Human iPSC 4R tauopathy model uncovers modifiers of tau propagation.

Tauopathies are age-associated neurodegenerative diseases whose mechanistic underpinnings remain elusive, partially due to a lack of appropriate human models. Here, we engineered human induced pluripotent stem cell (hiPSC)-derived neuronal lines to express 4R Tau and 4R Tau carrying the P301S MAPT mutation when differentiated into neurons. 4R-P301S neurons display progressive Tau inclusions upon seeding with Tau fibrils and recapitulate features of tauopathy phenotypes including shared transcriptomic signatures, autophagic body accumulation, and reduced neuronal activity. A CRISPRi screen of genes associated with Tau pathobiology identified over 500 genetic modifiers of seeding-induced Tau propagation, including retromer VPS29 and genes in the UFMylation cascade. In progressive supranuclear palsy (PSP) and Alzheimer's Disease (AD) brains, the UFMylation cascade is altered in neurofibrillary-tangle-bearing neurons. Inhibiting the UFMylation cascade in vitro and in vivo suppressed seeding-induced Tau propagation. This model provides a robust platform to identify novel therapeutic strategies for 4R tauopathy.

Idea engines: Unifying innovation & obsolescence from markets & genetic evolution to science.

Innovation and obsolescence describe dynamics of ever-churning and adapting social and biological systems, concepts that encompass field-specific formulations. We formalize the connection with a reduced model of the dynamics of the "space of the possible" (e.g., technologies, mutations, theories) to which agents (e.g., firms, organisms, scientists) couple as they grow, die, and replicate. We predict three regimes: The space is finite, ever growing, or a Schumpeterian dystopia in which obsolescence drives the system to collapse. We reveal a critical boundary at which the space of the possible fluctuates dramatically in size, displaying recurrent periods of minimal and of veritable diversity. When the space is finite, corresponding to physically realizable systems, we find surprising structure. This structure predicts a taxonomy for the density of agents near and away from the innovative frontier that we compare with distributions of firm productivity, COVID diversity, and citation rates for scientific publications. Our minimal model derived from first principles aligns with empirical examples, implying a follow-the-leader dynamic in firm cost efficiency and biological evolution, whereas scientific progress reflects consensus that waits on old ideas to go obsolete. Our theory introduces a fresh and empirically testable framework for unifying innovation and obsolescence across fields.

An autosomal-dominant childhood-onset disorder associated with pathogenic variants in VCP.

Valosin-containing protein (VCP) is an AAA+ ATPase that plays critical roles in multiple ubiquitin-dependent cellular processes. Dominant pathogenic variants in VCP are associated with adult-onset multisystem proteinopathy (MSP), which manifests as myopathy, bone disease, dementia, and/or motor neuron disease. Through GeneMatcher, we identified 13 unrelated individuals who harbor heterozygous VCP variants (12 de novo and 1 inherited) associated with a childhood-onset disorder characterized by developmental delay, intellectual disability, hypotonia, and macrocephaly. Trio exome sequencing or a multigene panel identified nine missense variants, two in-frame deletions, one frameshift, and one splicing variant. We performed in vitro functional studies and in silico modeling to investigate the impact of these variants on protein function. In contrast to MSP variants, most missense variants had decreased ATPase activity, and one caused hyperactivation. Other variants were predicted to cause haploinsufficiency, suggesting a loss-of-function mechanism. This cohort expands the spectrum of VCP-related disease to include neurodevelopmental disease presenting in childhood.

Polypathologic Associations with Gray Matter Atrophy in Neurodegenerative Disease.

Mixed pathologies are common in neurodegenerative disease; however, antemortem imaging rarely captures copathologic effects on brain atrophy due to a lack of validated biomarkers for non-Alzheimer's pathologies. We leveraged a dataset comprising antemortem MRI and postmortem histopathology to assess polypathologic associations with atrophy in a clinically heterogeneous sample of 125 human dementia patients (41 female, 84 male) with T1-weighted MRI ≤ 5 years before death and postmortem ordinal ratings of amyloid-[Formula: see text], tau, TDP-43, and [Formula: see text]-synuclein. Regional volumes were related to pathology using linear mixed-effects models; approximately 25% of data were held out for testing. We contrasted a polypathologic model comprising independent factors for each proteinopathy with two alternatives: a model that attributed atrophy entirely to the protein(s) associated with the patient's primary diagnosis and a protein-agnostic model based on the sum of ordinal scores for all pathology types. Model fits were evaluated using log-likelihood and correlations between observed and fitted volume scores. Additionally, we performed exploratory analyses relating atrophy to gliosis, neuronal loss, and angiopathy. The polypathologic model provided superior fits in the training and testing datasets. Tau, TDP-43, and [Formula: see text]-synuclein burden were inversely associated with regional volumes, but amyloid-[Formula: see text] was not. Gliosis and neuronal loss explained residual variance in and mediated the effects of tau, TDP-43, and [Formula: see text]-synuclein on atrophy. Regional brain atrophy reflects not only the primary molecular pathology but also co-occurring proteinopathies; inflammatory immune responses may independently contribute to degeneration. Our findings underscore the importance of antemortem biomarkers for detecting mixed pathology.

Cellular processing of α-synuclein fibrils results in distinct physiological C-terminal truncations with a major cleavage site at residue Glu 114.

α-synuclein (αS) is an abundant, neuronal protein that assembles into fibrillar pathological inclusions in a spectrum of neurodegenerative diseases that include Lewy body diseases (LBD) and Multiple System Atrophy (MSA). The cellular and regional distributions of pathological inclusions vary widely between different synucleinopathies contributing to the spectrum of clinical presentations. Extensive cleavage within the carboxy (C)-terminal region of αS is associated with inclusion formation, although the events leading to these modifications and the implications for pathobiology are of ongoing study. αS preformed fibrils can induce prion-like spread of αS pathology in both in vitro and animal models of disease. Using C truncation-specific antibodies, we demonstrated here that prion-like cellular uptake and processing of αS preformed fibrils resulted in two major cleavages at residues 103 and 114. A third cleavage product (122 αS) accumulated upon application of lysosomal protease inhibitors. In vitro, both 1-103 and 1-114 αS polymerized rapidly and extensively in isolation and in the presence of full-length αS. 1-103 αS also demonstrated more extensive aggregation when expressed in cultured cells. Furthermore, we used novel antibodies to αS cleaved at residue Glu114, to assess x-114 αS pathology in postmortem brain tissue from patients with LBD and MSA, as well as three different transgenic αS mouse models of prion-like induction. The distribution of x-114 αS pathology was distinct from that of overall αS pathology. These studies reveal the cellular formation and behavior of αS C-truncated at residues 114 and 103 as well as the disease dependent distribution of x-114 αS pathology.

Comparison of histological delineations of medial temporal lobe cortices by four independent neuroanatomy laboratories.

The medial temporal lobe (MTL) cortex, located adjacent to the hippocampus, is crucial for memory and prone to the accumulation of certain neuropathologies such as Alzheimer's disease neurofibrillary tau tangles. The MTL cortex is composed of several subregions which differ in their functional and cytoarchitectonic features. As neuroanatomical schools rely on different cytoarchitectonic definitions of these subregions, it is unclear to what extent their delineations of MTL cortex subregions overlap. Here, we provide an overview of cytoarchitectonic definitions of the entorhinal and parahippocampal cortices as well as Brodmann areas (BA) 35 and 36, as provided by four neuroanatomists from different laboratories, aiming to identify the rationale for overlapping and diverging delineations. Nissl-stained series were acquired from the temporal lobes of three human specimens (two right and one left hemisphere). Slices (50 µm thick) were prepared perpendicular to the long axis of the hippocampus spanning the entire longitudinal extent of the MTL cortex. Four neuroanatomists annotated MTL cortex subregions on digitized slices spaced 5 mm apart (pixel size 0.4 µm at 20× magnification). Parcellations, terminology, and border placement were compared among neuroanatomists. Cytoarchitectonic features of each subregion are described in detail. Qualitative analysis of the annotations showed higher agreement in the definitions of the entorhinal cortex and BA35, while the definitions of BA36 and the parahippocampal cortex exhibited less overlap among neuroanatomists. The degree of overlap of cytoarchitectonic definitions was partially reflected in the neuroanatomists' agreement on the respective delineations. Lower agreement in annotations was observed in transitional zones between structures where seminal cytoarchitectonic features are expressed less saliently. The results highlight that definitions and parcellations of the MTL cortex differ among neuroanatomical schools and thereby increase understanding of why these differences may arise. This work sets a crucial foundation to further advance anatomically-informed neuroimaging research on the human MTL cortex.

SpaGCN: Integrating gene expression, spatial location and histology to identify spatial domains and spatially variable genes by graph convolutional network.

Recent advances in spatially resolved transcriptomics (SRT) technologies have enabled comprehensive characterization of gene expression patterns in the context of tissue microenvironment. To elucidate spatial gene expression variation, we present SpaGCN, a graph convolutional network approach that integrates gene expression, spatial location and histology in SRT data analysis. Through graph convolution, SpaGCN aggregates gene expression of each spot from its neighboring spots, which enables the identification of spatial domains with coherent expression and histology. The subsequent domain guided differential expression (DE) analysis then detects genes with enriched expression patterns in the identified domains. Analyzing seven SRT datasets using SpaGCN, we show it can detect genes with much more enriched spatial expression patterns than competing methods. Furthermore, genes detected by SpaGCN are transferrable and can be utilized to study spatial variation of gene expression in other datasets. SpaGCN is computationally fast, platform independent, making it a desirable tool for diverse SRT studies.

Annexin A11 aggregation in FTLD-TDP type C and related neurodegenerative disease proteinopathies.

TAR DNA-binding protein 43 (TDP-43) is an RNA binding protein found within ribonucleoprotein granules tethered to lysosomes via annexin A11. TDP-43 protein forms inclusions in many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP) and limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC). Annexin A11 is also known to form aggregates in ALS cases with pathogenic variants in ANXA11. Annexin A11 aggregation has not been described in sporadic ALS, FTLD-TDP or LATE-NC cases. To explore the relationship between TDP-43 and annexin A11, genetic analysis of 822 autopsy cases was performed to identify rare ANXA11 variants. In addition, an immunohistochemical study of 368 autopsy cases was performed to identify annexin A11 aggregates. Insoluble annexin A11 aggregates which colocalize with TDP-43 inclusions were present in all FTLD-TDP Type C cases. Annexin A11 inclusions were also seen in a small proportion (3-6%) of sporadic and genetic forms of FTLD-TDP types A and B, ALS, and LATE-NC. In addition, we confirm the comingling of annexin A11 and TDP-43 aggregates in an ALS case with the pathogenic ANXA11 p.G38R variant. Finally, we found abundant annexin A11 inclusions as the primary pathologic finding in a case of progressive supranuclear palsy-like frontotemporal dementia with prominent striatal vacuolization due to a novel variant, ANXA11 p.P75S. By immunoblot, FTLD-TDP with annexinopathy and ANXA11 variant cases show accumulation of insoluble ANXA11 including a truncated fragment. These results indicate that annexin A11 forms a diverse and heterogeneous range of aggregates in both sporadic and genetic forms of TDP-43 proteinopathies. In addition, the finding of a primary vacuolar annexinopathy due to ANXA11 p.P75S suggests that annexin A11 aggregation is sufficient to cause neurodegeneration.

MSUT2 regulates tau spreading via adenosinergic signaling mediated ASAP1 pathway in neurons.

Inclusions comprised of microtubule-associated protein tau (tau) are implicated in a group of neurodegenerative diseases, collectively known as tauopathies, that include Alzheimer's disease (AD). The spreading of misfolded tau "seeds" along neuronal networks is thought to play a crucial role in the progression of tau pathology. Consequently, restricting the release or uptake of tau seeds may inhibit the spread of tau pathology and potentially halt the advancement of the disease. Previous studies have demonstrated that the Mammalian Suppressor of Tauopathy 2 (MSUT2), an RNA binding protein, modulates tau pathogenesis in a transgenic mouse model. In this study, we investigated the impact of MSUT2 on tau pathogenesis using tau seeding models. Our findings indicate that the loss of MSUT2 mitigates human tau seed-induced pathology in neuron cultures and mouse models. In addition, MSUT2 regulates many gene transcripts, including the Adenosine Receptor 1 (A1AR), and we show that down regulation or inhibition of A1AR modulates the activity of the "ArfGAP with SH3 Domain, Ankyrin Repeat, and PH Domain 1 protein" (ASAP1), thereby influencing the internalization of pathogenic tau seeds into neurons resulting in reduction of tau pathology.

Impact of Magnetic Resonance Imaging Markers on the Diagnostic Performance of the International Parkinson and Movement Disorder Society Multiple System Atrophy Criteria.

BACKGROUND: Multiple system atrophy is a neurodegenerative disease with α-synuclein aggregation in glial cytoplasmic inclusions, leading to dysautonomia, parkinsonism, and cerebellar ataxia. OBJECTIVE: The aim of this study was to validate the accuracy of the International Parkinson and Movement Disorder Society Multiple System Atrophy clinical diagnostic criteria, particularly considering the impact of the newly introduced brain magnetic resonance imaging (MRI) markers. METHODS: Diagnostic accuracy of the clinical diagnostic criteria for multiple system atrophy was estimated retrospectively in autopsy-confirmed patients with multiple system atrophy, Parkinson's disease, progressive supranuclear palsy, and corticobasal degeneration. RESULTS: We identified a total of 240 patients. Sensitivity of the clinically probable criteria was moderate at symptom onset but improved with disease duration (year 1: 9%, year 3: 39%, final ante mortem record: 77%), whereas their specificity remained consistently high (99%-100% throughout). Sensitivity of the clinically established criteria was low during the first 3 years (1%-9%), with mild improvement at the final ante mortem record (22%), whereas specificity remained high (99%-100% throughout). When MRI features were excluded from the clinically established criteria, their sensitivity increased considerably (year 1: 3%, year 3: 22%, final ante mortem record: 48%), and their specificity was not compromised (99%-100% throughout). CONCLUSIONS: The International Parkinson and Movement Disorder Society multiple system atrophy diagnostic criteria showed consistently high specificity and low to moderate sensitivity throughout the disease course. The MRI markers for the clinically established criteria reduced their sensitivity without improving specificity. Combining clinically probable and clinically established criteria, but disregarding MRI features, yielded the best sensitivity with excellent specificity and may be most appropriate to select patients for therapeutic trials. © 2024 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Impact of Preoperative Factors in Patients With IBD on Postoperative Length of Stay: A National Surgical Quality Improvement Program-Inflammatory Bowel Disease Collaborative Analysis.

BACKGROUND: Patients with IBD are challenging to manage perioperatively because of disease complexity and multiple comorbidities. OBJECTIVE: To identify whether preoperative factors and operation type were associated with extended postoperative length of stay after IBD-related surgery, defined by 75th percentile or greater (n = 926; 30.8%). DESIGN: This was a cross-sectional study based on a retrospective multicenter database. SETTING: The National Surgery Quality Improvement Program-Inflammatory Bowel Disease Collaborative captured data from 15 high-volume sites. PATIENTS: A total of 3008 patients with IBD (1710 with Crohn's disease and 1291 with ulcerative colitis) with a median postoperative length of stay of 4 days (interquartile range, 3-7) from March 2017 to February 2020. MAIN OUTCOME MEASURES: The primary outcome was extended postoperative length of stay. RESULTS: On multivariable logistic regression, increased odds of extended postoperative length of stay were associated with multiple demographic and clinical factors (model p < 0.001, area under receiver operating characteristic curve = 0.85). Clinically significant contributors that increased postoperative length of stay were rectal surgery (vs colon; OR, 2.13; 95% CI, 1.52-2.98), new ileostomy (vs no ileostomy; OR, 1.50; 95% CI, 1.15-1.97), preoperative hospitalization (OR, 13.45; 95% CI, 10.15-17.84), non-home discharge (OR, 4.78; 95% CI, 2.27-10.08), hypoalbuminemia (OR, 1.66; 95% CI, 1.27-2.18), and bleeding disorder (OR, 2.42; 95% CI, 1.22-4.82). LIMITATIONS: Retrospective review of only high-volume centers. CONCLUSIONS: Patients with IBD who were preoperatively hospitalized, who had non-home discharge, and who underwent rectal surgery had the highest odds of extended postoperative length of stay. Associated patient characteristics included bleeding disorder, hypoalbuminemia, and ASA classes 3 to 5. Chronic corticosteroid, immunologic, small molecule, and biologic agent use were insignificant on multivariable analysis. See Video Abstract. IMPACTO DE LOS FACTORES PREOPERATORIOS EN PACIENTES CON ENFERMEDAD INFLAMATORIA INTESTINAL EN LA DURACIN DE LA ESTANCIA POSTOPERATORIA UN ANLISIS COLABORATIVO DEL PROGRAMA NACIONAL DE MEJORA DE LA CALIDAD QUIRRGICAENFERMEDAD INFLAMATORIA INTESTINAL: ANTECEDENTES:Los pacientes con enfermedad inflamatoria intestinal son difíciles de manejar perioperatoriamente debido a la complejidad de la enfermedad y a múltiples comorbilidades.OBJETIVO:Este estudio tuvo como objetivo identificar si los factores preoperatorios y el tipo de operación se asociaron con una estadía postoperatoria prolongada después de una cirugía relacionada con enfermedad inflamatoria intestinal, definida por el percentil 75 o mayor (n = 926, 30.8%).DISEÑO:Este fue un estudio transversal basado en una base de datos multicéntrica retrospectiva.ESCENARIO:Datos capturados de quince sitios de alto volumen en El Programa Nacional de Mejoramiento de la Calidad de la Cirugía-Enfermedad Intestinal Inflamatoria en colaboración.PACIENTES:Un total de 3,008 pacientes con enfermedad inflamatoria intestinal (1,710 con enfermedad de Crohn y 1,291 con colitis ulcerosa) con una mediana de estancia postoperatoria de 4 días (RIC 3-7) desde marzo de 2017 hasta febrero de 2020.PRINCIPALES MEDIDAS DE RESULTADO:El resultado primario fue la extensión de la estancia postoperatoria.RESULTADOS:En la regresión logística multivariable, el aumento de las probabilidades de prolongar la estancia postoperatoria se asoció con múltiples factores demográficos y clínicos (modelo p<0.001, área bajo la curva ROC - 0.85). Los contribuyentes clínicamente significativos que aumentaron la duración de la estancia postoperatoria fueron la cirugía rectal (frente al colon) (OR 2.13, IC del 95 %: 1.52 a 2.98), una nueva ileostomía (frente a ninguna ileostomía) (OR 1.50, IC del 95 %: 1.15 a 1.97), hospitalización preoperatoria (OR 13.45, IC 95% 10.15-17.84), alta no domiciliaria (OR 4.78, IC 95% 2.27-10.08), hipoalbuminemia (OR 1.66, IC 95% 1.27-2.18) y trastorno hemorrágico (OR 2.42, IC 95% 1.22-4.82).LIMITACIONES:Revisión retrospectiva de solo centros de alto volumen.CONCLUSIONES:Los pacientes con enfermedad inflamatoria intestinal que fueron hospitalizados antes de la operación, que tuvieron alta no domiciliaria y que se sometieron a cirugía rectal tuvieron las mayores probabilidades de prolongar la estancia postoperatoria. Las características asociadas de los pacientes incluyeron trastorno hemorrágico, hipoalbuminemia y clases ASA 3-5. El uso crónico de corticosteroides, inmunológicos, agentes de moléculas pequeñas y de agentes biológicos no fue significativo en el análisis multivariable. (Traducción-Dr. Jorge Silva Velazco ).

A Comparison of Plastic Surgery Authorship Trends Under Single Versus Double-Blinded Review.

INTRODUCTION: Research is key to academic advancement in plastic surgery. However, access to publication opportunities may be inequitable as seen in other fields. We compared authorship trends of plastic surgery manuscripts that underwent single-blinded review (SBR) versus double-blinded review (DBR) to identify potential disparities in publication opportunities. METHODS: Publications from two plastic surgery journals using SBR and two using DBR from September 2019 to September 2021 were evaluated. Name and institution of the article's first and senior author and journal's editor-in-chief (EIC) were recorded. Chi-squared and Fisher's exact analyses were used to compare author characteristics between SBR and DBR articles. RESULTS: Of 2500 manuscripts, 65.7% underwent SBR and 34.3% underwent DBR. SBR articles had higher percentages of women as first authors (31.9% versus 24.3%, P < 0.001) but lower percentages of first (50.7% versus 71.2%, P < 0.001) and senior (49.6% versus 70.3%, P < 0.001) authors from international institutions. First (26.0% versus 12.9%, P < 0.001) and senior (27.9% versus 18.0%, P = 0.007) authors of SBR articles tended to have more plastic surgery National Institutes of Health funding. Journals using SBR tended to have higher rates of authorship by EICs or authors sharing institutions with the EIC (P ≤ 0.005). CONCLUSIONS: While associated with greater female first authorship suggesting potential efforts toward gender equity in academia, SBR of plastic surgery articles tends to favor authors from institutions with higher National Institutes of Health funding and disadvantage authors from international or lower-resourced programs. Careful consideration of current peer-review proceedings may make publication opportunities more equitable.

Characterization of Microwave Generator Energy and Ablation Volumes following Transarterial Embolization in an In Vivo Porcine Liver Model.

PURPOSE: To characterize the relationship between ablation zone volume (AZV) and microwave ablation (MWA) energy in an in vivo porcine liver model following arterial embolization. MATERIALS AND METHODS: With Institutional Animal Care and Use Committee (IACUC) approval, 11 female swine underwent either right (n = 5) or left (n = 6) hepatic artery embolization under fluoroscopic guidance. Subsequently, ultrasound (US)-guided MWA was performed in each liver segment (left lateral, left medial, right medial, and right lateral) at either 30 W (n = 4 lobes), 60 W (n = 4), 65 W (n = 20), 90 W (n = 8), 120 W (n = 4), or 140 W (n = 4) continuously for 5 minutes. Postprocedural volumetric segmentation was performed on standardized multiphase T1 magnetic resonance (MR) imaging sequences. RESULTS: Mean AZVs in embolized lobes (15.8 mL ± SD 10.6) were significantly larger than those in nonembolized lobes (11.2 mL ± SD 6.5, P < .01). MWA energy demonstrated significant positive linear correlation with both embolized (R2 = 0.66, P < .01) and nonembolized (R2 = 0.64, P < .01) lobes. The slope of the linear models corresponded to a 0.95 mL/kJ (SD ± 0.16) and 0.54 mL/kJ (SD ± 0.09) increase in ablation volume per applied kilojoule of energy (E) in embolized and nonembolized lobes, respectively. In the multivariate model, embolization status significantly modified the relationship between E and AZV as described by the following interaction term: 0.42∗E∗(embolization status) (P = .031). CONCLUSIONS: Linear models demonstrated a near 1.8-fold increase in ratio of AZV per unit E, R(AZV:E), when applied to embolized lobes relative to nonembolized lobes. Absolute AZV differences between embolized and nonembolized lobes were greater at higher-power MWA.

Impaired ribosome-associated quality control of C9orf72 arginine-rich dipeptide-repeat proteins.

Protein quality control pathways have evolved to ensure the fidelity of protein synthesis and efficiently clear potentially toxic protein species. Defects in ribosome-associated quality control and its associated factors have been implicated in the accumulation of aberrant proteins and neurodegeneration. C9orf72 repeat-associated non-AUG translation has been suggested to involve inefficient translation elongation, lead to ribosomal pausing and activation of ribosome-associated quality control pathways. However, the role of the ribosome-associated quality control complex in the processing of proteins generated through this non-canonical translation is not well understood. Here we use reporter constructs containing the C9orf72-associated hexanucleotide repeat, ribosome-associated quality control complex deficient cell models and stain for ribosome-associated quality control markers in C9orf72-expansion carrier human tissue to understand its role in dipeptide-repeat protein pathology. Our studies show that canonical ribosome-associated quality control substrates products are efficiently cleared by the ribosome-associated quality control complex in mammalian cells. Furthermore, using stalling reporter constructs, we show that repeats associated with the C9orf72-expansion induce ribosomal stalling when arginine (R)-rich dipeptide-repeat proteins are synthesized in a length-dependent manner. However, despite triggering this pathway, these arginine-rich dipeptide-repeat proteins are not efficiently processed by the core components of the ribosome-associated quality control complex (listerin, nuclear-export mediator factor and valosin containing protein) partly due to lack of lysine residues, which precludes ubiquitination. Deficient processing by this complex may be implicated in C9orf72-expansion associated disease as dipeptide-repeat protein inclusions were observed to be predominantly devoid of ubiquitin and co-localize with nuclear-export mediator factor in mutation carriers' frontal cortex and cerebellum tissue. These findings suggest that impaired processing of these arginine-rich dipeptide-repeat proteins derived from repeat-associated non-AUG translation by the ribosome-associated quality control complex may contribute to protein homeostasis dysregulation observed in C9orf72-expansion amyotrophic lateral sclerosis and frontotemporal degeneration neuropathogenesis.

Data-driven neuropathological staging and subtyping of TDP-43 proteinopathies.

TAR DNA-binding protein-43 (TDP-43) accumulation is the primary pathology underlying several neurodegenerative diseases. Charting the progression and heterogeneity of TDP-43 accumulation is necessary to better characterize TDP-43 proteinopathies, but current TDP-43 staging systems are heuristic and assume each syndrome is homogeneous. Here, we use data-driven disease progression modelling to derive a fine-grained empirical staging system for the classification and differentiation of frontotemporal lobar degeneration due to TDP-43 (FTLD-TDP, n = 126), amyotrophic lateral sclerosis (ALS, n = 141) and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) with and without Alzheimer's disease (n = 304). The data-driven staging of ALS and FTLD-TDP complement and extend previously described human-defined staging schema for ALS and behavioural variant frontotemporal dementia. In LATE-NC individuals, progression along data-driven stages was positively associated with age, but negatively associated with age in individuals with FTLD-TDP. Using only regional TDP-43 severity, our data driven model distinguished individuals diagnosed with ALS, FTLD-TDP or LATE-NC with a cross-validated accuracy of 85.9%, with misclassifications associated with mixed pathological diagnosis, age and genetic mutations. Adding age and SuStaIn stage to this model increased accuracy to 92.3%. Our model differentiates LATE-NC from FTLD-TDP, though some overlap was observed between late-stage LATE-NC and early-stage FTLD-TDP. We further tested for the presence of subtypes with distinct regional TDP-43 progression patterns within each diagnostic group, identifying two distinct cortical-predominant and brainstem-predominant subtypes within FTLD-TDP and a further two subcortical-predominant and corticolimbic-predominant subtypes within ALS. The FTLD-TDP subtypes exhibited differing proportions of TDP-43 type, while there was a trend for age differing between ALS subtypes. Interestingly, a negative relationship between age and SuStaIn stage was seen in the brainstem/subcortical-predominant subtype of each proteinopathy. No subtypes were observed for the LATE-NC group, despite aggregating individuals with and without Alzheimer's disease and a larger sample size for this group. Overall, we provide an empirical pathological TDP-43 staging system for ALS, FTLD-TDP and LATE-NC, which yielded accurate classification. We further demonstrate that there is substantial heterogeneity amongst ALS and FTLD-TDP progression patterns that warrants further investigation in larger cross-cohort studies.

Pathological combinations in neurodegenerative disease are heterogeneous and disease-associated.

Pathologies that are causative for neurodegenerative disease (ND) are also frequently present in unimpaired, older individuals. In this retrospective study of 1647 autopsied individuals, we report the incidence of 10 pathologies across ND and normal ageing in attempt to clarify which pathological combinations are disease-associated and which are ageing-related. Eight clinically defined groups were examined including unimpaired individuals and those with clinical Alzheimer's disease, mixed dementia, amyotrophic lateral sclerosis, frontotemporal degeneration, multiple system atrophy, probable Lewy body disease or probable tauopathies. Up to seven pathologies were observed concurrently resulting in a heterogeneous mix of 161 pathological combinations. The presence of multiple additive pathologies associated with older age, increasing disease duration, APOE e4 allele and presence of dementia across the clinical groups. Fifteen to 67 combinations occurred in each group, with the unimpaired group defined by 35 combinations. Most combinations occurred at a <5% prevalence including 86 that were present in only one or two individuals. To better understand this heterogeneity, we organized the pathological combinations into five broad categories based on their age-related frequency: (i) 'Ageing only' for the unimpaired group combinations; (ii) 'ND only' if only the expected pathology for that individual's clinical phenotype was present; (iii) 'Other ND' if the expected pathology was not present; (iv) 'ND + ageing' if the expected pathology was present together with ageing-related pathologies at a similar prevalence as the unimpaired group; and (v) 'ND + associated' if the expected pathology was present together with other pathologies either not observed in the unimpaired group or observed at a greater frequency. ND only cases comprised a minority of cases (19-45%) except in the amyotrophic lateral sclerosis (56%) and multiple system atrophy (65%) groups. The ND + ageing category represented 9-28% of each group, but was rare in Alzheimer's disease (1%). ND + associated combinations were common in Alzheimer's disease (58%) and Lewy body disease (37%) and were observed in all groups. The Ageing only and Other ND categories accounted for a minority of individuals in each group. This observed heterogeneity indicates that the total pathological burden in ND is frequently more than a primary expected clinicopathological correlation with a high frequency of additional disease- or age-associated pathologies.

Valence and interactions in judicial voting.

The collective statistics of voting on judicial courts present hints about their inner workings. Many approaches for studying these statistics, however, assume that judges' decisions are conditionally independent: a judge reaches a decision based on the case at hand and his or her personal views. In reality, judges interact. We develop a minimal model that accounts for judge bias, depending on the context of the case, and peer interaction. We apply the model to voting data from the US Supreme Court. We find strong evidence that interaction is an important factor across natural courts from 1946 to 2021. We also find that, after accounting for interaction, the recovered biases differ from highly cited ideological scores. Our method exemplifies how physics and complexity-inspired modelling can drive the development of theoretical models and improved measures for political voting. This article is part of the theme issue 'A complexity science approach to law and governance'.

A Stepwise Interventional Strategy for the Removal of Adherent Totally Implanted Central Venous Access Port Catheters.

BACKGROUND: To evaluate the safety and effectiveness of a stepwise interventional strategy for the removal of adherent totally implanted central venous access port catheters, consisting of a guidewire support, antegrade coaxial separation, and retrograde coaxial separation with increasing technical complexity. METHODS: This study has a retrospective design. Thirty-two patients who had failed routine removal of the port catheter and were then transferred to interventional radiology between November 2017 and December 2023 were reviewed. The technical success and complication rates were recorded. RESULTS: All adherent catheters were successfully removed without catheter fragmentation, using guidewire support (n = 21), antegrade coaxial separation (n = 5), and retrograde coaxial separation (n = 6). The technical success rate was 100%, and no complications occurred. CONCLUSIONS: The proposed stepwise interventional strategy successfully removed adherent port catheters, with good safety and high effectiveness. It appeared to reduce the incidence of catheter fracture during the removal of adherent totally implantable central venous access port catheters.

Contrast-Enhanced Ultrasound of the Chest in Children and Adolescents: A Pilot Study for Assessment of Added Diagnostic Value.

OBJECTIVES: To determine the added diagnostic value of contrast-enhanced ultrasound (CEUS) in pediatric chest abnormalities by comparing interpretation of CEUS studies and confidence level to conventional US studies. METHODS: CEUS studies in patients with a variety of clinically suspected chest abnormalities performed between 2016 and 2020 were reviewed and compared to same-day conventional US studies. Examinations were independently interpreted by 4 radiologists blinded to clinical and other imaging data. Rater confidence was classified as low, moderate, or high. Diagnostic accuracy was determined by comparing image interpretation to patient outcome as the ground truth. Interobserver agreement was also assessed. RESULTS: Sixteen patients (10 male) with 18 CEUS studies were included. Median rater agreement with ground truth was significantly higher for CEUS (100%) than conventional US (50%; P = .004). Median rater confidence was high (3.0) for CEUS, and low-moderate (1.5) for conventional US (P < .001). CEUS sensitivity (54.6-81.8%) and specificity (63.4-100.0%) were greater than conventional US (45.5-72.7% and 12.5-63.5%, respectively). CEUS false positives (0-4) and false negatives (2-5) were fewer than conventional US (4-7 and 3-6, respectively). Except for one rater pair where agreement was substantial (κ = .78, P < .01), inter-rater agreement for CEUS for all other rater pairs was nonsignificant (κ = .25-0.51, P ≥ .07). Agreement for conventional US was moderate and statistically significant for 3 rater pairs (κ = .55-0.78) and nonsignificant for the remaining 3 rater pairs (P ≥ .06). CONCLUSIONS: CEUS adds diagnostic value to the assessment of a variety of chest abnormalities. The data support further evaluation of the role of CEUS as a non-invasive, problem-solving technique in children.

Growth, death, and resource competition in sessile organisms.

Population-level scaling in ecological systems arises from individual growth and death with competitive constraints. We build on a minimal dynamical model of metabolic growth where the tension between individual growth and mortality determines population size distribution. We then separately include resource competition based on shared capture area. By varying rates of growth, death, and competitive attrition, we connect regular and random spatial patterns across sessile organisms from forests to ants, termites, and fairy circles. Then, we consider transient temporal dynamics in the context of asymmetric competition, such as canopy shading or large colony dominance, whose effects primarily weaken the smaller of two competitors. When such competition couples slow timescales of growth to fast competitive death, it generates population shocks and demographic oscillations similar to those observed in forest data. Our minimal quantitative theory unifies spatiotemporal patterns across sessile organisms through local competition mediated by the laws of metabolic growth, which in turn, are the result of long-term evolutionary dynamics.