familial aggregation

Human γD-crystallin belongs to a crucial family of proteins known as crystallins located in the fiber cells of the human lens. Since crystallins do not undergo any turnover after birth, they need to possess remarkable thermodynamic stability. However, their sporadic misfolding and aggregation, triggered by environmental perturbations or genetic mutations, constitute the molecular basis of cataracts, which is the primary cause of blindness in the globe according to the World Health Organization. Here, we investigate the impact of high pressure on the conformational landscape of wild-type HγD-crystallin using replica exchange molecular dynamics simulations augmented with principal component analysis...

Low-valent nickelates have recently been shown to be key intermediates in challenging cross-coupling reactions using aryl ethers as electrophiles. Key for the success of these transformations is the activation of the substrate through π-coordination to the nickelate intermediate, however there is still limited knowledge about the fundamental structure and coordination chemistry of these heterobimetallic complexes. Herein, we report the synthesis, structures, and spectroscopic analysis of a diverse family of alkali-metal nickelates derived from phenyl-alkali-metal reagents and Ni( ttt -CDT), where ttt -CDT = trans , trans , trans -1,5,9-cyclododecatriene...

Hyperphosphorylated TAR DNA-binding protein 43 (TDP-43) aggregates in the cytoplasm of neurons is the neuropathological hallmark of amyotrophic lateral sclerosis (ALS) and a group of neurodegenerative diseases collectively referred to as TDP-43 proteinopathies that includes frontotemporal dementia, Alzheimer's disease, and limbic onset age-related TDP-43 encephalopathy. The mechanism of TDP-43 phosphorylation is poorly understood. Previously we reported casein kinase 1 epsilon gene (CSNK1E gene encoding CK1ε protein) as being tightly correlated with phosphorylated TDP-43 (pTDP-43) pathology...

Developmental and functional defects in the lymphatic system are responsible for primary lymphoedema (PL). PL is a chronic debilitating disease caused by increased accumulation of interstitial fluid, predisposing to inflammation, infections and fibrosis. There is no cure, only symptomatic treatment is available. Thirty-two genes or loci have been linked to PL, and another 22 are suggested, including Hepatocyte Growth Factor (HGF). We searched for HGF variants in 770 index patients from the Brussels PL cohort...

In our study, we assessed the effects of verbenone, the most widely studied bark beetle aggregation inhibitor, on saproxylic beetles in a Mediterranean pine forest in Tuscany. Verbenone pouches were devised in the laboratory and then applied to Ips sexdentatus pheromone traps so that their catches could be compared to those of traps containing just the pheromone. The trial was carried out in spring-summer 2023, and insect catches were collected every two weeks. A total of 9440 beetles were collected that belonged to 32 different families and 57 species...

The pygmy grasshopper, Zhengitettix transpicula , is a Chinese endemic species with an exceedingly limited distribution and fragile population structure, rendering it vulnerable to extinction. We present a high-continuity, chromosome-scale reference genome assembly to elucidate this species' distinctive biology and inform conservation. Employing an integrated sequencing approach, we achieved a 970.40 Mb assembly with 96.32% coverage across seven pseudo-chromosomes and impressive continuity (N50 > 220 Mb)...

Alkaline phosphatase (ALP) is known as one of the most crucial members of the phosphatase family and encompasses the enormous ability to hydrolyze the phosphate group in various biomolecules; by this, it regulates several events in the pool of biological medium. Owing to its overexpression in various cancer cells, recently, its potential has evolved as a prominent biomarker in cancer research. In this article, we have underlined the recent advances (2019 onwards) of alkaline phosphatase in the arena of emerging cancer theranostics...

BACKGROUND: The most fatal form of Visceral leishmaniasis or kala-azar is caused by the intracellular protozoan parasite Leishmania donovani. The life cycle and the infection pathway of the parasite are regulated by the small GTPase family of Rab proteins. The involvement of Rab proteins in neurodegenerative amyloidosis is implicated in protein misfolding, secretion abnormalities and dysregulation. The inter and intra-cellular shuttlings of Rab proteins are proposed to be aggregation-prone...

BACKGROUND: Differences in the preoperative characteristics and weight loss outcomes after sleeve gastrectomy (SG) between patients with familial aggregation of obesity (FAO) and patients with sporadic obesity (SO) have not been elucidated. AIM: To explore the impact of SG on weight loss and the alleviation of obesity-related comorbidities in individuals with FAO. METHODS: A total of 193 patients with obesity who underwent SG were selected...

Early onset familial Alzheimer's disease (FAD) with APP, PS1/2 (presenilins) mutation accounts for only a small portion of AD cases, and most are late-onset sporadic. However, majority of AD mouse models are developed to mimic the genetic cause of human AD by overexpressing mutated forms of human APP, PS1/2, and/or Tau protein, though there is no Tau mutation in AD, and no single mouse model recapitulates all aspects of AD pathology. Here, we report Thy1-ApoE4/C/EBPβ double transgenic mouse model that demonstrates key AD pathologies in an age-dependent manner in absence of any human APP or PS1/2 mutation...

PROBLEM: Equity, diversity, and inclusion (EDI) efforts have accelerated over the past several years, without a traditional guidebook that other missions often have. To evaluate progress over time, departments of family medicine are seeking ways to measure their current EDI state. Across the specialty, unity regarding which EDI metrics are meaningful is absent, and discordance even exists about what should be measured. APPROACH: This paper provides a general metrics framework, including a wide array of possibilities to consider measuring, for assessing individual departmental progress in this broad space...

The aggregation of superoxide dismutase 1 (SOD1) results in amyloid deposition and is involved in familial amyotrophic lateral sclerosis, a fatal motor neuron disease. There have been extensive studies of its aggregation mechanism. Noncanonical amino acid 5-cyano-tryptophan (5-CN-Trp), which has been incorporated into the amyloid segments of SOD1 as infrared probes to increase the structural sensitivity of IR spectroscopy, is found to accelerate the overall aggregation rate and potentially modulate the aggregation process...

Chestnut blight (caused by Cryphonectria parasitica ), together with Phytophthora root rot (caused by Phytophthora cinnamomi ), has nearly extirpated American chestnut ( Castanea dentata ) from its native range. In contrast to the susceptibility of American chestnut, many Chinese chestnut ( C. mollissima ) genotypes are resistant to blight. In this research, we performed a series of genome-wide association studies for blight resistance originating from three unrelated Chinese chestnut trees (Mahogany, Nanking and M16) and a Quantitative Trait Locus (QTL) study on a Mahogany-derived inter-species F2 family...

BACKGROUND: Growing demands on educators have resulted in increased levels of burnout and stress and decreasing wellbeing. This study aimed to establish expert consensus on the key characteristics required in prospective educator wellbeing initiatives. METHODS: The Delphi approach is a process of forecasting that is based on the aggregated opinion of panel members (or experts) within a field of study. Using a Delphi approach, academic and practitioner expertise were sought over a two-rounds, with 17 and 14 participants in each round respectively...

Orb2 the Drosophila homolog of cytoplasmic polyadenylation element binding (CPEB) protein forms prion-like oligomers. These oligomers consist of Orb2A and Orb2B isoforms and their formation is dependent on the oligomerization of the Orb2A isoform. Drosophila with a mutation diminishing Orb2A's prion-like oligomerization forms long-term memory but fails to maintain it over time. Since this prion-like oligomerization of Orb2A plays a crucial role in the maintenance of memory, here, we aim to find what regulates this oligomerization...

INTRODUCTION: In the first randomised controlled trial of a dementia training and support intervention in UK homecare agencies, we aimed to assess: acceptability of our co-designed, manualised training, delivered by non-clinical facilitators; outcome completion feasibility; and costs for a future trial. METHODS: This cluster-randomised (2:1) single-blind, feasibility trial involved English homecare agencies. Intervention arm agency staff were offered group videocall sessions: 6 over 3 months, then monthly for 3 months (NIDUS-professional)...

Intracellular aggregation of fused in sarcoma (FUS) is associated with the pathogenesis of familial amyotrophic lateral sclerosis (ALS). Under stress, FUS forms liquid droplets via liquid-liquid phase separation (LLPS). Two types of wild-type FUS LLPS exist in equilibrium: low-pressure LLPS (LP-LLPS) and high-pressure LLPS (HP-LLPS); the former dominates below 2 kbar and the latter over 2 kbar. Although several disease-type FUS variants have been identified, the molecular mechanism underlying accelerated cytoplasmic granule formation in ALS patients remains poorly understood...

Non-clustered protocadherins (ncPcdhs) are adhesive molecules with spatio-temporally regulated overlapping expression in the developing nervous system. Although their unique role in neurogenesis has been widely studied, their combinatorial role in brain physiology and pathology is poorly understood. Using probabilistic cell typing by in situ sequencing, we demonstrate combinatorial inter- and intra-familial expression of ncPcdhs in the developing mouse cortex and hippocampus, at single-cell resolution. We discovered the combinatorial expression of Protocadherin-19 ( Pcdh19 ), a protein involved in PCDH19-clustering epilepsy, with Pcdh1 , Pcdh9 or Cadherin 13 ( Cdh13 ) in excitatory neurons...

Acrokeratoelastoidosis (AKE) is a rare autosomal dominant hereditary skin disease characterized by small, round-oval, flat-topped keratotic papules on the palms, soles and dorsal aspect of hands or feet. The causative gene for AKE remains unidentified. This study aims to identify the causative gene of AKE and explore the underlying biological mechanisms. A large, three-generation Chinese family exhibiting classic AKE symptoms was identified. A genome-wide linkage analysis and whole-exome sequencing were employed to determine the causative gene...

3-Hydroxyhexan-2-one (3-C6-ketol) has emerged as the most conserved pheromone structure within the beetle family Cerambycidae. In this study, we report the sex-specific production of this compound by males of 12 species of South American cerambycid beetles. Males of Chrysoprasis chalybea Redtenbacher and Mallosoma zonatum (Sahlberg) (Tribe Dichophyiini), and Ambonus lippus (Germar), Eurysthea hirta (Kirby), Pantonyssus nigriceps Bates, Stizocera plicicollis (Germar), and Stizocera tristis (Guérin-Méneville) (Elaphidiini) produced 3R-C6-ketol as a single component, whereas males of Neoclytus pusillus (Laporte & Gory) (Clytini), Aglaoschema concolor (Gounelle), Orthostoma abdominale (Gyllenhal) (Compsocerini), Dorcacerus barbatus (Olivier), and Retrachydes thoracicus thoracicus (Olivier) (Trachyderini) produced 3R-C6-ketol, along with lesser amounts of other compounds...