Miracle-dz/UniFAR-FTUs huggingface dataset:
Design, synthesis, biological evaluation and molecular dynamics simulation studies of (R)-5-methylthiazolidin-4-One derivatives as megakaryocyte protein tyrosine phosphatase 2 (PTP-MEG2) inhibitors for the treatment of type 2 diabetes

Abstract PTP-MEG2 plays a significant role in insulin production and is able to enhance insulin signaling and improve insulin sensitivity. So, PTP-MEG2 inhibitors are closely associated with type 2 diabetes therapy. A series of novel (R)-5-methylthiazolidin-4-one derivatives were designed and synthesized, and their PTP-MEG2 inhibitory activities (IC50) were determined. Among the desired compounds, 1h shares the highest inhibitory activity (IC50 = 1.34 μM) against PTP-MEG2. Additionally, various post-dynamic analyses confirmed that when compound 1h bound to the PTP-MEG2, the protein conformations became unstable and the function of the pTyr recognition loop (Asn331-Cys338) would be disturbed. And thus, the ideal conformations needed for the catalytic activity was difficult to be maintained. In brief, these might be how the compound 1h worked. Furthermore, we also found that the key residues Arg332 would play a critical role in disturbing the residue interactions. AbbreviationsDCCM dynamic cross-correlation mappingDMF N,N-dimethylformamideDSSP definition of secondary structure of proteinsFOXO forkhead transcription factorsMD molecular dynamicsPCA principal component analysisPDB protein data bankPTKs protein tyrosine kinasesPTPs protein tyrosine phosphatasesPTP-MEG2 megakaryocyte protein tyrosine phosphatase 2RIN residue interaction networkRING Residue Interaction Network GeneratorRMSD root means square deviationRMSF root mean square fluctuation Communicated by Ramaswamy H. Sarma
Single-Particle Enumeration-based Sensitive Glutathione S-Transferase Assay with Fluorescent Conjugated Polymer Nanoparticle.

Glutathione S-transferase (GST) is a group of multifunctional enzyme and participates in many physiological processes, such as xenobiotic biotransformation, drug metabolism and degradation of toxic products. Herein, we demonstrate a label-free fluorescent conjugated polymer nanoparticles (FCPNPs)-based single-particle enumeration (SPE) method for the sensitive GST assay. Fluorescence resonance energy transfer (FRET) is formed between the glutathione modified FCPNPs (FCPNPs-GSH) and polyethyleneimine capped gold nanoparticles (GNPs@PEI). Therefore, the fluorescence of FCPNPs-GSH is quenched remarkably. In the presence of GST, GNPs@PEI stay away from FCPNPs-GSH due to the specific interaction between FCPNPs-GSH and GST, leading to the inhibition of FRET. As a result, the fluorescence emission of FCPNPs-GSH is restored, which is reflected as the increase of the number of fluorescent particle in the microscopic image. By statistically counting the target concentration-dependent fluorescent particle number, accurate quantification of GST is achieved. The linear range from 0.01 to 6 μg/mL is obtained for GST assay and the limit-of-detection (LOD) is 1.03 ng/mL, which is much lower than the ensemble fluorescence spectra measurements in bulk solution. In urine sample assay, satisfactory recoveries in the range of 97.5-106.5. 0% are achieved. Because of the high sensitivity and excellent specificity, this method can be extended to other disease-related biomolecules detection in the future.
Towards Digital Mathematical Library: Optical CharacterRecognition of Mathematical Texts

This paper describes a prototype of the OCR math engine built in the DML-CZ project. Solution stands on the combination of FineReader and InftyReader programmes. The achieved error rate (counting not only character errors, but also errors in the recognition of structure of mathematics notation) decreased from an initial 12\% to under 1\%.
Clustering Neural Patterns in Kernel Reinforcement Learning Assists Fast Brain Control in Brain-Machine Interfaces

Neuroprosthesis enables the brain control on the external devices purely using neural activity for paralyzed people. Supervised learning decoders recalibrate or re-fit the discrepancy between the desired target and decoder’s output, where the correction may over-dominate the user’s intention. Reinforcement learning decoder allows users to actively adjust their brain patterns through trial and error, which better represents the subject’s motive. The computational challenge is to quickly establish new state-action mapping before the subject becomes frustrated. Recently proposed quantized attention-gated kernel reinforcement learning (QAGKRL) explores the optimal nonlinear neural-action mapping in the Reproducing Kernel Hilbert Space (RKHS). However, considering all past data in RKHS is less efficient and sensitive to detect the new neural patterns emerging in brain control. In this paper, we propose a clustering-based kernel RL algorithm. New neural patterns emerge and are clustered to represent the novel knowledge in brain control. The current neural data only activate the nearest subspace in RKHS for more efficient decoding. The dynamic clustering makes our algorithm more sensitive to new brain patterns. We test our algorithm on both the synthetic and real-world spike data. Compared with QAGKRL, our algorithm can achieve a quicker knowledge adaptation in brain control with less computational complexity.
Systemic administration of the cyclin-dependent kinase inhibitor (S)-CR8 selectively reduces escalated ethanol intake in dependent rats.

BACKGROUND Chronic exposure to ethanol and other drugs of abuse can alter the expression and activity of cyclin-dependent kinase 5 (CDK5) and its cofactor p35, but the functional implication of CDK5 signaling in the regulation of ethanol-related behaviors remains unknown. In the present study, we sought to determine whether CDK5 activity plays a role in the escalation of ethanol self-administration triggered by dependence. METHODS We tested the effect of systemically administered (S)-CR8, a non-selective CDK inhibitor, on operant responding for ethanol or saccharin, a highly palatable reinforcer, in adult male Wistar rats. Half of the rats were made ethanol-dependent via chronic intermittent ethanol inhalation (CIE). We then sought to identify a possible neuroanatomical locus for the behavioral effect of (S)-CR8 by quantifying protein levels of CDK5 and p35 in subregions of the extended amygdala and prefrontal cortex from ethanol-naïve, non-dependent, and dependent rats at the expected time of ethanol self-administration. We also analyzed the phosphorylation of four CDK5 substrates and of the CDK substrate consensus motif. RESULTS (S)-CR8 dose-dependently reduced ethanol self-administration in dependent rats. It had no effect on water or saccharin self-administration, nor in non-dependent rats. The abundance of CDK5 or p35 was not altered in any of the brain regions analyzed. In the bed nucleus of the stria terminalis, CDK5 abundance was negatively correlated with intoxication levels during ethanol vapor exposure but there was no effect of dependence on the phosphorylation ratio of CDK5 substrates. In contrast, ethanol dependence increased the phosphorylation of low-molecular weight CDK substrates in the basolateral amygdala. CONCLUSIONS The selective effect of (S)-CR8 on excessive ethanol intake has potential therapeutic value for the treatment of alcohol use disorders. Our data do not support the hypothesis that this effect would be mediated by the inhibition of upregulated CDK5 activity in the extended amygdala nor prefrontal cortex. However, increased activity of CDKs other than CDK5 in the basolateral amygdala may contribute to excessive ethanol consumption in alcohol dependence. Other (S)-CR8 targets may also be implicated. This article is protected by copyright. All rights reserved.
Risk factors for early bleeding complications after lung transplantation – a retrospective cohort study

Risk factors for early bleeding complications after lung transplantation are not well described. Our aim was to evaluate coagulation test results and the use of extracorporeal membrane oxygenation as risk factors for bleeding after lung transplantation. We analyzed a single‐center cohort of bilateral lung transplants between January 2009 and August 2015. Predictors of severe postoperative bleeding (bleeding requiring reoperation within 48 h of transplantation) were assessed using multivariable logistic regression. The effect of bleeding on survival was assessed using a Cox proportional‐hazards model. Twenty‐nine (4.5%) of 641 patients experienced severe postoperative bleeding. Postoperative fibrinogen levels (OR = 0.99, 95% CI 0.98–0.995, P = 0.001; per mg/dl increase) and pre‐ and postoperative use of extracorporeal membrane oxygenation (OR = 14.41% 95% CI 5.4–40.19, P < 0.001 and OR = 4.25, 95% CI 1.0–11.09, P = 0.002, respectively) were associated with an increased risk of severe postoperative bleeding. Severe postoperative bleeding was associated with decreased survival within 60 days after transplantation (adjusted HR = 5.73, 95% CI 2.52–13.02, P < 0.001). Low postoperative fibrinogen levels, and pre‐ and postoperative use of extracorporeal membrane oxygenation were risk factors for bleeding after lung transplantation.
Recent Progress in CVD Growth of 2D Transition Metal Dichalcogenides and Related Heterostructures

In recent years, 2D layered materials have received considerable research interest on account of their substantial material systems and unique physicochemical properties. Among them, 2D layered transition metal dichalcogenides (TMDs), a star family member, have already been explored over the last few years and have exhibited excellent performance in electronics, catalysis, and other related fields. However, to fulfill the requirement for practical application, the batch production of 2D TMDs is essential. Recently, the chemical vapor deposition (CVD) technique was considered as an elegant alternative for successfully growing 2D TMDs and their heterostructures. The latest research advances in the controllable synthesis of 2D TMDs and related heterostructures/superlattices via the CVD approach are illustrated here. The controlled growth behavior, preparation strategies, and breakthroughs on the synthesis of new 2D TMDs and their heterostructures, as well as their unique physical phenomena, are also discussed. Recent progress on the application of CVD‐grown 2D materials is revealed with particular attention to electronics/optoelectronic devices and catalysts. Finally, the challenges and future prospects are considered regarding the current development of 2D TMDs and related heterostructures.
Mass spectrometric investigations into the brain delivery of abacavir, stavudine and didanosine in a rodent model

Abstract HIV replication in the brain is unopposed due to reduced antiretroviral drug penetration into the central nervous system (CNS). Prevalence of HIV-associated neurocognitive disorder (HAND) has increased severely in patients living with HIV despite current treatments. The aims of this study were to evaluate the brain bio-distribution of alternative nucleoside reverse transcriptase inhibitors, abacavir, stavudine and didanosine in the CNS and to determine their localization patterns in the brain. Sprague-Dawley rats received 50 mg kg−1 single i.p dose of each drug. Mass spectrometric techniques were then used to investigate the pharmacokinetics and localization patterns of these drugs in the brain using LC-MS/MS and mass spectrometric imaging (MSI), respectively. Abacavir, stavudine and didanosine reached the Brain Cmax with concentration of 831.2, 1300 and 43.37 ngmL−1, respectively. Based on MSI analysis Abacavir and Stavudine were located in brain regions that are strongly implicated in the progression of HAND. Abacavir and Stavudine penetrated into CNS, reaching a Cmax that was above the IC50 for HIV (457.6 and 112.0 ngmL−1, respectively), however, it was noted ddI showed poor entry within the brain, therefore, it is recommended that this drug cannot be considered for treating CNS-HIV.
Support to informal caregivers of patients with severe chronic obstructive pulmonary disease: a qualitative study of caregivers’ and professionals’ experiences in Swedish hospitals

Objectives Informal caregivers of patients with chronic obstructive pulmonary disease (COPD) experience a heavy caregiver burden, but few studies have explored what support they need. The aim of this study was to describe perceptions of healthcare support to informal caregivers, both from the family caregiver’s and the staff’s perspective. Design A qualitative interview study involving semi-structured interviews and analysed with content analysis. Participants In total, 54 participated: 36 informal caregivers of patients with severe (stage 3–4) COPD and 17 healthcare staff. Results Two main themes emerged from the analysis: (1) Ambiguity impedes provision of support. Both caregivers and staff experienced ambiguity. The informal caregivers needed emotional, practical and informational support but talked about unclear expectations, while the staff described an uncertainty about their duties regarding the families. There were no routines to unburden the families. Moreover, language and cultural barriers hampered their efforts. (2) Knowledgeable and perceptive communication is key to support. Both caregivers and staff described positive experiences of dialogue. The dialogue may facilitate means to caregiver support and was a support in itself. Conclusions Our findings suggest that strategies and routines for caregiver support, including communication skills among the staff, should be developed, to move toward the family perspective advocated in palliative- and nursing family care.
Bone Metabolism Impairment in Heart Transplant: Results From a Prospective Cohort Study

Background. Data on the prevention of fractures after heart transplant (HTx) are controversial in the literature. Understanding the effects of HTx on bone may guide appropriate treatments in this high-risk population. Methods. Seventy adult HTx patients were followed for 12 months. Clinical and laboratory parameters, bone mineral density, microarchitecture, and vertebral fractures were assessed at baseline (after intensive care unit discharge) and at 6 and 12 months. Patients received recommendations regarding calcium intake and vitamin D supplementation after HTx. Results. At baseline, 27% of patients had osteoporosis, associated with the length of hospitalization before HTx (P = 0.001). Bone mineral density decreased in the first 6 months, with partial recovery later. Bone microarchitecture deteriorated, mainly in the trabecular bone in the first 6 months and cortical bone in the subsequent 6 months. At baseline, 92.9% of patients had vitamin D levels <30 ng/mL and 20.0% <10 ng/mL. Patients also had calcium at the lower limit of normal, high alkaline phosphatase, and high bone resorption biomarker. These abnormalities were suggestive of impaired bone mineralization and normalized at 6 months with correction of vitamin D deficiency. The majority of vertebral fractures were identified at baseline (23% of patients). After multivariate analyses, only a lower fat mass persisted as a risk factor for vertebral fractures (odds ratio, 1.23; 95% confidence interval, 1.04-1.47; P = 0.012). Conclusions. High frequencies of densitometric osteoporosis, vitamin D deficiency, bone markers abnormalities, and vertebral fractures were observed shortly after HTx. Calcium and vitamin D supplementation should be the first step in correcting bone mineralization impairment before specific osteoporosis treatment.
Quantifying cellular protrusion in alginate capsules with covalently crosslinked shells

Abstract This work describes viability and distribution of INS-1E beta cells in shell-crosslinked alginate capsules, focussing on cells located near the capsule surface. Capsules were formed by air-shearing alginate suspensions of INS-1E cells into a gelling bath, and coating with poly-l-lysine (PLL) and 50% hydrolysed poly(methylvinylether-alt-maleic anhydride) to form crosslinked networks reinforcing the capsule surfaces. The percentage of cells at the capsule surface were determined using 2D and 3D confocal colocalization mapping. Encapsulated INS-1E cells showed high cell viability and progressive cell clustering out to six weeks. About 30% of cells were initially colocated with the 20 micrometer thick alginate-PLL-PMM50 shell, with 7% of cells protruded at the capsule surfaces, both reflecting random cell distributions. Protruding cells may cause cell-based immune responses, weaken capsules, and potentially result in cell escape from the capsules. The data shown indicate that reinforcing capsules with crosslinked shells may assist in preventing cell exposure and escape.
Comparison of carcinogenic potency across life stages: implications for the assessment of transplacental cancer risk

ABSTRACT Cancer development from in utero exposure has been documented for a variety of agents with the most commonly studied compounds exhibiting mutagenic and genotoxic carcinogen properties. Age-dependent adjustment factors (ADAFs) are applied by the US Environmental Protection Agency to many such carcinogens when assessing cancer risk from early postnatal (PN) exposures; however, this approach has not been widely considered for transplacental (TP) exposure. To explore this question and further evaluate prenatal susceptibility a database of early life animal studies developed by California Office of Environmental Health Hazard Assessment (OEHHA) enhanced with additional literature searching was evaluated. Nine genotoxic carcinogens and one mixture (cigarette smoke) have data available via TP only, PN only and adult-only protocols. Potency comparisons across these lifestages displayed similarly greater potency in male liver and brain compared to adult-only exposure. Both TP and PN exposures were not markedly different than adult-only for other targets such as female liver and blood-borne tumors. Similarity in TP and PN targets and potency for carcinogen action suggests that a 10-fold ADAF may be applied for TP exposure as is currently applied to PN exposure. A similar conclusion was reached by OEHHA. The implications of this heightened TP vulnerability are greatest for less-than-lifetime exposure and this approach might be used to assess the level of cancer risk from exposures during pregnancy. A case example employing a mutagenic flame retardant was used to exemplify application of a TP ADAF for evaluating risks during pregnancy.
Fabrication Techniques for Vascular and Vascularized Tissue Engineering

Impaired or damaged blood vessels can occur at all levels in the hierarchy of vascular systems from large vasculatures such as arteries and veins to meso‐ and microvasculatures such as arterioles, venules, and capillary networks. Vascular tissue engineering has become a promising approach for fabricating small‐diameter vascular grafts for occlusive arteries. Vascularized tissue engineering aims to fabricate meso‐ and microvasculatures for the prevascularization of engineered tissues and organs. The ideal small‐diameter vascular graft is biocompatible, bridgeable, and mechanically robust to maintain patency while promoting tissue remodeling. The desirable fabricated meso‐ and microvasculatures should rapidly integrate with the host blood vessels and allow nutrient and waste exchange throughout the construct after implantation. A number of techniques used, including engineering‐based and cell‐based approaches, to fabricate these synthetic vasculatures are herein explored, as well as the techniques developed to fabricate hierarchical structures that comprise multiple levels of vasculature.
An update on emerging drugs in osteosarcoma: towards tailored therapies?

ABSTRACT Introduction: Current treatment of conventional and non-conventional high-grade osteosarcoma (HGOS) is based on the surgical removal of primary tumor and, when possible, of metastases and local reccurrence, together with systemic pre- and post-operative chemotherapy with drugs that have been used since decades. Areas covered: This review is intended to summarize the new agents and therapeutic strategies that are under clinical evaluation in HGOS, with the aim to increase the cure probability of this highly malignant bone tumor, which has not significantly improved during the last 30–40 years. The list of drugs, compounds and treatment modalities presented and discussed here has been generated by considering only those that are included in presently ongoing and recruiting clinical trials, or which have been completed in the last 2 years with reported results, on the basis of the information obtained from different and continuously updated databases. Expert opinion: Despite HGOS is a rare tumor, several clinical trials are presently evaluating different treatment strategies, which may hopefully positively impact on the outcome of patients who experience unfavorable prognosis when treated with conventional therapies.
MP2RAGE multispectral voxel‐based morphometry in focal epilepsy

We assessed the applicability of MP2RAGE for voxel‐based morphometry. To this end, we analyzed its brain tissue segmentation characteristics in healthy subjects and the potential for detecting focal epileptogenic lesions (previously visible and nonvisible). Automated results and expert visual interpretations were compared with conventional VBM variants (i.e., T1 and T1 + FLAIR). Thirty‐one healthy controls and 21 patients with focal epilepsy were recruited. 3D T1‐, T2‐FLAIR, and MP2RAGE images (consisting of INV1, INV2, and MP2 maps) were acquired on a 3T MRI. The effects of brain tissue segmentation and lesion detection rates were analyzed among single‐ and multispectral VBM variants. MP2‐single‐contrast gave better delineation of deep, subcortical nuclei but was prone to misclassification of dura/vessels as gray matter, even more than conventional‐T1. The addition of multispectral combinations (INV1, INV2, or FLAIR) could markedly reduce such misclassifications. MP2 + INV1 yielded generally clearer gray matter segmentation allowing better differentiation of white matter and neighboring gyri. Different models detected known lesions with a sensitivity between 60 and 100%. In non lesional cases, MP2 + INV1 was found to be best with a concordant rate of 37.5%, specificity of 51.6% and concordant to discordant ratio of 0.60. In summary, we show that multispectral MP2RAGE VBM (e.g., MP2 + INV1, MP2 + INV2) can improve brain tissue segmentation and lesion detection in epilepsy.
Low-Rank Matrix Learning Using Biconvex Surrogate Minimization

Many machine learning problems involve learning a low-rank positive semidefinite matrix. However, existing solvers for this low-rank semidefinite program (SDP) are often expensive. In this paper, by factorizing the target matrix as a product of two matrices and using a Courant penalty to penalize for their difference, we reformulate the SDP as a biconvex optimization problem. This allows the use of multiconvex optimization techniques to define simple surrogates, which can be minimized easily by block coordinate descent. Moreover, while traditionally this biconvex problem approaches the original problem only when the penalty parameter is infinite, we show that the two problems are equivalent when the penalty parameter is sufficiently large. Experiments on a number of SDP applications in machine learning show that the proposed algorithm is as accurate as other state-of-the-art algorithms, but is much faster, especially on large data sets.