Miracle-dz/UniFAR-FTUs huggingface dataset:
Alterations of Sleep and Sleep Oscillations in the Hemiparkinsonian Rat

Our previous studies in the rat model of Parkinson’s disease (PD) cholinopathy demonstrated the sleep-related alterations in electroencephalographic (EEG) oscillations at the cortical and hippocampal levels, cortical drives, and sleep spindles (SSs) as the earliest functional biomarkers preceding hypokinesia. Our aim in this study was to follow the impact of a unilateral substantia nigra pars compacta (SNpc) lesion in rat on the cortical and hippocampal sleep architectures and their EEG microstructures, as well as the cortico-hippocampal synchronizations of EEG oscillations, and the SS and high voltage sleep spindle (HVS) dynamics during NREM and REM sleep. We performed unilateral SNpc lesions using two different concentrations/volumes of 6-hydroxydopamine (6-OHDA; 12 μg/1 μl or 12 μg/2 μl). Whereas the unilateral dopaminergic neuronal loss >50% throughout the overall SNpc rostro-caudal dimension prolonged the Wake state, with no change in the NREM or REM duration, there was a long-lasting theta amplitude augmentation across all sleep states in the motor cortex (MCx), but also in the CA1 hippocampus (Hipp) during both Wake and REM sleep. We demonstrate that SS are the hallmarks of NREM sleep, but that they also occur during REM sleep in the MCx and Hipp of the control rats. Whereas SS are always longer in REM vs. NREM sleep in both structures, they are consistently slower in the Hipp. The dopaminergic neuronal loss increased the density of SS in both structures and shortened them in the MCx during NREM sleep, without changing the intrinsic frequency. Conversely, HVS are the hallmarks of REM sleep in the control rats, slower in the Hipp vs. MCx, and the dopaminergic neuronal loss increased their density in the MCx, but shortened them more consistently in the Hipp during REM sleep. In addition, there was an altered synchronization of the EEG oscillations between the MCx and Hipp in different sleep states, particularly the theta and sigma coherences during REM sleep. We provide novel evidence for the importance of the SNpc dopaminergic innervation in sleep regulation, theta rhythm generation, and SS/HVS dynamics control. We suggest the importance of the underlying REM sleep regulatory substrate to HVS generation and duration and to the cortico-hippocampal synchronizations of EEG oscillations in hemiparkinsonian rats.
Asymptotic Optimality of Mixture Rules for Detecting Changes in General Stochastic Models

The paper addresses a sequential changepoint detection problem for a general stochastic model, assuming that the observed data may be non-i.i. d. (i.e., dependent and non-identically distributed) and prior distribution of the change point is arbitrary. Tartakovsky and Veeravalli (2005), Baron and Tartakovsky (2006), and, more recently, Tartakovsky (2017) developed a general asymptotic theory of changepoint detection for non-i.i. d. stochastic models, assuming certain stability of the log-likelihood ratio process, in the case of simple hypotheses when both pre-change and post-change models are completely specified. However, in most applications, the post-change distribution is not completely known. In the present paper, we generalize previous results to the case of parametric uncertainty, assuming that the parameter of the post-change distribution is unknown. We introduce two detection rules based on mixtures–the mixture Shiryaev rule and the mixture Shiryaev–Roberts rule–and study their asymptotic properties in the Bayesian context. In particular, we provide sufficient conditions under which these rules are first-order asymptotically optimal, minimizing moments of the delay to detection as the probability of false alarm approaches zero.
A Bayesian Account of the Sensory-Motor Interactions Underlying Symptoms of Tourette Syndrome

Tourette syndrome is a hyperkinetic movement disorder. Characteristic features include tics, recurrent movements that are experienced as compulsive and “unwilled”; uncomfortable premonitory sensations that resolve through tic release; and often, the ability to suppress tics temporarily. We demonstrate how these symptoms and features can be understood in terms of aberrant predictive (Bayesian) processing in hierarchical neural systems, explaining specifically: why tics arise, their “unvoluntary” nature, how premonitory sensations emerge, and why tic suppression works—sometimes. In our model, premonitory sensations and tics are generated through over-precise priors for sensation and action within somatomotor regions of the striatum. Abnormally high precision of priors arises through the dysfunctional synaptic integration of cortical inputs. These priors for sensation and action are projected into primary sensory and motor areas, triggering premonitory sensations and tics, which in turn elicit prediction errors for unexpected feelings and movements. We propose experimental paradigms to validate this Bayesian account of tics. Our model integrates behavioural, neuroimaging, and computational approaches to provide mechanistic insight into the pathophysiological basis of Tourette syndrome.
GM-CSF Promotes the Expansion and Differentiation of Cord Blood Myeloid-Derived Suppressor Cells, Which Attenuate Xenogeneic Graft-vs.-Host Disease

Myeloid-derived suppressor cells (MDSCs) are increased in tumor patients. Studies have shown generation of MDSCs from human peripheral blood mononuclear cells (PBMCs) by various cytokine combinations. However, large scale expansion of human MDSCs has not been demonstrated or applied in clinic settings. We investigated which cytokine combinations among GM-CSF/SCF, G-CSF/SCF, or M-CSF/SCF efficiently expand and differentiate human MDSCs following culture CD34+ cells of umbilical cord blood (CB). GM-CSF/SCF showed the greatest expansion of MDSCs. Up to 108 MDSCs (HLA-DRlowCD11b+CD33+) could be produced from 1 unit of CB following 6 weeks of continuous culture. MDSCs produced from culture of CD34+ cells with GM-CSF/SCF for 6 weeks had the greatest suppressive function of T cell proliferation and had the highest expression of immunosuppressive molecules including iNOS, arginase 1 and IDO compared to those differentiated with G-CSF/SCF or M-CSF/SCF. MDSCs secreted IL-10, TGB-β, and VEGF. The infusion of expanded MDSCs significantly prolonged the survival and decreased the GVHD score in a NSG xenogeneic model of GVHD. Injected MDSCs increased IL-10 and TGF-β but decreased the level of TNF-α and IL-6 in the serum of treated mice. Notably, FoxP3 expressing regulatory T (Treg) cells were increased while IFN-γ (Th1) and IL-17 (Th17) producing T cells were decreased in the spleen of MDSC treated mice compared to untreated GVHD mice. Our results demonstrate that human MDSCs are generated from CB CD34+ cells using GM-CSF/SCF. These MDSCs exhibited potent immunosuppressive function, suggesting that they are useable as a treatment for inflammatory diseases such as GVHD.
A Novel Predictive Model to Estimate the Number of Mature Oocytes Required for Obtaining at Least One Euploid Blastocyst for Transfer in Couples Undergoing in vitro Fertilization/Intracytoplasmic Sperm Injection: The ART Calculator

The POSEIDON group (Patient-Oriented Strategies Encompassing IndividualizeD Oocyte Number) has introduced “the ability to retrieve the number of oocytes needed to achieve at least one euploid embryo for transfer” as an intermediate marker of successful outcome in IVF/ICSI cycles. This study aimed to develop a novel calculator to predict the POSEIDON marker. We analyzed clinical and embryonic data of infertile couples who underwent IVF/ICSI with the intention to have trophectoderm biopsy for preimplantation genetic testing for aneuploidy. We used the negative binomial distribution to model the number of euploid blastocysts and the adaptive LASSO (Least Absolute Shrinkage and Selection Operator) method for variable selection. The fitted model selected female age, sperm source used for ICSI, and the number of mature (metaphase II) oocytes as predictors (p < 0.0001). Female age was the most important factor for predicting the probability of a blastocyst being euploid given each mature oocyte (loglikelihood of age [adjusted for sperm source]: 30.9; df = 2; p < 0.0001). The final predictive model was developed using logistic regression analysis, and internally validated by the holdout method. The predictive ability of the model was assessed by the ROC curve, which resulted in an area under the curve of 0.716. Using the final model and mathematical equations, we calculated the individualized probability of blastocyst euploidy per mature retrieved oocyte and the minimum number of mature oocytes required to obtain ≥1 euploid blastocyst—with their 95% confidence interval [CI]—for different probabilities of success. The estimated predicted probabilities of a mature oocyte turn into a euploid blastocyst decreased progressively with female age and was negatively modulated overall by use of testicular sperm across age (p < 0.001). A calculator was developed to make two types of predictions automatically, one using pretreatment information to estimate the minimum number of mature oocytes to achieve ≥1 euploid blastocyst, and another based on the actual number of mature oocytes collected/accumulated to estimate the chances of having a euploid blastocyst using that oocyte cohort for IVF/ICSI. The new ART calculator may assist in clinical counseling and individualized treatment planning regarding the number of oocytes required for at least one euploid blastocyst in IVF/ICSI procedures.
Eco-Friendly Extraction of Sinapine From Residues of Mustard Production

In this study, our efforts were focused on the optimization of phenolic compounds - mainly sinapine - extraction from residues of industrial mustard production. A preliminary work was conducted to discuss the way data from Folin-Ciocalteu analytical method are reported and exploited in the literature, and to determine whether methanol can be replaced by ethanol as extracting solvent. As this first question had found a positive answer, an optimization of the extraction process on crude and pretreated industrial residue was achieved using a Response Surface Methodology (RSM). Optimal conditions obtained through this Design of Experiments (DoE) allowed the extraction of more than 10 mg/g of defatted and dried matter (aka DDM) of phenolics from defatted and dried matter, and 13 mg/g DDM of phenolics from non-pretreated matter (results expressed as equivalent of DDM).
Early Life Stress Delays Sexual Maturation in Female Mice

In humans, some forms of early life stress (ELS) have been linked with precocious puberty, altered brain maturation, and increased risk for a variety of forms of pathology. Interestingly, not all forms of ELS have been found to equally impact these metrics of maturation. In recent work, we have found that ELS in the form of limited bedding (LB) from P4 to P11, was associated with precocious hippocampus maturation in males and increased risk for depressive-like pathology and attentional disturbance in female mice. Here, we sought to test whether ELS in the form of LB also impacted the timing of sexual maturation in female mice. To establish rate of somatic and sexual development, distinct cohorts of mice were tested for weight gain, timing of vaginal opening, and development of estrous cycling. ELS animals weighed significantly less than controls at every timepoint measured. Onset of vaginal opening was tracked from P21 to 40, and ELS was found to significantly delay the onset of vaginal opening. To test the impact of ELS on estrous cycle duration and regularity, vaginal cytology was assessed in independent groups of animals using either a continuous sampling (daily from P40 to P57) or random sampling approach (single swab at P35, P50, or P75). ELS did impact measures of estrous cycling, but these effects were dependent upon the sampling method used. We also tested the impact of ELS on anxiety-like behaviors over development and across the estrous cycle. We observed a developmental increase in anxiety-like behavior in control but not ELS mice. No effect of estrous cycle stage was found on anxiety-like behavior for either group of mice. Together these results provide evidence that ELS in the form of LB delays somatic and sexual development. Additional work will be required to determine the mechanism by which ELS impacts these measures, and if these effects are common to other models of ELS in rodents.
Genomic Insights of Halophilic Planococcus maritimus SAMP MCC 3013 and Detail Investigation of Its Biosurfactant Production

Moderate halophilic bacteria thrive in saline conditions and produce biosurfactant (BS) which facilitates the oil scavenging activity in the oil polluted surroundings. Production of such unusual bioactive molecules plays a vital role for their survival in an extreme and adverse environment. Current research deals with isolation of Planococcus maritimus strain SAMP MCC 3013 from Indian Arabian coastline sea water for BS production. The bacterium tolerated up to 2.7 M NaCl demonstrating osmotic stress bearable physiological systems. We used integrated approach to explore the genomic insight of the strain SAMP and displayed the presence of gene for BS biosynthesis. The genome analysis revealed this potential to be intrinsic to the strain. Preliminary screening techniques viz., surface tension (SFT), drop collapse (DC) and oil displacement (OD) showed SAMP MCC 3013 as a potent BS producer. BS reduced SFT of phosphate buffer saline (PBS) pH: 7.0 from 72 to 30 mN/m with a critical micelle concentration (CMC) value of 1.3 mg/mL. Subsequent investigation on chemical characterization, using thin layer chromatography (TLC), Fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (1H NMR and 13C NMR) and liquid chromatography mass spectrometry (LC-MS) revealed terpene containing BS having sugar, lipid moieties. The genomic sequence analysis of P. maritimus SAMP showed complete genes in the pathway for the synthesis of terpenoid. Probably terpenoid is the accountable backbone molecule for the BS production, but the later stages of terpenoid conversion to the BS could not be found. Moreover, it is important to highlight that till today; no single report documents the in-detailed physico-chemical characterization of BS from Planococcus sp. Based on genomic and functional properties, the term terpene containing BS is denoted for the surfactant produced by P. maritimus.
Differential Function of Melatonin MT1 and MT2 Receptors in REM and NREM Sleep

The pathophysiological function of the G-protein coupled melatonin MT1 and MT2 receptors has not yet been well-clarified. Recent advancements using selective MT1/ MT2 receptor ligands and MT1/MT2 receptor knockout mice have suggested that the activation of the MT1 receptors are mainly implicated in the regulation of rapid eye movement (REM) sleep, whereas the MT2 receptors selectively increase non-REM (NREM) sleep. Studies in mutant mice show that MT1 knockout mice have an increase in NREM sleep and a decrease in REM sleep, while MT2 knockout mice a decrease in NREM sleep. The localization of MT1 receptors is also distinct from MT2 receptors; for example, MT2 receptors are located in the reticular thalamus (NREM area), while the MT1 receptors in the Locus Coeruleus and lateral hypothalamus (REM areas). Altogether, these findings suggest that these two receptors not only have a very specialized function in sleep, but that they may also modulate opposing effects. These data also suggest that mixed MT1-MT2 receptors ligands are not clinically recommended given their opposite roles in physiological functions, confirmed by the modest effects of melatonin or MT1/MT2 non-selective agonists when used in both preclinical and clinical studies as hypnotic drugs. In sum, MT1 and MT2 receptors have specific roles in the modulation of sleep, and consequently, selective ligands with agonist, antagonist, or partial agonist properties could have therapeutic potential for sleep; while the MT2 agonists or partial agonists might be indicated for NREM-related sleep and/or anxiety disorders, the MT1 agonists or partial agonists might be so for REM-related sleep disorders. Furthermore, MT1 but not MT2 receptors seem involved in the regulation of the circadian rhythm. Future research will help further develop MT1 and/or MT2 receptors as targets for neuropsychopharmacology drug development.
Emerging Roles of Neuronal Ca2+ Sensor-1 in Cardiac and Neuronal Tissues: A Mini Review

The EF-hand calcium (Ca2+)-binding protein, neuronal Ca2+ sensor-1 (NCS-1/frequenin), is predominantly expressed in neuronal tissues and plays a crucial role in neuronal functions, including synaptic transmission and plasticity. NCS-1 has diverse functional roles, as elucidated in the past 15 years, which include the regulation of phosphatidylinositol 4-kinase IIIβ (PI-4K-β) and several ion channels such as voltage-gated K+ and Ca2+ channels, the D2 dopamine receptors, and inositol 1,4,5-trisphosphate receptors (InsP3Rs). Functional analyses demonstrated that NCS-1 enhances exocytosis and neuronal survival after injury, as well as promotes learning and memory in mice. NCS-1 is also expressed in the heart including the Purkinje fibers (PFs) of the conduction system. NCS-1 interacts with KV4 K+ channels together with dipeptidyl peptidase-like protein-6 (DPP-6), and this macromolecule then composes the transient outward current in PFs and contributes to the repolarization of PF action potential, thus being responsible for idiopathic arrhythmia. Moreover, NCS-1 expression was reported to be significantly high at the immature stage and at hypertrophy in adults. That report demonstrated that NCS-1 positively regulates cardiac contraction in immature hearts by increasing intracellular Ca2+ signals through interaction with InsP3Rs. With the related signals, NCS-1 activates nuclear Ca2+ signals, which would be a mechanism underlying hormone-induced cardiac hypertrophy. Furthermore, NCS-1 contributes to stress tolerance in cardiomyocytes by activating mitochondrial detoxification pathways, with a key role in Ca2+-dependent pathways. In this review, we will discuss recent findings supporting the functional significance of NCS-1 in the brain and heart and will address possible underlying molecular mechanisms.
Role of Connexin-Based Gap Junction Channels in Communication of Myelin Sheath in Schwann Cells

Peripheral nerves have the capacity to conduct action potentials along great distances and quickly recover following damage which is mainly due to Schwann cells (SCs), the most abundant glial cells of the peripheral nervous system (PNS). SCs wrap around an axonal segment multiple times, forming a myelin sheath, allowing for a significant increase in action potential conduction by insulating the axons. Mature myelin consists of compact and non-compact (or cytoplasmic) myelin zones. Non-compact myelin is found in paranodal loops bordering the nodes of Ranvier, and in the inner and outermost cytoplasmic tongues and is the region in which Schmidt-Lanterman incisures (SLI; continuous spirals of overlapping cytoplasmic expansions within areas of compact myelin) are located. Using different technologies, it was shown that the layers of non-compact myelin could be connected to each other by gap junction channels (GJCs), formed by connexin 32 (Cx32), and their relative abundance allows for the transfer of ions and different small molecules. Likewise, Cx29 is expressed in the innermost layer of the myelin sheath. Here it does not form GJCs but colocalizes with Kv1, which implies that the SCs play an active role in the electrical condition in mammals. The critical role of GJCs in the functioning of myelinating SCs is evident in Charcot-Marie-Tooth disease (CMT), X-linked form 1 (CMTX1), which is caused by mutations in the gap junction protein beta 1 (GJB1) gene that codes for Cx32. Although the management of CMT symptoms is currently supportive, there is a recent method for targeted gene delivery to myelinating cells, which rescues the phenotype in KO-Cx32 mice, a model of CMTX1. In this mini-review article, we discuss the current knowledge on the role of Cxs in myelin-forming SCs and summarize recent discoveries that may become a real treatment possibility for patients with disorders such as CMT.
Sinusoidal-Based Lowband Synthesis for Artificial Speech Bandwidth Extension

Conventional narrowband (NB) telephony suffers from limited acoustic bandwidth at the receiver side, leading to degraded speech quality and intelligibility. In this paper, artificial speech bandwidth extension (ABE) of NB speech toward missing frequencies below about 300 Hz (low-frequency band, LB) is proposed to enhance the speech quality. The LB-ABE in this paper is employed together with a preexisting ABE toward high-frequency components to obtain spectrally balanced speech signals. In an instrumental quality assessment, the spectral distance in the LB was improved by more than 5 dB compared to NB speech. In a subjective listening test, the gap of speech quality between wideband and NB speech was significantly reduced when employing the proposed ABE toward low frequencies. The LB extension was found to further improve the preexisting ABE toward higher frequencies by a significant 0.26 CMOS points.
Immune Modulation in HLA-G Expressing Head and Neck Squamous Cell Carcinoma in Relation to Human Papilloma Virus Positivity: A Study From Northeast India

Background: Tumor specific ectopic expression of the immunomodulatory molecule, HLA-G is known to mediate immune tolerance and promote carcinogenesis. Viruses too employ strategies to evade immune surveillance. Considering the role of both HLA-G and HPV in tumor growth and progression, it is pertinent to investigate the relationship between HLA-G and HPV in context of immune modulation in HNSCC. Method: A hospital based case–control study was conducted in histopathologically confirmed HNSCC tissues. HLA-G isoform expression and HPV association studies were carried out and mRNA levels of HLA-G, markers of proliferation and differentiation (ki-67, keratin 18, cyclin D1), immune checkpoint molecules (IL-10, PD-1. TGF-β), SOCS (SOCS1 and SOCS3) and pro-inflammatory cytokine IFN-γ were determined. Results: Higher expression of HLA-G was noted in HPV positive tumors (5.14 fold, p = 0.002). HLA-G7 was the most frequent isoform (29/80) found in HNSCC particularly in HPV positive tumors (13/16). In HPV negative tumors, all the checkpoint molecules were upregulated along with pro–inflammatory IFN-γ. In contrast, in HPV positive tumors, IFN-γ expression was higher (2.12 fold) but levels of IL-10, PD-1, TGF-β, SOCS1 and SOCS3 were markedly lower (fold change of IL-10 = 0.37, PD1 = 0.41, TGF-β = 0.17, SOCS1 = 0.055, SOCS3 = 0.027). HPV positive tumors were more proliferative and differentiated with higher expression of ki-67 and keratin18 (6.25 fold, p = 0.079 and 10.62 fold, p = 0.009). Decreased expression of cyclin D1 was noted in HPV positive tumors (6.94 fold, p = 0.006) than HPV negative tumors (17.69 fold). Also, HLA-G7 expressing HPV positive tumors showed lowest expression of cyclin D1. Interestingly, SOCS showed normal expression in HLA-G7 expressing HPV negative tumors (1.2 and 1.4 fold). IFN-γ was downregulated in HPV positive tumors without HLA-G7 (0.31 fold). Conclusion: Our data suggests that SOCS were downregulated irrespective of HLA-G positivity and IFN- γ expression appeared to be mediated by HLA-G. SOCS are reported to have anti-tumor activity and also SOCS and soluble HLA-G are known to interfere with cell cycle progression. Hence, through regulating HLA-G expression, HPV positive tumors could mediate immune suppression by manipulating SOCS, IFN-γ, IL-10 and cyclin D1 pathways which needs further exploration.