Structural basis of respiratory complex adaptation to cold temperatures.

In response to cold, mammals activate brown fat for respiratory-dependent thermogenesis reliant on the electron transport chain. Yet, the structural basis of respiratory complex adaptation upon cold exposure remains elusive. Herein, we combined thermoregulatory physiology and cryoelectron microscopy (cryo-EM) to study endogenous respiratory supercomplexes from mice exposed to different temperatures. A cold-induced conformation of CI:III2 (termed type 2) supercomplex was identified with a ∼25° rotation of CIII2 around its inter-dimer axis, shortening inter-complex Q exchange space, and exhibiting catalytic states that favor electron transfer. Large-scale supercomplex simulations in mitochondrial membranes reveal how lipid-protein arrangements stabilize type 2 complexes to enhance catalytic activity. Together, our cryo-EM studies, multiscale simulations, and biochemical analyses unveil the thermoregulatory mechanisms and dynamics of increased respiratory capacity in brown fat at the structural and energetic level.

Mechanisms of mitochondrial respiratory adaptation.

Mitochondrial energetic adaptations encompass a plethora of conserved processes that maintain cell and organismal fitness and survival in the changing environment by adjusting the respiratory capacity of mitochondria. These mitochondrial responses are governed by general principles of regulatory biology exemplified by changes in gene expression, protein translation, protein complex formation, transmembrane transport, enzymatic activities and metabolite levels. These changes can promote mitochondrial biogenesis and membrane dynamics that in turn support mitochondrial respiration. The main regulatory components of mitochondrial energetic adaptation include: the transcription coactivator peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1α (PGC1α) and associated transcription factors; mTOR and endoplasmic reticulum stress signalling; TOM70-dependent mitochondrial protein import; the cristae remodelling factors, including mitochondrial contact site and cristae organizing system (MICOS) and OPA1; lipid remodelling; and the assembly and metabolite-dependent regulation of respiratory complexes. These adaptive molecular and structural mechanisms increase respiration to maintain basic processes specific to cell types and tissues. Failure to execute these regulatory responses causes cell damage and inflammation or senescence, compromising cell survival and the ability to adapt to energetically demanding conditions. Thus, mitochondrial adaptive cellular processes are important for physiological responses, including to nutrient availability, temperature and physical activity, and their failure leads to diseases associated with mitochondrial dysfunction such as metabolic and age-associated diseases and cancer.

Tetracyclines activate mitoribosome quality control and reduce ER stress to promote cell survival.

Mitochondrial diseases are a group of disorders defined by defects in oxidative phosphorylation caused by nuclear- or mitochondrial-encoded gene mutations. A main cellular phenotype of mitochondrial disease mutations is redox imbalances and inflammatory signaling underlying pathogenic signatures of these patients. One method to rescue this cell death vulnerability is the inhibition of mitochondrial translation using tetracyclines. However, the mechanisms whereby tetracyclines promote cell survival are unknown. Here, we show that tetracyclines inhibit the mitochondrial ribosome and promote survival through suppression of endoplasmic reticulum (ER) stress. Tetracyclines increase mitochondrial levels of the mitoribosome quality control factor MALSU1 (Mitochondrial Assembly of Ribosomal Large Subunit 1) and promote its recruitment to the mitoribosome large subunit, where MALSU1 is necessary for tetracycline-induced survival and suppression of ER stress. Glucose starvation induces ER stress to activate the unfolded protein response and IRE1α-mediated cell death that is inhibited by tetracyclines. These studies establish a new interorganelle communication whereby inhibition of the mitoribosome signals to the ER to promote survival, implicating basic mechanisms of cell survival and treatment of mitochondrial diseases.

Rapid and accurate alignment of nucleotide conversion sequencing reads with HISAT-3N.

Sequencing technologies using nucleotide conversion techniques such as cytosine to thymine in bisulfite-seq and thymine to cytosine in SLAM seq are powerful tools to explore the chemical intricacies of cellular processes. To date, no one has developed a unified methodology for aligning converted sequences and consolidating alignment of these technologies in one package. In this paper, we describe hierarchical indexing for spliced alignment of transcripts-3 nucleotides (HISAT-3N), which can rapidly and accurately align sequences consisting of any nucleotide conversion by leveraging the powerful hierarchical index and repeat index algorithms originally developed for the HISAT software. Tests on real and simulated data sets show that HISAT-3N is faster than other modern systems, with greater alignment accuracy, higher scalability, and smaller memory requirements. HISAT-3N therefore becomes an ideal aligner when used with converted sequence technologies.

HIV testing at visits to US emergency departments: 2021 update.

In this updated cross-sectional analysis of the National Hospital Ambulatory Medical Care Survey, we found that among the 2.5 million more weighted emergency department (ED) visits in 2021 compared with 2020, there was an insignificant increase in HIV testing per ED visit in 2021 compared with 2020 (0.81% to 0.86%). This suggests HIV testing during ED visits did not increase in line with rebounding visit volumes after the pandemic nadir.

Persistent elevation in incidence of pneumonia in children in England, 2023/24.

Since November 2023, the absolute number of attendances at emergency departments for pneumonia among children aged 5-14 years in England have been above expected levels for the time of year. This increased signal peaked during March 2024 but then persisted into early summer 2024 despite decreases in prevalence of seasonal respiratory pathogens. Record linkage between emergency department and laboratory databases points to this unusual activity being driven largely by Mycoplasma pneumoniae.

SeqWho: reliable, rapid determination of sequence file identity using k-mer frequencies in Random Forest classifiers.

MOTIVATION: With the vast improvements in sequencing technologies and increased number of protocols, sequencing is being used to answer complex biological problems. Subsequently, analysis pipelines have become more time consuming and complicated, usually requiring highly extensive prevalidation steps. Here, we present SeqWho, a program designed to assess heuristically the quality of sequencing files and reliably classify the organism and protocol type by using Random Forest classifiers trained on biases native in k-mer frequencies and repeat sequence identities. RESULTS: Using one of our primary models, we show that our method accurately and rapidly classifies human and mouse sequences from nine different sequencing libraries by species, library and both together, 98.32%, 97.86% and 96.38% of the time, respectively. Ultimately, we demonstrate that SeqWho is a powerful method for reliably validating the quality and identity of the sequencing files used in any pipeline. AVAILABILITY AND IMPLEMENTATION: https://github.com/DaehwanKimLab/seqwho. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Peroxisomal-derived ether phospholipids link nucleotides to respirasome assembly.

The protein complexes of the mitochondrial electron transport chain exist in isolation and in higher order assemblies termed supercomplexes (SCs) or respirasomes (SC I+III2+IV). The association of complexes I, III and IV into the respirasome is regulated by unknown mechanisms. Here, we designed a nanoluciferase complementation reporter for complex III and IV proximity to determine in vivo respirasome levels. In a chemical screen, we found that inhibitors of the de novo pyrimidine synthesis enzyme dihydroorotate dehydrogenase (DHODH) potently increased respirasome assembly and activity. By-passing DHODH inhibition via uridine supplementation decreases SC assembly by altering mitochondrial phospholipid composition, specifically elevated peroxisomal-derived ether phospholipids. Cell growth rates upon DHODH inhibition depend on ether lipid synthesis and SC assembly. These data reveal that nucleotide pools signal to peroxisomes to modulate synthesis and transport of ether phospholipids to mitochondria for SC assembly, which are necessary for optimal cell growth in conditions of nucleotide limitation.

Evaluation of CI electrode position from imaging: comparison of an automated technique with the established manual method.

BACKGROUND: A manual evaluation of the CI electrode position from CT and DVT scans may be affected by diagnostic errors due to cognitive biases. The aim of this study was to compare the CI electrode localization using an automated method (image-guided cochlear implant programming, IGCIP) with the clinically established manual method. METHODS: This prospective experimental study was conducted on a dataset comprising N=50 subjects undergoing cochlear implantation with a Nucleus® CI532 or CI632 Slim Modiolar electrode. Scalar localization, electrode-to-modiolar axis distances (EMD) and angular insertion depth (aDOI) were compared between the automated IGCIP tool and the manual method. Two raters made the manual measurements, and the interrater reliability (±1.96·SD) was determined as the reference for the method comparison. The method comparison was performed using a correlation analysis and a Bland-Altman analysis. RESULTS: Concerning the scalar localization, all electrodes were localized both manually and automatically in the scala tympani. The interrater differences ranged between ±0.2 mm (EMD) and ±10° (aDOI). There was a bias between the automatic and manual method in measuring both localization parameters, which on the one hand was smaller than the interrater variations. On the other hand, this bias depended on the magnitude of the EMD respectively aDOI. A post-hoc analysis revealed that the deviations between the methods were likely due to a different selection of mid-modiolar axis. CONCLUSIONS: The IGCIP is a promising tool for automated processing of CT and DVT scans and has useful functionality such as being able to segment the cochlear using post-operative scans. When measuring EMD, the IGCIP tool is superior to the manual method because the smallest possible distance to the axis is determined depending on the cochlear turn, whereas the manual method selects the helicotrema as the reference point rigidly. Functionality to deal with motion artifacts and measurements of aDOI according to the consensus approach are necessary, otherwise the IGCIP is not unrestrictedly ready for clinical use.

Trends in female first-author abstracts at the Society for Academic Emergency Medicine Annual Meeting, 1990-2020.

OBJECTIVES: To describe first author gender differences and characteristics in 1) Society for Academic Emergency Medicine (SAEM) Annual Meeting abstracts and 2) resulting manuscript publications. METHODS: We performed cross-sectional evaluation of SAEM abstracts from 1990, 1995, 2000, 2005, 2010, 2015, and 2020, compiling and reviewing a random sample of 100 abstracts for each year (total n = 700 abstracts). We documented abstract characteristics, including first author gender, and used the 2020 SAEM scoring rubric. We then searched PubMed to identify manuscript publications resulting from abstracts from 1990 to 2015 (n = 600). Finally, among abstracts that resulted in manuscript publication, we identified first and last author gender on both the abstracts and the resulting publication. RESULTS: Overall, 29% (202/695; n = 5 missing gender) of abstracts had female first authors. Female first authors increased over time (e.g., 17% in 1990 to 35% in 2020). Abstract quality scores were similar (both median [interquartile range] of 11 ([9-12]). Overall, 42% (n = 254/600) of abstracts resulted in a manuscript publication, 39% (n = 65/202) with female and 44% (n = 189/493) with male first authors (p = 0.26). The median time (IQR) from abstract to manuscript publication was longer for abstracts with female first authors vs. those with male first authors (2 [1-3] years and 1 [1, 2] years, p < 0.02); 77% and 78% of publications resulting from abstracts with female and male first authors, respectively, had the same first author. Female first author abstracts more often converted to a male first author manuscript publication (18%, n = 12/65) compared to male first author abstracts converting to female first author publications (7%, n = 14/189). CONCLUSIONS: A minority of SAEM abstracts, and manuscript publications resulting from them, had female first authors. Abstracts with female first authors took longer to achieve manuscript publication, and almost a fifth of female first author abstracts resulted in male first author manuscript publication.

Characteristics of California Emergency Departments in Centers for Disease Control and Prevention-Designated HIV Priority Counties.

BACKGROUND: Refocused national HIV testing initiatives include a geographic focus. OBJECTIVE: Using a geographic focus, we sought to identify which emergency departments (EDs) might be the most efficient targets for future HIV testing efforts, using California as an example. METHODS: Retrospective analysis of California EDs, emergency physicians, and patients served, along with county-level estimates of HIV prevalence and proportion of the population living in poverty. Emphasis was placed on characterizing EDs affiliated with teaching hospitals and those located in Centers for Disease Control (CDC) and Prevention HIV priority counties. RESULTS: Of the 320 EDs studied, 178 were in priority counties, 29 were affiliated with teaching hospitals, and 24 had both characteristics. Of the 12,869,889 ED visits included, 61.8% occurred in priority counties, 14.7% in EDs affiliated with teaching hospitals, and 12.0% in EDs with both characteristics. The subset of EDs in priority counties with teaching hospital affiliations (compared with priority and nonpriority county ED groups without a teaching hospital affiliation) had higher overall median visit volumes and higher proportions of visits by at-risk and CDC-targeted populations (e.g., individuals who were homeless, those who identified as Black or African American race, and those who identified as Hispanic or Latino ethnicity, all p < 0.01). CONCLUSIONS: EDs in priority counties affiliated with teaching hospitals are major sources of health care in California. These EDs more often serve populations disproportionately impacted by HIV. These departments are efficient targets to direct testing efforts. Increasing testing in these EDs could reduce the burden of undiagnosed HIV in California.

Role of Suprathermal Chemistry on the Evolution of Carbon Oxides and Organics within Interstellar and Cometary Ices.

ConspectusLaboratory-based experimental astrochemistry regularly entails simulation of astrophysical environments whereby low-temperature condensed ices are exposed to radiation from ultraviolet (UV) photons or energetic charged particles. Here, excited atoms/radicals are generated that are not in thermal equilibrium with their surroundings (i.e., they are nonthermal, or suprathermal). These species can surpass typical reaction barriers and partake in unusual chemical processes leading to novel molecular species. Often, these are uniquely observable under low-temperature conditions where the surrounding ice matrix can stabilize excited intermediates that would otherwise fall apart. Fourier-transform infrared (FTIR) spectroscopy is traditionally utilized to monitor the evolution of chemical species within ices in situ during radiolysis. Yet, the characterization and quantification of novel species and radicals formed within astrophysical ices is often hindered since many of these cannot be synthesized by traditional synthetic chemistry. Computational approaches can provide fundamental vibrational frequencies and isotopic shifts to help aid in assignments alongside infrared intensities and Raman activities to quantify levels of production. In this Account, we begin with a brief history and background regarding the composition and radiation of interstellar ices. We review details of some of the early work on carbon oxides produced during the radiolysis of pure carbon dioxide ices and contention around the carrier of an absorption feature that could potentially be a product of radiation. We then provide an overview of current and emerging experimental methodologies and some of the chemistries that occur via nonthermal processes during radiolysis of low-temperature ices. Next, we detail computational approaches to reliably predict vibrational frequencies, infrared intensities, and Raman activities based on our recent work. Our focus then turns to studies on the formation of complex organics and carbon oxides, highlighting those aided by computational approaches and their role in astrochemistry. Some recent controversies regarding assignments alongside our recent results on the characterization of novel carbon oxide species are discussed. We present an argument for the potential role of carbon oxides within cometary ices as parent molecular species for small volatiles. We provide an overview of some of the complex organic species that can be formed within interstellar and cometary ices that contain either carbon monoxide or carbon dioxide. We examine how Raman spectroscopy could potentially be leveraged to help determine and characterize carbon oxides in future experiments as well as how computational approaches can aid in these assignments. We conclude with brief remarks on future directions our research group is taking to unravel astrochemically relevant carbon oxides using combined computational and experimental approaches.

Further delineation of phenotypic spectrum of SCN2A-related disorder.

SCN2A-related disorders include intellectual disability, autism spectrum disorder, seizures, episodic ataxia, and schizophrenia. In this study, the phenotype-genotype association in SCN2A-related disorders was further delineated by collecting detailed clinical and molecular characteristics. Using previously proposed genotype-phenotype hypotheses based on variant function and position, the potential of phenotype prediction from the variants found was examined. Patients were identified through the Deciphering Developmental Disorders study and gene matching strategies. Phenotypic information and variant interpretation evidence were collated. Seventeen previously unreported patients and five patients who had been previously reported (but with minimal phenotypic and segregation data) were included (10 males, 12 females; median age 10.5 years). All patients had developmental delays and the majority had intellectual disabilities. Seizures were reported in 15 of 22 (68.2%), four of 22 (18.2%) had autism spectrum disorder and no patients were reported with episodic ataxia. The majority of variants were de novo. One family had presumed gonadal mosaicism. The correlation of the use of sodium channel-blocking antiepileptic drugs with phenotype or genotype was variable. These data suggest that variant type and position alone can provide some predictive information about the phenotype in a proportion of cases, but more precise assessment of variant function is needed for meaningful phenotype prediction.

United States 2020 Emergency Medicine Resident Workforce Analysis.

STUDY OBJECTIVE: To characterize the emergency medicine resident physician workforce and the residency programs training them. METHODS: We identified emergency medicine residents in the 2020 American Medical Association (AMA) Physician Masterfile, analyzed demographic information, mapped both county-level population-adjusted and hospital referral region densities, and compared 2020 versus 2008 resident physician densities. We also analyzed all Accreditation Council for Graduate Medical Education (ACGME)-accredited emergency medicine residency programs from 2013 to 2020, mapped state-level population-adjusted densities, and identified temporal trends in program location and state-level program densities. All population-adjusted densities were calculated using the US Census Bureau resident population estimates. RESULTS: There were 6,993 emergency medicine residents in the 2020 AMA dataset with complete information. Most of them (98%) were in urban areas. Compared with 2008, per 100,000 US population, this represents disproportionate increases in urban areas (total [0.5], urban [0.5], large rural [0.2] and small rural [0.05]). We further identified 160 (2013) to 265 (2020) residency programs using the ACGME data. The new programs were 3-year training programs that were disproportionately added to states with an already higher number of programs (Florida [5 to 19], Michigan [11 to 25], New York [21 to 31], Ohio [9 to 18], Pennsylvania [12 to 21], California [14 to 22]). CONCLUSION: The number of emergency medicine residency programs has increased; most new programs were added to the states that already had emergency medicine residency programs. There is an emergency physician "desert" in the rural United States, lacking both residents and residency training programs. This analysis provides essential context to the ongoing conversation about the future of the emergency physician workforce.

Evaluation of a Transimpedance Matrix Algorithm to Detect Anomalous Cochlear Implant Electrode Position.

INTRODUCTION: Transimpedance measurements from cochlear implant electrodes have the potential to identify anomalous electrode array placement, such as tip fold-over (TFO) or fold-back, basal electrode kinking, or buckling. Analysing transimpedance may thus replace intraoperative or post-operative radiological imaging to detect any potential misplacements. A transimpedance algorithm was previously developed to detect deviations from a normal electrode position with the aim of intraoperatively detecting TFO. The algorithm had been calibrated on 35 forced, tip folded electrode arrays in six temporal bones to determine the threshold criterion required to achieve a sensitivity of 100%. Our primary objective here was to estimate the specificity of this TFO algorithm in patients, in a prospective study, for a series of electrode arrays shown to be normally inserted by post-operative imaging. METHODS: Intracochlear voltages were intraoperatively recorded for 157 ears, using Cochlear's Custom Sound™ EP 5 electrophysiological software (Cochlear Ltd., Sydney, NSW, Australia), for both Nucleus® CI512 and CI532 electrode arrays. The algorithm analysed the recorded 22 × 22 transimpedance matrix (TIM) and results were displayed as a heatmap intraoperatively, only visible to the technician in the operating theatre. After all clinical data were collected, the algorithm was evaluated on the bench. The algorithm measures the transimpedance gradients and corresponding phase angles (θ) throughout the TIM and calculates the gradient phase range. If this was greater than the predetermined threshold, the algorithm classified the electrode array insertion as having a TFO. RESULTS: Five ears had no intraoperative TIM and four anomalous matrices were identified from heatmaps and removed from the specificity analysis. Using the 148 remaining data sets (n = 103 CI532 and n = 45 CI512), the algorithm had an average specificity of 98.6% (95.80%-99.75%). CONCLUSION: The algorithm was found to be an effective screening tool for the identification of TFOs. Its specificity was within acceptable levels and resulted in a positive predictive value of 76%, with an estimated incidence of fold-over of 4% in perimodiolar arrays. This would mean 3 out of 4 cases flagged as a fold-over would be correctly identified by the algorithm, with the other being a false positive. The measurements were applied easily in theatre allowing it to be used as a routine clinical tool for confirming correct electrode placement.

Development of Custom Sound® Pro software utilising big data and its clinical evaluation.

OBJECTIVES: To inform and optimise a cochlear implant (CI) fitting software design through an analysis of big data to define array-specific comfort (C) level profiles, frequently-used MAP parameters, and the minimum number of Neural Response Telemetry thresholds (tNRT) needed to create an accurate profile. To evaluate the software's ease of use and completion time for AutoNRT®s. DESIGN: MAPs analysis. Clinical study evaluating software use in creating MAPs, addressing sound-quality issues and setting patient goals. STUDY SAMPLE: MAPs (N = 39,885); CI recipients (N = 47) and clinicians (N = 19). RESULTS: Distinct C-level profiles were observed for lateral-wall, contour, and slim-modiolar electrode arrays. Default settings were used for most MAP parameters (13/16) except for Pulse Width, Rate, and Maxima. Nine tNRT measurements were required for an accurate C-level profile. Measurement-time of nine tNRTs via the new algorithm was comparable to five tNRTs using the previous algorithm. Nearly all (99%) clinical tasks were completed by clinicians with the first use of the software. Most CI recipients (79.5%) rated goal-setting as valuable. CONCLUSION: Custom Sound Pro fitting software developed based on big data analysis incorporates a guided fitting workflow and expected fitting ranges. It helps to improve clinical efficiency, is easy to use and supports patient-centred care.

Examining Parity among Black and Hispanic Resident Physicians.

BACKGROUND: The US physician workforce does not represent the racial or ethnic diversity of the population it serves. OBJECTIVES: To assess whether the proportion of US physician trainees of Black race and Hispanic ethnicity has changed over time and then provide a conceptual projection of future trends. DESIGN: Cross-sectional, retrospective, analysis based on 11 years of publicly available data paired with recent US census population estimates. PARTICIPANTS: A total of 86,303 (2007-2008) to 103,539 (2017-2018) resident physicians in the 20 largest US Accreditation Council for Graduate Medical Education resident specialties. MAIN MEASURES: Changes in proportion of physician trainees of Black race and Hispanic ethnicity per academic year. Projected number of years it will then take, for specialties with positive changes, to reach proportions of Black race and Hispanic ethnicity comparable to that of the US population. KEY RESULTS: Among the 20 largest specialty training programs, Radiology was the only specialty with a statistically significant increase in the proportion of Black trainees, but it could take Radiology 77 years to reach levels of Black representation comparable to that of the US population. Obstetrics/Gynecology, Emergency Medicine, Internal Medicine/Pediatrics, and Orthopedic Surgery demonstrated a statistically significant increase in the proportion of Hispanic trainees, but it could take these specialties 35, 54, 61, and 93 years respectively to achieve Hispanic representation comparable to that of the US population. CONCLUSIONS: Among US residents in the 20 largest specialties, no specialty represented either the Black or Hispanic populations in proportions comparable to the overall US population. Only a small number of specialties demonstrated statistically significant increases. This conceptual projection suggests that current efforts to promote diversity are insufficient.

Assessing visual search performance using a novel dynamic naturalistic scene.

Daily activities require the constant searching and tracking of visual targets in dynamic and complex scenes. Classic work assessing visual search performance has been dominated by the use of simple geometric shapes, patterns, and static backgrounds. Recently, there has been a shift toward investigating visual search in more naturalistic dynamic scenes using virtual reality (VR)-based paradigms. In this direction, we have developed a first-person perspective VR environment combined with eye tracking for the capture of a variety of objective measures. Participants were instructed to search for a preselected human target walking in a crowded hallway setting. Performance was quantified based on saccade and smooth pursuit ocular motor behavior. To assess the effect of task difficulty, we manipulated factors of the visual scene, including crowd density (i.e., number of surrounding distractors) and the presence of environmental clutter. In general, results showed a pattern of worsening performance with increasing crowd density. In contrast, the presence of visual clutter had no effect. These results demonstrate how visual search performance can be investigated using VR-based naturalistic dynamic scenes and with high behavioral relevance. This engaging platform may also have utility in assessing visual search in a variety of clinical populations of interest.

Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar Atrophy, and Osteopenia.

Approximately one in every 200 mammalian proteins is anchored to the cell membrane through a glycosylphosphatidylinositol (GPI) anchor. These proteins play important roles notably in neurological development and function. To date, more than 20 genes have been implicated in the biogenesis of GPI-anchored proteins. GPAA1 (glycosylphosphatidylinositol anchor attachment 1) is an essential component of the transamidase complex along with PIGK, PIGS, PIGT, and PIGU (phosphatidylinositol-glycan biosynthesis classes K, S, T, and U, respectively). This complex orchestrates the attachment of the GPI anchor to the C terminus of precursor proteins in the endoplasmic reticulum. Here, we report bi-allelic mutations in GPAA1 in ten individuals from five families. Using whole-exome sequencing, we identified two frameshift mutations (c.981_993del [p.Gln327Hisfs∗102] and c.920delG [p.Gly307Alafs∗11]), one intronic splicing mutation (c.1164+5C>T), and six missense mutations (c.152C>T [p.Ser51Leu], c.160_161delinsAA [p.Ala54Asn], c.527G>C [p.Trp176Ser], c.869T>C [p.Leu290Pro], c.872T>C [p.Leu291Pro], and c.1165G>C [p.Ala389Pro]). Most individuals presented with global developmental delay, hypotonia, early-onset seizures, cerebellar atrophy, and osteopenia. The splicing mutation was found to decrease GPAA1 mRNA. Moreover, flow-cytometry analysis of five available individual samples showed that several GPI-anchored proteins had decreased cell-surface abundance in leukocytes (FLAER, CD16, and CD59) or fibroblasts (CD73 and CD109). Transduction of fibroblasts with a lentivirus encoding the wild-type protein partially rescued the deficiency of GPI-anchored proteins. These findings highlight the role of the transamidase complex in the development and function of the cerebellum and the skeletal system.

Maximized lateral inhibition in paired magnetic domain wall racetracks for neuromorphic computing.

Lateral inhibition is an important functionality in neuromorphic computing, modeled after the biological neuron behavior that a firing neuron deactivates its neighbors belonging to the same layer and prevents them from firing. In most neuromorphic hardware platforms lateral inhibition is implemented by external circuitry, thereby decreasing the energy efficiency and increasing the area overhead of such systems. Recently, the domain wall-magnetic tunnel junction (DW-MTJ) artificial neuron is demonstrated in modeling to be intrinsically inhibitory. Without peripheral circuitry, lateral inhibition in DW-MTJ neurons results from magnetostatic interaction between neighboring neuron cells. However, the lateral inhibition mechanism in DW-MTJ neurons has not been studied thoroughly, leading to weak inhibition only in very closely-spaced devices. This work approaches these problems by modeling current- and field- driven DW motion in a pair of adjacent DW-MTJ neurons. We maximize the magnitude of lateral inhibition by tuning the magnetic interaction between the neurons. The results are explained by current-driven DW velocity characteristics in response to an external magnetic field and quantified by an analytical model. Dependence of lateral inhibition strength on device parameters is also studied. Finally, lateral inhibition behavior in an array of 1000 DW-MTJ neurons is demonstrated. Our results provide a guideline for the optimization of lateral inhibition implementation in DW-MTJ neurons. With strong lateral inhibition achieved, a path towards competitive learning algorithms such as the winner-take-all are made possible on such neuromorphic devices.