosis Infection Impacts the Expression of Functional Protein Domains

Previously, we reported that infection of human macrophages with Mycobacterium tuberculosis (Mtb) results in massive alterations in the pattern of RNA splicing in the host. The finding gained significance since alternate spliced variants of a same gene may have substantially different structure, function, stability, interaction partners, localization, and so forth, owing to inclusion or exclusion of specific exons. To establish a proof‐of‐concept; on how infection‐induced RNA splicing could impact protein functions, here we used RNA‐seq data from THP‐1 macrophages that were infected with clinical isolate of Mtb. In addition to re‐establishing the fact that Mtb infection may cause strain specific alterations in RNA splicing, we also developed a new analysis pipeline resulting in characterization of domain maps of the transcriptome post‐infection. For the sake of simplicity, we restricted our analysis to all the kinases in the human genome and considered only pfam classified protein domains and checked their frequency of inclusion or exclusion due to alternate splicing across the conditions and time points. We report massive alterations in the domain architecture of most regulated proteins across the entire kinases highlighting the physiological importance of such an understanding. This study paves way for more detailed analysis of different functional classes of proteins and perturbations to their domain architecture as a consequence of mycobacterial infections. Such analysis would yield unprecedented depth to our understanding of host‐pathogen interaction and allow in a more systematic manner targeting of host pathways for controlling the infections. © 2018 The Authors. IUBMB Life published by Wiley Periodicals, Inc. on behalf of International Union of Biochemistry and Molecular Biology, 70(9):845–854, 2018
Skin resident memory T‐cell population is not constructed effectively in systemic sclerosis

Systemic sclerosis (SSc) is characterized by tissue fibrosis, vascular damage and dysregulation of immune system1 . Regarding the contribution of circulating T cells, over-production of IL-13 by circulating effector/memory T cells is reported to be critical for more severe cutaneous disease2 . Another report demonstrates that a dysfunction of regulatory T cells with lower CD69 expression underlies the immune dysfunction in SSc. This article is protected by copyright. All rights reserved.
Superior Intrinsic Mitochondrial Respiration in Women Than in Men

Sexual dimorphism is apparent in humans, however, to date no studies have investigated mitochondrial function focusing on intrinsic mitochondrial respiration (i.e., mitochondrial respiration for a given amount of mitochondrial protein) and mitochondrial oxygen affinity (p50mito) in relation to biological sex in human. A skeletal muscle biopsy was donated by nine active women, and ten men matched for maximal oxygen consumption (VO2max) and by nine endurance trained men. Intrinsic mitochondrial respiration, assessed in isolated mitochondria, was higher in women compared to men when activating complex I (CIP) and complex I+II (CI+IIP) (p < 0.05), and was similar to trained men (CIP, p = 0.053; CI+IIP, p = 0.066). Proton leak and p50mito were higher in women compared to men independent of VO2max. In conclusion, significant novel differences in mitochondrial oxidative function, intrinsic mitochondrial respiration and p50mito exist between women and men. These findings may represent an adaptation in the oxygen cascade in women to optimize muscle oxygen uptake to compensate for a lower oxygen delivery during exercise.
Impacts of dietary exposure to sodium or potassium salts of nitrate and nitrite on the development of Drosophila melanogaster

Abstract The effects of four food additives, namely sodium nitrite (NaNO2), sodium nitrate (NaNO3), potassium nitrite (KNO2), and potassium nitrate (KNO3), on animal development were evaluated by using Drosophila melanogster, a model organism. Adult male and female flies were allowed to breed in culture medium, each containing one of 4 concentrations, i.e.10, 20, 30 or 40 mM of the above mentioned salts. The concentration of 40 mM, NaNO2 and KNO2 completely arrested the development of the flies. Of the different concentrations of the four salts tested, exposure of flies to 30 mM NaNO2 exhibited only significant delays in the initial appearances of third instar larvae, pupae and young adults, along with huge reduction in the number of pupae and young adults compared to controls. Rearrangements like inversions, deletion looping, regional shrinking, as well as highly enlarged puffing, etc. were also observed in the polytene chromosomes of the third instar larvae exposed to 30 mM NaNO2. Developmental outcomes of the flies exposed to varying concentrations of NaNO3 and KNO3 did not differ significantly from the controls. Owing to the extensive genetic homology between Drosophila and human and the successful uses of this fly as models in developmental and toxicological studies, we speculate that the experimental results exhibited by this organism in our study strongly advocate for abstaining from the dietary use of NaNO2 and KNO2 during human pregnancies to avoid possible negative developmental outcomes.
Comparison between selected hormone and protein levels in serum and prostate tissue homogenates in men with benign prostatic hyperplasia and metabolic disorders

Purpose The purpose of the study was to assess the relationship between changes in the levels of selected hormones in serum and prostate tissue homogenate in regard to metabolic disorders in patients with diagnosed, surgically treated benign prostatic hyperplasia (BPH). Patients and methods The study involved a group of 154 men with a diagnosis of BPH with metabolic syndrome (MetS) and without MetS. The serum levels of the hormones – total testosterone, free testosterone, insulin, dehydroepiandrosterone sulfate, estradiol, luteinizing hormone, sex hormone binding globulin (SHBG), and insulin-like growth factor-1 (IGF-1) – were determined using the ELISA method. Prostate tissue sections obtained from the patients during transurethral resection of the prostate were frozen in liquid nitrogen. We determined the levels of the same hormones. Results There was a statistically significant difference between the groups in terms of serum SHBG levels, but not in the prostate tissue SHBG levels. A similar relationship was observed in regard to IGF-1, the serum levels of which were significantly higher in patients with MetS. MetS had an effect on the ratio of hormone levels in serum to their levels in the prostate tissue. Correlations between the levels of biochemical parameters and the levels of hormones in serum and the prostate tissue of BPH patients with and without MetS demonstrate that serum SHBG levels correlated weakly with waist size and triglyceride levels. Conclusion The occurrence of MetS in BPH patients was associated with changes in the levels of hormones and proteins. These changes, however, were not always equivalent to changes in the levels of these parameters in prostate tissue. It should also be mentioned that MetS in BPH patients had an influence on a quantitative balance between the levels of SHBG in serum and prostate tissue.
Optic neuritis in the diagnosis of MS

In the current era, therapeutic strategies used in the care of patients with multiple sclerosis (MS) are rapidly evolving. Ergo, it is important to maintain rigorous diagnostic standards, both to facilitate early identification of patients with MS who would benefit from treatment and to avoid potential harm to individuals who do not harbor the diagnosis.
Current landscape and future directions of biomarkers for predicting responses to immune checkpoint inhibitors

Immune checkpoint inhibitors (ICIs), represented by anti-CTLA-4 or anti-PD-1/anti-PD-L1 pathway antibodies, have led to a revolution in cancer treatment modalities. ICIs have unique clinical benefits, such as effectiveness against a broad range of tumor types, strong overall impact on survival, and persistent responses after the cessation of therapy. However, only a subset of patients responds to these therapies, and a small proportion of patients even experience rapid progression or an increased risk of death. Therefore, it is imperative to optimize patient selection for treatment. This review focuses on the mechanisms of tumor escape from immune surveillance, the composition and activity of a preexisting immune infiltrate, the degree of tumor foreignness (as reflected by the mutational burden, expression of viral genes, and driver gene mutations), and host factors (including peripheral blood biomarkers, genetic polymorphisms, and gut microbiome) to summarize current evidence on the biomarkers of responses to ICIs and explore the future prospects in this field.
Contralateral monoarthritis exacerbated chronic constriction injury-induced pain hypersensitivity through upregulating inducible nitric oxide synthase

Introduction High comorbidity of osteoarthritis (OA) and neuropathic pain has been reported in aged patients. Evidence shows that central sensitization of pain processing occurs in late-phase OA and may facilitate the development of neuropathic pain. Few studies reveal whether acute monoarthritis (MA) aggravates neuropathic pain on the opposite side of the body from the injury. Methods To address whether neuropathic pain is affected by contralateral MA through distinct inflammatory pathway, MA was induced by intra-articular injection of complete Freund’s adjuvant (CFA) into the right tibiotarsal joint, and neuropathic pain was established by chronic constriction injury (CCI) of the left sciatic nerve. Results We observed that MA aggravated mechanical allodynia and thermal hyperalgesia in CCI rats. Furthermore, MA affected the other side of the spinal cord in multiple aspects, including the upregulation of iNOS mRNA and the enhancement of forskolin-induced facilitation of excitatory synaptic transmission in the spinal cord dorsal horn substantia gelatinosa neurons. Discussion Interestingly, intrathecal injection of 1400W, an antagonist of iNOS, attenuated intensity of pain behaviors in CCI rats with contralateral MA to similar levels in CCI rats without MA, and also normalized the facilitatory effect of forskolin on excitatory synaptic transmission in the spinal cord dorsal horn neurons in contralateral MA rats. Therefore, contralateral MA worsened CCI-induced pain hypersensitivity probably through upregulating iNOS and enhancing the facilitation of synaptic transmission following CCI. Conclusion Inhibiting the iNOS might be a potential therapeutic strategy for concurrent OA and neuropathic pain.
Hepatic Ischemic Preconditioning Alleviates Ischemia-Reperfusion Injury by Decreasing TIM4 Expression

Ischemia-reperfusion injury (IRI) of the liver is a primary cause of post-liver-surgery complications and ischemic preconditioning (IPC) has been verified to protect against ischemia-reperfusion injury. TIM-4 activation plays an important role in macrophage mediated hepatic IRI. This study aimed to determine whether IPC protects against hepatic IRI through inhibiting TIM-4 activation. In this study, a model of warm liver ischemia (90 min) and reperfusion for 6 h was used. Mice were subjected to ischemia-reperfusion injury with or without ischemic preconditioning and TIM4 blocking antibody. Western blot was determined to detect the expression of TIM4 protein and mitochondrial apoptosis-related protein expression. Liver function was evaluated using the level of alanine transaminase (ALT) and aspartate transaminase (AST), cell apoptosis and pathological examination. We found that compared with the control group, ischemic preconditioning reduced IRI by decreasing hepatocyte apoptosis, ALT, AST, CD68 and CD3 positive cells, tissue myeloperoxidase activity(MPO), and downregulating TIM-4 expression. TIM4 blocking could reduce CD68 and CD3 positive cells in liver. Furthermore, activated monocytes transfusion significantly abolished the protect effect of IPC with increased hepatocyte apoptosis, ALT, AST, CD68 and CD3 positive cells while TIM-4 knockdown monocytes lost this effect. These results suggested that IPC protects against hepatic IRI by downregulating TIM-4 and indicated TIM-4 would be a novel therapeutic target to minimize IRI.
Melatonin protects against chromium (VI) induced hepatic oxidative stress and toxicity: Duration dependent study with realistic dosage

Abstract The present study was undertaken to assess the degree of oxidative stress and toxic effects induced by chromium on hepatic tissue in male Wistar rats exposed to a realistic dosage of Cr(VI) (20 mg/kg/b.w./day) through drinking water, based on the levels of these metals found in the environment, for a duration of 15, 30 and 60 days. The protective effect of melatonin (10 mg/kg) was also studied by simultaneous administration with the metal. Levels of enzymatic and non-enzymatic antioxidants as well as lipid peroxidation were assessed. There was a significant decrease in enzymatic as well as non-enzymatic antioxidants and an increase in the lipid peroxidation level, which were prevented and maintained at near-normal levels by the administration of melatonin in all treatment periods. Metal accumulation was maximal at 15 days, with gradual decreases till 60 days. Histopathological observations also demonstrated the fact that Cr (VI) exposure leads to cytological lesions in the hepatic tissue promoting cellular necrotic/apoptotic changes, while melatonin was able to counteract insults induced by Cr (VI) at all treatment periods. It also prevented alterations in insulin and glucose levels. Overall, the present study suggests a duration-dependent effect of Cr on hepatic oxidative stress and cytotoxicity and shows the potent activity of melatonin in preventing the negative effects of Cr (VI).
Attitudes and Practices from People of a Mayan Community of Mexico, Related to Tick-Borne Diseases: Implications for the Design of Prevention Programs

Background: Tick-borne diseases are caused by several pathogens whose transmission could be associated to the life conditions of communities settled in endemic areas. We aimed to determine the knowledge, attitudes, and practices related to the exposition and prevention of tick-borne diseases among people living in a typical Mayan community of Yucatan, Mexico between Dec 2012 and May 2013. Methods: A directed survey was applied to 212 (100%) householders (women and men) from Teabo, Yucatan, Mexico. Answers and field notes were recorded and analyzed with central statistics. Results: People have been bitten at least once in the community, but the majority of them consider those bites innocuous. In addition, people do not consider prevention measures, and only a few mentioned the use of some chemicals on their backyards. Conclusion: This study found little awareness among the participants regarding the importance and the transmission of these diseases even though they possess a vast knowledge regarding ticks. Therefore, educational strategies and prevention programs that include these habits for its modification are required to minimize the exposition to the vectors.
Three-level spaser for next-generation luminescent nanoprobe

Delayed spasing dots with ~3-nm spectral width, ~1 mJ cm−2 threshold, and ~102-μs lifetime were developed for a bionanoprobe. The development of modern biological and medical science highly depends on advanced luminescent probes. Current probes typically have wide emission spectra of 30 to 100 nm, which limits the number of resolvable colors that are simultaneously labeled on samples. Spasers, the abbreviation for surface plasmon lasers, have ultranarrow lasing spectra by stimulated light amplification in the plasmon nanocavity. However, high threshold (>102 mJ cm−2) and short lasing lifetime (approximately picoseconds to nanoseconds) still remain obstacles for current two-level spaser systems. We demonstrated a new type of a three-level spaser using triplet-state electrons. By prolonging the upper state lifetime and controlling the energy transfer, high gain compensation was generated. This probe, named delayed spasing dots (dsDs), about 50 to 60 nm in size, exhibited a spectral linewidth of ~3 nm, an ultralow threshold of ~1 mJ cm−2, and a delayed lasing lifetime of ~102 μs. As the first experimental realization of the three-level spaser system, our results suggested a general strategy to tune the spasing threshold and dynamics by engineering the energy level of the gain medium and the energy transfer process. These dsDs have the potential to become new-generation luminescent probes for super-multiplex biological analysis without disturbance from short lifetime background emission.
The Role of Statistical Learning in Understanding and Treating Spoken Language Outcomes in Deaf Children With Cochlear Implants.

Purpose Statistical learning-the ability to learn patterns in environmental input-is increasingly recognized as a foundational mechanism necessary for the successful acquisition of spoken language. Spoken language is a complex, serially presented signal that contains embedded statistical relations among linguistic units, such as phonemes, morphemes, and words, which represent the phonotactic and syntactic rules of language. In this review article, we first review recent work that demonstrates that, in typical language development, individuals who display better nonlinguistic statistical learning abilities also show better performance on different measures of language. We next review research findings that suggest that children who are deaf and use cochlear implants may have difficulties learning sequential input patterns, possibly due to auditory and/or linguistic deprivation early in development, and that the children who show better sequence learning abilities also display improved spoken language outcomes. Finally, we present recent findings suggesting that it may be possible to improve core statistical learning abilities with specialized training and interventions and that such improvements can potentially impact and facilitate the acquisition and processing of spoken language. Method We conducted a literature search through various online databases including PsychINFO and PubMed, as well as including relevant review articles gleaned from the reference sections of other review articles used in this review. Search terms included various combinations of the following: sequential learning, sequence learning, statistical learning, sequence processing, procedural learning, procedural memory, implicit learning, language, computerized training, working memory training, statistical learning training, deaf, deafness, hearing impairment, hearing impaired, DHH, hard of hearing, cochlear implant(s), hearing aid(s), and auditory deprivation. To keep this review concise and clear, we limited inclusion to the foundational and most recent (2005-2018) relevant studies that explicitly included research or theoretical perspectives on statistical or sequential learning. We here summarize and synthesize the most recent and relevant literature to understanding and treating language delays in children using cochlear implants through the lens of statistical learning. Conclusions We suggest that understanding how statistical learning contributes to spoken language development is important for understanding some of the difficulties that children who are deaf and use cochlear implants might face and argue that it may be beneficial to develop novel language interventions that focus specifically on improving core foundational statistical learning skills.
A bright future? Optogenetics in the periphery for pain research and therapy.

Optogenetics describes the technique of expressing lightactivatable proteins, called opsins, in a genetically and/or anatomically restricted population of cells, permitting temporally precise and selective manipulation of the activity of the targeted population. This makes it possible to dissect the physiological role of specific neuronal populations in different phases of pain processing (also reviewed in Refs. 14,22,83). Targeted neuronal expression of channelrhodopsin-2 (ChR2), a light-activated cation channel cloned from the single-cell algae Chlamydomonas reinhardtii, provided the first evidence that optically activated channels can manipulate neuronal activity. Since this discovery, a wide variety of opsins have been identified in nature or engineered to permit manipulation of neuronal activity (depolarization/activation or hyperpolarization/inhibition), intracellular signaling, and gene expression in a temporally precise and cell-type– specific manner (reviewed in Refs. 33,49,62,77). Mutagenesis and genomic screening has expanded the opsin tool box to include opsins with faster kinetics, permitting more precise control of activity patterns; bistable opsins, permitting sustained activation or inhibition with only brief light pulses; and opsins activated at longer wavelengths (red-shifted opsins), permitting improved light penetration through tissues. In addition to direct effects on membrane potential, other opsins, most of which have been molecularly engineered, can initiate more complex signaling processes, such as G-protein-coupled receptor (GPCR) downstream signaling and regulation of gene expression. These opsins extend the advantages of optogenetic manipulations beyond direct effects on membrane potential, furthering the utility of these approaches in manipulating both excitable and nonexcitable cells. This ever-expanding set of optogenetic tools has provided many elegant approaches for manipulating activity and signaling in cells, and has led to an explosion of new findings in systems neuroscience. However, widespread implementation of optogenetics in studies of the peripheral nervous system (PNS) presents 2 major obstacles. The first is that there are challenges in producing consistent and robust genetically restricted expression of opsins in neurons of the PNS, as viral and transgenic tools are more limited and less established as compared to central nervous system (CNS) applications. The second challenge is consistent and restricted delivery of light to the neurons expressing these opsins. Overcoming these obstacles is critical to realizing the full potential of optogenetic manipulations in the PNS.
Drug response to PD-1/PD-L1 blockade: based on biomarkers

In recent years, immunotherapies targeting programmed death-1 (PD-1)/programmed death ligand 1 (PD-L1) have provided great hopes for patients with cancer. A successful anti-PD-1/PD-L1 therapy includes not only the elimination of immunosuppressive tumor cells but also the rejuvenation of exhausted T cells. Nevertheless, the efficacy of therapy is still low, so that biomarker-driven therapy has attracted more and more attention to identify patients who are likely to benefit from therapy and to reduce unnecessary disease progression. While many studies have focused on characteristics of tumor biopsies, biomarkers linked to T cell exhaustion and rejuvenation have just become new hot spots in drug response studies. However, no biomarker is perfect in drug response prediction currently, so there is an urgent need for other biomarkers to compensate for the deficiency. In this review, we summarize some approved and candidate biomarkers predictive of drug response before and during PD-1/PD-L1 blockade, including those characterizing responsive or suppressive tumor cells and those evaluating the T cell rejuvenation. Overall, we set up a comprehensive network of biomarkers of tumor characteristics and T cell rejuvenation, predicting drug response before and during anti-PD-1/PD-L1 therapies.