Mcfaddentrue2675

Ultra-slow, ∼0.1-Hz variations in the oxygenation level of brain blood are widely used as an fMRI-based surrogate of "resting-state" neuronal activity. The temporal correlations among these fluctuations across the brain are interpreted as "functional connections" for maps and neurological diagnostics. Ultra-slow variations in oxygenation follow a cascade. First, they closely track changes in arteriole diameter. Second, interpretable functional connections arise when the ultra-slow changes in amplitude of γ-band neuronal oscillations, which are shared across even far-flung but synaptically connected brain regions, entrain the ∼0.1-Hz vasomotor oscillation in diameter of local arterioles. Significant confounds to estimates of functional connectivity arise from residual vasomotor activity as well as arteriole dynamics driven by self-generated movements and subcortical common modulatory inputs. Last, methodological limitations of fMRI can lead to spurious functional connections. The neuronal generator of ultra-slow variations in γ-band amplitude, including that associated with self-generated movements, remains an open issue.The neuroanatomical basis behind acupuncture practice is still poorly understood. Here, we used intersectional genetic strategy to ablate NPY+ noradrenergic neurons and/or adrenal chromaffin cells. Using endotoxin-induced systemic inflammation as a model, we found that electroacupuncture stimulation (ES) drives sympathetic pathways in somatotopy- and intensity-dependent manners. Low-intensity ES at hindlimb regions drives the vagal-adrenal axis, producing anti-inflammatory effects that depend on NPY+ adrenal chromaffin cells. High-intensity ES at the abdomen activates NPY+ splenic noradrenergic neurons via the spinal-sympathetic axis; these neurons engage incoherent feedforward regulatory loops via activation of distinct adrenergic receptors (ARs), and their ES-evoked activation produces either anti- or pro-inflammatory effects due to disease-state-dependent changes in AR profiles. The revelation of somatotopic organization and intensity dependency in driving distinct autonomic pathways could form a road map for optimizing stimulation parameters to improve both efficacy and safety in using acupuncture as a therapeutic modality.The SARS-CoV-2 pandemic has resulted in millions of infections, yet the role of host immune responses in early COVID-19 pathogenesis remains unclear. By investigating 17 acute and 24 convalescent patients, we found that acute SARS-CoV-2 infection resulted in broad immune cell reduction including T, natural killer, monocyte, and dendritic cells (DCs). DCs were significantly reduced with functional impairment, and ratios of conventional DCs to plasmacytoid DCs were increased among acute severe patients. Besides lymphocytopenia, although neutralizing antibodies were rapidly and abundantly generated in patients, there were delayed receptor binding domain (RBD)- and nucleocapsid protein (NP)-specific T cell responses during the first 3 weeks after symptoms onset. Moreover, acute RBD- and NP-specific T cell responses included relatively more CD4 T cells than CD8 T cells. Our findings provided evidence that impaired DCs, together with timely inverted strong antibody but weak CD8 T cell responses, could contribute to acute COVID-19 pathogenesis and have implications for vaccine development.Multiple morphological abnormalities of the sperm flagella (MMAF) is a severe form of asthenoteratozoospermia. Although recent studies have revealed several MMAF-associated genes and demonstrated MMAF to be a genetically heterogeneous disease, at least one-third of the cases are still not well understood for their etiology. Here, we identified bi-allelic loss-of-function variants in CFAP58 by using whole-exome sequencing in five (5.6%) unrelated individuals from a cohort of 90 MMAF-affected Chinese men. Each of the men harboring bi-allelic CFAP58 variants presented typical MMAF phenotypes. Transmission electron microscopy demonstrated striking flagellar defects with axonemal and mitochondrial sheath malformations. CFAP58 is predominantly expressed in the testis and encodes a cilia- and flagella-associated protein. Immunofluorescence assays showed that CFAP58 localized at the entire flagella of control sperm and predominantly concentrated in the mid-piece. Immunoblotting and immunofluorescence assays showed that the abundances of axoneme ultrastructure markers SPAG6 and SPEF2 and a mitochondrial sheath protein, HSP60, were significantly reduced in the spermatozoa from men harboring bi-allelic CFAP58 variants. We generated Cfap58-knockout mice via CRISPR/Cas9 technology. The male mice were infertile and presented with severe flagellar defects, consistent with the sperm phenotypes in MMAF-affected men. Overall, our findings in humans and mice strongly suggest that CFAP58 plays a vital role in sperm flagellogenesis and demonstrate that bi-allelic loss-of-function variants in CFAP58 can cause axoneme and peri-axoneme malformations leading to male infertility. This study provides crucial insights for understanding and counseling of MMAF-associated asthenoteratozoospermia.

Although many people who use drugs meet criteria for vaccination against hepatitis A virus (HAV) and hepatitis B virus (HBV), estimates of susceptibility (ie, lack of immunity) are not well established. This study sought to identify the prevalence of and characteristics associated with HAV and HBV susceptibility among people who use drugs attending an urban syringe services program.

We initiated this seroprevalence study in 2018 among 438 clients of a syringe services program who met study criteria, including provision of a blood specimen and a self-reported history of drug use. We assessed HAV and HBV susceptibility and infection via serological testing. We examined associations between participant characteristics and serology status by using descriptive statistics and multivariable logistic regression models.

Of the initial 438 clients identified, 353 (80.6%) met study criteria. Of 352 participants with conclusive HAV test results, 48.6% (n = 171) were HAV susceptible; of 337 participants with conclus who use drugs. These findings highlight the need for increased HAV and HBV vaccination efforts among people who use drugs.This paper investigated a 60-item version of the Multidimensional Inventory of Dissociation (MID) with the potential to capture the full range of dissociative symptoms that characterize each of the dissociative disorders (DD). The 28-item Dissociative Experiences Scale (DES) was designed to capture a wide range of dissociative phenomena, but college population studies indicate it may not be adept at identifying the full range of dissociative symptoms and disorders. The 218-item MID has the advantage of capturing the full range of dissociative symptoms and has diagnostic capabilities for all DSM-5 DD, but the disadvantage of taking considerably longer than the DES to complete. Using university students and staff (N = 313), this paper investigated a 60-item version of the MID with the potential to capture the full range of dissociative symptoms that characterize each of the DD. Results indicate the MID-60 has a nearly identical factor structure to the full MID, excellent internal reliability, and content and convergent validity. Using the MID-60, at least 8% of participants at an Australian university were positive for a DD and, on average, participants self-reported having dissociative experiences 13% of the time. The present study's findings suggest the MID-60 is a promising alternative to the DES, with results about the prevalence of DDs and dissociative experiences consistent with those found using clinical interviews and the DES.

To study the environmental radiation effects of wild animals after the Fukushima Dai-ichi nuclear power plant accident, we assessed effects on hematopoietic progenitor cells (HPCs) in large Japanese field mice (

).

A. MDL-800 clinical trial speciosus were collected from three contaminated sites and control area. The air dose-rates at the control and contaminated areas were 0.96 ± 0.05 μGy/d (Hirosaki), 14.4 ± 2.4 μGy/d (Tanashio), 208.8 ± 31.2 μGy/d (Ide), 470.4 ± 93.6 μGy/d (Omaru), respectively. We investigated possible DNA damage and pro-inflammatory markers in the bone marrow (BM) cells. The colony-forming potential of BM cells was estimated by the number of HPC colony-forming cells. Radiation-induced genomic instability (RIGI) in HPCs was also analyzed by quantifying delayed DNA damage in CFU-GM clones.

Although no significant differences in DNA damage and inflammation markers in BM cells from control and contaminated areas, the number of HPC colonies exhibited an inverse correlation with air dose-rate. With regard to RIGI, no significant differences in DNA damage of CFU-GM clones between the mice from the control and the three contaminated areas.

Our study suggests that low dose-rate radiation of more than 200 Gy/d reduced HPCs, possibly eliminating genomically unstable HPCs.

Our study suggests that low dose-rate radiation of more than 200 Gy/d reduced HPCs, possibly eliminating genomically unstable HPCs.The Chemohormonal Therapy vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer (CHAARTED) was a randomized phase III trial that evaluated the outcomes of men with metastatic prostate cancer who received castration with or without docetaxel. Patients from this trial were genotyped in a recent study to detect HSD3B1 variance and to determine 2-y freedom from castration-resistant prostate cancer as well as overall survival. The results of this study identified HSD3B1 as a possible biomarker that can be used to predict response to therapy in patients with metastatic disease.Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of cardiovascular death and hospitalization for heart failure in patients with chronic heart failure. Initially, these drugs were believed to have a profile similar to diuretics or hemodynamically active drugs, but they do not rapidly reduce natriuretic peptides or cardiac filling pressures, and they exert little early benefit on symptoms, exercise tolerance, quality of life, or signs of congestion. Clinically, the profile of SGLT2 inhibitors resembles that of neurohormonal antagonists, whose benefits emerge gradually during sustained therapy. In experimental models, SGLT2 inhibitors produce a characteristic pattern of cellular effects, which includes amelioration of oxidative stress, mitigation of mitochondrial dysfunction, attenuation of proinflammatory pathways, and a reduction in myocardial fibrosis. These cellular effects are similar to those produced by angiotensin converting enzyme inhibitors, β-blockers, mineralocorticoid receptor antagonists, and neprilysin inhibitors. At a molecular level, SGLT2 inhibitors induce transcriptional reprogramming of cardiomyocytes that closely mimics that seen during nutrient deprivation. This shift in signaling activates the housekeeping pathway of autophagy, which clears the cytosol of dangerous cytosolic constituents that are responsible for cellular stress, thereby ameliorating the development of cardiomyopathy. Interestingly, similar changes in cellular signaling and autophagic flux have been seen with inhibitors of the renin-angiotensin system, β-blockers, mineralocorticoid receptor antagonists, and neprilysin inhibitors. The striking parallelism of these molecular, cellular, and clinical profiles supports the premise that SGLT2 inhibitors should be regarded as neurohormonal antagonists when prescribed for the treatment of heart failure with a reduced ejection fraction.