Phase separation by low complexity domains promotes stress granule assembly and drives pathological fibrillization.

Stress granules are membrane-less organelles composed of RNA-binding proteins (RBPs) and RNA. Functional impairment of stress granules has been implicated in amyotrophic lateral sclerosis, frontotemporal dementia, and multisystem proteinopathy-diseases that are characterized by fibrillar inclusions of RBPs. Genetic evidence suggests a link between persistent stress granules and the accumulation of pathological inclusions. Here, we demonstrate that the disease-related RBP hnRNPA1 undergoes liquid-liquid phase separation (LLPS) into protein-rich droplets mediated by a low complexity sequence domain (LCD). While the LCD of hnRNPA1 is sufficient to mediate LLPS, the RNA recognition motifs contribute to LLPS in the presence of RNA, giving rise to several mechanisms for regulating assembly. Importantly, while not required for LLPS, fibrillization is enhanced in protein-rich droplets. We suggest that LCD-mediated LLPS contributes to the assembly of stress granules and their liquid properties and provides a mechanistic link between persistent stress granules and fibrillar protein pathology in disease.

BioAutoML: automated feature engineering and metalearning to predict noncoding RNAs in bacteria.

Recent technological advances have led to an exponential expansion of biological sequence data and extraction of meaningful information through Machine Learning (ML) algorithms. This knowledge has improved the understanding of mechanisms related to several fatal diseases, e.g. Cancer and coronavirus disease 2019, helping to develop innovative solutions, such as CRISPR-based gene editing, coronavirus vaccine and precision medicine. These advances benefit our society and economy, directly impacting people's lives in various areas, such as health care, drug discovery, forensic analysis and food processing. Nevertheless, ML-based approaches to biological data require representative, quantitative and informative features. Many ML algorithms can handle only numerical data, and therefore sequences need to be translated into a numerical feature vector. This process, known as feature extraction, is a fundamental step for developing high-quality ML-based models in bioinformatics, by allowing the feature engineering stage, with design and selection of suitable features. Feature engineering, ML algorithm selection and hyperparameter tuning are often manual and time-consuming processes, requiring extensive domain knowledge. To deal with this problem, we present a new package: BioAutoML. BioAutoML automatically runs an end-to-end ML pipeline, extracting numerical and informative features from biological sequence databases, using the MathFeature package, and automating the feature selection, ML algorithm(s) recommendation and tuning of the selected algorithm(s) hyperparameters, using Automated ML (AutoML). BioAutoML has two components, divided into four modules: (1) automated feature engineering (feature extraction and selection modules) and (2) Metalearning (algorithm recommendation and hyper-parameter tuning modules). We experimentally evaluate BioAutoML in two different scenarios: (i) prediction of the three main classes of noncoding RNAs (ncRNAs) and (ii) prediction of the eight categories of ncRNAs in bacteria, including housekeeping and regulatory types. To assess BioAutoML predictive performance, it is experimentally compared with two other AutoML tools (RECIPE and TPOT). According to the experimental results, BioAutoML can accelerate new studies, reducing the cost of feature engineering processing and either keeping or improving predictive performance. BioAutoML is freely available at https://github.com/Bonidia/BioAutoML.

BioDeepfuse: a hybrid deep learning approach with integrated feature extraction techniques for enhanced non-coding RNA classification.

The accurate classification of non-coding RNA (ncRNA) sequences is pivotal for advanced non-coding genome annotation and analysis, a fundamental aspect of genomics that facilitates understanding of ncRNA functions and regulatory mechanisms in various biological processes. While traditional machine learning approaches have been employed for distinguishing ncRNA, these often necessitate extensive feature engineering. Recently, deep learning algorithms have provided advancements in ncRNA classification. This study presents BioDeepFuse, a hybrid deep learning framework integrating convolutional neural networks (CNN) or bidirectional long short-term memory (BiLSTM) networks with handcrafted features for enhanced accuracy. This framework employs a combination of k-mer one-hot, k-mer dictionary, and feature extraction techniques for input representation. Extracted features, when embedded into the deep network, enable optimal utilization of spatial and sequential nuances of ncRNA sequences. Using benchmark datasets and real-world RNA samples from bacterial organisms, we evaluated the performance of BioDeepFuse. Results exhibited high accuracy in ncRNA classification, underscoring the robustness of our tool in addressing complex ncRNA sequence data challenges. The effective melding of CNN or BiLSTM with external features heralds promising directions for future research, particularly in refining ncRNA classifiers and deepening insights into ncRNAs in cellular processes and disease manifestations. In addition to its original application in the context of bacterial organisms, the methodologies and techniques integrated into our framework can potentially render BioDeepFuse effective in various and broader domains.

Measuring ART Adherence Among Young Adults with Perinatally Acquired HIV: Comparison Between Self-report, Telephone-Based Pill Count, and Objective Pharmacologic Measures.

Tenofovir diphosphate (TVF-DP) can be quantified in red blood cells (RBCs) and dried blood spots (DBS) and can objectively measure ART adherence and predict viral suppression. Data on the association of TFV-DP with viral load are very limited in adolescents and young adults (AYA) living with perinatally-acquired HIV (PHIV), as are data comparing TFV-DP to other measures of ART adherence, such as self-report and unannounced telephone pill count. Viral load and ART adherence (self-report, TFV-DP and unannounced telephone pill count) were assessed and compared among 61 AYAPHIV recruited from an ongoing longitudinal study (CASAH) in New York City.

Tenofovir diphosphate in dried blood spots and HIV-1 resistance in South Africa.

BACKGROUND: Suboptimal antiretroviral (ART) adherence can lead to virologic failure with consequent HIV-1 resistance. Tenofovir diphosphate (TFV-DP) in dried blood spots (DBS) is a powerful biomarker of cumulative adherence, predictive of future viremia. It has been associated with resistance in Persons With HIV (PWH) in South Africa and the US. We explored the relationship of TFV-DP concentrations with antiretroviral drug resistance at the time of treatment failure in SA. METHODS: Adult PWH from health clinics in Cape Town, South Africa on efavirenz-based first-line ART containing tenofovir disoproxil fumarate (TDF) with an undetectable (< 50 copies/mL) HIV-1 viral load (VL) were prospectively enrolled in an observational cohort for 12 months. Monthly study visits included blood collection for HIV-1 VL and DBS for TFV-DP. The first confirmed viral breakthrough (VB) > 400 copies/mL triggered HIV-1 genotyping at the subsequent visit. An electronic adherence (EA) device monitored ART adherence in real-time, estimated as a percent for the 30-days prior to VB. Wilcoxon rank sum test was used to compare median [IQR] TFV-DP by genotype outcome. RESULTS: Of 250 individuals, (n = 195, 78% women), 21 experienced VB, with a median of 5 [4;7] months on study, and a median EA of 33.3 [13.3;53.3]%. Demographic characteristics between those with and without VB were similar. Median VL at VB was 4.0 [3.2;4.5] log copies/mL. TFV-DP concentrations trended down towards the VB visit. Median TFV-DP concentrations were significantly higher in those HIV-1 genotype did not amplify due to being virally suppressed at the subsequent visit (n = 10; 380 [227-661] fmol/punch, p = 0.035; EA 45 [24.9; 59.2]%); than in those who were successfully genotyped with evidence of drug resistance (n = 5, 241 [150-247] fmol/punch, EA 20 [6.7;36.7]%) and in individuals who did not have resistance (n = 3, 39.9 [16.6; 93.9] fmol/punch; EA 33.3 [16-38]%). Three genotype collections were not done. Only non-nucleoside reverse transcriptase inhibitor-associated mutations were identified on resistance testing. (K103N, E138K, Y118H). CONCLUSION: TFV-DP in DBS showed a step-wise inverse relationship with VB and drug resistance, with evidence of low cumulative ART adherence in PWH who developed antiretroviral resistance. Monitoring TFV-DP concentrations could be a valuable tool for predicting future VB and future resistance.

Opportunistic Use of Lumbar Magnetic Resonance Imaging for Osteoporosis Screening.

Magnetic resonance imaging (MRI) is a routine assessment before spine surgery. We found that the opportunistic use of MRI with the vertebral bone quality (VBQ) score has good diagnostic ability, with a threshold value of VBQ > 3.0, in recognizing patients who may need further osteoporosis evaluation. INTRODUCTION: The purpose of this study was to determine whether the opportunistic use of magnetic resonance imaging (MRI) is useful for identifying spine surgical patients who need further osteoporosis evaluation. METHODS: This retrospective study evaluated 83 thoracolumbar spine surgery patients age ≥ 50 who received T1-weighted MRI. Opportunistic MRI was evaluated with the vertebral bone quality (VBQ) score, VBQ (fat) score, and signal-to-noise ratio (SNR). Each uses the median L1-L4 vertebral body signal intensities (SI) divided by either the L3 cerebrospinal fluid (CSF) SI, average SI of the L1 and S1 dorsal fat, or standard deviation (SD) of the background SI dorsal to the skin. Single-level VBQ was calculated as the ratio of the L1 vertebral body and L1 CSF SIs. Receiver-operator curve analysis was performed to determine diagnostic ability. RESULTS: The mean age was 70.10, 80% were female, and 96% were Caucasian. The mean ± SD VBQ, single-level VBQ, VBQ (fat), and SNR were 3.39 ± 0.68, 3.56 ± 0.81, 3.95 ± 1.89, and 113.18 ± 77.26, respectively. Using area under the curve, the diagnostic ability of VBQ, single-level VBQ, VBQ (fat), and SNR for clinical osteoporosis were 0.806, 0.779, 0.608, and 0.586, respectively. Diagnostic threshold values identified with optimal sensitivity and specificity were VBQ of 2.95 and single-level VBQ of 3.06. CONCLUSION: Opportunistic use of MRI is a simple, effective tool that may help recognize patients who are at risk for complications related to bone disease. A VBQ > 3.0 can identify patients who need additional diagnostic evaluation.

Effect of degeneration on bone mineral density, trabecular bone score and CT Hounsfield unit measurements in a spine surgery patient population.

This study investigated the impact of spinal degeneration on bone mineral density (BMD), trabecular bone score (TBS), and CT Hounsfield units in an at-risk population. We found that BMD was increased by degeneration, whereas TBS and HU were unaffected. These findings support that TBS is not adversely affected by spinal degeneration. INTRODUCTION: This study evaluated the impact of spinal degeneration on BMD and TBS measured by dual-energy x-ray absorptiometry (DXA) and on CT HU in a spine surgery patient population. METHODS: A retrospective study of 63 patients referred for consideration of spine surgery or with history of spine surgery was performed. Patients were included if a DXA scan and a CT containing the lumbar spine were obtained within 18 months of each other. DXA data were collected and analyzed by vertebral level. Individual vertebrae were assessed for degenerative changes by qualitative evaluation of the anterior and posterior elements using CT. Degeneration scores were compared to BMD T-scores, TBS and CT HU at individual vertebral levels L1-4, and after applying International Society for Clinical Densitometry (ISCD) criteria for excluding vertebrae from diagnostic consideration. RESULTS: Mean patient age and BMI were 67.2 years and 27.8 kg/m2, respectively; 79.4% were female. Mean (SD) lowest T-scores of the hip, spine, and lowest overall T-score were - 1.3 (1.4), - 1.7 (0.9), and - 1.9 (1.0), respectively. Osteoporosis was present by T-score in 38% and osteopenia in 52%; 10% had a history of osteoporotic fracture. The mean degeneration score of individual vertebrae was 4.1 on a 0-6 scale. T-score correlated moderately with degeneration score (Spearman's rho 0.484, p < 0.001), whereas TBS and HU were unrelated. ISCD excluded vertebrae had a higher degeneration score than included vertebrae (p = < 0.001). CONCLUSIONS: In a spine surgery population, TBS and CT HU values are unrelated to degeneration score and thus appear unaffected by lumbar vertebral degenerative changes. Additionally, these data support the ISCD criteria for vertebral exclusion.

Metabolome fingerprints, performance and carcass quality of beef calves supplemented with antibiotic free additive.

The aim of this study was to investigate the effects of probiotics on pre-weaning performance, muscle, and fat deposition and serum metabolite profiles in male and female Senepol calves. Thirty new-born Senepol calves, 15 males and 15 females, were randomly allocated to the following treatments: CON a control group that received the basal creep feeding diet and PRO animals that received the basal diet with addition of 2 g/100 kg of body weight (BW) of probiotic. PRO supplementation did not change the DMI but increased average BW, final BW, ADG relative to animals fed CON. Additionally, PRO improved LMA and marbling. Regardless of the serum metabolite profile, the important metabolites for discriminating PRO and CON were glutamine, leucine, creatine, acetate, creatinine, arginine, glutamate, hippurate, glycerol, carnitine, lactate, carnosine, myo-inositol and histidine. According to gender, males had an overabundance of glutamine, glycerol, isoleucine, creatinine and glucose, whereas females had an overabundance of acetyl carnitine, glutamate and carnitine. In conclusion, the addition of PRO in the pre-weaning diet of calves increases performance, weight at weaning and muscle and fat deposition on the carcass, improving proteins and fatty acid metabolism, the immune system response and rumen development.

Kidney functions adaptations of professional soccer players in response to an entire game season.

This study investigated the renal function of soccer players after an entire game-season. Thirty-five athletes recruited to play for the Macae Futebol Clube were invited for this study, of which 18 athletes completed the entire game season. Blood and 24-hour urine were collected at the beginning (Pre-Season) and the end of the game season (Post-Season). Kidney functions were assessed by calculating the urinary excretion, clearance, and fractional excretion of the selected solutes. Plasma creatinine, sodium, total protein, and osmolality were lower in the Post-Season . In contrast, plasma urea was higher in the Post-Season period. Urinary excretion of urea was reduced while albumin excretion was higher in comparison to Pre-Season. The clearances of creatinine, total proteins, and albumin were higher in the Post-Season period. In accordance, the fractional excretion of albumin increased. On the other hand, the clearance and fractional excretion of urea was lower in the Post-Season period. These results show that soccer-associated exercise throughout the entire game-season induces kidney functions adaptations that may prevent dehydration in these athletes through increased urea reabsorption to conserve water. In addition, this data corroborates to increased glomerular permeability to plasma proteins, such as albumin, that soccer players may experience.

Realist analysis of whether emergency departments with primary care services generate 'provider-induced demand'.

BACKGROUND: It is not known whether emergency departments (EDs) with primary care services influence demand for non-urgent care ('provider-induced demand'). We proposed that distinct primary care services in EDs encourages primary care demand, whereas primary care integrated within EDs may be less likely to cause additional demand. We aimed to explore this and explain contexts (C), mechanisms (M) and outcomes (O) influencing demand. METHODS: We used realist evaluation methodology and observed ED service delivery. Twenty-four patients and 106 staff members (including Clinical Directors and General Practitioners) were interviewed at 13 EDs in England and Wales (240 hours of observations across 30 days). Field notes from observations and interviews were analysed by creating 'CMO' configurations to develop and refine theories relating to drivers of demand. RESULTS: EDs with distinct primary care services were perceived to attract demand for primary care because services were visible, known or enabled direct access to health care services. Other influencing factors included patients' experiences of accessing primary care, community care capacity, service design and population characteristics. CONCLUSIONS: Patient, local-system and wider-system factors can contribute to additional demand at EDs that include primary care services. Our findings can inform service providers and policymakers in developing strategies to limit the effect of potential influences on additional demand when demand exceeds capacity.

Information Theory for Biological Sequence Classification: A Novel Feature Extraction Technique Based on Tsallis Entropy.

In recent years, there has been an exponential growth in sequencing projects due to accelerated technological advances, leading to a significant increase in the amount of data and resulting in new challenges for biological sequence analysis. Consequently, the use of techniques capable of analyzing large amounts of data has been explored, such as machine learning (ML) algorithms. ML algorithms are being used to analyze and classify biological sequences, despite the intrinsic difficulty in extracting and finding representative biological sequence methods suitable for them. Thereby, extracting numerical features to represent sequences makes it statistically feasible to use universal concepts from Information Theory, such as Tsallis and Shannon entropy. In this study, we propose a novel Tsallis entropy-based feature extractor to provide useful information to classify biological sequences. To assess its relevance, we prepared five case studies: (1) an analysis of the entropic index q; (2) performance testing of the best entropic indices on new datasets; (3) a comparison made with Shannon entropy and (4) generalized entropies; (5) an investigation of the Tsallis entropy in the context of dimensionality reduction. As a result, our proposal proved to be effective, being superior to Shannon entropy and robust in terms of generalization, and also potentially representative for collecting information in fewer dimensions compared with methods such as Singular Value Decomposition and Uniform Manifold Approximation and Projection.

17-ß-Estradiol increases macrophage activity through activation of the G-protein-coupled estrogen receptor and improves the response of female mice to Cryptococcus gattii.

Cryptococcus gattii (Cg) is one of the agents of cryptococcosis, a severe systemic mycosis with a higher prevalence in men than women, but the influence of the female sex hormone, 17-ß-estradiol (E2), on cryptococcosis remains unclear. Our study shows that female mice presented delayed mortality, increased neutrophil recruitment in bronchoalveolar lavage fluid, and reduced fungal load after 24 hr of infection compared to male and ovariectomised female mice (OVX). E2 replacement restored OVX female survival. Female macrophages have more efficient fungicidal activity, which was increased by E2 and reversed by the antagonist of G-protein-coupled oestrogen receptor (GPER), which negatively modulates PI3K activation. Furthermore, E2 induces a reduction in Cg cell diameter, cell charge, and antioxidant peroxidase activity. In conclusion, female mice present improved control of Cg infection, and GPER is important for E2 modulation of the female response.

An Exploratory Study of the Texture Research Investigational Platform (TRIP) to Evaluate Bone Texture Score of Distal Femur DXA Scans - A TBS-Based Approach.

Poor bone status is associated with increased complications following orthopedic surgery. Therefore, assessing site-specific skeletal status prior to or after orthopedic surgery to optimize outcomes is appealing. The trabecular bone score (TBS) approach, a surrogate for microarchitecture, was adapted to the Texture Research Investigational Platform (TRIP), which allows assessment of many skeletal sites imaged by various modalities. TRIP generates a bone texture score (TBS ORTHO), which could potentially guide surgical decision-making and offer insight into postsurgical fracture risk. As distal femur bone loss occurs following total knee arthroplasty (TKA), we hypothesized that TBS ORTHO after TKA would identify poorer texture in the operated femur compared to the nonoperated. We evaluated 30 subjects (15 M/15 F) with unilateral TKA 2-5 yr previously, mean age 67.9 yr and body mass index 30 kg/m2. Using a Lunar iDXA, lumbar spine and entire femur scans were obtained, the latter using the atypical femur fracture feature. Distal femur bone mineral density (BMD) and TBS ORTHO were obtained using manual regions of interest (ROI) at 15% and 25% of leg length from the intercondylar notch. TBS ORTHO was determined using distal femur DICOM images and TRIP v1.0 (Medimaps, France). Differences in operated vs nonoperated femur were evaluated by paired t test. As previously reported, operated leg BMD was approx 10% lower at 15% and 25% ROIs. Similarly, TBS ORTHO values in the operated leg were approx 5% lower (p < 0.05) at these same ROIs. Distal femur TBS ORTHO and BMD were largely unrelated. TBS ORTHO reproducibility at these ROIs was approx 3.5%. In conclusion, this pilot study documents the feasibility of reproducibly obtaining distal femur TBS ORTHO values. Lower values were observed in the surgical leg, consistent with the bone loss that follows TKA. Further work is indicated to refine TRIP use and evaluate whether such data provides guidance for surgical decision-making and improves periprosthetic fracture prediction.

In infants with sufficient vitamin D status at birth, vitamin D supplementation does not impact immune development.

BACKGROUND: Low vitamin D levels have been associated with allergic diseases. Vitamin D has potent immunomodulatory properties, but the mechanisms remain unclear. We have investigated the effect of oral vitamin D supplementation on circulating immune cell phenotypes in infants. METHOD: A double-blinded randomised controlled trial was conducted to investigate the effect of oral vitamin D supplementation (400 IU/d) on eczema and immune development. A subset of 78 infants was included in this analysis. Phenotypic analysis of immune cell subsets was performed using flow cytometry. RESULTS: Vitamin D supplementation resulted in median 25(OH)D levels of 80.5 vs 59.5 nmol/L in the placebo group at 3 months of age (P = .002) and 87.5 vs 77 nmol/L at 6 months of age (P = .08). We observed significant changes in immune cell composition from birth (cord blood) to 6 months of age. Vitamin D supplementation did not impact these changes, nor did immune cell composition correlate with plasma 25(OH)D levels. Through exploratory analysis, we identified possible associations with eczema development and increased abundance of naïve CD4- T cells at birth, as well as associations with basophils, iNKT and central memory CD4+ T cells, and altered expression patterns of IgE receptor (FcεR1) on monocytes and dendritic cells with eczema at 6 months. CONCLUSIONS: Vitamin D supplementation in infants who were vitamin D sufficient at birth did not affect developmental changes in immune cells during the first 6 months of life. However, immune cell profiles at birth and at 6 months of age were associated with early life eczema.

Direct infant UV light exposure is associated with eczema and immune development.

BACKGROUND: Suboptimal vitamin D levels during critical periods of immune development have emerged as an explanation for higher rates of allergic diseases associated with industrialization and residing at higher latitudes. OBJECTIVE: We sought to determine the effects of early postnatal vitamin D supplementation on infant eczema and immune development. METHODS: By using a double-blind randomized controlled trial, newborn infants were randomized to receive vitamin D supplementation (400 IU/d) or a placebo until 6 months of age. Some infants also wore personal UV dosimeters to measure direct UV light (290-380 nm) exposure. Infant vitamin D levels were measured at 3 and 6 months of age. Eczema, wheeze, and immune function outcomes were assessed at 6 months of age. RESULTS: At 3 (P < .01) and 6 (P = .02) months of age, vitamin D levels were greater for the vitamin D-supplemented group than the placebo group, but there was no difference in eczema incidence between groups. Infants with eczema were found to have had less UV light exposure (median, 555 Joules per square meter [J/m2; interquartile range, 322-1210 J/m2]) compared with those without eczema (median, 998 J/m2 [interquartile range, 676-1577 J/m2]; P = .02). UV light exposure was also inversely correlated with IL-2, GM-CSF, and eotaxin production to Toll-like receptor ligands. CONCLUSION: This study is the first to demonstrate an association between greater direct UV light exposures in early infancy with lower incidence of eczema and proinflammatory immune markers by 6 months of age. Our findings indicate that UV light exposure appears more beneficial than vitamin D supplementation as an allergy prevention strategy in early life.

The Building Blocks of Battery Technology: Using Modified Tower Block Game Sets to Explain and Aid the Understanding of Rechargeable Li-Ion Batteries.

While Li-ion batteries are abundant in everyday life from smart phones to electric vehicles, there are a lack of educational resources that can explain their operation, particularly their rechargeable nature. It is also important that any such resource can be understood by a wide range of age groups and backgrounds. To this end, we describe how modified tower block games sets, such as Jenga, can be used to explain the operation of Li-ion batteries. The sets can also be utilized to explain more advanced topics such as battery degradation and challenges with charging these batteries at high rates. In order to make the resource more inclusive, we also illustrate modifications to prepare tactile tower block sets, so that the activity is also suitable for blind and partially sighted students. Feedback from a range of groups supports the conclusion that the tower block sets are a useful tool to explain Li-ion battery concepts.

DXA evaluation of femoral bone mineral density and cortical width in patients with prior total knee arthroplasty.

Periprosthetic fractures after total knee arthroplasty (TKA) have devastating consequences. Osteoporosis increases periprosthetic fracture risk, but distal femur bone mineral density (BMD) is not measured post-TKA. This study measured distal femur BMD and cortical width; both were lower in the TKA compared to the non-operated leg. BMD measurement reproducibility was good. Standardized DXA regions of interest are proposed. INTRODUCTION: Periprosthetic fractures following total knee arthroplasty (TKA) are not rare. We hypothesized that TKA is associated with low BMD, potentially increasing periprosthetic fracture risk. However, distal femur dual energy x-ray (DXA) measurement is virtually never performed after TKA due to lack of standardized approaches. Thus, this study's aims were to develop standard DXA femur regions of interest (ROIs), assess cortical width, and determine measurement reproducibility in TKA patients. METHODS: Thirty adults (15 M/15 F) age 59-80 years with unilateral, primary TKA within 2-5 years had femoral DXA scans performed in duplicate using a Lunar iDXA densitometer. In prior work, we established that femur BMD was lowest in the distal metaphysis and highest in mid-shaft. Thus, BMD and cortical width were measured at 15%, 25%, and 60% of the femur length measured from the distal notch. Femur BMD and cortical width were compared between limbs (TKA vs. non-operated side) by paired t test. RESULTS: BMD was 3.2-9.9% lower (p < 0.001) in the operated femur at all custom ROIs; substantial between individual differences existed with some up to 30% lower. Cortical width was lower (p < 0.05) at the 25% ROI on the TKA side. BMD reproducibility was excellent; CV 0.85-1.33%. CONCLUSIONS: Distal femur BMD can be reproducibly measured using DXA and is ~ 10% lower on the TKA leg. Similarly, medial and lateral cortices are thinner at the 25% ROI. These bone changes likely increase periprosthetic fracture risk. Further work to define and mitigate periprosthetic fracture risk after TKA is needed.

How do morphological sharpness measures relate to puncture performance in viperid snake fangs?

It makes intuitive sense that you need a sharp tool to puncture through a tough material. The typical approach to evaluating sharpness in biological puncturing tools is to treat morphological measurements as a proxy for puncture ability. However, there are multiple approaches to measuring sharpness, and the relative influence of morphology on function remains unclear. Our goal is to determine what aspects of tip morphology have the greatest impact on puncture ability, using ( a) viper fangs and ( b) engineered punches to isolate the effects of different sharpness measures. Our results indicate that tip included angle is the strongest predictor of puncture performance in both viper fangs and engineered punches. For puncture tools with small included angles, sharpness index (based on the radius of curvature) also affects puncture ability. Finally, we found that punches serve as good predictors of fang performance at small angles and sharpness index values.

Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS.

Algorithms designed to identify canonical yeast prions predict that around 250 human proteins, including several RNA-binding proteins associated with neurodegenerative disease, harbour a distinctive prion-like domain (PrLD) enriched in uncharged polar amino acids and glycine. PrLDs in RNA-binding proteins are essential for the assembly of ribonucleoprotein granules. However, the interplay between human PrLD function and disease is not understood. Here we define pathogenic mutations in PrLDs of heterogeneous nuclear ribonucleoproteins (hnRNPs) A2B1 and A1 in families with inherited degeneration affecting muscle, brain, motor neuron and bone, and in one case of familial amyotrophic lateral sclerosis. Wild-type hnRNPA2 (the most abundant isoform of hnRNPA2B1) and hnRNPA1 show an intrinsic tendency to assemble into self-seeding fibrils, which is exacerbated by the disease mutations. Indeed, the pathogenic mutations strengthen a 'steric zipper' motif in the PrLD, which accelerates the formation of self-seeding fibrils that cross-seed polymerization of wild-type hnRNP. Notably, the disease mutations promote excess incorporation of hnRNPA2 and hnRNPA1 into stress granules and drive the formation of cytoplasmic inclusions in animal models that recapitulate the human pathology. Thus, dysregulated polymerization caused by a potent mutant steric zipper motif in a PrLD can initiate degenerative disease. Related proteins with PrLDs should therefore be considered candidates for initiating and perhaps propagating proteinopathies of muscle, brain, motor neuron and bone.

DXA Measured Distal Femur Bone Mineral Density in Patients After Total Knee Arthroplasty: Method Development and Reproducibility.

INTRODUCTION: Total knee arthroplasty (TKA) is increasingly being performed. Distal femur periprosthetic fracture is a potentially catastrophic complication following TKA and existing data document substantial distal femur bone mineral density (BMD) loss following TKA. However, distal femur BMD is virtually never measured clinically as no consensus approach exists. This pilot study's purpose was to define regional BMD variation throughout the femur, suggest standard dual-energy X-ray absorptiometry (DXA) regions of interest (ROIs) and evaluate BMD reproducibility at these ROIs. METHODS: Thirty volunteers 2-5 yr post TKA had both entire femurs imaged twice using a Lunar iDXA with subject repositioning between scans; the atypical femur fracture feature of enCORE software was utilized. To define femoral BMD distribution, custom 1 cm ROIs were stacked one atop the other starting at the intercondylar notch and continuing to the base of the lesser trochanter. Femur length was measured with the ruler tool to calculate distance at 5% increments. ROIs encompassing each 5% increment were utilized to measure BMD at each location. Descriptive statistics were used to determine mean BMD at each ROI and reproducibility at the 15%, 25%, 45%, 60%, and 80% ROIs. RESULTS: The 5 and 10% ROIs included prosthetic and/or patella, causing high BMD values. Distal femur BMD was lowest at the 15% ROI and was higher (p < 0.05) at each more proximal ROI to 45%, then plateaued from 45% to 75%. BMD reproducibility at these regions was excellent; coefficient of variation (CV) from ∼1% to 3.5%. As periprosthetic fractures generally occur in the distal femur, we propose measuring femur BMD using ROIs placed at 15% and 25%. A 60% region could also be used as a highly cortical site. CONCLUSION: Existing DXA capabilities allow distal femur BMD measurement with good reproducibility. Further research using standardized ROIs to assess distal femur BMD loss after TKA, and interventions to mitigate this loss, is indicated.