Miracle-dz/UniFAR-FTUs huggingface dataset:
TAK-063, a Novel Phosphodiesterase 10A Inhibitor, Protects from Striatal Neurodegeneration and Ameliorates Behavioral Deficits in the R6/2 Mouse Model of Huntington’s Disease

Huntington’s disease (HD) is characterized by progressive loss of striatal medium spiny neurons (MSNs) that constitute direct and indirect pathways: the indirect pathway MSNs is more vulnerable than the direct pathway MSNs. Impairment of cAMP/cGMP signaling by mutant huntingtin is hypothesized as the molecular mechanism underlying degeneration of MSNs. Phosphodiesterase 10A (PDE10A) is selectively expressed in MSNs and degrades both cAMP and cGMP; thus, PDE10A inhibition can restore impaired cAMP/cGMP signaling. Compared with other PDE10A inhibitors, a novel PDE10A inhibitor 1-[2-fluoro-4-(1H-pyrazol-1-yl)phenyl]-5-methoxy-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-4(1H)-one (TAK-063) showed comparable activation of the indirect pathway MSNs, whereas it produced partial activation of the direct pathway MSNs by its faster off-rate property. In this study, we report the effects of TAK-063 on striatal neurodegeneration and behavioral deficits in the R6/2 mouse model of HD. TAK-063 at 0.5 or 5 mg/kg/day was orally administrated from 4.5–5 to 12 weeks of age, and the effects of TAK-063 were characterized over this period. Repeated treatment with TAK-063 suppressed the reduction of brain-derived neurotrophic factor levels, prevented striatal neurodegeneration, and suppressed increase in seizure frequency, but did not prevent the suppression of body weight gain. As for motor deficits, TAK-063 suppressed the development of clasping behavior and motor dysfunctions, including decreased motor activity in the open field, but did not improve the impairment in motor coordination on the rotarod. Regarding cognitive functions, TAK-063 improved deficits in procedural learning, but was ineffective for deficits in contextual memory. These results suggest that TAK-063 reduces striatal neurodegeneration and ameliorates behavioral deficits in R6/2 mice.
Characterization of a Muscle-specific Enhancer in Human MuSK Promoter Reveals the Essential Role of Myogenin in Controlling Activity-dependent Gene Regulation*

Neuromuscular synaptogenesis is initiated by the release of agrin from motor neurons and the activation of the receptor tyrosine kinase, MuSK, in the postsynaptic membrane. MuSK gene expression is regulated by nerve-derived agrin and muscle activity. Agrin stimulates synapse-specific MuSK gene expression by activating GABPαβ transcription factors in endplate-associated myonuclei. In contrast, the mechanism by which muscle activity regulates MuSK gene expression is not known. We report on a 60-bp MuSK enhancer that confers promoter regulation by muscle differentiation, changes in intracellular calcium, and muscle activity. Within this enhancer, we identified a single E-box that is essential for this regulation. This E-box binds myogenin, and we showed that myogenin is necessary for not only MuSK but also nAChR gene regulation by muscle activity. Surprisingly, the same E-box functions in vivo to mediate muscle-specific and differentiation-dependent gene induction in zebrafish, suggesting an evolutionary conserved mechanism of regulation of synaptic protein gene expression.
Costly Long‐Short Strategies Under Short‐Sale Constraints: Chinese Evidence

Long-short portfolios based on market anomalies are subject to ubiquitous short-sale constraints. Few studies directly quantify the impact of shorting on long-short strategies, largely due to the complexity of the shorting practice. We examine the Chinese market, in which the scope of the short-sale constraint and the shorting cost are clearly specified. Among size, value, and momentum strategies, we find that only size earns significant profits before short-sale constraints are considered. Imposing the scope of short-sale constraint by selling only shortable stocks does not materially change the profits. Deducting shorting costs, however, essentially wipes off all the profits of long-short portfolios.
Functional Instability of the Ankle: Differences in Patterns of Ankle and Knee Movement Prior To and Post Landing in a Single Leg Jump

The aim of this study was to investigate motor control in subjects with functional instability of the ankle joint. This was achieved by analysing patterns of lower extremity motion prior to and immediately following landing during single leg jumping in subjects with functional instability of the ankle. Fourteen subjects with unilateral functional instability and 10 healthy control subjects performed single leg jumps from a 40 cm height whilst angular displacement of their ankle and knee joints were recorded. Subjects with functional instability demonstrated significantly greater ankle dorsiflexion over the period encompassing 10 ms pre landing to 20 ms post landing (p < 0.05). They also exhibited a significantly greater level of knee flexion than controls over the period from 20 ms pre landing to 60 ms post landing (p < 0.05). The timing of these significant differences leads us to conclude that they do not arise as a result of reflexively mediated peripheral events following landing.
Apoptosis Generates Stable Fragments of Human Type I Keratins*

Type I and II keratins help maintain the structural integrity of epithelial cells. Since apoptosis involves progressive cell breakdown, we examined its effect on human keratin polypeptides 8, 18, and 19 (K8, K18, K19) that are expressed in simple-type epithelia as noncovalent type I (K18, K19) and type II (K8) heteropolymers. Apoptosis induces rapid hyperphosphorylation of most known K8/18 phosphorylation sites and delayed formation of K18 and K19 stable fragments. In contrast, K8 is resistant to proteolysis and remains associated with the K18 fragments. Transfection of phosphorylation/glycosylation-mutant K8 and K18 does not alter fragment formation. The protein domains of the keratin fragments were determined using epitope-defined antibodies, and microsequencing indicated that K18 cleavage occurs at a conserved caspase-specific aspartic acid. The fragments are found preferentially within the detergent-insoluble pool and can be generated, in a phosphorylation-independent manner, by incubating keratins with caspase-3 or with detergent lysates of apoptotic cells but not with lysates of nonapoptotic cells. Our results indicate that type I keratins are targets of apoptosis-activated caspases, which is likely a general feature of keratins in most if not all epithelial cells undergoing apoptosis. Keratin hyperphosphorylation occurs early but does not render the keratins better substrates of the downstream caspases.
The Impact of Active Site Mutations of South African HIV PR on Drug Resistance: Insight from Molecular Dynamics Simulations, Binding Free Energy and Per‐Residue Footprints

Molecular dynamics simulations and binding free energy calculations were used to provide an understanding of the impact of active site drug‐resistant mutations of the South African HIV protease subtype C (C‐SA HIV PR), V82A and V82F/I84V on drug resistance. Unique per‐residue interaction energy ‘footprints’ were developed to map the overall drug‐binding profiles for the wild type and mutants. Results confirmed that these mutations altered the overall binding landscape of the amino acid residues not only in the active site region but also in the flaps as well. Four FDA‐approved drugs were investigated in this study; these include ritonavir (RTV), saquinavir (SQV), indinavir (IDV), and nelfinavir (NFV). Computational results compared against experimental findings were found to be complementary. Against the V82F/I84V variant, saquinavir, indinavir, and nelfinavir lose remarkable entropic contributions relative to both wild‐type and V82A C‐SA HIV PRs. The per‐residue energy ‘footprints’ and the analysis of ligand–receptor interactions for the drug complexes with the wild type and mutants have also highlighted the nature of drug interactions. The data presented in this study will prove useful in the design of more potent inhibitors effective against drug‐resistant HIV strains.
The cytotoxic effects of dimethyl sulfoxide in mouse preimplantation embryos: a mechanistic study

Rationale: Dimethyl sulfoxide (DMSO) is commonly used as a solvent for water-insoluble substances, a vehicle for drug therapy, and a cryoprotectant for cultured cells. DMSO induced embryonic defects and its mechanism of action remains unclear. The rationale is based on the assumption that DMSO supplementation should induce long-term negative effects on both pre- and post-implantation embryo development. Methods: DMSO induced oxidative stress, ER stress, autophagy, mitophagy, signaling responsible genes and proteins were determined by RT-qPCR, Western blotting, immunofluorescence, and confocal microscopy. DMSO induced mitochondrial dysfunction was measured by transmission electron microcopy and JC-1 assay. Apoptosis was estimated using TUNEL and comet assay. Post-implantation embryo developmental capability was estimated by implantation site and fetus numbers. Results: Exposure to DMSO induced an early oxidative stress response within 0.5 to 2 h in 1-cell zygotes by disrupting the balance of pro- and anti-oxidants. Notably, DMSO-treated 2-cell embryos showed increased expression of unfolded protein response genes such as Hspa5, Hsp90b1, Ddit3, Atf4, and Xbp1. As a result, the development of many embryos is arrested at the 2-cell, 4-cell, or morula stages in a dose-dependent manner. Further, DMSO-induced endoplasmic reticulum stress increased mitochondrial Ca2+ levels, induced mitochondrial depolarization/dysfunction, and induced apoptotic cell death via the JNK/ATF2-dependent pathway. Consequently, treatment with DMSO increased the expression of autophagy initiation-, phagophore elongation-, and autophagosome formation-related genes, as well as localization of PINK1/Parkin, which are the main mediators of mitophagy, in mitochondria. Interestingly, DMSO causes cytotoxic effects in preimplantation embryos by inducing extensive mitophagy and autophagy. Especially, DMSO treatment decreased the inner cell mass and trophectoderm cell numbers as well as mRNA expression of B3gnt5 and Wnt3a in developed blastocysts, which decreased the implantation and developmental rates of full-term offspring after being transferred into pseudopregnant mice. Conclusion: These results provide a significant contribution to finding effective protective agents to combat DMSO mediated reproductive toxicity for application in human embryos in the near future.
The Rise of Radicalism and Terrorism in Indonesia and Malaysia

This article examines the dynamics of radicalism and terrorism in Indonesia and Malaysia and how government from both countries responded to the rise of radicalism and terrorism . It discusses the development of terrorism in Southeast Asia from the period of Darul Islam in 1950s to Jama’ah Islamiyah in 2000s. In addition, it argues that Indonesia and Malaysia have become barometer of terrorism networks in Southeast Asia. Radicalism and terrorism networks also have transformed the character of Islam in Southeast Asia, and this certainly challenges the future of mainstream Muslims in the region who are recognized as maintaining moderate and peaceful Islam. This is based on interviews to terrorist and former terrorist detainees and government officials in Indonesia and Malaysia. It also comes from analysis of books and documents from radical-jihadist organizations and government. It recommends state and civil society policy to unite in preventing and countering radicalism and terrorism in Southeast Asia, especially in Indonesia and Malaysia.
Teachersr Perception on the Development of Local History Digital Teaching Material in Surakarta

Technology utilization supports global information current to be accessible through internet. This condition is in contradiction with the limited access to information about local history. Students’ emotional closeness to surrounding environment is a historical learning source valuable to the learning process in the class. For that reason, the local historical development should utilize digital technology. History teacher is one of main components in the learning process utilizing digital book. This research aimed to describe history teachers’ perception on the development of local history digital material. Qualitative method was employed in this study. Data collection was carried out using interview and questionnaire to explore the respondents’ view on the development of local history digital material. The subject of research consisted of 20 history teachers in Surakarta. Data analysis was carried out using an interactive model of analysis. The findings of research showed that history teachers in Surakarta had positive perception on the development of local history digital material. Teachers were motivated to utilize technology in the learning. The main constraint included limited number of writings on local history in Surakarta and teachers’ inadequate ability of mastering
Ethanol is self-administered into the nucleus accumbens shell, but not the core: evidence of genetic sensitivity.

BACKGROUND A previous study indicated that selectively bred alcohol-preferring (P) rats self-administered ethanol (EtOH) directly into the posterior ventral tegmental area at lower concentrations than Wistar rats. The present study was undertaken to determine involvement of the nucleus accumbens (Acb) with EtOH reinforcement, and a relationship between genetic selection for high alcohol preference and sensitivity of the Acb to the reinforcing effects of EtOH. METHODS Adult P and Wistar rats were assigned to groups that self-infused 0 to 300 mg% EtOH into the Acb shell (AcbSh) or Acb Core (AcbC). Rats were placed into 2-lever (active and inactive) operant chambers and given EtOH for the first 4 sessions (acquisition), artificial cerebrospinal fluid (aCSF) for sessions 5 and 6 (extinction), and EtOH again in session 7 (reinstatement). Responding on the active lever produced a 100-nl injection of the infusate. RESULTS Alcohol-preferring rats self-infused 75 to 300 mg% EtOH, whereas Wistar rats reliably self-infused 100 and 300 mg% EtOH into the AcbSh. Both P and Wistar rats reduced responding on the active lever when aCSF was substituted for EtOH, and reinstated responding in session 7 when EtOH was restored. EtOH was not self-infused into the AcbC by P or Wistar rats. CONCLUSIONS The present results indicate that the AcbSh, but not AcbC, is a neuroanatomical structure that mediates the reinforcing actions of EtOH. The data also suggest that, compared to Wistar rats, the AcbSh of P rats is more sensitive to the reinforcing effects of EtOH.
Development and psychometric properties of the Sensory Responsiveness Questionnaire (SRQ)

Purpose. Individuals with Sensory Modulation Disorder (SMD) are characterized by an inability to normally grade the degree, intensity and nature of their responses to sensory input and are limited in their ability to fully participate in daily life activities, and attain optimal quality of life. Most existing diagnostic tools are intended for paediatric populations. A questionnaire that assesses the intensity of the affective-emotive responsiveness of adults to stimuli in all sensory modalities and the frequency of such responses for diagnosing adults with disorders in sensory modulation is necessary. This article describes the development and assessment of the psychometric properties of a novel instrument, the Sensory Responsiveness Questionnaire (SRQ), for this purpose (see Appendix). Method. The SRQ evolved through three developmental phases (Pilot, Version-I, and the most recent Version-II). Each phase comprised several studies conducted to further refine the instrument and to examine its psychometric properties with adults with Sensory Modulation Disorder versus SMD-free individuals (n=39 for the pilot version, n=399 for Version-I, and n=48 for Version-II). Results. The scales of Version-II indicated high test-retest reliability, moderate criterion validity and strong significant construct validity. Conclusion. There is strong indication that the SRQ can be used to diagnose adults with SMD.
Exploiting Die-to-Die Thermal Coupling in 3-D IC Placement

In this paper, we propose two methods used in 3-D IC placement that efficiently exploit the die-to-die thermal coupling in the stack. First, through-silicon vias (TSVs) are spread on each die to reduce the local power density and vertically aligned across dies simultaneously to increase thermal conductivity to the heatsink. Second, we move high-power logic cells to the location that has higher conductivity to the heatsink while moving TSVs in the upper dies so that high-power cells are vertically overlapping below the TSVs. These methods are employed in a force-directed 3-D placement successfully and outperform several state-of-the-art placers published in recent literature. We obtain 3-D placement results with shorter routed wirelength at similar temperature. We also obtain 3-D placement results with lower temperatures at similar routed wirelengths.
Monitoring Cavitation Regime From Pressure and Optical Sensors: Comparing Methods Using Wavelet Decomposition for Signal Processing

A cavitating two-phase flow of water in a pipe with area shrinkage was experimentally investigated, acquiring at high sampling rate pressure signals and images of the cavitating flow-field. The fluctuations of the pressure measurements in the internal orifice and of the intensity level of the images' pixels were decomposed using the wavelet transform to analyze the frequency distribution of the signals energy with respect to the flow behavior and to highlight the influence of temperature on the phenomena under investigation. It was shown that the energy content at each frequency band of the acquired signals is well related to cavitation flow-field behavior.
Clothing Adjustments for Concealed Soft Body Armor During Moderate Physical Exertion

Previous research has studied the impact of Level II concealed soft body armor (SBA) on the augmentation of heat storage in a hot environment simulating a typical summer day in the southeastern United States (wet bulb globe temperature [WBGT] = 30°C) and noted a significant difference between macro- and micro-WBGTs. The purpose of this study was to characterize the microclimate (micro-WBGT) under a concealed Level II SBA during 60 min of moderately intense work at two separate macro-WBGTs (26°C and 30°C), and to establish WBGT corrections to allow prediction of heat strain in an individual wearing a concealed Level II SBA. A single trial was performed with nine volunteers (27 ± 4 years) outfitted with a simulated standard law enforcement uniform and a traditional concealed Level II SBA, in a moderately warm environment (WBGT = 26°C). Each participant performed cycles of 12 min of walking (1.25 L · min−1) and 3 min of arm curls (14.3 kg, 0.6 L · min−1) with a 5 min rest after every other cycle, for a total of 60 minutes. This trial was compared to an identical previously completed 60-min work bout at 30°C. A two-way repeated measures ANOVA with Post hoc Bonferroni and paired samples t-test analysis was conducted. A greater difference between macro- micro-WBGTs existed at 26°C compared to the 30°C macro-WBGT. Under these conditions, a moderate work in Level II SBA requires a WBGT correction of 8.9°C and 6.2°C at macro-WBGTs of 26°C and 30°C, respectively. A modified simple linear regression prediction model was established for mean Micro-WBGT for each macro-WBGTs after the plateau point at the 30 min mark. The derivation regressions at 26°C (R2 = 0.99), and 30°C (R2 = 0.99) indicate that micro-WBGT could be predicted for each 15 minutes time at both macro-WBGTs tested for individuals doing moderate intensity (300 Kcals · hr−1) work wearing concealed Level II SBA.
Latent class analysis of ADHD and comorbid symptoms in a population sample of adolescent female twins.

Attention-deficit/hyperactivity disorder (ADHD) is a phenotypically heterogeneous and highly heritable syndrome. which commonly co-occurs with other psychiatry disorders. To assess the role of genetic influences in ADHD, we used latent class analysis (LCA) to identify subtypes of ADHD taking into account its comorbidity with separation anxiety, oppositional defiant disorder (ODD), and three major depression symptoms. A structured interview was used to collect diagnostic data from a population sample of 2,904 adolescent female twins and their parents. LCA was applied to ADHD. separation anxiety. ODD symptom profiles obtained from the twins' parents, and major depression symptom profiles obtained from the twins' self-report. Odds ratios were used to test for familiality of class membership by examining the effect of zygosity on twin concordance within and between latent classes. Structural equation modeling was used to compute heritabilities for latent class membership. LCA revealed three ADHD categories of clinical interest: an inattentive subtype without comorbidity, a second inattentive subtype with increased number of ODD symptoms. and a combined inattentive/hyperactive-impulsive type with elevated levels of ODD, separation anxiety, and depressive symptoms. LCA also distinguished an ODD class and a separation anxiety class, each without increased levels of other comorbid symptoms; a second ODD class co-occurring with increased separation anxiety and depression symptoms; and a pure depression class. Odds ratios for MZ contrasted with DZ twin concordance for individual latent class membership ranged from 2.5 to 19.4. Overall, 66% of MZ pairs, but only 36% of DZ pairs, were assigned to the same latent class, consistent with a genetic hypothesis for latent class membership. Individual class membership was shown to have high heritability ranging from . 34-. 85. The pattern of latent classes suggested that in the general female adolescent population, there are three highly heritable ADHD subtypes, two of which are comorbid with other disorders. These classes were consistent with a genetic hypothesis for ADHD, with each class potentially reflecting a unique genetic subtype.
Osteopontin expression in acute renal allograft rejection.

BACKGROUND Osteopontin (OPN) is a potent chemoattractant for mononuclear cells that is up-regulated in various inflammatory states of the kidney. The role of OPN and its expression in human renal allograft rejection are unknown. METHODS We examined by immunohistochemistry and in situ hybridization, renal biopsies from patients with acute rejection (N= 22), protocol biopsies without rejection (N= 9), and perioperative donor biopsies (N= 35) for intrarenal expression of OPN, and its correlation with clinical, laboratory, and histopathologic parameters. In the rejection biopsies, interstitial monocyte/macrophage infiltration, tubulointerstitial cell proliferation/regeneration and apoptosis were investigated. RESULTS In the majority of rejection biopsies, OPN expression by proximal tubular epithelium was widespread, and tended to be enhanced in the tubules surrounded by numerous inflammatory cells. Conversely, in patients that did not experience episodes of rejection and in donor biopsies, OPN expression by proximal tubules was nil or weak. OPN mRNA was colocalized with its translated protein in the renal tubular epithelium. OPN expression positively correlated with the degree of interstitial inflammation (P < 0.05), CD68+ monocyte infiltration (P < 0.01), Ki-67+ regenerating tubular and interstitial cells (P < 0.05 and P < 0.005, respectively), but not with terminal deoxynucleotidyl transferase (TdT)-mediated deoxyuridine triphosphate (dUTP) nick-end labeling (TUNEL)-positive apoptotic tubular cells. CONCLUSION These data suggest that inducible expression of OPN in the tubular epithelium may have a pathogenic role in acute renal allograft rejection by mediating interstitial monocyte infiltration and possibly tubular regeneration.