Longevity, enhanced memory, and altered density of dendritic spines in hippocampal CA3 and dentate gyrus after hemizygous deletion of Pde2a in mice.

Studies using acute or subchronic pharmacological inhibition of phosphodiesterase 2 A (PDE2A) have led to its proposal as a target for treatment of cognitive deficits associated with neuropsychiatric and neurodegenerative disease. However, the impact of continuous inhibition of PDE2A on memory is unknown. Moreover, the neuroanatomical regions mediating memory enhancement have not been categorically identified.

Selective oxidation of active site aromatic residues in engineered Cu proteins.

Recent studies have revealed critical roles for the local environments surrounding metallocofactors, such as the newly identified Cu site in particulate methane monooxygenases (pMMOs) and the second sphere aromatic residues in lytic polysaccharide monooxygenases (LPMOs), implicated in the protection against oxidative damage. However, these features are subjects of continued debate. Our work utilizes biotin-streptavidin (Sav) technology to develop artificial metalloproteins (ArMs) that mimic the active sites of natural copper metalloenzymes.

Risk Factors of Reoperation in Patients with Intestinal Behçet's Disease Treated by Initial Bowel Resection.

: Intestinal Behçet's disease (iBD) often requires surgical intervention, with a significant proportion of patients needing reoperation. This study aimed to investigate the risk factors associated with reoperation in patients with iBD who underwent initial bowel resection and to evaluate the perioperative and long-term outcomes in these patients. : This was a retrospective case-control study analyzing patients who underwent their initial bowel resection due to iBD between 2005-2021 at a tertiary referral hospital.

Opioid prescriptions following behavioral health training among primary care providers.

Background: Overdose deaths due to opioids are a major concern in the United States. Physicians often report inadequate training in chronic pain and substance use disorder management. Here, we evaluate whether a specialized program, the Train New Trainers Primary Care Psychiatry (TNT PCP) Fellowship, affected opioid prescription practices among primary care physicians.

Cell-Free Screening, Production and Animal Testing of a STI-Related Chlamydial Major Outer Membrane Protein Supported in Nanolipoproteins.

Background: Vaccine development against Chlamydia, a prevalent sexually transmitted infection (STI), is imperative due to its global public health impact. However, significant challenges arise in the production of effective subunit vaccines based on recombinant protein antigens, particularly with membrane proteins like the Major Outer Membrane Protein (MOMP).

Methods: Cell-free protein synthesis (CFPS) technology is an attractive approach to address these challenges as a method of high-throughput membrane protein and protein complex production coupled with nanolipoprotein particles (NLPs).

Spectral Pyrometry for Practical Temperature Measurement in the TEM.

Recent work in ultra-high temperature in situ electron microscopy has presented the need for accurate, contact-free temperature determination at the microscale. Optical measurement based on thermal radiation (pyrometry) is an attractive solution but can be difficult to perform correctly due to effects, such as emissivity and optical transmission, that must be accounted for. Here, we present a practical guide to calibrating and using a spectral pyrometry system, including example code, using a Czerny-Turner spectrometer attached to a transmission electron microscope.

Deciphering decadal urban ozone trends from historical records since 1980.

Ozone pollution is a major environmental threat to human health. Timely assessment of ozone trends is crucial for informing environmental policy. Here we show that for the most recent decade (2013-2022) in the northern hemisphere, warm-season (April-September) mean daily 8-h average maximum ozone increases much faster in urban regions with top ozone levels (mainly in the North China Plain, 1.

mA Reader PRRC2A Promotes Colorectal Cancer Progression via CK1ε-Mediated Activation of WNT and YAP Signaling Pathways.

Colorectal cancer (CRC) is the third most common cancer type and the second highest mortality rate among cancers. However, the mechanisms underlying CRC progression remain to be fully understood. In this work, a recently identified mA-modified RNA reader protein Proline-rich Coiled-coil 2a (PRRC2A) is markedly upregulated in CRC, and intestinal epithelium-specific deletion of Prrc2a significantly suppressed tumor cell growth, stemness, and migratory capacity, while its overexpression promoted these behaviors.

Cellular retinoic acid-binding proteins regulate germ cell proliferation and sex determination in zebrafish.

Cellular retinoic acid (RA)-binding proteins (Crabps) solubilize intracellular RA and transport it to its nuclear receptors or cytoplasmic degradation enzymes. Despite their extreme conservation across chordates, genetic studies of Crabp function have revealed few essential functions. We have generated loss-of-function mutations in all four zebrafish Crabps and find essential roles for Crabp2 proteins in gonad development and sex determination.

Introspective psychophysics for the study of subjective experience.

Studying subjective experience is hard. We believe that pain is not identical to nociception, nor pleasure a computational reward signal, nor fear the activation of "threat circuitry". Unfortunately, introspective self-reports offer our best bet for accessing subjective experience, but many still believe that introspection is "unreliable" and "unverifiable".

Optimal metacognitive decision strategies in signal detection theory.

Signal detection theory (SDT) has long provided the field of psychology with a simple but powerful model of how observers make decisions under uncertainty. SDT can distinguish sensitivity from response bias and characterize optimal decision strategies. Whereas classical SDT pertains to "type 1" judgments about the world, recent work has extended SDT to quantify sensitivity for metacognitive or "type 2" judgments about one's own type 1 processing, e.

In vivo photoreceptor base editing ameliorates rhodopsin-E150K autosomal-recessive retinitis pigmentosa in mice.

Rhodopsin, the prototypical class-A G-protein coupled receptor, is a highly sensitive receptor for light that enables phototransduction in rod photoreceptors. Rhodopsin plays not only a sensory role but also a structural role as a major component of the rod outer segment disc, comprising over 90% of the protein content of the disc membrane. Mutations in which lead to structural or functional abnormalities, including the autosomal recessive E150K mutation, result in rod dysfunction and death.

The CYK-4 GAP domain regulates cortical targeting of centralspindlin to promote contractile ring assembly and facilitate ring dissolution.

During cytokinesis, an equatorial contractile ring partitions the cell contents. Contractile ring assembly requires an equatorial zone of active GTP-bound RhoA generated by the guanine nucleotide exchange factor ECT2. ECT2 is activated by centralspindlin, a complex composed of two molecules each of kinesin-6 and CYK4.

PTEN deletion in the adult dentate gyrus induces epilepsy.

Embryonic and early postnatal promotor-driven deletion of the phosphatase and tensin homolog (PTEN) gene results in neuronal hypertrophy, hyperexcitable circuitry and development of spontaneous seizures in adulthood. We previously documented that focal, vector-mediated PTEN deletion in mature granule cells of the adult dentate gyrus triggers dramatic growth of cell bodies, dendrites, and axons, similar to that seen with early postnatal PTEN deletion. Here, we assess the functional consequences of focal, adult PTEN deletion, focusing on its pro-epileptogenic potential.

Calcineurin/NFAT inhibitors maintain cognition in a preclinical prevention study in an aging canine model of Alzheimer disease.

Brain signaling of calcineurin (CN) and nuclear factor of activated T-cells (NFAT) transcription factor increases in Alzheimer disease (AD) and is associated with synaptic loss, neurodegeneration, neuroinflammation, amyloid-β (Aβ) production, and cognitive decline. CN/NFAT inhibitors ameliorate these neuropathologies in mouse models of AD. Further, chronic use of tacrolimus in transplant patients reduces risk of AD.

Piezo1-mediated mechanotransduction enhances macrophage oxidized low-density lipoprotein uptake and atherogenesis.

Macrophages in the vascular wall ingest and clear lipids, but abundant lipid accumulation leads to foam cell formation and atherosclerosis, a pathological condition often characterized by tissue stiffening. While the role of biochemical stimuli in the modulation of macrophage function is well studied, the role of biophysical cues and the molecules involved in mechanosensation are less well understood. Here, we use genetic and pharmacological tools to show extracellular oxidized low-density lipoproteins (oxLDLs) stimulate Ca signaling through activation of the mechanically gated ion channel Piezo1.

SPOP-mediated RIPK3 destabilization desensitizes LPS/sMAC/zVAD-induced necroptotic cell death.

RIPK1/RIPK3-MLKL signaling molecules are fundamental in initiating necroptotic cell death, but their roles in the development of colon cancer are unclear. This study reports that RIPK3 interacted with SPOP, a component of the E3 ligase within the Cul3 complex. This interaction leads to K48-linked ubiquitination and subsequent proteasomal degradation of RIPK3.

Diversity of human skin three-dimensional organotypic cultures.

Recently, significant strides have been made in the development of high-fidelity skin organoids, encompassing techniques such as 3D bioprinting, skin-on-a-chip systems, and models derived from pluripotent stem cells (PSCs), replicating appendage structures and diverse skin cell types. Despite the emergence of these state-of-the-art skin engineering models, human organotypic cultures (OTCs), initially proposed in the 1970s, continue to reign as the predominant in vitro cultured three-dimensional skin model in the field of tissue engineering. This enduring prevalence is owed to their cost-effectiveness, straight forward setup, time efficiency, and faithful representation of native human skin.

Single cell and TCR analysis of immune cells from AAV gene therapy-dosed Duchenne muscular dystrophy patients.

Clinical trials for Duchenne muscular dystrophy (DMD) are assessing the therapeutic efficacy of systemically delivered adeno-associated virus (AAV) carrying a modified transgene. High vector doses (>1E14 vg/kg) are needed to globally transduce skeletal muscles; however, such doses trigger immune-related adverse events. Mitigating these immune responses is crucial for widespread application of AAV-based therapies.

Nicotine and a positive allosteric modulator of m1 muscarinic receptor increase NMDA/AMPA ratio in the hippocampus and medial prefrontal cortex.

Chronic nicotine exposure has been shown to improve memory in rodents. However, the molecular mechanism for such an enhancement remains poorly understood. Chronic nicotine exposure increases NMDA/AMPA ratio due to enhanced NMDAR-mediated responses in hippocampal CA1 pyramidal cells and facilitates LTP.

Cas9/guide RNA-based gene-drive dynamics following introduction and introgression into diverse anopheline mosquito genetic backgrounds.

Background: Novel technologies are needed to combat anopheline vectors of malaria parasites as the reductions in worldwide disease incidence has stalled in recent years. Gene drive-based approaches utilizing Cas9/guide RNA (gRNA) systems are being developed to suppress anopheline populations or modify them by increasing their refractoriness to the parasites. These systems rely on the successful cleavage of a chromosomal DNA target site followed by homology-directed repair (HDR) in germline cells to bias inheritance of the drive system.