Miracle-dz/UniFAR-FTUs huggingface dataset:
Investigation to Explain Bioequivalence Failure in Pravastatin Immediate-Release Products

The purpose of this work is to explore the predictive ability of the biopharmaceutics classification system (BCS) biowaiver based on the dissolution methods for two pravastatin test products, where one of them showed bioequivalence (BE) while the other test failed (non-bioequivalence, or NBE), and to explore the reasons for the BE failure. Experimental solubility and permeability data confirmed that pravastatin is a BCS class III compound. The permeability experiments confirmed that the NBE formulation significantly increased pravastatin permeability, and could explain its higher absorption rate and higher Cmax. This finding highlights the relevance of requiring similar excipients for BCS class III drugs. The BCS-based biowaiver dissolution tests at pH 1.2, 4.5, and 6.8, with the paddle apparatus at 50 rpm in 900 mL media, were not able to detect differences in pravastatin products, although the NBE formulation exhibited a more rapid dissolution at earlier sampling times. Dissolution tests conducted in 500 mL did not achieve complete dissolution, and both formulations were dissimilar because the amount dissolved at 15 min was less than 85%. The difference was less than 10% at pH 1.2 and 4.5, while at pH 6.8 f2, results reflected the Cmax rank order.
Cocaine Dysregulates Dynorphin Modulation of Inhibitory Neurotransmission in the Ventral Pallidum in a Cell-Type-Specific Manner

Cocaine-driven changes in the modulation of neurotransmission by neuromodulators are poorly understood. The ventral pallidum (VP) is a key structure in the reward system, in which GABA neurotransmission is regulated by opioid neuropeptides, including dynorphin. However, it is not known whether dynorphin acts differently on different cell types in the VP and whether its effects are altered by withdrawal from cocaine. Cocaine-driven changes in the modulation of neurotransmission by neuromodulators are poorly understood. The ventral pallidum (VP) is a key structure in the reward system, in which GABA neurotransmission is regulated by opioid neuropeptides, including dynorphin. However, it is not known whether dynorphin acts differently on different cell types in the VP and whether its effects are altered by withdrawal from cocaine. Here, we trained wild-type, D1-Cre, A2A-Cre, or vGluT2-Cre:Ai9 male and female mice in a cocaine conditioned place preference protocol followed by 2 weeks of abstinence, and then recorded GABAergic synaptic input evoked either electrically or optogenetically onto identified VP neurons before and after applying dynorphin. We found that after cocaine CPP and abstinence dynorphin attenuated inhibitory input to VPGABA neurons through a postsynaptic mechanism. This effect was absent in saline mice. Furthermore, this effect was seen specifically on the inputs from nucleus accumbens medium spiny neurons expressing either the D1 or the D2 dopamine receptor. Unlike its effect on VPGABA neurons, dynorphin surprisingly potentiated the inhibitory input on VPvGluT2 neurons, but this effect was abolished after cocaine CPP and abstinence. Thus, dynorphin has contrasting influences on GABA input to VPGABA and VPvGluT2 neurons and these influences are affected differentially by cocaine CPP and abstinence. Collectively, our data suggest a role for dynorphin in withdrawal through its actions in the VP. As VPGABA and VPvGluT2 neurons have contrasting effects on drug-seeking behavior, our data may indicate a complex role for dynorphin in withdrawal from cocaine. SIGNIFICANCE STATEMENT The ventral pallidum consists mainly of GABAergic reward-promoting neurons, but it also encloses a subgroup of aversion-promoting glutamatergic neurons. Dynorphin, an opioid neuropeptide abundant in the ventral pallidum, shows differential modulation of GABA input to GABAergic and glutamatergic pallidal neurons and may therefore affect both the rewarding and aversive aspects of withdrawal. Indeed, abstinence after repeated exposure to cocaine alters dynorphin actions in a cell-type-specific manner; after abstinence dynorphin suppresses the inhibitory drive on the “rewarding” GABAergic neurons but ceases to modulate the inhibitory drive on the “aversive” glutamatergic neurons. This reflects a complex role for dynorphin in cocaine reward and abstinence.
Restoration of Walking After Surgical Management of Equinus in a Non‐ambulatory Child With Duchenne Muscular Dystrophy: A Case Presentation

Duchenne muscular dystrophy (DMD) is a neuromuscular condition characterized by progressive muscle weakness and contractures resulting in loss of ambulation in childhood. The use of corticosteroids has generally replaced surgical management and long-leg bracing to prolong the ambulatory period. Once a child has lost the ability to walk independently there is currently no reported treatment to restore ambulation. We describe the rare case of a 13-year-old patient who was non-ambulatory for 18 months and receiving eteplirsen, an exon-skipping drug (Sarepta Therapeutics, Inc., Cambridge, MA), who regained household and classroom ambulation following surgical management of his equinus contractures.
Does the expression of the ACVR2A gene affect the development of colorectal cancer?

Abstract Colorectal cancer has become a serious problem, especially in highly developed countries. As reported by the World Health Organization, the number of colon cancer cases in the world in 2012 amounted to 1.36 million. It is the second most common cancer in females (614,000 cases, 9.2% of the total) and the third in males (746,000 cases, 10.0% of the total) worldwide. It is believed that TGFβ pathway elements are involved in the pathogenesis of colorectal cancer. This study assessed one of these elements, the ACVR2A gene. Qualitative and quantitative analyses of the ACVR2A gene in 84 patients with colorectal cancer was performed. There was no statistically significant association between ACVR2A gene expression and age, gender, histological type, grading of tumor, vascular invasion, and presence of lymphocytes in tumor tissue. No association was observed between the ACVR2A gene expression level and the presence of metastases in regional lymph nodes and distant metastases. In this study, larger tumors (T3 and T4) were characterized by higher ACVR2A expression compared to smaller tumors (T1 and T2). This may indicate an association between ACVR2A expression and the severity of pathological changes in the tumor growth process.
The effect of the Hambisela programme on stress levels and quality of life of primary caregivers of children with cerebral palsy: A pilot study

Background Caregivers of children with cerebral palsy (CP) are at risk of having high stress levels and poor quality of life (QOL) which could have a detrimental effect on themselves and their children. Taking caregivers’ well-being into consideration is therefore important when providing rehabilitation to children with CP. Interventions to mediate primary caregiver stress and QOL using an educational tool have not been tested in this population in South Africa. Objectives The aim of this study was to determine the effect of a group-based educational intervention, Hambisela, on stress levels and QOL of primary caregivers of children with CP in Mamelodi, a township in Gauteng, South Africa. Method Eighteen primary caregivers of children with CP participated in a quasi-experimental pretest–post-test pilot study. Hambisela, a group-based educational intervention, was carried out once a week over 8 consecutive weeks. Caregiver stress and QOL were assessed before and after the intervention using the Parenting Stress Index-Short Form (PSI-SF) and the Paediatric Quality of Life-Family Impact Module (PedsQLTM-FIM). Sociodemographic information was assessed using a demographic questionnaire. The Gross Motor Function Classification System (GMFCS) was used to assess the gross motor level of severity of CP in the children. Results Data were collected for 18 participants at baseline and 16 participants at follow-up. At baseline, 14 (87.5%) participants had clinically significant stress which reduced to 11 (68.8%) at follow-up. There was no significant change in primary caregiver’s stress levels (p = 0.72) and QOL (p = 0.85) after the Hambisela programme. Higher levels of education were moderately associated with lower levels of primary caregiver stress (r = −0.50; p = 0.03). Conclusion Most primary caregivers in this pilot study suffered from clinically significant stress levels. Hambisela, as an educational intervention, was not effective in reducing the stress or improving the QOL in these primary caregivers of children with CP. Future studies with a larger sample size are needed to investigate the high stress levels of primary caregivers of children with CP. Clinical implications Rehabilitation services for children with disabilities should include assessments to identify caregivers with high stress levels. Holistic management programmes should also include care for the carers.
Risk Assessment and Implications of Schoolchildren Exposure to Classroom Heavy Metals Particles in Jeddah, Saudi Arabia

Classrooms Air Conditioner Filter (CACF) particles represent all of the exposed particles that have migrated to the interior environment. This study was conducted to assess the heavy metals contamination in CACF particles from Jeddah primary schools located in urban, suburban and residential areas; and to evaluate their health risks of children exposure (non-carcinogenic and carcinogenic). Heavy metals levels in CACF particles of schools were in the following order: urban schools > suburban schools > residential schools. Fe, Mn and Zn were the dominant species. Geo-accumulation index (Igeo), contamination factor (CF) and pollution load index (PLI) values indicated that the contamination levels was in the following order Cd > Pb > Zn > As > Cu > Ni > Mn > Cr > Co >V > Fe. School CACF particles was moderately contaminated with As and Zn and moderately to heavily contaminated with Pb and Cd. Enrichment factors (EFs) indicated that Zn, Cd, Pb, As and Cu in CACF particles were severe enriched. The hazard quotient (HQs) and hazards index (HI) values for heavy metals were lower than the acceptable level of one. As, Pb, Cr and Mn were exhibited high non-cancer effects for children. The lifetime cancer risk (LCR) and total lifetime cancer risk (TLCR), HQs and HI values for the different exposure pathways of heavy metals decreased in the following order: ingestion > dermal contact > inhalation. Carcinogenic and non-carcinogenic risk rank order of schools were urban schools > suburban schools > residential schools. The LCR and TLCR of heavy metals was in the following order: Co > Ni >Cr > Cd > As > Pb. The ingestion lifetime cancer risk (LCRing) and TLCR values from exposure to Ni and Cr in urban and suburban schools, Cd in urban schools, and Co in all Jeddah schools only exceed the acceptable range (1 × 10−6–1 × 10−4) Only LCRing and TLCR values from exposure to ∑ carcinogens exceed the acceptable level.
The Role of Stigma Management in HIV Treatment Adherence

Social stigma is linked to improper HIV treatment adherence, but how stigma impairs adherence outcomes is poorly understood. This study included 93 people living with HIV in the United States who participated in focus groups or one-on-one interviews regarding how stigma might affect medication management. Latent content analysis and constant comparative techniques of participant responses that were produced three thematic groupings that described how participants (a) orient to HIV stigma, (b) manage HIV stigma in ways that directly impair treatment adherence, and (c) manage HIV stigma in ways that may indirectly impair adherence. These findings illustrate the need to understand how patients orient to HIV stigma when prescribing medications and the complications that are inherent to such assessments. In addition, these findings provide a simple framework for organizing the different ways in which stigma management strategies may disrupt treatment adherence. Conceptually, these findings also offer a paradigm shift to extent theories on disclosure and concealment, in which only disclosure has been cast as an active process. These findings demonstrate how concealment is far from a passive default, often requiring enormous effort. Ultimately, these findings may guide intervention programs that help to entirely eliminate HIV by promoting optimized counseling and subsequent treatment adherence.
Design and Implementation of Searching SVM Optimal Training Parameter Set Based on Shared Dot Product Matrix

The Optimal Training Parameter Combination (OPTC) is the core of the support vector machines (SVM) to construct application model. However, the calculated amount of searching OTPC of SVM is extremely huge, which is time-consuming during the process of implementation by the software. To solve this issue, we propose a Shared Dot Product Matrix (SDPM) algorithm. The algorithm computes the dot product of all training data sets and stores them simultaneously, which achieves an ultra-fast processing speed. Meanwhile, the hardware/software co-design architecture for searching OTPC of SVM is proposed to corporate the data processing. The implementation and test results have shown that, the software and hardware collaboration system proposed in this paper has the performance that is 30 times faster in searching speed than software-based LIBSVM.
Metabolic partitioning of sucrose and seasonal changes in fat turnover rate in ruby-throated hummingbirds (Archilochus colubris)

ABSTRACT Hummingbirds fuel their high energy needs with the fructose and glucose in their nectar diets. These sugars are used both to fuel immediate energy needs and to build fat stores to fuel future fasting periods. Fasting hummingbirds can deplete energy stores in only hours and need to be continuously replacing these stores while feeding and foraging. Whether and how hummingbirds partition dietary fructose and glucose towards immediate oxidation versus fat storage is unknown. Using a chronic stable isotope tracer methodology, we examined whether glucose or fructose is preferentially used for de novo lipogenesis in ruby-throated hummingbirds (Archilochus colubris). Potential seasonal changes were correlated with variation in the overall daily energy expenditure. We fed ruby-throated hummingbirds sucrose-based diets enriched with 13C on either the glucose or the fructose portion of the disaccharide for 5 days. Isotopic incorporation into fat stores was measured via the breath 13C signature while fasting (oxidizing fat) during the winter and summer seasons. We found greater isotopic enrichment of fat stores when glucose was labelled compared with fructose, suggesting preference for glucose as a substrate for fatty acid synthesis. We also found a seasonal effect on fat turnover rate. Faster turnover rates occurred during the summer months, when birds maintained lower body mass, fat stores and exhibited higher daily nectar intake compared with winter. This demonstrates that fat turnover rate can substantially vary with changing energy expenditure and body composition; however, the partitioning of sucrose towards de novo fatty acid synthesis remains constant. Summary: Hummingbirds alter fat turnover rates seasonally, with faster turnover during the summer, when they are lighter and have high daily energy expenditure. However, the preference for glucose as a substrate for fatty acid synthesis over fructose does not change seasonally.
Inequity in consumption of goods and services adds to racial–ethnic disparities in air pollution exposure

Significance Racial–ethnic disparities in pollution exposure and in consumption of goods and services in the United States are well documented. Some may find it intuitive that, on average, black and Hispanic minorities bear a disproportionate burden from the air pollution caused mainly by non-Hispanic whites, but this effect has not previously been directly established, let alone quantified. Our “pollution inequity” metric is generalizable to other pollution types and provides a simple and intuitive way of expressing a disparity between the pollution that people cause and the pollution to which they are exposed. Our results are timely, given public debate on issues relating to race, equity, and the regulation of pollution. Fine particulate matter (PM2.5) air pollution exposure is the largest environmental health risk factor in the United States. Here, we link PM2.5 exposure to the human activities responsible for PM2.5 pollution. We use these results to explore “pollution inequity”: the difference between the environmental health damage caused by a racial–ethnic group and the damage that group experiences. We show that, in the United States, PM2.5 exposure is disproportionately caused by consumption of goods and services mainly by the non-Hispanic white majority, but disproportionately inhaled by black and Hispanic minorities. On average, non-Hispanic whites experience a “pollution advantage”: They experience ∼17% less air pollution exposure than is caused by their consumption. Blacks and Hispanics on average bear a “pollution burden” of 56% and 63% excess exposure, respectively, relative to the exposure caused by their consumption. The total disparity is caused as much by how much people consume as by how much pollution they breathe. Differences in the types of goods and services consumed by each group are less important. PM2.5 exposures declined ∼50% during 2002–2015 for all three racial–ethnic groups, but pollution inequity has remained high.
Random Telegraph Noises from the Source Follower, the Photodiode Dark Current, and the Gate-Induced Sense Node Leakage in CMOS Image Sensors †

In this paper we present a systematic approach to sort out different types of random telegraph noises (RTN) in CMOS image sensors (CIS) by examining their dependencies on the transfer gate off-voltage, the reset gate off-voltage, the photodiode integration time, and the sense node charge retention time. Besides the well-known source follower RTN, we have identified the RTN caused by varying photodiode dark current, transfer-gate and reset-gate induced sense node leakage. These four types of RTN and the dark signal shot noises dominate the noise distribution tails of CIS and non-CIS chips under test, either with or without X-ray irradiation. The effect of correlated multiple sampling (CMS) on noise reduction is studied and a theoretical model is developed to account for the measurement results.
Fine-Tuning of σE Activation Suppresses Multiple Assembly-Defective Mutations in Escherichia coli

Gram-negative bacteria, such as Escherichia coli, inhabit a natural environment that is prone to flux. In order to cope with shifting growth conditions and the changing availability of nutrients, cells must be capable of quickly responding to stress. Stress response pathways allow cells to rapidly shift gene expression profiles to ensure survival in this unpredictable environment. Here we describe a mutant that partially activates the σE stress response pathway. The elevated basal level of this stress response allows the cell to quickly respond to overwhelming stress to ensure cell survival. ABSTRACT The Gram-negative outer membrane (OM) is a selectively permeable asymmetric bilayer that allows vital nutrients to diffuse into the cell but prevents toxins and hydrophobic molecules from entering. Functionally and structurally diverse β-barrel outer membrane proteins (OMPs) build and maintain the permeability barrier, making the assembly of OMPs crucial for cell viability. In this work, we characterize an assembly-defective mutant of the maltoporin LamB, LamBG439D. We show that the folding defect of LamBG439D results in an accumulation of unfolded substrate that is toxic to the cell when the periplasmic protease DegP is removed. Selection for suppressors of this toxicity identified the novel mutant degSA323E allele. The mutant DegSA323E protein contains an amino acid substitution at the PDZ/protease domain interface that results in a partially activated conformation of this protein. This activation increases basal levels of downstream σE stress response signaling. Furthermore, the enhanced σE activity of DegSA323E suppresses a number of other assembly-defective conditions without exhibiting the toxicity associated with high levels of σE activity. We propose that the increased basal levels of σE signaling primes the cell to respond to envelope stress before OMP assembly defects threaten cell viability. This finding addresses the importance of envelope stress responses in monitoring the OMP assembly process and underpins the critical balance between envelope defects and stress response activation. IMPORTANCE Gram-negative bacteria, such as Escherichia coli, inhabit a natural environment that is prone to flux. In order to cope with shifting growth conditions and the changing availability of nutrients, cells must be capable of quickly responding to stress. Stress response pathways allow cells to rapidly shift gene expression profiles to ensure survival in this unpredictable environment. Here we describe a mutant that partially activates the σE stress response pathway. The elevated basal level of this stress response allows the cell to quickly respond to overwhelming stress to ensure cell survival.
Epiphyte associations and canopy soil volume: nutrient capital and factors influencing soil retention in the canopy.

Canopy soil (CS) volume reflect epiphyte community maturity, but little is known about the factors that retain CS or species succession in it. Humus fern species (e.g. Phlebodium areolatum), appear capable of retaining CS. In 10 Quercus spp. we sampled 987 epiphyte mats to test the role of the common epiphyte species and crown traits determining CS volume, to infer successional stages and to identify pioneer and late successional species. Branch traits (height, diameter and inclination), CS volume and coverage of the epiphyte species were determined for each mat. Nutrient content was determined in CS random samples of 12 epiphyte associations and sizes (one sample of each size quintile). 60% of the mats lack of CS. Coverage of P. areolatum was the main variable explaining CS volume and this species was present in 46.8% of those with CS. Epiphyte composition was highly variable, but pioneer (species appearing in monospecific mats, without CS) and late successional species could be identified. CS-nutrient content was similar among the associations of epiphytes. Mg, Ca and pH decreased with CS volume while P and N increased. Phlebodium areolatum is associated with high CS volumes and could act as a key species in its retention. Monospecific mats of pioneer species lack CS or have little volume, while it is much in mats with late successional species, but, the mechanisms of CS formation and nutrient retention in response to interaction between epiphyte species remain to be tested.
The human DEPhOsphorylation Database DEPOD: 2019 update

Abstract The human Dephosphorylation Database (DEPOD) is a manually curated resource that harbors human phosphatases, their protein and non-protein substrates, dephosphorylation sites and the associated signaling pathways. We report here an update to DEPOD by integrating and/or linking to annotations from 69 other open access databases including disease associations, phosphorylating kinases, protein interactions, and also genome browsers. We also provide tools to visualize protein interactions, protein structures, phosphorylation networks, evolutionary conservation of proteins, dephosphorylation sites, and short linear motifs within various proteins. The updated version of DEPOD contains 254 human phosphatases, 336 protein and 83 non-protein substrates, and 1215 manually curated phosphatase-substrate relationships. In addition, we have improved the data access as all the data in DEPOD can now be easily downloaded in a user-friendly format. With multiple significant improvements, DEPOD continues serving as a key resource for research on phosphatase-kinase networks. Database URL: www.depod. org