Prenatal Maternal Psychological Distress During the COVID-19 Pandemic and Newborn Brain Development.

Importance: Elevated maternal psychological distress during pregnancy is associated with altered fetal brain development. During the COVID-19 pandemic, prenatal maternal psychological distress more than doubled. Objective: To examine the association of the pandemic and rising maternal psychological distress with brain growth in newborns using quantitative 3-dimensional volumetric magnetic resonance imaging (MRI). Design, Setting, and Participants: This prospective cross-sectional study recruited mother-infant dyads at Children's National Hospital, Washington, DC, during the COVID-19 pandemic (June 1, 2020, to June 30, 2022) into a longitudinal infant brain development study and compared them with an existing normative healthy cohort (recruited March 1, 2014, to December 31, 2019). Exclusion criteria included multiple gestation pregnancy, known or suspected congenital infection, documented chromosomal abnormalities, or any maternal contraindication to MRI, as well as prenatal COVID-19 exposure. Infants with structural brain abnormalities or a postnatal confirmation of a genetic syndrome were excluded. Exposure: Psychological distress during COVID-19 pandemic. Main Outcomes and Measures: Prenatal maternal mental health was evaluated using the Spielberger State-Trait Anxiety Inventory and the Perceived Stress Scale. Neonates underwent nonsedated brain MRI. An ordinary least squares linear regression model was used to measure the differences in regional brain volumes of neonates born before vs during the pandemic with and without exposure to elevated prenatal maternal psychological distress after adjustment for neonatal sex and gestational age at MRI and maternal age and educational level. Results: A total of 159 mother-infant dyads were included in the analysis: 103 before and 56 during the pandemic (median gestational age of infants, 39.6 [IQR, 38.4-40.4] weeks; median maternal age, 34.5 [IQR, 31.0-37.0] years). Eighty-three infants (52.2%) were female. Among the mothers, 130 (81.8%) had a college degree and 87 (54.7%) had a graduate degree. Forty-four mothers (27.7%) identified as Asian, Hispanic, or multiracial; 27 (17.0%), as Black; and 88 (55.3%), as White. Scores on anxiety and stress measures were significantly increased in the pandemic cohort. Infants of mothers with elevated maternal distress showed median reductions in white matter (-0.36 [95% CI, -0.61 to -0.11] cm3; Q < .001), right hippocampal (-0.35 [95% CI, -0.65 to -0.06] cm3; Q = .04), and left amygdala (-0.49 [95% CI, -0.84 to -0.13] cm3; Q = .03) volumes compared with infants of mothers with low distress levels. After adjusting for the cohort effect of the pandemic, elevated trait anxiety remained significantly associated with decreased left amygdalar volumes (-0.71 [95% CI, -1.12 to -0.29]; Q < .001). Conclusions and Relevance: In this cross-sectional study of maternal-infant dyads prior to and during the COVID-19 pandemic, regional neonatal brain volumes were associated with elevated maternal psychological distress.

Interruption of Endolysosomal Trafficking After Focal Brain Ischemia.

A typical neuron consists of a soma, a single axon with numerous nerve terminals, and multiple dendritic trunks with numerous branches. Each of the 100 billion neurons in the brain has on average 7,000 synaptic connections to other neurons. The neuronal endolysosomal compartments for the degradation of axonal and dendritic waste are located in the soma region. That means that all autophagosomal and endosomal cargos from 7,000 synaptic connections must be transported to the soma region for degradation. For that reason, neuronal endolysosomal degradation is an extraordinarily demanding and dynamic event, and thus is highly susceptible to many pathological conditions. Dysfunction in the endolysosomal trafficking pathways occurs in virtually all neurodegenerative diseases. Most lysosomal storage disorders (LSDs) with defects in the endolysosomal system preferentially affect the central nervous system (CNS). Recently, significant progress has been made in understanding the role that the endolysosomal trafficking pathways play after brain ischemia. Brain ischemia damages the membrane fusion machinery co-operated by N-ethylmaleimide sensitive factor (NSF), soluble NSF attachment protein (SNAP), and soluble NSF attachment protein receptors (SNAREs), thus interrupting the membrane-to-membrane fusion between the late endosome and terminal lysosome. This interruption obstructs all incoming traffic. Consequently, both the size and number of endolysosomal structures, autophagosomes, early endosomes, and intra-neuronal protein aggregates are increased extensively in post-ischemic neurons. This cascade of events eventually damages the endolysosomal structures to release hydrolases leading to ischemic brain injury. Gene knockout and selective inhibition of key endolysosomal cathepsins protects the brain from ischemic injury. This review aims to provide an update of the current knowledge, future research directions, and the clinical implications regarding the critical role of the neuronal endolysosomal trafficking pathways in ischemic brain injury.

Interruption of endolysosomal trafficking leads to stroke brain injury.

BACKGROUND AND PURPOSE: Dysfunction of the endolysosomal system can cause cell death. A key molecule for controlling the endolysosomal trafficking activities is the N-ethylmaleimide-sensitive factor (NSF) ATPase. This study investigates the cascades of NSF ATPase inactivation events, endolysosomal damage, cathepsin release, and neuronal death after focal brain ischemia. METHODS: A total of 62 rats were used in this study. They were subjected to sham surgery or 2 h of focal brain ischemia followed by 1, 4, and 24 h of reperfusion. Confocal microscopy and Western blot analysis were utilized to analyze the levels, redistribution, and co-localization of key proteins of the Golgi apparatus, late endosomes, endolysosomes, and lysosomes. Light and electron microscopy were used to examine the histopathology, protein aggregation, and endolysosomal ultrastructures. RESULTS: Two hours of focal brain ischemia in rats led to acute neuronal death at the striatal core in 4 h and a slower type of neuronal death in the neocortical area during 1-24 h reperfusion periods. Confocal microscopy showed that NSF immunoreactivity was irreversibly and selectively depleted from most, if not all, post-ischemic penumbral neurons. Western blot analysis further demonstrated that NSF depletion from brain sections was due to its deposition into dense inactive aggregates that could not be recognized by the NSF antibody. Commitantly, the Golgi apparatus was completely fragmented and cathepsin B (CTSB)-containing endolysosomal structures, as well as p62/SQSTM1- and EEA1-immunopositive structures were massively accumulated in the post-ischemic penumbral neurons. Ultimately, CTSB was released into the cytoplasm and extracellular space, causing stroke brain injury. CONCLUSION: Stroke Inactivates NSF, resulting in disruption of the reforming of functional endolysosomal compartments, blockade of the endocytic and autophagic pathways, a large scale of CTSB release into the cytoplasm and extracellular space, and stroke brain injury in the rat model.

Eradication and Sensitization of Methicillin Resistant Staphylococcus aureus to Methicillin with Bioactive Extracts of Berry Pomace.

The therapeutic roles of phenolic blueberry (Vaccinium corymbosum) and blackberry (Rubus fruticosus) pomace (commercial byproduct) extracts (BPE) and their mechanism of actions were evaluated against methicillin resistant Staphylococcus aureus (MRSA). Five major phenolic acids of BPE, e.g., protocatechuic, p. coumaric, vanillic, caffeic, and gallic acids, as well as crude BPE completely inhibited the growth of vegetative MRSA in vitro while BPE+methicillin significantly reduced MRSA biofilm formation on plastic surface. In addition, BPE restored the effectiveness of methicillin against MRSA by down-regulating the expression of methicillin resistance (mecA) and efflux pump (norA, norB, norC, mdeA, sdrM, and sepA) genes. Antibiogram with broth microdilution method showed that MIC of methicillin reduced from 512 µg/mL to 4 µg/mL when combined with only 200 µg Gallic Acid Equivalent (GAE)/mL of BPE. Significant reduction in MRSA adherence to and invasion into human skin keratinocyte Hek001 cells were also noticed in the presence of BPE. BPE induced anti-apoptosis and anti-autophagy pathways through overexpression of Bcl-2 gene and down-regulation of TRADD and Bax genes (inducers of apoptosis pathway) in Hek001 cells. In summary, novel and sustainable prophylactic therapy can be developed with BPE in combination with currently available antibiotics, especially methicillin, against skin and soft tissue infections with MRSA.