gamma-Secretase substrate selectivity can be modulated directly via interaction with a nucleotide-binding site

gamma-Secretase is an unusual protease with an intramembrane catalytic site that cleaves many type I membrane proteins, including the amyloid beta-protein (Abeta) precursor (APP) and the Notch receptor. Genetic and biochemical studies have identified four membrane proteins as components of gamma-secretase: heterodimeric presenilin composed of its N- and C-terminal fragments, nicastrin, Aph-1, and Pen-2. Here we demonstrated that certain compounds, including protein kinase inhibitors and their derivatives, act directly on purified gamma-secretase to selectively block cleavage of APP- but not Notch-based substrates. Moreover, ATP activated the generation of the APP intracellular domain and Abeta, but not the generation of the Notch intracellular domain by the purified protease complex, and was a direct competitor of the APP-selective inhibitors, as were other nucleotides. In accord, purified gamma-secretase bound specifically to an ATP-linked resin. Finally, a photoactivable ATP analog specifically labeled presenilin 1-C-terminal fragments in purified gamma-secretase preparations; the labeling was blocked by ATP itself and APP-selective gamma-secretase inhibitors. We concluded that a nucleotide-binding site exists within gamma-secretase, and certain compounds that bind to this site can specifically modulate the generation of Abeta while sparing Notch. Drugs targeting the gamma-secretase nucleotide-binding site represent an attractive strategy for safely treating Alzheimer disease

Cell Type-Specific Transcriptomics Reveals that Mutant Huntingtin Leads to Mitochondrial RNA Release and Neuronal Innate Immune Activation

The mechanisms by which mutant huntingtin (mHTT) leads to neuronal cell death in Huntington’s disease (HD) are not fully understood. To gain new molecular insights, we used single nuclear RNA sequencing (snRNA-seq) and translating ribosome affinity purification (TRAP) to conduct transcriptomic analyses of caudate/putamen (striatal) cell type-specific gene expression changes in human HD and mouse models of HD. In striatal spiny projection neurons, the most vulnerable cell type in HD, we observe a release of mitochondrial RNA (mtRNA) (a potent mitochondrial-derived innate immunogen) and a concomitant upregulation of innate immune signaling in spiny projection neurons. Further, we observe that the released mtRNAs can directly bind to the innate immune sensor protein kinase R (PKR). We highlight the importance of studying cell type-specific gene expression dysregulation in HD pathogenesis and reveal that the activation of innate immune signaling in the most vulnerable HD neurons provides a novel framework to understand the basis of mHTT toxicity and raises new therapeutic opportunities

Prognostic algorithms for post-discharge readmission and mortality among mother-infant dyads: an observational study protocol

IntroductionIn low-income country settings, the first six weeks after birth remain a critical period of vulnerability for both mother and newborn. Despite recommendations for routine follow-up after delivery and facility discharge, few mothers and newborns receive guideline recommended care during this period. Prediction modelling of post-delivery outcomes has the potential to improve outcomes for both mother and newborn by identifying high-risk dyads, improving risk communication, and informing a patient-centered approach to postnatal care interventions. This study aims to derive post-discharge risk prediction algorithms that identify mother-newborn dyads who are at risk of re-admission or death in the first six weeks after delivery at a health facility.MethodsThis prospective observational study will enroll 7,000 mother-newborn dyads from two regional referral hospitals in southwestern and eastern Uganda. Women and adolescent girls aged 12 and above delivering singletons and twins at the study hospitals will be eligible to participate. Candidate predictor variables will be collected prospectively by research nurses. Outcomes will be captured six weeks following delivery through a follow-up phone call, or an in-person visit if not reachable by phone. Two separate sets of prediction models will be built, one set of models for newborn outcomes and one set for maternal outcomes. Derivation of models will be based on optimization of the area under the receiver operator curve (AUROC) and specificity using an elastic net regression modelling approach. Internal validation will be conducted using 10-fold cross-validation. Our focus will be on the development of parsimonious models (5–10 predictor variables) with high sensitivity (>80%). AUROC, sensitivity, and specificity will be reported for each model, along with positive and negative predictive values.DiscussionThe current recommendations for routine postnatal care are largely absent of benefit to most mothers and newborns due to poor adherence. Data-driven improvements to postnatal care can facilitate a more patient-centered approach to such care. Increasing digitization of facility care across low-income settings can further facilitate the integration of prediction algorithms as decision support tools for routine care, leading to improved quality and efficiency. Such strategies are urgently required to improve newborn and maternal postnatal outcomes. Clinical trial registrationhttps://clinicaltrials.gov/, identifier (NCT05730387)

Predictor variables for post-discharge mortality modelling in infants: a protocol development project

Background: Over two-thirds of the five million annual deaths in children under five occur in infants, mostly in developing countries and many after hospital discharge. However, there is a lack of understanding of which children are at higher risk based on early clinical predictors. Early identification of vulnerable infants at high-risk for death post-discharge is important in order to craft interventional programs. Objectives: To determine potential predictor variables for post-discharge mortality in infants less than one year of age who are likely to die after discharge from health facilities in the developing world. Methods: A two-round modified Delphi process was conducted, wherein a panel of experts evaluated variables selected from a systematic literature review. Variables were evaluated based on (1) predictive value, (2) measurement reliability, (3) availability, and (4) applicability in low-resource settings. Results: In the first round, 18 experts evaluated 37 candidate variables and suggested 26 additional variables. Twenty-seven variables derived from those suggested in the first round were evaluated by 17 experts during the second round. A final total of 55 candidate variables were retained. Conclusion: A systematic approach yielded 55 candidate predictor variables to use in devising predictive models for post-discharge mortality in infants in a low-resource setting

Correction: Mutations in LRRK2 linked to Parkinson disease sequester Rab8a to damaged lysosomes and regulate transferrin-mediated iron uptake in microglia

[This corrects the article DOI: 10.1371/journal.pbio.3001480.]

The phase diagram of NiSi under the conditions of small planetary interiors

The phase diagram of NiSi has been determined using in situ synchrotron X-ray powder diffraction multi-anvil experiments to 19 GPa, with further preliminary results in the laser-heated diamond cell reported to 60 GPa. The low-pressure MnP-structured phase transforms to two different high-pressure phases depending on the temperature: the ε-FeSi structure is stable at temperatures above ∼1100 K and a previously reported distorted-CuTi structure (with Pmmn symmetry) is stable at lower temperature. The invariant point is located at 12.8 ± 0.2 GPa and 1100 ± 20 K. At higher pressures, ε -FeSi-structured NiSi transforms to the CsCl structure with CsCl-NiSi as the liquidus phase above 30 GPa. The Clapeyron slope of this transition is -67 MPa/K. The phase boundary between the ε -FeSi and Pmmn structured phases is nearly pressure independent implying there will be a second sub-solidus invariant point between CsCl, ε -FeSi and Pmmn structures at higher pressure than attained in this study. In addition to these stable phases, the MnP structure was observed to spontaneously transform at room temperature to a new orthorhombic structure (also with Pnma symmetry) which had been detailed in previous ab initio simulations. This new phase of NiSi is shown here to be metastable

SMC complexes differentially compact mitotic chromosomes according to genomic context

Structural maintenance of chromosomes (SMC) protein complexes are key determinants of chromosome conformation. Using Hi-C and polymer modelling, we study how cohesin and condensin, two deeply conserved SMC complexes, organize chromosomes in the budding yeast Saccharomyces cerevisiae. The canonical role of cohesin is to co-align sister chromatids, while condensin generally compacts mitotic chromosomes. We find strikingly different roles for the two complexes in budding yeast mitosis. First, cohesin is responsible for compacting mitotic chromosome arms, independently of sister chromatid cohesion. Polymer simulations demonstrate that this role can be fully accounted for through cis-looping of chromatin. Second, condensin is generally dispensable for compaction along chromosome arms. Instead, it plays a targeted role compacting the rDNA proximal regions and promoting resolution of peri-centromeric regions. Our results argue that the conserved mechanism of SMC complexes is to form chromatin loops and that distinct SMC-dependent looping activities are selectively deployed to appropriately compact chromosomes

Parkinson’s disease-linked LRRK2 is expressed in circulating and tissue immune cells and upregulated following recognition of microbial structures

Sequence variants at or near the leucine-rich repeat kinase 2 (LRRK2) locus have been associated with susceptibility to three human conditions: Parkinson disease (PD), Crohn’s disease and leprosy. Because all three disorders represent complex diseases with evidence of inflammation, we hypothesized a role for LRRK2 in immune cell functions