Causal associations between scapular morphology and shoulder condition estimated with Bayesian statistics.

While there is a reported correlation between shoulder condition and scapular morphology, the precise impact of typical anatomical variables remains a subject of ongoing debate. This study aimed to evaluate this causal association, by emphasizing the importance of scientific modeling before statistical analysis. We examined the effect of scapular anatomy on shoulder condition, and conditioning on sex, age, height, and weight. We considered the two most common pathologies: primary osteoarthritis (OA) and cuff tear arthropathy (CTA). We combined the other pathologies into a single category (OTH) and included a control category (CTRL) of adult subjects without pathology. We represented acromion and glenoid morphology by acromion angle (AA), acromion posterior angle (APA), acromion tilt angle (ATA), glenoid inclination angle (GIA), and glenoid version angle (GVA). GVA was negative for posterior orientation. These variables were automatically calculated from CT scans of 396 subjects in the 4 shoulder condition groups by a deep learning model. We applied do-calculus to assess the identifiability of the causal associations and used a multinomial logistic regression Bayesian model to estimate them. To isolate the effect of each anatomical variable on each shoulder condition, we increased it from -2 to 2 z-score while constraining all other variables to their average value, and reported the effect on shoulder condition probability as percentage points (pp) for females and males. Increasing AA reduced the probability of OA by 44 pp for females and 17 pp for males while increasing the probability of CTA by 36 pp for females and 33 pp for males. Increasing APA raised the probability of OA by 15 pp for females and 4 pp for males and increased the probability of CTA by 12 pp for females and 4 pp for males. Increasing ATA increased the probability of OA by 15 pp for females but decreased it by 25 pp for males, while also raising the probability of CTA by 11 pp for females and 21 pp for males. Increasing GIA decreased the probability of OA by 55 pp for females and 23 pp for males while increasing the probability of CTA by 45 pp for females and 31 pp for males. GVA (more anterior), decreased the probability of OA by 33 pp for females and 63 pp for males. The effects of APA and ATA were less important compared to the other variables. Overall, morphological effects were more pronounced for females than for males, except for GVA's impact on OA. We developed a Bayesian causal model to answer interventional questions about the scapular anatomy's effect on shoulder condition. Our results, consistent with clinical knowledge, hold promise for aiding in early pathology detection and optimizing surgical planning within clinical settings

Accelerated neuronal and synaptic maturation by BrainPhys medium increases Aβ secretion and alters Aβ peptide ratios from iPSC-derived cortical neurons

One of the neuropathological hallmarks of Alzheimer’s disease (AD) is cerebral deposition of amyloid plaques composed of amyloid β (Aβ) peptides and the cerebrospinal fluid concentrations of those peptides are used as a biomarker for AD. Mature induced pluripotent stem cell (iPSC)-derived cortical neurons secrete Aβ peptides in ratios comparable to those secreted to cerebrospinal fluid in human, however the protocol to achieve mature neurons is time consuming. In this study, we investigated if differentiation of neuroprogenitor cells (NPCs) in BrainPhys medium, previously reported to enhance synaptic function of neurons in culture, would accelerate neuronal maturation and, thus increase Aβ secretion as compared to the conventional neural maintenance medium. We found that NPCs cultured in BrainPhys displayed increased expression of markers for cortical deep-layer neurons, increased synaptic maturation and number of astroglial cells. This accelerated neuronal maturation was accompanied by increased APP processing, resulting in increased secretion of Aβ peptides and an increased Aβ38 to Aβ40 and Aβ42 ratio. However, during long-term culturing in BrainPhys, non-neuronal cells appeared and eventually took over the cultures. Taken together, BrainPhys culturing accelerated neuronal maturation and increased Aβ secretion from iPSC-derived cortical neurons, but changed the cellular composition of the cultures

Tauopathy-Associated Tau Fragment Ending at Amino Acid 224 Is Generated by Calpain-2 Cleavage

BACKGROUND: Tau aggregation in neurons and glial cells characterizes tauopathies as Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD). Tau proteolysis has been proposed as a trigger for tau aggregation and tau fragments have been observed in brain and cerebrospinal fluid (CSF). Our group identified a major tau cleavage at amino acid (aa) 224 in CSF; N-terminal tau fragments ending at aa 224 (N-224) were significantly increased in AD and lacked correlation to total tau (t-tau) and phosphorylated tau (p-tau) in PSP and CBD. OBJECTIVE: Previous studies have shown cleavage from calpain proteases at sites adjacent to aa 224. Our aim was to investigate if calpain-1 or -2 could be responsible for cleavage at aa 224. METHODS: Proteolytic activity of calpain-1, calpain-2, and brain protein extract was assessed on a custom tau peptide (aa 220-228), engineered with fluorescence resonance energy transfer (FRET) technology. Findings were confirmed with in-gel trypsination and mass spectrometry (MS) analysis of brain-derived bands with proteolytic activity on the FRET substrate. Finally, knock-down of the calpain-2 catalytic subunit gene (CAPN2) was performed in a neuroblastoma cell line (SH-SY5Y). RESULTS: Calpain-2 and brain protein extract, but not calpain-1, showed proteolytic activity on the FRET substrate. MS analysis of active gel bands revealed presence of calpain-2 subunits, but not calpain-1. Calpain-2 depletion and chemical inhibition suppressed proteolysis of the FRET substrate. CAPN2 knock-down caused a 76.4% reduction of N-224 tau in the cell-conditioned media. CONCLUSIONS: Further investigation of the calpain-2 pathway in the pathogenesis of tauopathies is encouraged

Structure and function of mammalian cilia

In the past half century, beginning with electron microscopic studies of 9 + 2 motile and 9 + 0 primary cilia, novel insights have been obtained regarding the structure and function of mammalian cilia. All cilia can now be viewed as sensory cellular antennae that coordinate a large number of cellular signaling pathways, sometimes coupling the signaling to ciliary motility or alternatively to cell division and differentiation. This view has had unanticipated consequences for our understanding of developmental processes and human disease

Herpes Simplex Virus 1 and 2 Infections during Differentiation of Human Cortical Neurons

Herpes simplex virus 1 (HSV-1) and 2 (HSV-2) can infect the central nervous system (CNS) with dire consequences; in children and adults, HSV-1 may cause focal encephalitis, while HSV-2 causes meningitis. In neonates, both viruses can cause severe, disseminated CNS infections with high mortality rates. Here, we differentiated human induced pluripotent stem cells (iPSCs) towards cortical neurons for infection with clinical CNS strains of HSV-1 or HSV-2. Progenies from both viruses were produced at equal quantities in iPSCs, neuroprogenitors and cortical neurons. HSV-1 and HSV-2 decreased viability of neuroprogenitors by 36.0% and 57.6% (p < 0.0001), respectively, 48 h post-infection, while cortical neurons were resilient to infection by both viruses. However, in these functional neurons, both HSV-1 and HSV-2 decreased gene expression of two markers of synaptic activity, CAMK2B and ARC, and affected synaptic activity negatively in multielectrode array experiments. However, unaltered secretion levels of the neurodegeneration markers tau and NfL suggested intact axonal integrity. Viral replication of both viruses was found after six days, coinciding with 6-fold and 22-fold increase in gene expression of cellular RNA polymerase II by HSV-1 and HSV-2, respectively. Our results suggest a resilience of human cortical neurons relative to the replication of HSV-1 and HSV-2