Miracle-dz/UniFAR-FTUs huggingface dataset:
Triangle collaboration assessment of autophagy, ER stress and hypoxia in leukemogenesis: a bright perspective on the molecular recognition of B-ALL

Abstract B-lineage acute lymphoblastic leukemia (B-ALL) is the most common acute leukemia in childhood and adults, which caused by many various crystalline and unclear agents. Owning to this matter, no significant progress has been made in the patients-recovery. Recently, autophagy pathway is considered as an ambiguous agent in leukemia evaluation. We aim to discover the expression levels of upstream autophagy-regulating genes in newly diagnosed B-ALL patients. In B-ALL group, BECN1, HIF1A and ERN1 expressions were significantly down-regulated, while BCL2 expression was up-regulated compared to the control group (p < .05). Moreover, there was significant positive correlation between the decreased BECN1 compared with Hypoxia and endoplasmic reticulum (ER) stress-related genes expression in the patients (p < .05). Our findings revealed that, ERN1 and ER stress pathway-related genes could be effective regulators of autophagy in B-ALL. More investigation is recommended to gain a deeper understanding into molecular pathophysiology of B-ALL to improve treatment and monitoring approaches in affected patients.
Stable contacts of naïve CD4 T cells with migratory dendritic cells are ICAM-1-dependent but dispensable for proliferation in vivo

ABSTRACT It is unclear if naïve T cells require dendritic cell ICAMs to proliferate inside lymph nodes. To check if and when CD4 lymphocytes use ICAMs on migratory DCs, wild-type and ICAM-1 and 2 double knock out bone marrow-derived DCs pulsed with saturating levels of an OT-II transgene-specific ovalbumin-derived peptide were co-transferred into skin-draining lymph nodes. Intravital imaging of OT-II lymphocytes entering these lymph nodes revealed that ICAM-1 and −2 deficient migratory DCs formed fewer stable conjugates with OT-II lymphocytes but promoted normal T cell proliferation. DC ICAMs were also not required for unstable TCR-dependent lymphocyte arrests on antigen presenting migratory DCs. Thus, rare antigen-stimulated ICAM-stabilized T-DC conjugates are dispensable for CD4 lymphocyte proliferation inside lymph nodes.
Transition-based combinatory categorial grammar parsing for English and Hindi

Given a natural language sentence, parsing is the task of assigning it a grammatical structure, according to the rules within a particular grammar formalism. Different grammar formalisms like Dependency Grammar, Phrase Structure Grammar, Combinatory Categorial Grammar, Tree Adjoining Grammar are explored in the literature for parsing. For example, given a sentence like “John ate an apple”, parsers based on the widely used dependency grammars find grammatical relations, such as that ‘John’ is the subject and ‘apple’ is the object of the action ‘ate’. We mainly focus on Combinatory Categorial Grammar (CCG) in this thesis. In this thesis, we present an incremental algorithm for parsing CCG for two diverse languages: English and Hindi. English is a fixed word order, SVO (Subject-VerbObject), and morphologically simple language, whereas, Hindi, though predominantly a SOV (Subject-Object-Verb) language, is a free word order and morphologically rich language. Developing an incremental parser for Hindi is really challenging since the predicate needed to resolve dependencies comes at the end. As previously available shift-reduce CCG parsers use English CCGbank derivations which are mostly right branching and non-incremental, we design our algorithm based on the dependencies resolved rather than the derivation. Our novel algorithm builds a dependency graph in parallel to the CCG derivation which is used for revealing the unbuilt structure without backtracking. Though we use dependencies for meaning representation and CCG for parsing, our revealing technique can be applied to other meaning representations like lambda expressions and for non-CCG parsing like phrase structure parsing. Any statistical parser requires three major modules: data, parsing algorithm and learning algorithm. This thesis is broadly divided into three parts each dealing with one major module of the statistical parser. In Part I, we design a novel algorithm for converting dependency treebank to CCGbank. We create Hindi CCGbank with a decent coverage of 96% using this algorithm. We also do a cross-formalism experiment where we show that CCG supertags can improve widely used dependency parsers. We experiment with two popular dependency parsers (Malt and MST) for two diverse languages: English and Hindi. For both languages, CCG categories improve the overall accuracy of both parsers by around 0.3-0.5% in all experiments. For both parsers, we see larger improvements specifically on dependencies at which they are known to be weak: long distance dependencies for Malt, and verbal arguments for MST. The result is particularly interesting in the case of the fast greedy parser (Malt), since
Lysophosphatidic Acid and Autotaxin-associated Effects on the Initiation and Progression of Colorectal Cancer

The intestinal epithelium interacts dynamically with the immune system to maintain its barrier function to protect the host, while performing the physiological roles in absorption of nutrients, electrolytes, water and minerals. The importance of lysophosphatidic acid (LPA) and its receptors in the gut has been progressively appreciated. LPA signaling modulates cell proliferation, invasion, adhesion, angiogenesis, and survival that can promote cancer growth and metastasis. These effects are equally important for the maintenance of the epithelial barrier in the gut, which forms the first line of defense against the milieu of potentially pathogenic stimuli. This review focuses on the LPA-mediated signaling that potentially contributes to inflammation and tumor formation in the gastrointestinal tract.
Sustained release of a model water-soluble compound via dry powder aerosolizable acetalated dextran microparticles

Abstract Objective: To design and characterize aerosol microparticles (MP) to provide sustained release of the water-soluble compound sulforhodamine B (SRB) and achieve effective aerosol dispersion. Significance: Modulating the release of water-soluble compounds remains a challenge in pulmonary drug delivery. Methods: SRB and water made up an aqueous solution, while acetalated dextran (Ac-Dex) and isopropyl alcohol made up an organic solution. The two solutions were mixed together, and the solution was spray dried to produce MP. MP were characterized for morphology, size, release kinetics, aerosol dispersion, and cellular interactions. Results: Ac-Dex MP exhibited corrugated morphology and aerodynamic diameters from 2.06 to 2.86 μm. MP deposited in all stages of a Next Generation Impactor, with >90% fine particle fraction. MP exhibited encapsulation efficiencies >129% with SRB loading values up to 16.7 μg SRB/mg MP. MP exhibited sustained release of SRB at pH 7 and fast release at pH 5. In vitro experiments showed minimal cytotoxicity, successful uptake of MP in epithelial cells, and no disruption to the integrity of epithelial monolayers. Conclusions: Ac-Dex MP systems demonstrated the ability to provide sustained the release of a water-soluble therapeutic in addition to effective aerosol dispersion for pulmonary applications. Graphical Abstract
Increased Activity in Patients with Cardiovascular Risk Factors Increases Heart Rate Variability

This study evaluated the effect of increased physical activity on high-frequency (HF) heart rate variability (HRV) during the first hour after sleep onset in patients with hypertension and/or stable angina pectoris. Physical activity and HF were measured using activity monitors and 24-hour Holter monitors at baseline and 6 months later. The physical activity increased in 28 patients (increase group) and decreased in 20 patients (decrease group) after 6 months. In this study, after 6 months, compared to the decreased physical activity group, the increased physical activity group showed a significant increase in the HF index during the first hour after sleep onset. Therefore, the increase in the HF index may have been due to the increase in physical activity. An increase in physical activity suggests that the quality of sleep early in the sleep cycle may be improved, which may affect the patient’s prognosis.
Next generation sequencing panel in undifferentiated autoinflammatory diseases identify patients with colchicine-responder recurrent fevers.

OBJECTIVES The number of innate immune system disorders classified as systemic autoinflammatory diseases (SAID) has increased in recent years. More than 70% of patients with clinical manifestations of SAID did not receive a molecular diagnosis, thus being classed as so-called undifferentiated or undefined SAID (uSAID). The aim of the present study was to evaluate a next-generation sequencing (NGS)-based clinically oriented protocol in patients with uSAID. METHODS We designed a NGS panel that included 41 genes clustered in seven subpanels. Patients with uSAID were classified into different groups according to their clinical features and sequenced for the coding portions of the 41 genes. RESULTS Fifty patients were enrolled in the study. Thirty-four patients (72%) displayed recurrent fevers not consistent with a PFAPA phenotype. Sixteen patients displayed a chronic inflammatory disease course. A total of 100 gene variants were found (mean 2 per patient; range 0-6), a quarter of which affected suspected genes. Mutations with a definitive diagnostic impact were detected in two patients. Patients with genetically negative recurrent fevers displayed a prevalent gastrointestinal, skin and articular involvement. Patients responded to steroids on demands (94%) and colchicine, with a response rate of 78%. CONCLUSION Even with a low molecular diagnostic rate, a NGS-based approach is able to provide a final diagnosis in a proportion of uSAID patients with evident cost-effectiveness. It also allows the identification of a subgroup of genetically negative patients with recurrent fever responding to steroid on demand and colchicine.
Less Is More: Norwegian Drug Regulation, Antibiotic Policy, and the “Need Clause”

Policy Points The current crisis of antibiotic resistance calls for policy reforms locally and globally. Historical insight in different regulatory systems can inform current decision making. A strong regulatory control implementing antimicrobial resistance concerns can ensure the combined objective of promoting access and limiting excess use by letting only certain drugs onto the market in compliance with public health needs. Regulation at this level also has powerful effects on consumption and needs to be considered as a tool for curbing antibiotic resistance. The Norwegian drug regulatory procedures was an example of how national drug regulatory authorities can promote innovation of new drugs that meet public health needs indirectly by accepting only drugs of added therapeutic value. Context Antibiotic resistance is an increasingly serious threat to global health that requires coordinated action. Most current policy efforts address the lack of medicines. There is also a need for new thinking on promoting access to all who are in need of antibiotics, while simultaneously curbing inappropriate use. As the situation calls for new approaches, we examined one drug regulatory system in which antimicrobial resistance (AMR) has been on the agenda for a long time. The Norwegian drug regulatory system, and particularly its “need clause,” has been invoked in international debates but not previously studied in detail. Methods We conducted a historical review of the Norwegian drug regulatory system by examining the archives of the Norwegian health authorities, the Norwegian Medicines Agency, and policy debates in the period. Findings The Norwegian drug regulatory system focused on the rational use of drugs, tied closely to public health needs. It was originally written to address unnecessary consumption of drugs, not consumer protection and safety. The most flexible element within this system stated that a drug must be “needed” in order to be registered. When antibiotic resistance became a concern, it limited the market entry of drugs considered to promote resistance, such as combination and broad‐spectrum products. This was a powerful and flexible regulatory device that also influenced drug consumption. Conclusions The need clause has lately been promoted as an alternative to address the current situation. The solutions to the problem of antibiotic resistance cannot be the same everywhere, and we do not argue that this drug regulatory system should be adopted globally. However, the current situation calls for consideration of many different aspects. This historical case demonstrates how regulatory procedures can be used to limit market entrance and promote appropriate use simultaneously.
Characterizing symbiont inheritance during host–microbiota evolution: Application to the great apes gut microbiota

Microbiota play a central role in the functioning of multicellular life, yet understanding their inheritance during host evolutionary history remains an important challenge. Symbiotic microorganisms are either acquired from the environment during the life of the host (i.e. environmental acquisition), transmitted across generations with a faithful association with their hosts (i.e. strict vertical transmission), or transmitted with occasional host switches (i.e. vertical transmission with horizontal switches). These different modes of inheritance affect microbes’ diversification, which at the two extremes can be independent from that of their associated host or follow host diversification. The few existing quantitative tools for investigating the inheritance of symbiotic organisms rely on cophylogenetic approaches, which require knowledge of both host and symbiont phylogenies, and are therefore often not well adapted to DNA metabarcoding microbial data. Here, we develop a model‐based framework for identifying vertically transmitted microbial taxa. We consider a model for the evolution of microbial sequences on a fixed host phylogeny that includes vertical transmission and horizontal host switches. This model allows estimating the number of host switches and testing for strict vertical transmission and independent evolution. We test our approach using simulations. Finally, we illustrate our framework on gut microbiota high‐throughput sequencing data of the family Hominidae and identify several microbial taxonomic units, including fibrolytic bacteria involved in carbohydrate digestion, that tend to be vertically transmitted.
New classifications of gastroesophageal reflux disease: an improvement for patient management?

ABSTRACT Introduction: Gastroesophageal reflux disease (GERD) is a very common and often debilitating disease. In the broad spectrum of GERD phenotypes, three main groups may be traditionally distinguished: 1) patients only affected by esophageal and/or extra-esophageal symptoms; 2) patients with erosive esophagitis and 3) patients with further complications. Areas covered: This review provides an overview on the current classifications of GERD patients, and their impact on their management. Expert opinion: In 2017, the GERD Consensus Working Group focused the attention on patients unresponsive to PPIs. In this scenario, a diagnosis of GERD might be confirmed by evident signs of erosive esophagitis and the finding of pH or multichannel intraluminal impedance-pH tests, such as more than 6%. The ‘Lyon Consensus’ panel of experts confirmed that positive indices of reflux-symptom association, without other altered parameters, represent reflux hypersensitivity. GERD requires a customized management; it is crucial to assess frequency and severity of symptoms and their response to an optimal course of therapy as well as to explore the endoscopic alterations and consider other diagnoses responsible for persistent symptoms.
Effects of trace metal elements on ultrastructural features of hepatopancreas of Armadillidium granulatum Brandt, 1833 (Crustacea, Isopoda)

This study was conducted to compare metals bioaccumulation in the terrestrial isopod Armadillidium granulatum collected from Ghar El Melh lagoon. We focused on recognizing the effects of trace elements on hepatopancreas functional role. To this end, isopod specimens were exposed for 3 weeks to sediments contaminated with cadmium, copper, zinc, mercury, and nickel. Three concentrations were used in duplicate for each experimental condition. At the end of the experiment, metal body burdens were determined using flame atomic absorption spectrometry. Results of the bioaccumulation factor (BAF) showed that the species A. granulatum was classified as a Cu macroconcentrator (BAF > 2) and a Zn deconcentrator (BAF < 2). Dose dependent morphological and histological changes were observed in the hepatopancreas cells using transmission electron microscopy. The predominant features were: microvillus border disruption, condensation of the cytoplasm with increasing endoplasmic reticulum, mitochondria, lysosomes and granules that accumulated metals in B and S cells. The number of lipid droplets decreased especially after Cd, Zn, Hg, and Ni treatments. This study demonstrated that the terrestrial isopod A. gramulatum could be a good indicator of soil metal contamination.
Let-7f-5p suppresses Th17 differentiation via targeting STAT3 in multiple sclerosis

T helper 17 (Th17) cells are regarded as key factors in the pathogenesis of multiple sclerosis (MS). Although the involvement of certain microRNAs (miRNAs) in the development of MS has been reported, their roles in Th17 cell differentiation and MS pathogenesis remain elusive. In this study, we identified that let-7f-5p expression is significantly downregulated in CD4+ T cells from MS patients and during the process of Th17 differentiation. The overexpression of let-7f-5p suppressed Th17 differentiation, whereas the knockdown of let-7f-5p expression enhanced this progress. We then explored the molecular mechanism through which let-7f-5p suppressed Th17 differentiation and identified signal transducer and activator of transcription 3 (STAT3), a pivotal transcription factor of Th17 cells, as a direct target of let-7f-5p. In contrast to the downregulated expression of let-7f-5p, STAT3 and p-STAT3 protein levels were dramatically upregulated and inversely correlated with let-7f-5p in peripheral blood CD4+ T cells from MS patients. In conclusion, let-7f-5p functions as a potential inhibitor of Th17 differentiation in the pathogenesis of MS by targeting STAT3 and may serve as a new therapeutic target.
In Response to Hemodynamic and Pharmacokinetic Analysis of Oxymetazoline Use During Nasal Surgery in Children

Thank you for your comments regarding our article “Hemodynamic and Pharmacokinetic Analysis of Oxymetazoline Use During Nasal Surgery in Children”. The authors are grateful that you found our study informative, as your work has been the motivation for our interest in this subject. Currently, the United States Food and Drug Administration (FDA) approves oxymetazoline use in patients who are ≥6 years of age. Unfortunately, pharmacokinetic studies that define the appropriate dosing of this medication in children, especially infants and toddlers, are lacking. These data are needed because it appears that oxymetazoline offers some clinical superiority over other agents. Similar to the case reported by Latham and Jardine, we reported significant hemodynamic effects following the placement of oxymetazoline-soaked pledgets into the nasal cavity of a 4-year-old child during a bilateral inferior turbinate reduction. Subsequently, we had additional anecdotal experience with an adolescent who developed hypertension, left ventricular strain, and pulmonary edema following the unrestricted intraoperative administration of oxymetazoline during closed reduction of a nasal fracture. Latham and Jardine demonstrated that when the bottle is inverted, as may occur when a patient is supine on the operating room table, the volume delivered is 15 to 80 times that delivered in the upright position. These results were independently verified by our group. The current study demonstrates that, despite the volumetric increase of oxymetazoline when administered by nasal pledgets, the serum concentration achieved was not excessive. Importantly, it does not lead to significant hemodynamic changes when used as described. Given the concerns outlined above, we agree wholeheartedly with Dr. Latham that some standardized method is needed for the administration of oxymetazoline. This can be accomplished by measuring out a specific volume of the liquid prior to administration and avoiding the use of an inverted over-the-counter bottle for administration. When oxymetazoline-soaked pledgets are used, the total volume of oxymetazoline should be limited and placement should minimize the potential for absorption from nonsurgical areas. Despite the widespread use of oxymetazoline in a variety of clinical settings, the reports of adverse effects remain rare, sporadic, and anecdotal. Although it may be that underreporting of serious adverse events is present, it may also be that these reports demonstrate that the life-threatening hemodynamic effects require a combination of factors to be present, which are yet to be elucidated. Additional research is needed to more clearly define the safe use of oxymetazoline in pediatric patients in various clinical settings.
Adaptive Neural Event-Triggered Control for Discrete-Time Strict-Feedback Nonlinear Systems

This paper proposes a novel event-triggered (ET) adaptive neural control scheme for a class of discrete-time nonlinear systems in a strict-feedback form. In the proposed scheme, the ideal control input is derived in a recursive design process, which relies on system states only and is unrelated to virtual control laws. In this case, the high-order neural networks (NNs) are used to approximate the ideal control input (but not the virtual control laws), and then the corresponding adaptive neural controller is developed under the ET mechanism. A modified NN weight updating law, nonperiodically tuned at triggering instants, is designed to guarantee the uniformly ultimate boundedness (UUB) of NN weight estimates for all sampling times. In virtue of the bounded NN weight estimates and a dead-zone operator, the ET condition together with an adaptive ET threshold coefficient is constructed to guarantee the UUB of the closed-loop networked control system through the Lyapunov stability theory, thereby largely easing the network communication load. The proposed ET condition is easy to implement because of the avoidance of: 1) the use of the intermediate ET conditions in the backstepping procedure; 2) the computation of virtual control laws; and 3) the redundant triggering of events when the system states converge to a desired region. The validity of the presented scheme is demonstrated by simulation results.