Data-driven discovery of cell-type-directed network-correcting combination therapy for Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder characterized by heterogeneous molecular changes across diverse cell types, posing significant challenges for treatment development. To address this, we introduced a cell-type-specific, multi-target drug discovery strategy grounded in human data and real-world evidence. This approach integrates single-cell transcriptomics, drug perturbation databases, and clinical records.

The GluA1 cytoplasmic tail regulates intracellular AMPA receptor trafficking and synaptic transmission onto dentate gyrus GABAergic interneurons, gating response to novelty.

The GluA1 subunit, encoded by the putative schizophrenia-associated gene GRIA1, is required for activity-regulated AMPA receptor (AMPAR) trafficking, and plays a key role in cognitive and affective function. The cytoplasmic, carboxy-terminal domain (CTD) is the most divergent region across AMPAR subunits. The GluA1 CTD has received considerable attention for its role during long-term potentiation (LTP) at CA1 pyramidal neuron synapses.

A Black Feminist Study of Black Mother-Daughter Sexual Communication.

There is a well-established body of literature on parent-child sexual communication (PCSC) among Black families. Still, most of this work focuses on reducing sexual risk behaviors among Black girls and focuses less on the multidimensionality of PCSC among Black parents and their daughters. In this qualitative study, we explored Black mother-daughter PCSC by analyzing interviews with 29 Black mothers in the U.

CHCHD2 mutant mice display mitochondrial protein accumulation and disrupted energy metabolism.

Mutations in the mitochondrial cristae protein CHCHD2 lead to a late-onset autosomal dominant form of Parkinson's disease (PD) which closely resembles idiopathic PD, providing the opportunity to gain new insights into the mechanisms of mitochondrial dysfunction contributing to PD. To begin to address this, we used CRISPR genome-editing to generate CHCHD2 T61I point mutant mice. CHCHD2 T61I mice had normal viability, and had only subtle motor deficits with no signs of premature dopaminergic (DA) neuron degeneration.

Sex-specific role for the long noncoding RNA Pnky in mouse behavior.

The aberrant expression of specific long noncoding RNAs (lncRNAs) has been associated with cognitive and psychiatric disorders. Although a growing number of lncRNAs are now known to regulate neural cell development and function, relatively few lncRNAs have been shown to underlie animal behavior. Pnky is an evolutionarily conserved, neural lncRNA that regulates brain development.

Classifying tetraspanins: A universal system for numbering residues and a proposal for naming structural motifs and subfamilies.

All tetraspanins have four transmembrane domains (TMs). The large extracellular loop (LEL) that connects the third and fourth TMs contains multiple secondary structures together with the family's signature Cys-Cys-Gly motif. These intriguing membrane proteins are involved in diverse and incompletely understood cellular processes including cell adhesion, tissue differentiation, immune cell maturation and host-parasite interactions.

Sex-specific role for the long noncoding RNA in mouse behavior.

The human brain expresses thousands of different long noncoding RNAs (lncRNAs), and aberrant expression of specific lncRNAs has been associated with cognitive and psychiatric disorders. While a growing number of lncRNAs are now known to regulate neural cell development and function, relatively few have been shown to underlie animal behavior, particularly with genetic strategies that establish lncRNA function in . is an evolutionarily conserved, neural lncRNA that regulates brain development.

Contributing factors to secondary traumatic stress and vicarious posttraumatic growth in therapists.

Alongside the recognized potential negative repercussions of working as a psychological therapist, there is growing interest in the potential positive impacts of engaging in such work. The current study used a cross-sectional online survey design to explore the impact of a range of demographic, work-related, and compassion-related factors on levels of secondary traumatic stress (STS) and vicarious posttraumatic growth (VPTG) in an international sample of 359 psychological therapists. Hierarchical multiple regressions demonstrated that burnout, lower levels of self-compassion, having a personal trauma history, reporting a higher percentage of working time with a trauma focus, and being female were the statistically significant contributors to STS scores, explaining 40.

Closing the Gender Gap in Healthcare Leadership: Can Administrative Fellowships Play a Role?

Goal: Although women make up most of the healthcare workforce, they are underrepresented in higher levels of leadership positions. Leadership development programs for early careerists, such as administrative fellowships, have been suggested as one strategy for accelerating gender equity in leadership roles. However, the potential impact of these programs has not yet been the subject of systematic evaluation.

Chemokine CXCL12 drives pericyte accumulation and airway remodeling in allergic airway disease.

Background: Airway remodeling is a significant contributor to impaired lung function in chronic allergic airway disease. Currently, no therapy exists that is capable of targeting these structural changes and the consequent loss of function. In the context of chronic allergic inflammation, pericytes have been shown to uncouple from the pulmonary microvasculature, migrate to areas of inflammation, and significantly contribute to airway wall remodeling and lung dysfunction.

Membrane Protein Production in the Yeast P. pastoris.

The first crystal structures of recombinant mammalian membrane proteins were solved using high-quality protein that had been produced in yeast cells. One of these, the rat Kv1.2 voltage-gated potassium channel, was synthesized in Pichia pastoris.

K1.1 preserves the neural stem cell pool and facilitates neuron maturation during adult hippocampal neurogenesis.

Adult hippocampal neurogenesis is critical for learning and memory, and aberrant adult neurogenesis has been implicated in cognitive decline associated with aging and neurological diseases [J. T. Gonçalves, S.

TAU ablation in excitatory neurons and postnatal TAU knockdown reduce epilepsy, SUDEP, and autism behaviors in a Dravet syndrome model.

Intracellular accumulation of TAU aggregates is a hallmark of several neurodegenerative diseases. However, global genetic reduction of TAU is beneficial also in models of other brain disorders that lack such TAU pathology, suggesting a pathogenic role of nonaggregated TAU. Here, conditional ablation of TAU in excitatory, but not inhibitory, neurons reduced epilepsy, sudden unexpected death in epilepsy, overactivation of the phosphoinositide 3-kinase-AKT-mammalian target of rapamycin pathway, brain overgrowth (megalencephaly), and autism-like behaviors in a mouse model of Dravet syndrome, a severe epileptic encephalopathy of early childhood.

The Role of ICL1 and H8 in Class B1 GPCRs; Implications for Receptor Activation.

The first intracellular loop (ICL1) of G protein-coupled receptors (GPCRs) has received little attention, although there is evidence that, with the 8 helix (H8), it is involved in early conformational changes following receptor activation as well as contacting the G protein β subunit. In class B1 GPCRs, the distal part of ICL1 contains a conserved RKLRCxR motif that extends into the base of the second transmembrane helix; this is weakly conserved as a [R/H]KL[R/H] motif in class A GPCRs. In the current study, the role of ICL1 and H8 in signaling through cAMP, Ca and ERK1/2 has been examined in two class B1 GPCRs, using mutagenesis and molecular dynamics.

Iduronate-2-sulfatase transport vehicle rescues behavioral and skeletal phenotypes in a mouse model of Hunter syndrome.

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by deficiency of the iduronate-2-sulfatase (IDS) enzyme, resulting in cellular accumulation of glycosaminoglycans (GAGs) throughout the body. Treatment of MPS II remains a considerable challenge as current enzyme replacement therapies do not adequately control many aspects of the disease, including skeletal and neurological manifestations. We developed an IDS transport vehicle (ETV:IDS) that is engineered to bind to the transferrin receptor; this design facilitates receptor-mediated transcytosis of IDS across the blood-brain barrier and improves its distribution into the brain while maintaining distribution to peripheral tissues.

Membrane protein extraction and purification using partially-esterified SMA polymers.

Styrene maleic acid (SMA) polymers have proven to be very successful for the extraction of membrane proteins, forming SMA lipid particles (SMALPs), which maintain a lipid bilayer around the membrane protein. SMALP-encapsulated membrane proteins can be used for functional and structural studies. The SMALP approach allows retention of important protein-annular lipid interactions, exerts lateral pressure, and offers greater stability than traditional detergent solubilisation.

The efficacy of public health information for encouraging radon gas awareness and testing varies by audience age, sex and profession.

Radioactive radon inhalation is a leading cause of lung cancer and underlies an ongoing public health crisis. Radon exposure prevention strategies typically begin by informing populations about health effects, and their initial efficacy is measured by how well and how fast information convinces individuals to test properties. This communication process is rarely individualized, and there is little understanding if messages impact diverse demographics equally.

The long goodbye on a disappearing, ancestral island: a just retreat from Isle de Jean Charles.

Climate change will necessitate evermore frequent and complex managed retreats in the future, and drafting policies that are equitable and just for those residents who are relocating will be essential. The USA's first federally funded, community-scale, climate-driven resettlement is currently underway in coastal Louisiana. In January 2016, the U.

Younger North Americans are exposed to more radon gas due to occupancy biases within the residential built environment.

Residential buildings can concentrate radioactive radon gas, exposing occupants to particle radiation that increases lung cancer risk. This has worsened over time in North America, with newer residences containing greater radon. Using data from 18,971 Canadian households, we calculated annual particle radiation dose rates due to long term residential radon exposure, and examined this as a function of occupant demographics.

Long-term potentiation is independent of the C-tail of the GluA1 AMPA receptor subunit.

We tested the proposal that the C-terminal domain (CTD) of the AMPAR subunit GluA1 is required for LTP. We found that a knock-in mouse lacking the CTD of GluA1 expresses normal LTP and spatial memory, assayed by the Morris water maze. Our results support a model in which LTP generates synaptic slots, which capture passively diffusing AMPARs.

Factors associated with provision of smoking cessation support to pregnant women - a cross-sectional survey of midwives in New South Wales, Australia.

Background: Smoking is the most important preventable cause of adverse pregnancy outcomes, but provision of smoking cessation support (SCS) to pregnant women is poor. We examined the association between midwives' implementation of SCS (5As - Ask, Advise, Assess, Assist, Arrange follow-up) and reported barriers/enablers to implementation.

Methods: On-line anonymous survey of midwives providing antenatal care in New South Wales (NSW), Australia, assessing provision of the 5As and barriers/enablers to their implementation, using the Theoretical Domains Framework (TDF).

Ligand-induced conformational changes in a SMALP-encapsulated GPCR.

The adenosine 2A receptor (AR), a G-protein-coupled receptor (GPCR), was solubilised and purified encapsulated in styrene maleic acid lipid particles (SMALPs). The purified AR-SMALP was associated with phospholipids characteristic of the plasma membrane of Pichia pastoris, the host used for its expression, confirming that the AR-SMALP encapsulated native lipids. The fluorescence spectrum of the AR-SMALP showed a characteristic broad emission peak at 330 nm, produced by endogenous Trp residues.

Calcitonin Receptor N-Glycosylation Enhances Peptide Hormone Affinity by Controlling Receptor Dynamics.

The class B G protein-coupled receptor (GPCR) calcitonin receptor (CTR) is a drug target for osteoporosis and diabetes. N-glycosylation of asparagine 130 in its extracellular domain (ECD) enhances calcitonin hormone affinity with the proximal GlcNAc residue mediating this effect through an unknown mechanism. Here, we present two crystal structures of salmon calcitonin-bound, GlcNAc-bearing CTR ECD at 1.

GluN2A NMDA Receptor Enhancement Improves Brain Oscillations, Synchrony, and Cognitive Functions in Dravet Syndrome and Alzheimer's Disease Models.

NMDA receptors (NMDARs) play subunit-specific roles in synaptic function and are implicated in neuropsychiatric and neurodegenerative disorders. However, the in vivo consequences and therapeutic potential of pharmacologically enhancing NMDAR function via allosteric modulation are largely unknown. We examine the in vivo effects of GNE-0723, a positive allosteric modulator of GluN2A-subunit-containing NMDARs, on brain network and cognitive functions in mouse models of Dravet syndrome (DS) and Alzheimer's disease (AD).