Miracle-dz/UniFAR-FTUs huggingface dataset:
Atorvastatin downregulates HSP22 expression in an atherosclerotic model in vitro and in vivo

One of the pathological functions of heat shock protein 22 (HSP22) is the association with inflammatory diseases and atherosclerosis. However, the effects of a high-fat diet (HFD) or oxidized low-density lipoprotein (ox-LDL) combined with atorvastatin (ATV) on HSP22 expression are entirely unknown. The present study investigated the effects of ATV on HSP22 expression in HFD-induced atherosclerotic apolipoprotein E-deficient (ApoE−/−) mice and in ox-LDL-induced human umbilical vein endothelial cells (HUVECs). Furthermore, the influence of HSP22-knockdown on the HFD- or ox-LDL-induced atherosclerotic model was also examined. It was found that HFD or ox-LDL treatment significantly increased HSP22 expression in the serum and aorta, accompanied by decreased phosphorylated (p)-endothelial nitric oxide synthase (p-eNOS) activity and activated p38 mitogen-activated protein kinase (MAPK). However, these effects were suppressed by treatment with ATV. Furthermore, HSP22-knockdown showed reduced ox-LDL-induced lesions, evidenced by increased p-eNOS activity and inactivated p38 MAPK, while suppression of cell proliferation inhibition and cell cycle arrest were also observed. Taken together, the results of this study suggest that HFD or ox-LDL increased the expression of HSP22 and p-p38 MAPK, and decreased the p-eNOS activity in vitro and in vivo, and ATV could reduce the effects by downregulating HSP22 expression.
IL-33 Induces Murine Intestinal Goblet Cell Differentiation Indirectly via Innate Lymphoid Cell IL-13 Secretion

Regulation of the intestinal mucus layer by goblet cells is important for preventing inflammation and controlling infection. IL-33, a cytokine upregulated in inflammatory bowel disease and helminth infection, induces intestinal goblet cells, but the mechanism remains unclear. Enteroids are three-dimensional structures of primary small intestinal epithelial cells that contain all differentiated intestinal epithelial cell types. We developed an enteroid–immune cell coculture model to determine the mechanism through which IL-33 affects intestinal goblet cell differentiation. We report that IL-33 does not directly induce goblet cell differentiation in murine enteroids; however, IL-13, a cytokine induced by IL-33, markedly induces goblet cells and gene expression consistent with goblet cell differentiation. When enteroids are cocultured with CD90+ mesenteric lymph node cells from IL-33–treated mice, IL-33 then induces IL-13 secretion by group 2 innate lymphoid cells and enteroid gene expression consistent with goblet cell differentiation. In cocultures, IL-33–induced Muc2 expression is dependent on enteroid Il4ra expression, demonstrating a requirement for IL-13 signaling in epithelial cells. In vivo, IL-33–induced intestinal goblet cell hyperplasia is dependent on IL-13. These studies demonstrate that IL-33 induces intestinal goblet cell differentiation not through direct action on epithelial cells but indirectly through IL-13 production by goup 2 innate lymphoid cells.
Use-Relationship Based Classification for Software Components

In recent years, the maintenance period of the software system is increasing. The size of the software system has grown, and the number of classes and the relationship between classes are also increasingly complicated. If we can categorize software components based on information such as functions and roles, we believe that these classified components can be understood together, and are useful for understanding the system. In this paper, we proposed a classification method for software components based on similarity of use relation. For each component, a set of components used by the component was analyzed. And then, for each pair of components, the distance was calculated from the coincidence of the two sets. A distance matrix was created and components were classified by hierarchical cluster analysis. We applied this method to jlGui consisting of 70 components. 8 clusters of 36 components were extracted from the 70 components. Characteristics of the extracted clusters were evaluated, and the content of each cluster was introduced as a case study. In 7 clusters out of the 8 clusters, components of the cluster were strongly similar with each other from the viewpoint of their functions. Through these experiments, we confirmed that our method is effective for classifying components of the target software, and is useful for understanding them.
Dihydromyricetin Inhibits Inflammation of Fibroblast-Like Synoviocytes through Regulation of Nuclear Factor-κB Signaling in Rats with Collagen-Induced Arthritis

Dihydromyricetin (DMY), the main flavonoid of Ampelopsis grossedentata, has potent anti-inflammatory activity. However, the effect of DMY on chronic autoimmune arthritis remains undefined. In this study, we investigated the therapeutic effects of DMY on collagen-induced arthritis (CIA). Wistar rats were immunized with bovine type II collagen to establish CIA and were then administered DMY intraperitoneally (5, 25, and 50 mg/kg) every other day for 5 weeks. Paw swelling, clinical scoring, and histologic analysis were assessed to determine the therapeutic effects of DMY on the development of arthritis in CIA rats. The results showed that treatment with DMY significantly reduced erythema and swelling in the paws of CIA rats. Pathologic analysis of the knee joints and peripheral blood cytokine assay results confirmed the antiarthritic effects of DMY on synovitis and inflammation. Fibroblast-like synoviocytes (FLSs) were isolated from the synovium of CIA rats and treated with 10 ng/ml interleukin (IL)-1β. DMY significantly inhibited the proliferation, migration, and inflammation of IL-1β–induced FLSs, whereas it significantly increased IL-1β–induced FLS apoptosis in a dose-dependent manner (6.25–25 μM). Moreover, DMY suppressed phosphorylation of IκB kinase (IKK) and inhibitor of NF-κB α and subsequently reduced the IL-1β–induced nucleus translocation of NF-κB in FLSs. Through a molecular docking assay, we demonstrated that DMY could directly bind to the Thr9 and Asp88 residues in IKKα and the Asp95, Asn142, and Gln167 residues in IKKβ. These findings demonstrate that DMY could alleviate inflammation in CIA rats and attenuate IL-1β–induced activities in FLSs through suppression of NF-κB signaling.
Opportunities and challenges for developing closed-loop bioelectronic medicines

The peripheral nervous system plays a major role in the maintenance of our physiology. Several peripheral nerves intimately regulate the state of the brain, spinal cord, and visceral systems. A new class of therapeutics, called bioelectronic medicines, are being developed to precisely regulate physiology and treat dysfunction using peripheral nerve stimulation. In this review, we first discuss new work using closed-loop bioelectronic medicine to treat upper limb paralysis. In contrast to open-loop bioelectronic medicines, closed-loop approaches trigger ‘on demand’ peripheral nerve stimulation due to a change in function (e.g., during an upper limb movement or a change in cardiopulmonary state). We also outline our perspective on timing rules for closed-loop bioelectronic stimulation, interface features for non-invasively stimulating peripheral nerves, and machine learning algorithms to recognize disease events for closed-loop stimulation control. Although there will be several challenges for this emerging field, we look forward to future bioelectronic medicines that can autonomously sense changes in the body, to provide closed-loop peripheral nerve stimulation and treat disease.
Exercise and cardiorespiratory fitness on subjective memory complaints

ABSTRACT The purpose of this study was to examine the association between exercise and estimated cardiorespiratory fitness on subjective memory complaints in young adults. Four-hundred and 64 young adult college students (18–35 yrs) completed an online survey. Exercise behavior was assessed from the Physical Activity Vital Signs Questionnaire. Cardiorespiratory fitness was evaluated from an algorithm that included an assessment of age, gender, body mass index, waist circumference, resting heart rate, habitual physical activity behavior, and smoking status. Subjective memory complaints were assessed using the Prospective-Retrospective Memory Questionnaire. Subjective memory complaints were common among this young adult sample. However, exercise was not statistically significantly associated with prospective (β = −0.002, P = 0.25) or retrospective (β = −0.001, P = 0.26) memory complaints. Results were similar for cardiorespiratory fitness. In conclusion, we did not observe an association between exercise and estimated cardiorespiratory fitness on subjective memory complaints in young adults.
An intelligent approach for examining and detecting target data fragments in suspected large storage drives

The ever increasing capacity of storage devices is becoming a formidable obstruction to the digital forensic community due to its substantial investigation time and preservation space requirements. However, the investigation process becomes more complicated, whenever the fragmented or partially overwritten drives need forensic consideration. It is becoming extremely necessary to unfold novel methods the examination of storage drives involving a bulk volume of data. In this paper, the differential evolution (DE) technique is utilized with an unsupervised mean‐shift clustering approach in the field of digital forensics for intelligently locating the traces of target file in suspected storage drives or raw images. The proposed methodology leverages the drives' geometrical information in DE for obtaining random sector samples followed by fitness value and sector hash computation. The clustering algorithm evaluates the obtained intelligence and assists in estimating the regions of forensic significance in the drive, instead of considering the entire drive contents. As an outcome, a proof‐of‐concept Python based command line tool has been developed and released to support the study and further enhancement. The experiments and case studies demonstrated using the drives of different capacities demonstrates the efficacy of the proposed method.
Human cytomegalovirus US21 protein is a viroporin that modulates calcium homeostasis and protects cells against apoptosis

Significance During coevolution with its host, human cytomegalovirus (HCMV) has invested a large part of its protein coding potential to ensure the dysregulation of the majority of cellular homeostatic circuits. Defining the role of these HCMV proteins is important to understand viral pathogenesis and to design new antiviral strategies able to exploit their functions. Here, we report on the functional characterization of the protein encoded by the US21 gene, the founding member of the HCMV US12 gene family. The pUS21 acts as a calcium-permeable multitransmembrane channel able to reduce the calcium content of intracellular stores; pUS21-mediated tampering with intracellular calcium homeostasis, in turn, decreases the cells’ susceptibility to apoptosis, thus contributing to the overall HCMV protein toolbox evolved to blunt apoptosis in infected cells. The human cytomegalovirus (HCMV) US12 gene family comprises a set of 10 contiguous genes (US12 to US21) with emerging roles in the regulation of virus cell tropism, virion composition, and immunoevasion. Of all of the US12 gene products, pUS21 shows the highest level of identity with two cellular transmembrane BAX inhibitor motif-containing (TMBIM) proteins: Bax inhibitor-1 and Golgi anti-apoptotic protein, both of which are involved in the regulation of cellular Ca2+ homeostasis and adaptive cell responses to stress conditions. Here, we report the US21 protein to be a viral-encoded ion channel that regulates intracellular Ca2+ homeostasis and protects cells against apoptosis. Indeed, we show pUS21 to be a 7TMD protein expressed with late kinetics that accumulates in ER-derived vesicles. Deletion or inactivation of the US21 gene resulted in reduced HCMV growth, even in fibroblasts, due to reduced gene expression. Ratiometric fluorescence imaging assays revealed that expression of pUS21 reduces the Ca2+ content of intracellular ER stores. An increase in cell resistance to intrinsic apoptosis was then observed as an important cytobiological consequence of the pUS21-mediated alteration of intracellular Ca2+ homeostasis. Moreover, a single point mutation in the putative pore of pUS21 impaired the reduction of ER Ca2+ concentration and attenuated the antiapoptotic activity of pUS21wt, supporting a functional link with its ability to manipulate Ca2+ homeostasis. Together, these results suggest pUS21 of HCMV constitutes a TMBIM-derived viroporin that may contribute to HCMV’s overall strategy to counteract apoptosis in infected cells.
Forensic Comparison of Automotive Aluminum Wheel Fragments Using Synchrotron Radiation X‐ray Fluorescence with 18‐ and 116‐keV Excitation X‐rays

The performance of synchrotron radiation X‐ray fluorescence (SR‐XRF) spectrometry for nondestructive discrimination of small fragments of automotive aluminum wheels was studied. Fragments (< 500 × 500 μm2) of 45 kinds of wheels were first analyzed by scanning electron microscopy–energy dispersive spectroscopy (SEM‐EDS) and then by SR‐XRF. Despite the Mg/Al intensity ratio being a useful identification index, SEM‐EDS was not efficient enough because of the absence of other meaningful indicators of comparison. Conversely, pairwise comparison was conducted and a 92.9% identification was achieved via SR‐XRF using 18‐keV X‐rays. Trace heavy elements in the high‐energy region were detected by SR‐XRF using 116‐keV X‐rays, and an 82.9% identification was obtained. Combined use of 18‐ and 116‐keV X‐rays allowed 98.2% identification. Hence, SR‐XRF is a powerful tool for nondestructive discrimination of automotive aluminum wheels with high precision using trace elements in a wide energy region.
A Photoresponsive Hyaluronan Hydrogel Nanocomposite for Dynamic Macrophage Immunomodulation

Macrophages are a predominant immune cell population that drive inflammatory responses and exhibit transitions in phenotype and function during tissue remodeling in disease and repair. Thus, engineering an immunomodulatory biomaterial has significant implications for resolving inflammation. Here, a biomimetic and photoresponsive hyaluronan (HA) hydrogel nanocomposite with tunable 3D extracellular matrix (ECM) adhesion sites for dynamic macrophage immunomodulation is engineered. Photodegradative alkoxylphenacyl‐based polycarbonate (APP) nanocomposites are exploited to permit user‐controlled Arg–Gly–Asp (RGD) adhesive peptide release and conjugation to a HA‐based ECM for real‐time integrin activation of macrophages encapsulated in 3D HA–APP nanocomposite hydrogels. It is demonstrated that photocontrolled 3D ECM–RGD peptide conjugation can activate αvβ3 integrin of macrophages, and periodic αvβ3 integrin activation can enhance anti‐inflammatory M2 macrophage polarization. Altogether, an emerging use of biomimetic, photoresponsive, and bioactive HA–APP nanocomposite hydrogel is highlighted to command 3D cell–ECM interactions for modulating macrophage polarization, which may shed light on cell–ECM interactions in innate immunity and inspire new biomaterial‐based immunomodulatory therapies.
Perilipin‐2 promotes obesity and progressive fatty liver disease in mice through mechanistically distinct hepatocyte and extra‐hepatocyte actions

Wild‐type mice and mice with hepatocyte‐specific or whole‐body deletions of perilipin‐2 (Plin2) were used to define hepatocyte and extra‐hepatocyte effects of altered cellular lipid storage on obesity and non‐alcoholic fatty liver disease (NAFLD) pathophysiology in a Western‐diet (WD) model of these disorders. Extra‐hepatocyte actions of Plin2 are responsible for obesity, adipose inflammation and glucose clearance abnormalities in WD‐fed mice. Hepatocyte and extra‐hepatic actions of Plin2 mediate fatty liver formation in WD‐fed mice through distinct mechanisms. Hepatocyte‐specific actions of Plin2 are primary mediators of immune cell infiltration and fibrotic injury in livers of obese mice.
Closing the Loop: Optimizing Diabetes Care in the Hospital by Addressing Dispersed Information in Electronic Health Records and Using Clinical Decision Support

Multiple factors hinder the management of diabetes in hospitals. Amid the demands of practice, health care providers must collect, collate, and analyze multiple data points to optimally interpret glucose control and manage insulin dosing. Such data points are commonly dispersed in different sections of electronic health records (EHR), and the system for data display and physician interaction with the EHR are often poorly conducive to seamless clinical decision making. In this perspective article, we examine challenges in the process of EHR data retrieval, interpretation and decision making, using glucose management as an exemplar. We propose a conceptual, systems-based design for closing the loop between data gathering, analysis and decision making in the management of inpatient diabetes. This concept capitalizes on attributes of the EHR that can enable automated recognition of cases and provision of clinical recommendations.
Context is Key: New Approaches to Neural Coherence Modeling

We formulate coherence modeling as a regression task and propose two novel methods to combine techniques from our setup with pairwise approaches. The first of our methods is a model that we call "first-next," which operates similarly to selection sorting but conditions decision-making on information about already-sorted sentences. The second consists of a technique for adding context to regression-based models by concatenating sentence-level representations with an encoding of its corresponding out-of-order paragraph. This latter model achieves Kendall-tau distance and positional accuracy scores that match or exceed the current state-of-the-art on these metrics. Our results suggest that many of the gains that come from more complex, machine-translation inspired approaches can be achieved with simpler, more efficient models.
Altered levels of focal adhesion and extracellular matrix‐receptor interacting proteins were identified in Hailey‐Hailey disease by quantitative iTRAQ proteome analysis

Benign chronic familial pemphigus or Hailey‐Hailey disease (HHD, OMIM 169600) is a rare, autosomal dominant blistering skin disorder characterized by suprabasal cell separation (acantholysis) of the epidermis. To date, the proteomic changes in skin lesions from HHD patients has not been reported yet. In this study, a sample of skin lesions from HHD patients was collected for isobaric tags for relative and absolute quantitation to analyze proteome changes compared with unaffected individuals. The 134 differentially expressed proteins were assigned to at least one Gene Ontology term, and 123 annotated proteins with significant matches were assigned to 187 known metabolic or signaling pathways listed in the Kyoto Encyclopedia of Genes and Genomes. Most of the altered proteins in skin lesions of HHD patients were enriched in pathways involved in the PI3K‐Akt signaling, focal adhesion, extracellular matrix (ECM)‐receptor interaction, and protein digestion and absorption, such as collagen family members, microfibril‐associated glycoprotein 4 and plakophilin. The changes of proteins related to cell adhesion, ECM‐receptor interaction, and protein folding and glycosylation suggested that strategy targeted to alter cell junction and extracellular microenvironment might provide a potential treatment for HHD.
Independent and joint associations of blood lipids and lipoproteins with lung cancer risk in Chinese males: A prospective cohort study

To investigate the independent and joint associations of blood lipids and lipoproteins with lung cancer risk in Chinese males, a prospective cohort study was conducted. A total of 109,798 males with baseline information on total cholesterol (TC), triglycerides (TG), low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C) and non‐HDL were prospectively observed from 2006 to 2015 for cancer incidence. Cox proportional hazards models and restricted cubic spline (RCS) analysis were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During a 9‐year follow‐up, a total of 986 lung cancer cases were identified. Multivariable analyses showed that both males with low TC (HRQ1vs.Q2 = 1.27, 95%CI: 1.02–1.60) and males with high TC (HRQ5vs.Q2 = 1.30, 95%CI: 1.04–1.63) had an increased lung cancer risk, and the U‐shaped association was also revealed in the RCS analysis (poverall = 0.013, pnonlinear = 0.006). Furthermore, both low TG (HRQ1vs.Q2 = 1.24, 95%CI: 0.99–1.54) and high TG (HRQ5vs.Q2 = 1.27, 95%CI: 1.01–1.59) were associated with increased lung cancer risk, while low LDL‐C (HRQ1vs.Q2 = 1.38, 95%CI: 1.11–1.72) was associated with increased lung cancer risk. When TC, TG and LDL‐C were considered jointly, the number of abnormal indicators was linearly associated with an increased risk of lung cancer (ptrend < 0.001), as subjects with three abnormal indicators had a twofold higher risk of developing lung cancer (HR = 2.02, 95%CI: 1.62–2.54). Notably, these associations were statistically significant among never smokers, never drinkers and overweight/obese males. These findings suggest that dyslipidemia may potentially be a modifiable risk factor that has key scientific and clinical significance for lung cancer prevention.
The return of gemtuzumab ozogamicin: a humanized anti-CD33 monoclonal antibody–drug conjugate for the treatment of newly diagnosed acute myeloid leukemia

Through the years gemtuzumab ozogamicin (GO) has moved from a panacea in the treatment of acute myeloid leukemia (AML) to a pariah and back again. Early promise of targeted therapy with accelerated approval in the United States in 2000 gave way to fear over increased toxicity in the absence of efficacy, which subsequently resulted in the drug manufacturer voluntarily withdrawing GO from the market in 2010. We outline the history of GO in terms of initial drug development and early clinical trials that ultimately led the way to GO frontline use in AML based on a series of Phase III studies. Among these studies, we discuss the similarities and differences in terms of dosing, frequency, response rates, and toxicities that ultimately led to the re-approval of GO in 2017 based on efficacy, particularly in patients with core-binding factor (CBF) leukemia. Herein, we also review the clinical efficacy of GO in the frontline treatment of acute promyelocytic leukemia, which is based on either initial patient high-risk disease or potential co-morbidities that preclude the use of arsenic trioxide (ATO). Finally, we assess the current evidence for biomarkers aside from initial cytogenetics that may predict a favorable response to GO.