Kinetochores grip microtubules with directionally asymmetric strength.

For accurate mitosis, all chromosomes must achieve "biorientation," with replicated sister chromatids coupled via kinetochores to the plus ends of opposing microtubules. However, kinetochores first bind the sides of microtubules and subsequently find plus ends through a trial-and-error process; accurate biorientation depends on the selective release of erroneous attachments. Proposed mechanisms for error-correction have focused mainly on plus-end attachments. Whether erroneous side attachments are distinguished from correct side attachments is unknown. Here, we show that side-attached kinetochores are very sensitive to microtubule polarity, gripping sixfold more strongly when pulled toward plus versus minus ends. This directionally asymmetric grip is conserved in human and yeast subcomplexes, and it correlates with changes in the axial arrangement of subcomplexes within the kinetochore, suggesting that internal architecture dictates attachment strength. We propose that the kinetochore's directional grip promotes accuracy during early mitosis by stabilizing correct attachments even before both sisters have found plus ends.

Neighborhood Deprivation and Association With Medical Complications, Emergency Department Use, and Readmissions in Shoulder Arthroplasty Patients.

Background: Social determinants of health are prognostic indicators for patients undergoing orthopedic procedures. Purpose: Using the area deprivation index (ADI), a validated, weighted index of material deprivation and poverty (a 0%-to-100% scale, with higher percentages indicating greater disadvantage), we sought to evaluate whether there are associations in shoulder arthroplasty patients between higher ADI and rates of (1) medical complications, (2) emergency department (ED) utilizations, (3) readmissions, and (4) costs. Methods: We queried the PearlDiver nationwide database for patients who had undergone primary shoulder arthroplasty from 2010 to 2020. Patients from regions associated with high ADI (95%+) were 1:1 propensity matched to a comparison group by age, sex, and Elixhauser Comorbidity Index. This yielded 49,440 patients in total. Outcomes included 90-day complications, ED utilizations, readmissions, and costs. Logistic regression models computed odds ratios (ORs) of ADI on the dependent variables. P values of < .05 were significant. Results: Patients from high ADI regions showed higher rates and odds of complications than those in the comparison group (10.84% vs 9.45%; OR: 1.10), including acute kidney injuries (1.73% vs 1.38%; OR: 1.23), urinary tract infections (3.19% vs 2.80%; OR: 1.13), and respiratory failures (0.49% vs 0.33%; OR: 1.44), but not increased ED visits (2.66% vs 2.71%; OR: 0.99) or readmissions (3.07% vs 2.96%; OR: 1.03). Patients from high ADI regions incurred higher costs on day of surgery ($8251 vs $7337) and at 90 days ($10,999 vs $9752). Conclusions: This 10-year retrospective database study found that patients from high ADI regions undergoing primary shoulder arthroplasty had increased rates of all 90-day medical complications, suggesting that measures of social determinants of health could inform health care policy and improve post-discharge care in these patients.

Three-dimensional, multi-wavelength beam formation with integrated metasurface optics for Sr laser cooling.

We demonstrate the formation of a complex, multi-wavelength, three-dimensional laser beam configuration with integrated metasurface (MS) optics. Our experiments support the development of a compact Sr optical-lattice clock, which leverages magneto-optical trapping at 461 nm and 689 nm without bulk free-space optics. We integrate six mm-scale metasurfaces on a fused silica substrate and illuminate them with light from optical fibers. The metasurfaces provide full control of beam pointing, divergence, and polarization to create the laser configuration for a magneto-optical trap. We report the efficiency and integration of the visible laser beam configuration, demonstrating the suitability of metasurface optics for atomic laser cooling.

Effect of data censoring on thoracic injury risk curves.

OBJECTIVE: The first objective was to evaluate the effect of using less censored (i.e., exact and interval-censored) data on thoracic injury risk curves and the resulting injury probabilities. The second objective was to generate new injury risk curves to predict Abbreviated Injury Scale (AIS) 3+ rib fractures based on chest deflection. METHODS: Two data sets consisting of postmortem human surrogate (PMHS) tests with multipoint chest deflection measurements were compiled: A less censored data set consisting of exact and interval-censored data and a doubly censored data set consisting of left- and right-censored data. Chest deflection data from both data sets were processed in a consistent manner to calculate the maximum deflections at different locations across the chest. Survival analysis methods were used to generate nonparametric and parametric injury risk curves for serious skeletal injury. The total sample sizes and proportions of less censored data used to generate the risk curves were varied for each curve to evaluate the effects of sample size and less censored data on risk curve shape and predicted injury thresholds. RESULTS: Increasing the proportion of less censored data resulted in steeper injury risk curves and a higher predicted risk for a given amount of deflection. Differences in injury risk were more pronounced in the upper half of the injury risk curves. Introducing less censored data also produced narrower confidence intervals. At a total sample size of 79, increasing the percentage of less censored data from 0 to 30 had minimal effect on the shape of the risk curve. CONCLUSIONS: Doubly censored chest deflection data have historically been used to generate thoracic injury risk curves for frontal motor vehicle crash events. This study found that incorporating less censored data into thoracic injury risk curves meaningfully affected the shape of the injury risk curves and their resulting injury risk predictions. All of the injury risk curves generated in the study predicted a lower threshold for serious rib fracture injury compared to previously developed injury risks curves that are currently in use in the field. Based on the results of this study, adding less censored data to injury risk curves should be strongly considered to improve thoracic injury risk curve prediction and confidence, especially for smaller sample sizes.

Inbreeding avoidance and cost in a small, isolated trout population.

The persistence of small populations is influenced by the degree and cost of inbreeding, with the degree of inbreeding depending on whether close-kin mating is passively or actively avoided. Few studies have simultaneously studied these factors. We examined inbreeding in a small, isolated population of westslope cutthroat trout using extensive genetic and demographic data. Passive inbreeding avoidance was low, with predicted lifetime dispersal of approximately 36 and 74 m for females and males, respectively. Additionally, we found limited evidence for active inbreeding avoidance during reproduction. Relatives remained spatially clustered into adulthood, and observed relatedness among mate pairs was greater than expected under random mating by 0.09, suggesting that inbreeding is a concern in this population. Further, we examined sex-specific inbreeding depression throughout the life cycle and provide evidence for inbreeding depression in some fitness components, including family size, juvenile survival and reproductive success. Our results suggest that, in an at-risk trout population, limited passive and active inbreeding avoidance lead to a higher degree of inbreeding than expected under random mating. Observed inbreeding, along with evidence for fitness reduction due to inbreeding depression, could put the population at a heightened risk of decline or extirpation.

Can adiposity measures enhance the predictive power of the triglyceride-glucose index for metabolic syndrome in adults in the United States?

BACKGROUND: Insulin resistance is a hallmark feature of metabolic syndrome (MetSyn). The triglyceride-glucose (TyG) index is considered a reliable surrogate measure of insulin resistance. However, the efficacy of the TyG-index combined with adiposity measures for identifying MetSyn in U.S. adults is unknown. METHODS: In the present cross-sectional study, 2746 men and women from the 2017-2020 National Health and Nutrition Examination Survey (NHANES) with physical and laboratory characteristics were included. Predictive powers (estimated by the area under the curve of receiver operating characteristic [ROC-AUC]) of TyG-index combined with adiposity for MetSyn were compared with other traditional surrogate markers of insulin resistance including the TyG index, homeostatic assessment of insulin resistance (HOMA-IR), 1/fasting insulin, and quantitative insulin sensitivity check index (QUICKI). RESULTS: Predictive power of TyG-WHtR (ROC-AUC: 0.875) for MetSyn was highest, followed by TyG-WC (0.866), TyG-BMI (0.845), TyG index (0.832), HOMA-IR (0.820), QUICKI (0.820) and 1/fasting insulin (0.786). TyG-WHtR and TyG-WC showed significantly higher ROC-AUCs compared with TyG-index, HOMA-IR, 1/fasting insulin, and QUICKI (p ≤ 0.001). CONCLUSIONS: TyG index combined with adiposity metrics is more effective in predicting MetSyn when compared to insulin resistance surrogates (TyG index, HOMA-IR, 1/fasting insulin, and QUICKI) which has been widely used in large cohort observational studies.

Correction: Impact of lanthanide ion complexation and temperature on the chemical reactivity of N,N,N',N'-tetraoctyl diglycolamide (TODGA) with the dodecane radical cation.

Correction for 'Impact of lanthanide ion complexation and temperature on the chemical reactivity of N,N,N',N'-tetraoctyl diglycolamide (TODGA) with the dodecane radical cation' by Gregory P. Horne et al., Phys. Chem. Chem. Phys., 2023, 25, 16404-16413, https://doi.org/10.1039/D3CP01119D.

Dominantly inherited muscle disorders: understanding their complexity and exploring therapeutic approaches.

Treatments for disabling and life-threatening hereditary muscle disorders are finally close to becoming a reality. Research has thus far focused primarily on recessive forms of muscle disease. The gene replacement strategies that are commonly employed for recessive, loss-of-function disorders are not readily translatable to most dominant myopathies owing to the presence of a normal chromosome in each nucleus, hindering the development of novel treatments for these dominant disorders. This is largely due to their complex, heterogeneous disease mechanisms that require unique therapeutic approaches. However, as viral and RNA interference-based therapies enter clinical use, key tools are now in place to develop treatments for dominantly inherited disorders of muscle. This article will review what is known about dominantly inherited disorders of muscle, specifically their genetic basis, how mutations lead to disease, and the pathomechanistic implications for therapeutic approaches.

Eosinophilic granulomatosis with polyangiitis associated with malignant arrhythmias: a case report.

Background: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare vasculitis associated with significant cardiac morbidity and mortality. This case report presents the diagnostic and management challenges of EGPA-related arrhythmias in a remote general hospital setting. Case summary: A 64-year-old Caucasian male presented with an indolent prodrome of fatigue, shortness of breath and anorexia, that culminated in an acute presentation with pulmonary embolism. His complicated clinical course included intracranial haemorrhage and refractory ventricular arrhythmias. Eosinophilia and sub-endocardial hypoattenuation observed on chest computed tomography were key findings that led to the diagnosis of EGPA. Multiple anti-arrhythmic therapies were required as temporary measures whilst control of the underlying eosinophilic inflammation was achieved.Once stable, the patient was transferred to a tertiary cardiac centre for further investigation and cardioverter-defibrillator implantation. With EGPA now well controlled, he has experienced no further ventricular arrhythmias and has fully recovered. Conclusion: Cardiac complications of EGPA, including ventricular arrhythmias, are difficult to manage without concurrent immunosuppression, which may itself further destabilize cardiac electrophysiology. The role of multiple imaging modalities in the diagnosis and monitoring of EGPA is emphasized, with cardiac magnetic resonance imaging playing a crucial role in detecting sub-endocardial fibrosis.

Auto-Abs neutralizing type I IFNs in patients with severe Powassan, Usutu, or Ross River virus disease.

Arboviral diseases are a growing global health concern. Pre-existing autoantibodies (auto-Abs) neutralizing type I interferons (IFNs) can underlie encephalitis due to West Nile virus (WNV) (∼40% of patients) and tick-borne encephalitis (TBE, due to TBE virus [TBEV]) (∼10%). We report here that these auto-Abs can also underlie severe forms of rarer arboviral infections. Auto-Abs neutralizing high concentrations of IFN-α2, IFN-ß, and/or IFN-ω are present in the single case of severe Powassan virus (POWV) encephalitis studied, two of three cases of severe Usutu virus (USUV) infection studied, and the most severe of 24 cases of Ross River virus (RRV) disease studied. These auto-Abs are not found in any of the 137 individuals with silent or mild infections with these three viruses. Thus, auto-Abs neutralizing type I IFNs underlie an increasing list of severe arboviral diseases due to Flaviviridae (WNV, TBEV, POWV, USUV) or Togaviridae (RRV) viruses transmitted to humans by mosquitos (WNV, USUV, RRV) or ticks (TBEV, POWV).

Tuning the Electronic Properties of Azophosphines as Ligands and Their Application in Base-Free Transfer Hydrogenation Catalysis.

The design and tuning of new ligands is crucial for unlocking new reactivity at transition metal centers. Azophosphines have recently emerged as a new class of 1,3-P,N ligands in ruthenium piano-stool complexes. This work shows that the azophosphine synthesis can tolerate N-aryl substituents with strongly electron-donating and electron-withdrawing para-R groups and that the nature of this R group can affect the spectroscopic and structural properties of the azophosphines, as measured by NMR spectroscopy, UV-vis spectroscopy, single-crystal X-ray diffraction, and DFT studies. Azophosphines are shown to be relatively weak phosphine donors, as shown by analysis of the 1 J P-Se coupling constants of the corresponding azophosphine selenides, but the donor properties can be fine tuned within this area of chemical space. Monodentate and bidentate Ru-azophosphine complexes were prepared, and their first use as a catalyst was probed. The Ru-azophosphine complexes were found to promote the transfer hydrogenation of acetophenone to 1-phenylethanol without the requirement of a harsh base additive, and the bidentate complex was more active than the monodentate analogue.

Structural identification of the RY12 domain of RyR1 as an ADP sensor and the target of the malignant hyperthermia therapeutic dantrolene.

Malignant hyperthermia (MH) is a life-threatening pharmacogenetic condition triggered by volatile anesthetics, which activate pathogenic RyR1 mutants. The small molecule therapeutic dantrolene has long been used to treat MH. However, the binding site and mechanism of dantrolene remain unclear. Here, we present cryo-EM structures of RyR1 bound to dantrolene and the MH trigger agent 4-chloro-m-cresol (4CmC), revealing the dantrolene and 4CmC binding sites in atomic detail. Dantrolene binds stacked with ATP or ADP in the RY12 domain at the corner of the receptor, inducing a conformational change in this domain which is allosterically coupled to pore closure. Functional analyses revealed that ATP or ADP was required for dantrolene inhibition, and a single point mutation that disrupts the peripheral ATP binding site abolished ATP/ADP-dependent dantrolene inhibition. Strikingly, in the absence of dantrolene, this site selectively binds two ADP molecules, suggesting a possible role in ATP/ADP ratio sensing.

A multi-year study of acoustic propagation and ambient sound in a Thalassia testudinum seagrass meadow in a shallow sub-tropical lagoona).

Seagrasses provide a multitude of ecosystem services and act as important carbon sinks. However, seagrass habitats are declining globally, and they are among the most threatened ecosystems on earth. For these reasons, long-term and continuous measurements of seagrass parameters are of primary importance for ecosystem health assessment and sustainable management. This paper presents results from both active and passive acoustical methods for ecosystem monitoring in seagrass meadows. From a propagation perspective, gas bodies contained within the seagrass tissue as well as photosynthetic-driven bubble production result in attenuation, dispersion, and scattering of sound that produce increased transmission loss. For the passive approach, the detachment of gas bubbles from the plants is an important component of the ambient soundscape. Examples of both techniques will be presented based on data collected as part of a two-year continuous deployment of an acoustical measurement system operating in a moderately dense seagrass bed dominated by Thalassia testudinum (turtle grass) in Corpus Christi Bay, Texas. The data show annual trends related to the seasonal growth pattern of Thalassia as well as diurnal trends correlated with photosynthetically active radiation.

The impact of biochar's physicochemical properties on sorption of perfluorooctanoic acid (PFOA).

To better characterize properties governing the sorption of per- and polyfluoroalkyl substances (PFAS) to biochar, twenty-three diverse biochars were characterized and evaluated as sorbents for perfluorooctanoic acid (PFOA). Biochars were produced at various temperatures, using two different technologies, and made from sewage sludge, food waste reject, wood wastes, and one reference substrate (wood pellets). The biochars were characterized in terms of surface area, pore volume and pore size distributions, elemental composition, leachable elements, ash content, pH, zeta potential, condensed aromatic carbon (ConAC) content (determined by benzenepolycarboxylic acid (BPCA) markers), and their -OH functional group content (infrared spectroscopy). PFOA sorption isotherms were determined using Polanyi-Dubinin-Manes (PDM) and Freundlich models. The sludge-based biochars [Freundlich coefficients (log KF) between 2.56 ±â€¯0.11 and 6.72 ±â€¯0.22 (µg/kg)/(µg/L)nF; fitted free energy of adsorption (E) and pore volume (Vo) from the PDM model between 13.27 and 17.26 kJ/mol, and 0.50 and 523.51 cm3/kg] outperformed wood biochars [log KF between 1.02 and 4.56 ±â€¯0.22 (µg/kg)/(µg/L)nF; E between 9.87 and 17.44 kJ/mol; Vo between 0.21 and 6.52 cm3/kg] as PFOA sorbents. Multivariate statistical analysis revealed that the sorption capacity was mainly controlled by pore volume within the pore diameter region that could accommodate the molecular size of PFOA (3-6 nm). Hydrophobic interactions between PFOA and aromatic carbon rich regions controlled sorption affinity, especially in the wood biochars.

Geochemical Decoupling of Iron and Zinc during Transformation of Zn-Bearing Ferrihydrite in Reducing Sediments.

The transformation of the mineral ferrihydrite in reducing environments, and its impact on the mobility of incorporated trace metals, has been investigated in model laboratory studies, but studies using complex soil or sediment matrices are lacking. Here, we studied the transformation of zinc (Zn)-bearing ferrihydrite labeled with 57Fe and mixed with natural sediments, incubated in reducing conditions for up to six months. We tracked the evolution of Fe and Zn speciation with 57Fe Mössbauer spectroscopy and with bulk and micro-X-ray absorption spectroscopy. We show that Fe was readily reduced and incorporated into a poorly crystalline mixed-valence Fe(II)-Fe(III) phase resembling green rust. In parallel, Zn was released in the surrounding porewater and scavenged by precipitation with available ligands, particularly as zinc sulfide (ZnS) or Zn-carbonates. Early in the mineral transformation process, the chemical behavior of Fe was decoupled from Zn, suppressing the impact of Zn on the rates and products of the ferrihydrite transformation. Our results underline the discrepancy between model experiments and complex field-like conditions and highlight the importance of sediment and soil geochemistry and ligand competition on the fate of divalent metal contaminants in the environment.

Bigger genomes provide environment-dependent growth benefits in grasses.

Increasing genome size (GS) has been associated with slower rates of DNA replication and greater cellular nitrogen (N) and phosphorus demands. Despite most plant species having small genomes, the existence of larger GS species suggests that such costs may be negligible or represent benefits under certain conditions. Focussing on the widespread and diverse grass family (Poaceae), we used data on species' climatic niches and growth rates under different environmental conditions to test for growth costs or benefits associated with GS. The influence of photosynthetic pathway, life history and evolutionary history on grass GS was also explored. We found that evolutionary history, photosynthetic pathway and life history all influence the distribution of grass species' GS. Genomes were smaller in annual and C4 species, the latter allowing for small cells necessary for C4 leaf anatomy. We found larger GS were associated with high N availability and, for perennial species, low growth-season temperature. Our findings reveal that GS is a globally important predictor of grass performance dependent on environmental conditions. The benefits for species with larger GS are likely due to associated larger cell sizes, allowing rapid biomass production where soil fertility meets N demands and/or when growth occurs via temperature-independent cell expansion.

Novel risk loci in LGI1-antibody encephalitis: genome-wide association study discovery and validation cohorts.

Encephalitis with antibodies to leucine-rich glioma-inactivated 1 (LGI1-Ab-E) is a common form of autoimmune encephalitis, presenting with seizures and neuropsychiatric changes, predominantly in older males. More than 90% of patients carry the human leucocyte antigen (HLA) class II allele, HLA-DRB1*07:01. However, this is also present in 25% of healthy controls. Therefore, we hypothesised the presence of additional genetic predispositions. In this genome-wide association study and meta-analysis, we studied a discovery cohort of 131 French LGI1-Ab-E and a validation cohort of 126 American, British and Irish LGI1-Ab-E patients, ancestry-matched to 2613 and 2538 European controls, respectively. Outside the known major HLA signal, we found two single nucleotide polymorphisms (SNPs) at genome-wide significance (p < 5 x 10-8), implicating PTPRD, a protein tyrosine phosphatase, and LINC00670, a non-protein coding RNA gene. Meta-analysis defined four additional non-HLA loci, including the protein coding COBL gene. Polygenic risk scores with and without HLA variants proposed a contribution of non-HLA loci. In silico network analyses suggested LGI1 and PTPRD mediated interactions via the established receptors of LGI1, ADAM22 and ADAM23. Our results identify new genetic loci in LGI1-Ab-E. These findings present opportunities for mechanistic studies and offer potential markers of susceptibility, prognostics and therapeutic responses.

Understanding Diversity, Equity, and Inclusion Roles in Academic Neurology Departments.

Academic neurology departments across the country have been rapidly adding diversity, equity, and inclusion (DEI) programs over the past 5-10 years. These programs frequently come with leadership roles that carry a variety of names and responsibilities, such as vice chair of DEI or diversity officer. Furthermore, there are roles for members of the department to be involved with DEI work without being designated the departmental DEI leader. This article provides a framework for understanding the different responsibilities that are typically associated with each of these roles, along with reasonable expectations to associate with the respective job titles. Our goal is to prevent departments from asking too much or expecting too little based on the job title and support provided to the people in these positions. Likewise, we hope to empower DEI leaders who are currently asked to perform duties beyond their scope to obtain the title and support they have earned. For each departmental DEI role, we review prerequisites to success and potential impediments.

Direct measurements of sediment geoacoustic properties in the New England Mud Patch and shelf breaka).

This paper reports on an original set of direct sound speed measurements collected with the acoustic coring system in the New England Mud Patch (NEMP) and shelf break area to the south. Cores collected within the NEMP show range-dependence of the mud with slower sound speed and lower attenuation on the west side. In the shelf break region, the highest sound speeds are observed between the 200- and 350-m isobaths. The depth-dependence of the mud layer in the NEMP includes a surficial layer with a negative sound speed gradient of 28 s-1. The remainder of the mud column has a weak positive sound speed gradient of 6.2 s-1 over an isovelocity layer. Comparison between in situ and ex situ sound speed measurements provides an assessment of the effects of sediment disturbance from gravity coring operations. Small differences in the upper 2.5 m were attributed to the changes in the geoacoustic properties caused by disturbance from the coring process. Below 2.5 m, the average difference is close to zero, suggesting that these sediments were minimally disturbed. Finally, an in situ measurement of shear speed was obtained near the depth of maximum penetration. The shear speed was well correlated with sound speed from approximately the same depth interval.