Miracle-dz/UniFAR-FTUs huggingface dataset:
Innovative Therapeutic Strategies for Effective Treatment of Brain Metastases

Brain metastases are the most prevalent of intracranial malignancies. They are associated with a very poor prognosis and near 100% mortality. This has been the case for decades, largely because we lack effective therapeutics to augment surgery and radiotherapy. Notwithstanding improvements in the precision and efficacy of these life-prolonging treatments, with no reliable options for adjunct systemic therapy, brain recurrences are virtually inevitable. The factors limiting intracranial efficacy of existing agents are both physiological and molecular in nature. For example, heterogeneous permeability, abnormal perfusion and high interstitial pressure oppose the conventional convective delivery of circulating drugs, thus new delivery strategies are needed to achieve uniform drug uptake at therapeutic concentrations. Brain metastases are also highly adapted to their microenvironment, with complex cross-talk between the tumor, the stroma and the neural compartments driving speciation and drug resistance. New strategies must account for resistance mechanisms that are frequently engaged in this milieu, such as HER3 and other receptor tyrosine kinases that become induced and activated in the brain microenvironment. Here, we discuss molecular and physiological factors that contribute to the recalcitrance of these tumors, and review emerging therapeutic strategies, including agents targeting the PI3K axis, immunotherapies, nanomedicines and MRI-guided focused ultrasound for externally controlling drug delivery.
Prognostic significance of glycemic control in burn injury patients: A study in Tertiary Care Hospital of Odisha

Background: Thermal injury is associated with anatomic, physiologic, endocrinologic, and immunologic alterations, which require specialized care. Advances in medical care have changed the principal cause of death in burn patients from burn shock to wound sepsis. An intervention that has drastically changed this outlook is early excision and primary closure of wounds. We used insulin for glycemic control and attenuating systemic inflammation. Materials and Methods: Patients admitted to S. C. B Medical College hospital were divided into 2 groups of 34 each: control group (n = 34) which did not receive insulin and study group (n = 34) which received insulin. Serum C-reactive protein (CRP), fibrinogen, albumin white blood cell, and blood cultures were done every 7th day. Results: Albumin levels decreased over 7 days followed by gradual recovery which was faster in the study group. CRP levels rose and attained its peak by day 14, then declined. CRP peak in the study group was found to be lower than control. Fibrinogen levels showed identical trend as CRP. Leukocytosis was higher in control compared to study group. Blood culture positive was higher in control compared to study group; Pseudomonas and Candida were most common organisms, but study group patients were resistant to Candida. Out of 29 deceased patients, 55% were from control group. Conclusions: Insulin administration in severely burned patients has demonstrated benefits among various parameters. In critically ill burn injury patients, obtaining tight glycemic control with intensive insulin therapy was shown to reduce morbidity and mortality.
Influence of Bromocriptine Plus Metformin Treatment on Glycaemia and Blood Pressure in Patients with Type 2 Diabetes Mellitus

Abstract Background and aims: Bromocriptine is a dopaminergic (D2) agonist that has shown hypoglycemic and normotensive activity in preclinical and clinical studies. The main objective of this study was to investigate the effect of bromocriptine plus metformin on glycaemia and blood pressure in patients with type 2 diabetes mellitus (T2DM). Material and methods: An open-label randomised controlled trial was conducted for three months. It involved two groups (n=10), each containing 2 women and 8 men with an average age of 50 years. One group was given monotherapy (MT) with metformin (850 mg every 12 h) and the other combined therapy (CT) with the same dose of metformin plus an increasing dose of bromocriptine (from 1.25 mg per day to 2.5 mg per day). The parameters monitored were glycaemia, glycated hemoglobin (HbA1c), serum creatinine, blood pressure, and the body mass index. Results: CT was able to significantly decrease the level of glycaemia, HbA1c and diastolic blood pressure, whereas MT had no effect on any of the measured variables. Conclusions: The ability of CT with bromocriptine and metformin to control glycaemia and produce a normotensive effect reaffirms its advantages for controlling T2DM. Further research is needed to improve this therapeutic strategy.
Uncovering the Neuroprotective Mechanisms of Curcumin on Transthyretin Amyloidosis

Transthyretin (TTR) amyloidoses (ATTR amyloidosis) are diseases associated with transthyretin (TTR) misfolding, aggregation and extracellular deposition in tissues as amyloid. Clinical manifestations of the disease are variable and include mainly polyneuropathy and/or cardiomyopathy. The reasons why TTR forms aggregates and amyloid are related with amino acid substitutions in the protein due to mutations, or with environmental alterations associated with aging, that make the protein more unstable and prone to aggregation. According to this model, several therapeutic approaches have been proposed for the diseases that range from stabilization of TTR, using chemical chaperones, to clearance of the aggregated protein deposited in tissues in the form of oligomers or small aggregates, by the action of disruptors or by activation of the immune system. Interestingly, different studies revealed that curcumin presents anti-amyloid properties, targeting multiple steps in the ATTR amyloidogenic cascade. The effects of curcumin on ATTR amyloidosis will be reviewed and discussed in the current work in order to contribute to knowledge of the molecular mechanisms involved in TTR amyloidosis and propose more efficient drugs for therapy.
Killing Mechanisms of Chimeric Antigen Receptor (CAR) T Cells

Effective adoptive T cell therapy (ACT) comprises the killing of cancer cells through the therapeutic use of transferred T cells. One of the main ACT approaches is chimeric antigen receptor (CAR) T cell therapy. CAR T cells mediate MHC-unrestricted tumor cell killing by enabling T cells to bind target cell surface antigens through a single-chain variable fragment (scFv) recognition domain. Upon engagement, CAR T cells form a non-classical immune synapse (IS), required for their effector function. These cells then mediate their anti-tumoral effects through the perforin and granzyme axis, the Fas and Fas ligand axis, as well as the release of cytokines to sensitize the tumor stroma. Their persistence in the host and functional outputs are tightly dependent on the receptor’s individual components—scFv, spacer domain, and costimulatory domains—and how said component functions converge to augment CAR T cell performance. In this review, we bring forth the successes and limitations of CAR T cell therapy. We delve further into the current understanding of how CAR T cells are designed to function, survive, and ultimately mediate their anti-tumoral effects.
Global Gene Expression of Seed Coat Tissues Reveals a Potential Mechanism of Regulating Seed Size Formation in Castor Bean

The physiological and molecular basis of seed size formation is complex, and the development of seed coat (derived from integument cells) might be a critical factor that determines seed size formation for many endospermic seeds. Castor bean (Ricinus communis L.), a model system of studying seed biology, has large and persistent endosperm with a hard seed coat at maturity. Here, we investigated the potential molecular mechanisms underlying seed size formation in castor bean by comparing the difference between global gene expression within developing seed coat tissues between the large-seed ZB107 and small-seed ZB306. First, we observed the cell size of seed coat and concluded that the large seed coat area of ZB107 resulted from more cell numbers (rather than cell size). Furthermore, we found that the lignin proportion of seed coat was higher in ZB306. An investigation into global gene expression of developing seed coat tissues revealed that 815 genes were up-regulated and 813 were down-regulated in ZB306 relative to ZB107. Interestingly, we found that many genes involved in regulating cell division were up-regulated in ZB107, whereas many genes involved in regulating lignin biosynthesis (including several NAC members, as well as MYB46/83 and MYB58/63) and in mediating programmed cell death (such as CysEP1 and βVPE) were up-regulated in ZB306. Furthermore, the expression patterns of the genes mentioned above indicated that the lignification of seed coat tissues was enhanced and occurred earlier in the developing seeds of ZB306. Taken together, we tentatively proposed a potential scenario for explaining the molecular mechanisms of seed coat governing seed size formation in castor bean by increasing the cell number and delaying the onset of lignification in seed coat tissues in large-seed ZB107. This study not only presents new information for possible modulation of seed coat related genes to improve castor seed yield, but also provides new insights into understanding the molecular basis of seed size formation in endospermic seeds with hard seed coat.
Embryo placement in IVF and reproductive outcomes: a cohort analysis and review

Objective: The objective of the present study was to determine the influence of the embryo placement depth on the endometrial cavity in relation to the reproductive outcomes, after frozen-thawed embryo transfer performed under transabdominal ultrasound guidance. Methods: Retrospective cohort study that evaluated the influence of the embryo placement depth in the endometrial cavity in relation to the reproductive outcomes of patients submitted to cryotransfer cycles at a private assisted reproduction clinic, from 2012 to 2017. The patients were classified according to three variables: <10mm, 10 to 15mm and >15mm. The primary outcome was clinical pregnancy, and the secondary outcomes were miscarriage, ongoing pregnancy and live birth. The data was summarized as relative risk, with a 95%CI. Results: Clinical and ongoing pregnancy rates were higher in the 10-15mm and >15mm Groups, when compared to the <10mm Group; there was no statistical difference between the groups in terms of miscarriage and live birth rates. We performed a subsequent analysis, using the same sample of patients, comparing only the <10mm and ≥10mm variables. The ≥10mm Group had better reproductive outcomes, with higher clinical and ongoing pregnancy rates. Conclusion: Pregnancy rates are influenced by embryo transfer site, and better results can be achieved when the tip of the catheter is placed in the central area of the endometrial cavity, especially when the distance from the endometrial fundus is >10mm.
Evaluation of time domain features using best feature subsets based on mutual information for detecting epilepsy

Abstract In this pattern recognition study of detecting epilepsy, the first time the authors have attempted to use time domain (TD) features such as waveform length (WL), number of zero-crossings (ZC) and number of slope sign changes (SSC) which are extracted from the discrete wavelet transform (DWT) for the detecting the epilepsy for University of Bonn datasets and real-time clinical data. The performance of these TD features is studied along with mean absolute value (MAV) which has been attempted by other researchers. The performance of the TD features derived from DWT is studied using naive Bayes (NB) and support vector machines (SVM) for five different datasets from University of Bonn with 14 different combinations datasets and 24 patients datasets from Christian Medical College and Hospital (CMCH), India database. Using feature selection and feature ranking based on the estimation of mutual information (MI), the significant features required for the classifier to get higher accuracy is obtained. Further, NB achieves 100% classification accuracy (CA) in distinguishing normal eyes open and epileptic dataset with top 4 ranked features and it gives 100% accuracy with top-ranked two features in using CMCH data.
Atrial fibrillation ablation in practice: assessing CABANA generalizability

AIMS The Catheter Ablation vs. Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial aimed to assess the impact of ablation on morbidity and mortality. This observational study was conducted in parallel to CABANA to assess trial generalizability. METHODS AND RESULTS Using a large US administrative database, we identified 183 760 patients with atrial fibrillation (AF) treated with ablation or medical therapy (antiarrhythmic or rate control drugs) between 1 August 2009 and 30 April 2016 (CABANA enrolment period). Propensity score weighting was used to balance patients treated with ablation (N = 12 032) or medical therapy alone (N = 171 728) on 90 dimensions. Ablation was associated with a reduction in the composite endpoint of all-cause mortality, stroke, major bleeding, and cardiac arrest [hazard ratio (HR) 0.75, 95% confidence interval (CI) 0.70-0.81; P < 0.001]. The majority of patients (73.8%) were potentially trial eligible; among whom the risk reduction associated with ablation was greatest (HR 0.70, 95% CI 0.63-0.77; P < 0.001). Among the 3.8% of patients who failed to meet the inclusion criterion, i.e. patients under 65 years without stroke risk factors, the event rates were low and there was no significant relationship with ablation (HR 0.67, 95% CI 0.29-1.56; P = 0.35). Among the 22.4% patients who met at least one of the trial exclusion criteria, there was a lesser but statistically significant reduction associated with ablation (HR 0.85, 95% CI 0.75-0.95; P = 0.01). CONCLUSION In routine clinical care, ablation was associated with a reduction in the primary CABANA composite endpoint of all-cause mortality, stroke, major bleeding, and cardiac arrest, particularly in patients who were eligible for the trial.
Mcidas mutant mice reveal a two-step process for the specification and differentiation of multiciliated cells in mammals

ABSTRACT Motile cilia on multiciliated cells (MCCs) function in fluid clearance over epithelia. Studies with Xenopus embryos and individuals with the congenital respiratory disorder reduced generation of multiple motile cilia (RGMC), have implicated the nuclear protein MCIDAS (MCI), in the transcriptional regulation of MCC specification and differentiation. Recently, a paralogous protein, geminin coiled-coil domain containing (GMNC), was also shown to be required for MCC formation. Surprisingly, in contrast to the presently held view, we find that Mci mutant mice can specify MCC precursors. However, these precursors cannot produce multiple basal bodies, and mature into single ciliated cells. We identify an essential role for MCI in inducing deuterosome pathway components for the production of multiple basal bodies. Moreover, GMNC and MCI associate differentially with the cell-cycle regulators E2F4 and E2F5, which enables them to activate distinct sets of target genes (ciliary transcription factor genes versus basal body amplification genes). Our data establish a previously unrecognized two-step model for MCC development: GMNC functions in the initial step for MCC precursor specification. GMNC induces Mci expression that drives the second step of basal body production for multiciliation. Highlighted Article: Two geminin family proteins function in mammalian multiciliated cell development: GMNC regulates precursor specification and MCIDAS induces multiple basal body formation for multiciliation.
Networks of electrostatic and hydrophobic interactions modulate the complex folding free energy surface of a designed βα protein

Significance Natural protein sequences have evolved to fold efficiently to their functional forms, traversing a relatively smooth energy surface with minimal frustration. The optimization of stability in de novo-designed proteins, without regard to dynamical processes required for function, can have unintended consequences on energy surfaces. Electrostatic and hydrophobic networks of side chains for Di-III_14, a small βα protein with a natural topology, create a rough energy surface whose high-energy states reflect the progressive unlocking of a tightly packed interior. Unbiased explorations of sequence space can reveal complex properties not seen in natural proteins, expanding our understanding of the relationships among sequence, structure, folding, and function of these ubiquitous biopolymers. The successful de novo design of proteins can provide insights into the physical chemical basis of stability, the role of evolution in constraining amino acid sequences, and the production of customizable platforms for engineering applications. Previous guanidine hydrochloride (GdnHCl; an ionic denaturant) experiments of a designed, naturally occurring βα fold, Di-III_14, revealed a cooperative, two-state unfolding transition and a modest stability. Continuous-flow mixing experiments in our laboratory revealed a simple two-state reaction in the microsecond to millisecond time range and consistent with the thermodynamic results. In striking contrast, the protein remains folded up to 9.25 M in urea, a neutral denaturant, and hydrogen exchange (HDX) NMR analysis in water revealed the presence of numerous high-energy states that interconvert on a time scale greater than seconds. The complex protection pattern for HDX corresponds closely with a pair of electrostatic networks on the surface and an extensive network of hydrophobic side chains in the interior of the protein. Mutational analysis showed that electrostatic and hydrophobic networks contribute to the resistance to urea denaturation for the WT protein; remarkably, single charge reversals on the protein surface restore the expected urea sensitivity. The roughness of the energy surface reflects the densely packed hydrophobic core; the removal of only two methyl groups eliminates the high-energy states and creates a smooth surface. The design of a very stable βα fold containing electrostatic and hydrophobic networks has created a complex energy surface rarely observed in natural proteins.
Bringing Blurry Alive at High Frame-Rate with an Event Camera

Event-based cameras can measure intensity changes (called `{\it events}') with microsecond accuracy under high-speed motion and challenging lighting conditions. With the active pixel sensor (APS), the event camera allows simultaneous output of the intensity frames. However, the output images are captured at a relatively low frame-rate and often suffer from motion blur. A blurry image can be regarded as the integral of a sequence of latent images, while the events indicate the changes between the latent images. Therefore, we are able to model the blur-generation process by associating event data to a latent image. Based on the abundant event data and the low frame-rate easily blurred images, we propose a simple and effective approach to reconstruct a high-quality and high frame-rate shape video. Starting with a single blurry frame and its event data, we propose the \textbf{Event-based Double Integral (EDI)} model. Then, we extend it to \textbf{ multiple Event-based Double Integral (mEDI)} model to get more smooth and convincing results based on multiple images and their events. We also provide an efficient solver to minimize the proposed energy model. By optimizing the energy model, we achieve significant improvements in removing general blurs and reconstructing high temporal resolution video. The video generation is based on solving a simple non-convex optimization problem in a single scalar variable. Experimental results on both synthetic and real images demonstrate the superiority of our mEDI model and optimization method in comparison to the state-of-the-art.
Identifying long-term periodic cycles and memories of collective emotion in online social media

Collective emotion has been traditionally evaluated by questionnaire survey on a limited number of people. Recently, big data of written texts on the Internet has been available for analyzing collective emotion for very large scales. Although short-term reflection between collective emotion and real social phenomena has been widely studied, long-term dynamics of collective emotion has not been studied so far due to the lack of long persistent data sets. In this study, we extracted collective emotion over a 10-year period from 3.6 billion Japanese blog articles. Firstly, we find that collective emotion shows clear periodic cycles, i.e., weekly and seasonal behaviors, accompanied with pulses caused by natural disasters. For example, April is represented by high Tension, probably due to starting school in Japan. We also identified long-term memory in the collective emotion that is characterized by the power-law decay of the autocorrelation function over several months.
Low Field-size, Rate-Optimal Streaming Codes for Channels With Burst and Random Erasures

In this paper, we design erasure-correcting codes for channels with burst and random erasures, when a strict decoding delay constraint is in place. We consider the sliding-window-based packet erasure model proposed by Badr et al., where any time-window of width $w$ contains either up to $a$ random erasures or an erasure burst of length at most $b$. One needs to recover any erased packet, where erasures are as per the channel model, with a strict decoding delay deadline of $\tau$ time slots. Presently existing rate-optimal constructions in the literature require, in general, a field-size which grows exponential in $\tau$, for a constant $\frac{a}{\tau}$. In this work, we present a new rate-optimal code construction covering all channel and delay parameters, which requires an $O(\tau^2)$ field-size. As a special case, when $(b-a)=1$, we have a field-size linear in $\tau$. We also present three other constructions having linear field-size, under certain constraints on channel and decoding delay parameters. As a corollary, we obtain low field-size, rate-optimal convolutional codes for any given column distance and column span. Simulations indicate that the newly proposed streaming code constructions offer lower packet-loss probabilities compared to existing schemes, for selected instances of Gilbert-Elliott and Fritchman channels.
Bayesian topology identification of linear dynamic networks

In networks of dynamic systems, one challenge is to identify the interconnection structure on the basis of measured signals. Inspired by a Bayesian approach in [1], in this paper, we explore a Bayesian model selection method for identifying the connectivity of networks of transfer functions, without the need to estimate the dynamics. The algorithm employs a Bayesian measure and a forward-backward search algorithm. To obtain the Bayesian measure, the impulse responses of network modules are modeled as Gaussian processes and the hyperparameters are estimated by marginal likelihood maximization using the expectation-maximization algorithm. Numerical results demonstrate the effectiveness of this method.