Miracle-dz/UniFAR-FTUs huggingface dataset:
Osteoblast Malfunction Caused by Cell Stress Response to Procollagen Misfolding in α2(I)‐G610C Mouse Model of Osteogenesis Imperfecta

Glycine (Gly) substitutions in collagen Gly‐X‐Y repeats disrupt folding of type I procollagen triple helix and cause severe bone fragility and malformations (osteogenesis imperfecta [OI]). However, these mutations do not elicit the expected endoplasmic reticulum (ER) stress response, in contrast to other protein‐folding diseases. Thus, it has remained unclear whether cell stress and osteoblast malfunction contribute to the bone pathology caused by Gly substitutions. Here we used a mouse with a Gly610 to cysteine (Cys) substitution in the procollagen α2(I) chain to show that misfolded procollagen accumulation in the ER leads to an unusual form of cell stress, which is neither a conventional unfolded protein response (UPR) nor ER overload. Despite pronounced ER dilation, there is no upregulation of binding immunoglobulin protein (BIP) expected in the UPR and no activation of NF‐κB signaling expected in the ER overload. Altered expression of ER chaperones αB crystalline and HSP47, phosphorylation of EIF2α, activation of autophagy, upregulation of general stress response protein CHOP, and osteoblast malfunction reveal some other adaptive response to the ER disruption. We show how this response alters differentiation and function of osteoblasts in culture and in vivo. We demonstrate that bone matrix deposition by cultured osteoblasts is rescued by activation of misfolded procollagen autophagy, suggesting a new therapeutic strategy for OI. © 2016 American Society for Bone and Mineral Research.
Effects of subthalamic stimulation on speech of consecutive patients with Parkinson disease

Objective: Subthalamic nucleus deep brain stimulation (STN-DBS) is an effective treatment for advanced Parkinson disease (PD). Following STN-DBS, speech intelligibility can deteriorate, limiting its beneficial effect. Here we prospectively examined the short- and long-term speech response to STN-DBS in a consecutive series of patients to identify clinical and surgical factors associated with speech change. Methods: Thirty-two consecutive patients were assessed before surgery, then 1 month, 6 months, and 1 year after STN-DBS in 4 conditions on- and off-medication with on- and off-stimulation using established and validated speech and movement scales. Fifteen of these patients were followed up for 3 years. A control group of 12 patients with PD were followed up for 1 year. Results: Within the surgical group, speech intelligibility significantly deteriorated by an average of 14.2% ± 20.15% off-medication and 16.9% ± 21.8% on-medication 1 year after STN-DBS. The medical group deteriorated by 3.6% ± 5.5% and 4.5% ± 8.8%, respectively. Seven patients showed speech amelioration after surgery. Loudness increased significantly in all tasks with stimulation. A less severe preoperative on-medication motor score was associated with a more favorable speech response to STN-DBS after 1 year. Medially located electrodes on the left STN were associated with a significantly higher risk of speech deterioration than electrodes within the nucleus. There was a strong relationship between high voltage in the left electrode and poor speech outcome at 1 year. Conclusion: The effect of STN-DBS on speech is variable and multifactorial, with most patients exhibiting decline of speech intelligibility. Both medical and surgical issues contribute to deterioration of speech in STN-DBS patients. Classification of evidence: This study provides Class III evidence that STN-DBS for PD results in deterioration in speech intelligibility in all combinations of medication and stimulation states at 1 month, 6 months, and 1 year compared to baseline and to control subjects treated with best medical therapy.
piggyBac Transposon Somatic Mutagenesis with an Activated Reporter and Tracker (PB-SMART) for Genetic Screens in Mice

Somatic forward genetic screens have the power to interrogate thousands of genes in a single animal. Retroviral and transposon mutagenesis systems in mice have been designed and deployed in somatic tissues for surveying hematopoietic and solid tumor formation. In the context of cancer, the ability to visually mark mutant cells would present tremendous advantages for identifying tumor formation, monitoring tumor growth over time, and tracking tumor infiltrations and metastases into wild-type tissues. Furthermore, locating mutant clones is a prerequisite for screening and analyzing most other somatic phenotypes. For this purpose, we developed a system using the piggyBac (PB) transposon for somatic mutagenesis with an activated reporter and tracker, called PB-SMART. The PB-SMART mouse genetic screening system can simultaneously induce somatic mutations and mark mutated cells using bioluminescence or fluorescence. The marking of mutant cells enable analyses that are not possible with current somatic mutagenesis systems, such as tracking cell proliferation and tumor growth, detecting tumor cell infiltrations, and reporting tissue mutagenesis levels by a simple ex vivo visual readout. We demonstrate that PB-SMART is highly mutagenic, capable of tumor induction with low copy transposons, which facilitates the mapping and identification of causative insertions. We further integrated a conditional transposase with the PB-SMART system, permitting tissue-specific mutagenesis with a single cross to any available Cre line. Targeting the germline, the system could also be used to conduct F1 screens. With these features, PB-SMART provides an integrated platform for individual investigators to harness the power of somatic mutagenesis and phenotypic screens to decipher the genetic basis of mammalian biology and disease.
Argument Interpretations in the Ditransitive Construction

An indirect object can be interpreted as a Provider or as a Recipient. The evidence considered in this article suggests that the two interpretations can be morphologically analytic in Chinese and typologically parametrized for certain natural classes of verbs in English and Chinese. Two VP projections are proposed for the ditransitive construction. The head of the lower VP can be phonologically realized or null. The content of the null verb is parametrized across languages. The contrasts in indirect object interpretations in these languages are explained in terms of the lexical meanings of the null verb. The contrasts in verb occurrence restrictions in these languages are accounted for by the interpretable feature compatibilities in head adjunction from the lower to the higher VP.
Treatment planning with corticospinal tract

BOLD fMRI information has been integrated into radiation treatment planning to identify and avoid the eloquent cortices adjacent to a brain tumor. However, BOLD fMRI is essentially restricted to locate the activation in the cortical area. The white matter appears to be more susceptible to damage during the treatment by the radiation. In order to limit consequences of radiation treatment to motor activity, it is important to limit exposure to the corticospinal track. The authors present a novel technique in radiation treatment planning, which utilizes both BOLD fMRI and its corticospinal track maps. This technique allows one to limit exposure to both the motor cortex and the corticospinal tracks during radiation treatment by identifying the former using BOLD fMRI and the latter by diffusion study. It is concluded that, in order to better preserve the motor system, it is essential that both BOLD fMRI and corticospinal track maps be used together. It is hoped that decreased radiation exposure to the corticospinal track will lead to decreased complications in the motor system. The treatment plan may be more difficult to design with both maps, since more restrictions are applied.
Challenges of Integrating Geospatial Technologies Into Rangeland Research and Management

Abstract With the development and commercial availability of submeter spatial resolution satellite imagery, geospatial tools can better accommodate the needs of range professionals than ever before. However, with these new tools comes a new set of challenges. Range managers and range scientists must now 1) better understand and take advantage of the geotechnical tools at their disposal, 2) collect field observations/measurements in ways that act synergistically with these tools, and 3) utilize high-accuracy global positioning system (GPS) receivers. To produce reliable rangeland models it is important to collect field data that correspond with what the satellite “sees. ” Further, it is frequently necessary to use high-resolution imagery, which subsequently necessitates the use of high-accuracy GPS receivers to ensure field data are recorded in the correct pixel and properly coregistered. This paper describes the results of research and experimentation that have led to the development of techniques to improve geospatial rangeland applications. For optimal classification accuracy, field data collected for use in remote sensing applications should estimate/measure ground cover using general vegetation community types and must never exceed 100%. Further, the field sample sites used for classification must be located using a GPS receiver with accuracy ≤ 50% of the size of satellite imagery pixels (e.g., if Landsat imagery is used—with 28.5-m pixels—the GPS receiver must be able to achieve ± 14 m accuracy with 95% confidence). Finally, a series of best practices are suggested to help range managers and range scientists better understand and implement geospatial technologies.
SUMOylation by the E3 Ligase TbSIZ1/PIAS1 Positively Regulates VSG Expression in Trypanosoma brucei

Bloodstream form trypanosomes avoid the host immune response by switching the expression of their surface proteins between Variant Surface Glycoproteins (VSG), only one of which is expressed at any given time. Monoallelic transcription of the telomeric VSG Expression Site (ES) by RNA polymerase I (RNA pol I) localizes to a unique nuclear body named the ESB. Most work has focused on silencing mechanisms of inactive VSG-ESs, but the mechanisms involved in transcriptional activation of a single VSG-ES remain largely unknown. Here, we identify a highly SUMOylated focus (HSF) in the nucleus of the bloodstream form that partially colocalizes with the ESB and the active VSG-ES locus. SUMOylation of chromatin-associated proteins was enriched along the active VSG-ES transcriptional unit, in contrast to silent VSG-ES or rDNA, suggesting that it is a distinct feature of VSG-ES monoallelic expression. In addition, sequences upstream of the active VSG-ES promoter were highly enriched in SUMOylated proteins. We identified TbSIZ1/PIAS1 as the SUMO E3 ligase responsible for SUMOylation in the active VSG-ES chromatin. Reduction of SUMO-conjugated proteins by TbSIZ1 knockdown decreased the recruitment of RNA pol I to the VSG-ES and the VSG-ES-derived transcripts. Furthermore, cells depleted of SUMO conjugated proteins by TbUBC9 and TbSUMO knockdown confirmed the positive function of SUMO for VSG-ES expression. In addition, the largest subunit of RNA pol I TbRPA1 was SUMOylated in a TbSIZ-dependent manner. Our results show a positive mechanism associated with active VSG-ES expression via post-translational modification, and indicate that chromatin SUMOylation plays an important role in the regulation of VSG-ES. Thus, protein SUMOylation is linked to active gene expression in this protozoan parasite that diverged early in evolution.
The Design Space of Register Renaming Techniques

Register renaming is a technique to remove false data dependencie-write after read (WAR) and write after write (WAW)-that occur in straight line code between register operands of subsequent instructions. By eliminating related precedence requirements in the execution sequence of the instructions, renaming increases the average number of instructions that are available for parallel execution per cycle. This results in increased IPC (number of instructions executed per cycle). The identification and exploration of the design space of register-renaming lead to a comprehensive understanding of this intricate technique. As this article shows, the design space of register renaming is spanned by four main dimensions: the scope of register renaming, the layout of the rename buffers, the method of register mapping, and the rename rate. Relevant aspects of the design space give rise to eight basic alternatives for register-renaming. In addition, the kind of operand fetch policy significantly affects how the processor carries out the rename process, which duplicates the eight basic alternatives to 16 possible implementation schemes. The article indicates which basic implementation scheme is used in relevant superscalar processors. As register renaming is usually implemented in conjunction with shelving, the underlying microarchitecture is assumed to employ shelving.
Trans-Golgi Network-Located AP1 Gamma Adaptins Mediate Dileucine Motif-Directed Vacuolar Targeting in Arabidopsis[C][W]

This work demonstrates that TGN-located AP1 complex mediates dileucine motif-directed vacuolar targeting via the interaction with this conserved sorting signal in plant cells. The deficiency of the AP1 gamma adaptins, as well as the mutations of the dileucine residues, resulted in the mislocalization of tonoplast proteins containing the dileucine motif. Membrane proteins on the tonoplast are indispensible for vacuolar functions in plants. However, how these proteins are transported to the vacuole and how they become separated from plasma membrane proteins remain largely unknown. In this study, we used Arabidopsis thaliana vacuolar ion transporter1 (VIT1) as a reporter to study the mechanisms of tonoplast targeting. We showed that VIT1 reached the tonoplast through a pathway involving the endoplasmic reticulum (ER), Golgi, trans-Golgi network (TGN), prevacuolar compartment, and tonoplast. VIT1 contains a putative N-terminal dihydrophobic type ER export signal, and its N terminus has a conserved dileucine motif (EKQTLL), which is responsible for tonoplast targeting. In vitro peptide binding assays with synthetic VIT1 N terminus identified adaptor protein complex-1 (AP1) subunits that interacted with the dileucine motif. A deficiency of AP1 gamma adaptins in Arabidopsis cells caused relocation of tonoplast proteins containing the dileucine motif, such as VIT1 and inositol transporter1, to the plasma membrane. The dileucine motif also effectively rerouted the plasma membrane protein SCAMP1 to the tonoplast. Together with subcellular localization studies showing that AP1 gamma adaptins localize to the TGN, we propose that the AP1 complex on the TGN mediates tonoplast targeting of membrane proteins with the dileucine motif.
An Analysis of the Ideological Content of Internationally-Developed British and American ELT Textbooks

This study examines the ideological content of six internationally-used ELT textbooks, three British and three American. Applying the theory and procedures of critical discourse analysis (CDA), three aspects of the conversations in the textbooks, i.e. content, relations, and positions were examined. Results suggest that in terms of content, British textbooks tend to entertain the students while American textbooks include more occupational and business-related issues. Regarding relations, characters in the conversations were placed in socially equal roles. Moreover, inequalities were rarely addressed in the interactions and there was little attempt to make learners aware of issues such as dialogue management strategies. Finally, characters in the conversations took mostly societal positions.
Childhood trauma mediates the association between ethnic minority status and more severe hallucinations in psychotic disorder

Background Ethnic minority status and childhood trauma are established risk factors for psychotic disorders. Both are found to be associated with increased level of positive symptoms, in particular auditory hallucinations. Our main aim was to investigate the experience and effect of childhood trauma in patients with psychosis from ethnic minorities, hypothesizing that they would report more childhood trauma than the majority and that this would be associated with more current and lifetime hallucinations. Method In this cross-sectional study we included 454 patients with a SCID-I DSM-IV diagnosis of non-affective or affective psychotic disorder. Current hallucinations were measured with the Positive and Negative Syndrome Scale (P3; Hallucinatory Behaviour). Lifetime hallucinations were assessed with the SCID-I items: auditory hallucinations, voices commenting and two or more voices conversing. Childhood trauma was assessed with the Childhood Trauma Questionnaire, self-report version. Results Patients from ethnic minority groups (n = 69) reported significantly more childhood trauma, specifically physical abuse/neglect, and sexual abuse. They had significantly more current hallucinatory behaviour and lifetime symptoms of hearing two or more voices conversing. Regression analyses revealed that the presence of childhood trauma mediated the association between ethnic minorities and hallucinations. Conclusions More childhood trauma in ethnic minorities with psychosis may partially explain findings of more positive symptoms, especially hallucinations, in this group. The association between childhood trauma and these first-rank symptoms may in part explain this group's higher risk of being diagnosed with a schizophrenia-spectrum diagnosis. The findings show the importance of childhood trauma in symptom development in psychosis.
Ignoring Commitment Is Costly: New Approaches Establish the Missing Link Between Commitment and Performance

The branch network of a bank was used toinvestigate the link between employee commitment andorganizational performance in terms of sales targets metand change in profits. Commitment was measured by the conventional Organizational CommitmentQuestionnaire (OCQ) and different variations of aspecifically designed new commitment scale. The approachtaken involved the application of multiple regressionanalysis. That way a variety of factors assumed tocontribute to performance, apart from commitment, couldbe included in the model and held constant. It emergedthat employee commitment is significantly related to the financial success of bank branches. Theresults varied depending on how commitment andperformance were measured. Supervisory commitmentappears to have a particularly strong impact on theoutcome indicators.
A Comparison of Self and Peer Reports in the Assessment of Middle School Bullying

Researchers examining the effectiveness of schoolwide anti-bullying programs typically use student self reports to measure reductions in bullying. In contrast, researchers who study peer aggression frequently employ peer nominations. This study compared self reports of bullying with peer nominations in a sample of 355 middle school students. Self report demonstrated low to moderate correspondence with peer nominations for bullying others (r = .18) and for victimization (.32). More than twice as many students were categorized as bullies using peer nomination (11%) as compared to self report (5%). Despite their limited agreement, both self- and peer-reported bullying/victimization were associated with school maladjustment. These results raise concern about the reliance on self or peer reports alone to assess the prevalence of middle school bullying.
PHARMACOKINETICS AND DISPOSITION

Objectives: To evaluate the possible pharmacokinetic interaction between nefazodone and lithium. Methods: Twelve healthy volunteers received nefazodone 200 mg b.i. d. for 5 days. A 4-day washout phase followed from day 6 to day 9. From day 10 to day 20, escalating doses of lithium 250 mg b.i. d. to 500 mg b.i. d. were given; the daily dose of 1000 mg was obtained on day 13. From day 16 to day 20, nefazodone 200 mg b.i. d. was added to the lithium dosing regimen. Venous blood sampling was performed on days 5, 15 and 20 for 0to 48-h-pharmacokinetic analysis. Nefazodone and its metabolites, hydroxynefazodone, mCPP and triazoledione were assayed by high-performance liquid chromatography (HPLC). Lithium was assayed by ̄ame photometry. Results: Co-administration of nefazodone did not modify pharmacokinetic parameters of lithium at steady-state. Comparison of the area under the plasma or serum concentration-versus-time curve calculated from 0±12 h (AUC0±12) of nefazodone and hydroxynefazodone revealed no signi®cant dierences when nefazodone was administered alone or with lithium. The mean maximum peak plasma concentration Cmax and AUC0±12 of meta-chlorophenyl-piperazine (mCPP) were signi®cantly reduced by 27% (P<0.001) and 16% (P<0.001) with the co-administration. The mean Cmax and AUC0±12 of triazoledione were reduced by 23% (P<0.005) and 16% (P<0.01) by the co-administration. Conclusion: Since there were no clinically signi®cant changes in the pharmacokinetics of the parent compounds or metabolites, and the combination was well tolerated, no dosage adjustments of nefazodone or lithium are necessary when they are co-administered.
THE "ECOLOGUE" APPROACH TO COMPUTATIONAL BUILDING LIFE CYCLE ANALYSIS

Construction and operation of buildings is internationally a major cause of resource depletion and environmental pollution. Computational performance evaluation tools could support the decision making process in the area of environmentally responsive building design and play an important role in environmental impact assessment, especially when a life cycle assessment (LCA) approach is used. LCA requires extensive data collection for each relevant component or process within the boundaries of the assessment. The typical building contains many products from different manufacturers which are assembled in ways often unique to an individual building. For comprehensive environmental impact analysis to be realized in a computational support tool for the building design domain, such tools must a) have an analysis method that considers the life cycle of building construction, operation, and decommissioning, b) have a representation that is able to accommodate the data and computability requirements of the analysis method and the analysis tool and c) be seamlessly integrated within a multi-aspect design analysis environment that can provide data on environmentally relevant building operation criteria. This paper describes the implementation of an application (ECOLOGUE) for comprehensive computational assessment of environmental impact indicators over the building life cycle. The application is embedded in a multi-aspect space-based building design and evaluation environment (SEMPER). The paper demonstrates the use and results of the ECOLOGUE system via illustrative examples.
Cloning and Expression of the Escherichia coli K1 Outer Membrane Protein A Receptor, a gp96 Homologue

ABSTRACT Escherichia coli is one of the most common gram-negative bacteria that cause meningitis in neonates. Our previous studies have shown that outer membrane protein A (OmpA) of E. coli interacts with a 95-kDa human brain microvascular endothelial cell (HBMEC) glycoprotein, Ecgp, for invasion. Here, we report the identification of a gene that encodes Ecgp by screening of an HBMEC cDNA expression library as well as by 5′ rapid amplification of cDNA ends. The sequence of the Ecgp gene shows that it is highly similar to gp96, a tumor rejection antigen-1, and contains an endoplasmic reticulum retention signal, KDEL. Overexpression of either Ecgp or gp96 in both HBMECs and CHO cells increases E. coli binding and invasion. We further show that Ecgp gene-transfected HBMECs express Ecgp on the cell surface despite the presence of the KDEL motif. Northern blot analysis of total RNA from various eukaryotic cells indicates that Ecgp is significantly expressed in HBMECs. Recombinant His-tagged Ecgp blocked E. coli invasion efficiently by binding directly to the bacteria. These results suggest that OmpA of E. coli K1 interacts with a gp96-like molecule on HBMECs for invasion.