Small Molecule Drug C381 Attenuates Brain Vascular Damage Following Repetitive Mild Traumatic Injury.

Traumatic brain injury (TBI) remains a significant public health concern, with no effective therapeutic interventions to ameliorate the enduring consequences. The prevailing understanding of TBI pathophysiology indicates a central role for vascular dysfunction. Transforming growth factor-β (TGF-β) is a multifunctional cytokine crucial for vascular development.

Human tNeurons reveal aging-linked proteostasis deficits driving Alzheimer's phenotypes.

Aging is a prominent risk factor for Alzheimer's disease (AD), but the cellular mechanisms underlying neuronal phenotypes remain elusive. Both accumulation of amyloid plaques and neurofibrillary tangles in the brain and age-linked organelle deficits are proposed as causes of AD phenotypes but the relationship between these events is unclear. Here, we address this question using a transdifferentiated neuron (tNeuron) model directly from human dermal fibroblasts.

Proteostasis and lysosomal repair deficits in transdifferentiated neurons of Alzheimer's disease.

Aging is the most prominent risk factor for Alzheimer's disease (AD). However, the cellular mechanisms linking neuronal proteostasis decline to the characteristic aberrant protein deposits in AD brains remain elusive. Here, we develop transdifferentiated neurons (tNeurons) from human dermal fibroblasts as a neuronal model that retains aging hallmarks and exhibits AD-linked vulnerabilities.

A constant pressure flowmeter for extreme-high vacuum.

We demonstrate operation of a constant-pressure flowmeter capable of generating and accurately measuring flows as low as 2 × 10 mol/s. Generation of such small flows is accomplished by using a small conductance element with ≈ 50 nL/s. Accurate measurement then requires both low outgassing materials (< 1 × 10 mol/s) and small volume changes (≈ 70 L).

Small molecule C381 targets the lysosome to reduce inflammation and ameliorate disease in models of neurodegeneration.

SignificanceNeurodegenerative diseases are poorly understood and difficult to treat. One common hallmark is lysosomal dysfunction leading to the accumulation of aggregates and other undegradable materials, which cause damage to brain resident cells. Lysosomes are acidic organelles responsible for breaking down biomolecules and recycling their constitutive parts.

A human brain vascular atlas reveals diverse mediators of Alzheimer's risk.

The human brain vasculature is of great medical importance: its dysfunction causes disability and death, and the specialized structure it forms-the blood-brain barrier-impedes the treatment of nearly all brain disorders. Yet so far, we have no molecular map of the human brain vasculature. Here we develop vessel isolation and nuclei extraction for sequencing (VINE-seq) to profile the major vascular and perivascular cell types of the human brain through 143,793 single-nucleus transcriptomes from 25 hippocampus and cortex samples of 9 individuals with Alzheimer's disease and 8 individuals with no cognitive impairment.

Exercise plasma boosts memory and dampens brain inflammation via clusterin.

Physical exercise is generally beneficial to all aspects of human and animal health, slowing cognitive ageing and neurodegeneration. The cognitive benefits of physical exercise are tied to an increased plasticity and reduced inflammation within the hippocampus, yet little is known about the factors and mechanisms that mediate these effects. Here we show that 'runner plasma', collected from voluntarily running mice and infused into sedentary mice, reduces baseline neuroinflammatory gene expression and experimentally induced brain inflammation.

Dysregulation of brain and choroid plexus cell types in severe COVID-19.

Although SARS-CoV-2 primarily targets the respiratory system, patients with and survivors of COVID-19 can suffer neurological symptoms. However, an unbiased understanding of the cellular and molecular processes that are affected in the brains of patients with COVID-19 is missing. Here we profile 65,309 single-nucleus transcriptomes from 30 frontal cortex and choroid plexus samples across 14 control individuals (including 1 patient with terminal influenza) and 8 patients with COVID-19.

Eliminating the middleman: ultraviolet scale realization using a laser-driven plasma light source.

After we replaced the argon mini-arc with a laser-driven light source in the Ultraviolet Spectral Comparator Facility at the National Institute of Standards and Technology (NIST), we realized that the optical power should be sufficient to use the comparator system for absolute-cryogenic radiometry. Calibrating working standard detectors directly against an absolute-cryogenic radiometer in the system used for calibrations would eliminate all uncertainties resulting from the use of transfer standards, which were calibrated in a separate system using a different light source and optics. The transfer standards are the middlemen we refer to in the title.

CoolMPS for robust sequencing of single-nuclear RNAs captured by droplet-based method.

Massively-parallel single-cell and single-nucleus RNA sequencing (scRNA-seq, snRNA-seq) requires extensive sequencing to achieve proper per-cell coverage, making sequencing resources and availability of sequencers critical factors for conducting deep transcriptional profiling. CoolMPS is a novel sequencing-by-synthesis approach that relies on nucleotide labeling by re-usable antibodies, but whether it is applicable to snRNA-seq has not been tested. Here, we use a low-cost and off-the-shelf protocol to chemically convert libraries generated with the widely-used Chromium 10X technology to be sequenceable with CoolMPS technology.

Physiological blood-brain transport is impaired with age by a shift in transcytosis.

The vascular interface of the brain, known as the blood-brain barrier (BBB), is understood to maintain brain function in part via its low transcellular permeability. Yet, recent studies have demonstrated that brain ageing is sensitive to circulatory proteins. Thus, it is unclear whether permeability to individually injected exogenous tracers-as is standard in BBB studies-fully represents blood-to-brain transport.

Extreme ultraviolet photon conversion efficiency of tetraphenyl butadiene.

Extreme ultraviolet (EUV) radiation can be converted to visible light using tetraphenyl butadiene (TPB) as a phosphor. 1 µm films of TPB were prepared using thermal vapor deposition of the pure material and by spin coating suspensions of TPB in high-molecular-weight polystyrene/toluene solutions. Calibrated sources and detectors were used to determine the effective photon conversion efficiency of the films for incident EUV radiation in the wavelength range of $125\;{\rm nm}\le\lambda\le 200\;{\rm nm}$125nm≤λ≤200nm.

Activation of the STING-Dependent Type I Interferon Response Reduces Microglial Reactivity and Neuroinflammation.

Brain aging and neurodegeneration are associated with prominent microglial reactivity and activation of innate immune response pathways, commonly referred to as neuroinflammation. One such pathway, the type I interferon response, recognizes viral or mitochondrial DNA in the cytoplasm via activation of the recently discovered cyclic dinucleotide synthetase cGAS and the cyclic dinucleotide receptor STING. Here we show that the FDA-approved antiviral drug ganciclovir (GCV) induces a type I interferon response independent of its canonical thymidine kinase target.

Broadband Radiometric LED Measurements.

At present, broadband radiometric measurements of LEDs with uniform and low-uncertainty results are not available. Currently, either complicated and expensive spectral radiometric measurements or broadband photometric LED measurements are used. The broadband photometric measurements are based on the CIE standardized V(λ) function, which cannot be used in the UV range and leads to large errors when blue or red LEDs are measured in its wings, where the realization is always poor.

High-resolution, vacuum-ultraviolet absorption spectrum of boron trifluoride.

In the course of investigations of thermal neutron detection based on mixtures of (10)BF3 with other gases, knowledge was required of the photoabsorption cross sections of (10)BF3 for wavelengths between 135 and 205 nm. Large discrepancies in the values reported in existing literature led to the absolute measurements reported in this communication. The measurements were made at the SURF III Synchrotron Ultraviolet Radiation Facility at the National Institute of Standards and Technology.

Hybrid simulation improves medical student procedural confidence during EM clerkship.

Background: Medical students have limited opportunities to perform and learn procedures on live patients. This is particularly concerning at the Uniformed Services University of the Health Sciences (USUHS), where graduates may be assigned to an operational military unit immediately following completion of internship. The authors implemented a new hybrid simulation lab for fourth-year medical students at the Uniformed Services University of the Health Sciences consisting of procedural skills training for seven core emergency medicine skills combined with complex patient cases using high fidelity simulators and standardized patients.

Argon mini-arc meets its match: use of a laser-driven plasma source in ultraviolet-detector calibrations.

The National Institute of Standards and Technology operates two spectral comparator facilities, both of which are used to provide detector calibrations from the ultraviolet to the near-infrared spectral range. One, the Ultraviolet Spectral Comparator Facility (UV SCF), has been in operation for more than two decades, providing one of the core calibration services. Recently, the illumination source used in the UV SCF has been changed from an argon mini-arc source to a laser-driven plasma light source.

Selective androgen receptor modulator RAD140 is neuroprotective in cultured neurons and kainate-lesioned male rats.

The decline in testosterone levels in men during normal aging increases risks of dysfunction and disease in androgen-responsive tissues, including brain. The use of testosterone therapy has the potential to increase the risks for developing prostate cancer and or accelerating its progression. To overcome this limitation, novel compounds termed "selective androgen receptor modulators" (SARMs) have been developed that lack significant androgen action in prostate but exert agonist effects in select androgen-responsive tissues.

New Wide Area Virtual Environment (WAVE) medical education.

Objective: Accomplish the first large-scale combat casualty training using multiple-modality hybrid simulation in the Uniformed Services University's one-of-a-kind three-dimensional Wide Area Virtual Environment (WAVE).

Methods: 91 first-year medical students (MS1) completed a WAVE training session as part of their Combat Medical Skills course. In teams of 6 students, they treated two combat casualties with blast wounds (one a SimMan 3G, and another a standardized patient) during15-minute scenarios in the WAVE.

Sex stratified neuronal cultures to study ischemic cell death pathways.

Sex differences in neuronal susceptibility to ischemic injury and neurodegenerative disease have long been observed, but the signaling mechanisms responsible for those differences remain unclear. Primary disassociated embryonic neuronal culture provides a simplified experimental model with which to investigate the neuronal cell signaling involved in cell death as a result of ischemia or disease; however, most neuronal cultures used in research today are mixed sex. Researchers can and do test the effects of sex steroid treatment in mixed sex neuronal cultures in models of neuronal injury and disease, but accumulating evidence suggests that the female brain responds to androgens, estrogens, and progesterone differently than the male brain.

Mechanisms of hemolysis-associated platelet activation.

Background: Intravascular hemolysis occurs after blood transfusion, in hemolytic anemias, and in other conditions, and is associated with hypercoagulable states. Hemolysis has been shown to potently activate platelets in vitro and in vivo, and several mechanisms have been suggested to account for this, including: (i) direct activation by hemoglobin (Hb); (ii) increase in reactive oxygen species (ROS); (iii) scavenging of nitric oxide (NO) by released Hb; and (iv) release of intraerythrocytic ADP.

Objective: To elucidate the mechanism of hemolysis-mediated platelet activation.

Sexually dimorphic response of TRPM2 inhibition following cardiac arrest-induced global cerebral ischemia in mice.

Transient global cerebral ischemia due to cardiac arrest followed by resuscitation (CA/CPR) causes significant neurological damage in vulnerable neuron populations within the brain, such as hippocampal CA1 neurons. In recent years, we have implicated the transient receptor potential M2 (TRPM2) channel as a mediator of ischemic injury to neurons. We previously demonstrated that genetic and pharmacological strategies that reduce TRPM2 function preferentially protect male neurons in vitro and reduce infarct volume following experimental stroke.

Angiotensin receptor type 1 single nucleotide polymorphism 1166A/C is associated with malignant arrhythmias and altered circulating miR-155 levels in patients with chronic heart failure.

Background: Sudden cardiac death (SCD) from ventricular tachyarrhythmias accounts for approximately 450,000 annual deaths in the United States; many of these cases involve patients with chronic heart failure (HF). Prediction of which HF patients are most susceptible to SCD is difficult, and it is uncertain whether gene polymorphisms associated with HF outcomes are also linked to arrhythmic risk.

Methods: We evaluated 485 patients with chronic HF to see whether the angiotensin receptor type 1 (AT1R) 1166A/C or angiotensin-converting enzyme insertion/deletion (ACE I/D) polymorphisms were associated with a higher rate of ventricular arrhythmias requiring implantable cardioverter defibrillator (ICD) therapies over a 5-year period.