Search

A genetically valid animal model could transform our understanding of schizophrenia (SCZ) disease mechanisms. Rare heterozygous loss-of-function (LoF) mutations in GRIN2A, encoding a subunit of the NMDA receptor, greatly increase the risk of SCZ. By transcriptomic, proteomic, and behavioral analyses, we report that heterozygous Grin2a mutant mice show (1) large-scale gene expression changes across multiple brain regions and in neuronal (excitatory and inhibitory) and non-neuronal cells (astrocytes and oligodendrocytes), (2) evidence of hypoactivity in the prefrontal cortex (PFC) and hyperactivity in the hippocampus and striatum, (3) an elevated dopamine signaling in the striatum and hypersensitivity to amphetamine-induced hyperlocomotion (AIH), (4) altered cholesterol biosynthesis in astrocytes, (5) a reduction in glutamatergic receptor signaling proteins in the synapse, and (6) an aberrant locomotor pattern opposite of that induced by antipsychotic drugs. These findings reveal potential pathophysiologic mechanisms, provide support for both the "hypo-glutamate" and "hyper-dopamine" hypotheses of SCZ, and underscore the utility of Grin2a-deficient mice as a genetic model of SCZ., Competing Interests: Declaration of interests M.S. is cofounder and SAB member of Neumora Therapeutics and serves on the SAB of Biogen, ArcLight, Vanqua Bio, and Proximity Therapeutics. M.S. is on the advisory board of Neuron. S.A.C. is a member of the scientific advisory boards of Kymera, PTM BioLabs, Seer, and PrognomIQ., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Synaptic dysfunction is implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BP). We use quantitative mass spectrometry to carry out deep, unbiased proteomic profiling of synapses purified from the dorsolateral prefrontal cortex of 35 cases of SCZ, 35 cases of BP, and 35 controls. Compared with controls, SCZ and BP synapses show substantial and similar proteomic alterations. Network analyses reveal upregulation of proteins associated with autophagy and certain vesicle transport pathways and downregulation of proteins related to synaptic, mitochondrial, and ribosomal function in the synapses of individuals with SCZ or BP. Some of the same pathways are similarly dysregulated in the synaptic proteome of mutant mice deficient in Akap11, a recently discovered shared risk gene for SCZ and BP. Our work provides biological insights into molecular dysfunction at the synapse in SCZ and BP and serves as a resource for understanding the pathophysiology of these disorders., Competing Interests: Declaration of interests M.S. is a scientific co-founder and senior advisory board member of Neumora Therapeutics and a senior advisory board member of Biogen, Vanqua Bio, ArcLight Therapeutics, and Cerevel Therapeutics., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The role of PPM1D mutations in de novo gliomagenesis has not been systematically explored. Here we analyze whole genome sequences of 170 pediatric high-grade gliomas and find that truncating mutations in PPM1D that increase the stability of its phosphatase are clonal driver events in 11% of Diffuse Midline Gliomas (DMGs) and are enriched in primary pontine tumors. Through the development of DMG mouse models, we show that PPM1D mutations potentiate gliomagenesis and that PPM1D phosphatase activity is required for in vivo oncogenesis. Finally, we apply integrative phosphoproteomic and functional genomics assays and find that oncogenic effects of PPM1D truncation converge on regulators of cell cycle, DNA damage response, and p53 pathways, revealing therapeutic vulnerabilities including MDM2 inhibition., (© 2022. The Author(s).)

Prokaryotic Argonautes (pAgo) are an increasingly well-studied class of guided endonucleases, and the underlying mechanisms by which pAgo generate nucleic acid guides in vivo remains an important topic of investigation. Recent insights into these mechanisms for the Argonaute protein from Thermus thermophilus has drawn attention to global sequence and structural feature preferences involved in oligonucleotide guide selection. In this work, we approach the study of guide sequence preferences in T. thermophilus Argonaute from a functional perspective. Screening a library of 1,968 guides against randomized single- and double-stranded DNA substrates, endonuclease activity associated with each guide was quantified using high-throughput capillary electrophoresis, and localized sequence preferences were identified which can be used to improve guide design for molecular applications. The most notable preferences include: a strong cleavage enhancement from a first position dT independent of target sequence; a significant decrease in activity with dA at position 12; and an impact of GC dinucleotides at positions 10 and 11. While this method has been useful in characterizing unique preferences of T. thermophilus Argonaute and criteria for creating efficient guides, it could be expanded further to rapidly characterize more recent mesophilic variants reported in the literature and drive their utility toward molecular tools in biology and genome editing applications., Competing Interests: At the time of this work, the authors were employed by New England Biolabs, Inc., which funded this work and is the manufacturer of reagents used in this manuscript, including Thermus thermophilus Argonaute. Even though the authors were employed and funded by New England Biolabs, Inc., this did not detract from the objectivity of data generation or its interpretation., (Copyright © 2021 Hunt, Tamanaha, Bonanno, Cantor and Tanner.)

T7 RNA Polymerase (RNAP) is a widely used enzyme with recent applications in the production of RNA vaccines. For over 50 years denaturing sequencing gels have been used as key analysis tools for probing the nucleotide addition mechanisms of T7 RNAP and other polymerases. However, sequencing gels are low-throughput limiting their utility for comprehensive enzyme analysis. Here, we report the development of HiKER; (High-throughput Kinetics using Capillary Electrophoresis and Robotics) a high-throughput pipeline to quantitatively measure enzyme kinetics. We adapted a traditional polymerase misincorporation assay for fluorescent detection at scale allowing rapid estimates of RNAP misincorporation in different experimental conditions. Using this platform with an OT-2 robotics system, ~1500 time points were collected in a single workday. T7 RNAP exhibited dramatic differences in both observed rate constant and amplitude depending on the mismatch examined. An average misincorporation frequency of ~45 misincorporations per million bases was estimated using HiKER and is consistent with previous studies. Misincorporation time courses for T3 RNAP and Sp6 RNAP were also collected and appeared similar to T7 RNAP suggesting conserved kinetic mechanisms. However, differences between the RNAPs were observed in extension from base mismatch experiments. This platform is affordable, open-source, and broadly applicable to many enzymes. [ABSTRACT FROM AUTHOR]

Introduction: Foot pain can be a significant burden for patients. Custom foot orthoses (CFOs) have been a mainstay in podiatry treatment for foot pain management and improving foot function. However, little is known about podiatrists' experience of prescribing CFOs or patient experience of using foot orthoses (FOs), including CFOs, for foot pain. Methods: A focus group (FG) discussion with three FOs users (Female = 2 and Male = 1) was conducted in November 2022 within a private podiatry practice. This group represented non‐experts from the general local population of individuals with existing or previous foot pain who have personally experienced using either over‐the‐counter FOs or CFOs. An online FG discussion with five musculoskeletal (MSK) specialist podiatrists (Female = 2 and Male = 3) was also conducted in December 2022. This group represented podiatrists with specialist knowledge in foot biomechanics and clinical experience in CFO provision. The FG discussions were recorded and lasted 49 and 57 min respectively. Transcribed data was manually coded, and a thematic analysis was undertaken to identify patterns within the collected data. Results: The participants in the patient FG detailed mixed experiences of the prescription process and CFOs received, with reports of limited involvement/input in their prescription, the need for frequent adjustments and high costs. The impact on footwear choices, replicability and transferability of CFOs into different types of shoes and technologies to aid design were also highlighted. In the podiatrist FG, lack of confidence in design and manufacture processes, prescription form language, relationship and communication building with manufacturers, variability in the CFOs issued and the need for better student education in CFO provision emerged as key themes. Conclusion: Patients and podiatrists shared similar views on CFO provision, namely poor communication with manufacturers leading to dissatisfaction with the CFOs prescribed causing negative impacts on patient experiences. Podiatrists called for greater education at registration level to increase new graduate podiatrist knowledge in CFO design and manufacture and better collaboration with manufacturing companies. [ABSTRACT FROM AUTHOR]

Gallium oxide (Ga2O3) is a wide-bandgap oxide semiconductor, with a bandgap of ∼4.9 eV, making it a promising material for power device applications. This study focuses on the effect of hydrochloric acid addition on the growth rate in homoepitaxial growth of β-Ga2O3 using a mist chemical vapor deposition method. For homoepitaxial growth on a (001) β-Ga2O3 substrate, we introduced different concentrations of HCl into the source solution to assess its impact on the growth rate, crystal structures, and surface morphologies of the films. At a growth temperature of 900 °C, HCl addition linearly increased film thickness, enhancing the growth rate by 4.8 times with 9.09 vol. % HCl. No peaks associated with other phases were exhibited by each sample, indicating pure homoepitaxial growth. When comparing samples with similar film thicknesses, the root-mean-square (rms) roughness was enhanced by 1/7 with an increase in the HCl concentration. However, at 800 °C, an increasing solution concentration caused pronounced step bunching and elevated rms roughness, in contrast with the minimal effect observed at 900 °C. In experiments with hydrochloric acid addition at 900 °C, we observed a striped morphology, which maintained consistent rms roughness despite higher temperature. [ABSTRACT FROM AUTHOR]

Background/Objectives: Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by elevated motor activity, impulsivity, and attention deficit. Approximately 5% of the population suffers from this disorder. Among the key explanations of ADHD, executive functions play an important role in understanding the symptomatology present in this disorder and in determining the main treatment strategies for affected patients. We present a systematic review that seeks to identify the treatment methods developed to support executive functions in individuals with ADHD. Methods: Articles were analyzed in the SCOPUS, PUBMED, and Science Direct databases. Initially, 739 articles were found. After applying inclusion and exclusion criteria, 30 articles remained and were included in the data extraction process. Results: Among the primary treatments identified, 14 studies propose psychological training for executive functions, 9 studies recommend medication, 5 studies suggest digital interventions, and 1 study advocates for sports as beneficial for executive functions. Conclusions: The data are discussed around the need to develop new proposals to enhance the executive functions of individuals with ADHD, thereby improving their performance in educational, personal, social, and family activities impacted by this disorder. [ABSTRACT FROM AUTHOR]

Cyclopropane fragments, which widely exist in marketed drugs and natural products, can confer special pharmacological properties to small-molecule drugs. Therefore, developing methods to construct cyclopropanes is of great significance. Nevertheless, the introduction of cyclopropane primarily relies on already-formed cyclopropyl groups, which significantly restricts the diversity of cyclopropane skeletons. Late-stage direct cyclopropanation is still a challenging task. Herein, a photo-induced intermolecular deoxycyclopropanation reaction that employs alcohols as substrates, and 1 mol.% of 2,3,5,6-tetrakis(carbazol-9-yl)-1,4-dicyanobenzene (4CzTPN) as organophotocatalyst is reported. This method proceeds with high transformation efficiency (up to 98% yield) and exhibits broad functional group tolerance, such as primary, secondary, and tertiary alcohols as well as various activated β-halogenated alkenes. This process is mild, easy to operate, and has low equipment requirements. The power of this technology is demonstrated by the late-stage functionalization of five marketed drugs and five natural products., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

Markerless motion capture system and X-ray fluoroscopy as two markerless measurement systems were introduced the application method in sports biomechanical areas. An overview of the technological process, data accuracy, suggested movements, and recommended body parts were explained. The markerless motion capture system consists of four parts: camera, body model, image feature, and algorithms. Even though the markerless motion capture system seems promising, it is not yet known whether these systems can be used to achieve the required accuracy and whether they can be appropriately used in sports biomechanics and clinical research. The biplane fluoroscopy technique analyzes motion data by collecting, image calibrating, and processing, which is effective for determining small joint kinematic changes and calculating joint angles. The method was used to measure walking and jumping movements primarily because of the experimental conditions and mainly detect the data of lower limb joints. [ABSTRACT FROM AUTHOR]

We report a new type of structural defect in β-Ga2O3 homoepitaxial thin films grown by metalorganic vapor phase epitaxy, which we have dubbed as "sympetalous defects." These consist of a line defect (for example, a nanotube defect) in the underlying substrate combined with a multi-faceted inverted polycrystalline pyramid in the epitaxial film, which may also be decorated with twinned polycrystalline grains. In plan-view atomic force, scanning electron, or optical microscopies, the sympetalous defects appear similar in shape to polygonal etch pits observed for single crystals. Photoluminescence microscopy exposed spots of polarization-dependent luminescence at these defects, different from the single crystal films' luminescence. Furthermore, some of the defects exhibited circular dichroism in their luminescence that we correlated with partial helices formed within the pits by the arrangement of linearly dichroic polycrystalline grains. Finally, the density of sympetalous defects agrees with the etch pit densities of the substrates. Understanding and controlling these defects will be of importance as they modify the local properties of films, affect fabricated device yields, and influence characterization experiments. [ABSTRACT FROM AUTHOR]

We performed Borrmann effect x-ray topography (XRT) to observe dislocations and other structural defects in a thick β-Ga2O3 (001) substrate. The Borrmann effect was realized by working in a symmetrical Laue geometry (g = 020). Anomalous transmission occurred under the exact Bragg condition, producing a strong diffraction beam that allowed us to image defects across the entire thickness of the substrate. The analysis clearly revealed straight b-axis screw-type and curved dislocations and allowed assessing the corresponding behaviors. Other structural defects, including pipe-shaped voids and dislocation loops produced by mechanical damage, were also observed. Finally, we compared Borrmann effect transmission topography and conventional reflection topography and explained the appearance of some characteristic defects in the two modes. Our results show that Borrmann effect XRT is a powerful and effective technique to study the spatial distribution and structural properties of defects in highly absorbing β-Ga2O3. [ABSTRACT FROM AUTHOR]

Background. The plantar soft tissue plays a critical role in absorbing shocks and attenuating excessive stresses during walking. Plantar soft tissue property and plantar pressure are critical information for footwear design and clinical assessment. The aim of this study was to investigate the relationship between plantar soft tissue hardness and plantar pressure during walking. Methods. 59 healthy volunteers (27 males and 32 females, aged 20 to 82) participated in this study. The plantar surface was divided into five regions: lateral rearfoot, medial rearfoot, lateral midfoot, lateral forefoot, and medial forefoot, and the plantar tissue hardness was tested using Shore durometer in each region. Average dynamic pressures in each region were analyzed for the five regions corresponding to the hardness tests. The relationship between hardness and average dynamic pressure was analyzed in each region. Results. The average hardness of the plantar soft tissue in the above five regions is as follows: lateral rearfoot (34.49 ± 6.77), medial rearfoot (34.47 ± 6.64), lateral midfoot (27.95 ± 6.13), lateral forefoot (29.72 ± 5.47), and medial forefoot (28.58 ± 4.41). Differences of hardness were observed between age groups, and hardness of plantar soft tissues in forefoot regions increased with age (P < 0.05). A negative relationship was found between plantar soft tissue hardness and pressure reduction at lateral rearfoot, medial rearfoot, and lateral midfoot (P < 0.05). Conclusion. The hardness of plantar soft tissues changes with age in healthy individuals, and there is a trend of increasing hardness of the plantar soft tissue with age. The plantar soft tissue hardness increases with plantar pressure. [ABSTRACT FROM AUTHOR]

Foot orthoses have been used for decades despite uncertainty surrunding their therapeutic efficacy. Orthoses have been used exclusively to affect neuro-biomechanical input and outcome variables, however, there is emerging evidence that therapeutic efficacy may be affected by a psychological stimulus. Critical appraisal of the literature highlights that there is no holistic model upon which foot orthosis practice is taught, practised nor investigated. This paper introduces a conceptual model of foot orthosis practice (Value Based Foot Orthosis Practice (VALUATOR) model) that embraces a broader range of factors that are pertinent to orthosis practice, incorporating contemporary health service behaviours and values into orthosis practice for the first time. Within the VALUATOR model, foot orthosis design and clinical value is considered along a bio-psycho-social-digital continuum that reflects the reality of foot orthosis practice. The model contextualises the variable outcomes that are observed in research and practice within 6 key areas: 1) value, 2) person-centered approach, 3) zone of optimal bio-psycho-social stress, 4) bio-psycho-social assessment, 5) monitoring, 6) primary and secondary clinical strategies. The VALUATOR model is targeted at students, lecturers, scientists and practitioners and includes carefully chosen terminology to support a robust basis for educational and scientific discussion. It is believed that it provides a contemporary viewpoint and a structured conceptual metaphor that builds on existing evidence from a wide range of sources, invites constructive intellectual debate, and is anchored in the experiences of practitioners too. Stress testing the VALUATOR model will help determine its model and support further developments and evolution of orthotic practice in a evidence based way. [ABSTRACT FROM AUTHOR]

The purpose of the present study is to examine the effect of information literacy skills instruction on the lifelong learning readiness of users in Iranian public libraries. To this end, 30 active users of two libraries were randomly placed in control and experimental groups. Information literacy skills were taught to the experimental group over one and a half months. The results revealed that information literacy instruction led to a significant increase in readiness for self-directed learning and readiness to overcome deterrents to participation. According to the findings, information literacy skills instruction made a significant difference to the information literacy of users in Iranian public libraries. The results of this study encourage public libraries to plan for the implementation of information literacy instruction in order to make public libraries lifelong learning centres. [ABSTRACT FROM AUTHOR]

Objective: Custom foot orthoses (CFOs) are typically used for the prevention and cure of lower extremity injuries (LEIs). Typically, CFOs are designed and prescribed based on iterative loops including: (1) follow-up loops between the patient and the physician, and (2) design feedback loops between the physician and the fabricator. The current prescription methodology has some deficiencies, i.e. excessive time to satisfactory treatment, and low repeatability in custom fabrication because of missing alignment, soft tissue considerations, and subjective feedback. There are significant opportunities to develop a new CFOs prescription procedure which can improve accuracy prior to the fabrication process by reducing time through minimizing iterations. Methods: First, a novel “rapid evaluate and adjust device” (READ) prescription methodology is proposed for CFO design by combining the follow-up loops with design feedback loop. To support the idea of the READ prescription method a novel 3D ergonomic measurement system (3DEMS) is developed. The 3DEMS is designed for the following key targets to: (1) improve the communication between the patient/physician and the fabricator, (2) reduce time to satisfactory treatment, (3) improve repeatability by considering the alignment and the soft tissue deformations, (4) archive digitally with minimal data, (5) reduce the system complexity, and (6) validate with plantar pressure measurements (i.e. Novel Pedar®). The design process of the 3DEMS involved the following steps: (1) 3D data collection at the desired loading, (2) nested optimization to determine optimal segment design, and (3) system fabrication considering alignment and feedback control. Results: The results show that the READ prescription method with 3DEMS can be used to recreate the medial longitudinal arch for a range of arch height indices (AHI) by using a minimal number of parameters i.e. 6 parameters, and significant increases in mean peak pressure are observed between optimized and barefoot or flat segments. Conclusion: This study establishes that the proposed READ prescription method with the 3DEMS may be used for CFOs prescription due to better communication between individuals in the follow-up and design loops, less time for satisfactory treatment, improved repeatability, archivable data, and low system complexity. Significance: The developed system may be used as measurement systems for CFOs, and in the future the proposed 3DEMS may prove highly important for the measurement of CFOs for flat feet. [ABSTRACT FROM AUTHOR]

Films of β-Ga2O3 grown by halide vapor phase epitaxy on native substrates were subjected to Ar inductively coupled plasma treatment. As a result, the built-in voltage of Ni Schottky diodes deposited on the plasma treated surfaces decreased from 1 V to −0.02 V due to the buildup of deep trap concentration in the near surface region. Deep level spectra measurements indicate a strong increase in the top ∼200 nm of the plasma treated layer of the concentration of E2* (Ec − 0.8 eV) and especially E3 (Ec − 1.05 eV) deep electron traps. Capacitance-voltage profiling with monochromatic illumination also indicated a large increase in the upper ∼100 nm of the film in the concentration of deep acceptors with optical threshold for an ionization of ∼2.3 eV and 3.1 eV. Such defects at the surface led to a significant increase in reverse current, an increase in the ideality factor in forward current, and a dramatic decrease in the diffusion length of nonequilibrium charge carriers from 450 nm to 150 nm. [ABSTRACT FROM AUTHOR]

Focuses on the structure of the DNA-binding domain of the human regulatory factor X 1 (hRFX1) protein, a transcriptional activator, linked cooperatively to a symmetrical X-box4,5. Effects of DNA-binding defects in RFX proteins; Unique characteristic of hRFX1; Proposed interactions between linker histones and DNA.

Focuses on the crystal structure of a ligand-binding intermediate in carbonmonoxy myoglobin that may have far-reaching implications for understanding the dynamics of ligand binding and catalysis. Physiologic function of myoglobin; Occurrence of ligand migration; Active site.

Transcripts of many enzymes involved in base excision repair (BER) undergo extensive alternative splicing, but functions of the corresponding alternative splice variants remain largely unexplored. In this review, we cover the studies describing the common alternatively spliced isoforms and disease-associated variants of DNA glycosylases, AP-endonuclease 1, and DNA polymerase beta. We also discuss the roles of alternative splicing in the regulation of their expression, catalytic activities, and intracellular transport. [ABSTRACT FROM AUTHOR]

ABSTRACT Web service composition can enhance the efficiency and agility of knowledge management by composing individual Web services together for complex business requirements. There are two main research streams in […]

YEARBOOK AUSTRALIA 2003 REPORTS THAT IN AUGUST 2001 THERE WERE 9596 schools in Australia (2003:305). It can be claimed with confidence that each of these has a library and that [...]

This article reports on an exploratory case study of a class of Year 4/5 government primary school students in the ACT. The purpose of this case study was to establish [...]