A Stress Reduction Intervention for Lactating Mothers Alters Maternal Gut, Breast Milk, and Infant Gut Microbiomes: Data from a Randomized Controlled Trial.

BACKGROUND: This secondary analysis of data from a randomized controlled trial (RCT) investigated how the maternal gut, breast milk, and infant gut microbiomes may contribute to the effects of a relaxation intervention, which reduced maternal stress and promoted infant weight gain. METHODS: An RCT was undertaken in healthy Chinese primiparous mother-infant pairs (340/7-376/7gestation weeks). Mothers were randomly allocated to either the intervention group (IG, listening to relaxation meditation) or the control group (CG). Outcomes were the differences in microbiome composition and the diversity in the maternal gut, breast milk, and infant gut at 1 (baseline) and 8 weeks (post-intervention) between IG and CG, assessed using 16S rRNA gene amplicon sequencing of fecal and breastmilk samples. RESULTS: In total, 38 mother-infant pairs were included in this analysis (IG = 19, CG = 19). The overall microbiome community structure in the maternal gut was significantly different between the IG and CG at 1 week, with the difference being more significant at 8 weeks (Bray-Curtis distance R2 = 0.04 vs. R2 = 0.13). Post-intervention, a significantly lower α-diversity was observed in IG breast milk (observed features: CG = 295 vs. IG = 255, p = 0.032); the Bifidobacterium genera presented a higher relative abundance. A significantly higher α-diversity was observed in IG infant gut (observed features: CG = 73 vs. IG = 113, p < 0.001). CONCLUSIONS: The findings were consistent with the hypothesis that the microbiome might mediate observed relaxation intervention effects via gut-brain axis and entero-mammary pathways; but confirmation is required.

Role of Microglia, Decreased Neurogenesis and Oligodendrocyte Depletion in Long COVID-Mediated Brain Impairments.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of a recent worldwide coronavirus disease-2019 (COVID-19) pandemic. SARS-CoV-2 primarily causes an acute respiratory infection but can progress into significant neurological complications in some. Moreover, patients with severe acute COVID-19 could develop debilitating long-term sequela. Long-COVID is characterized by chronic symptoms that persist months after the initial infection. Common complaints are fatigue, myalgias, depression, anxiety, and "brain fog," or cognitive and memory impairments. A recent study demonstrated that a mild COVID-19 respiratory infection could generate elevated proinflammatory cytokines and chemokines in the cerebral spinal fluid. This commentary discusses findings from this study, demonstrating that even a mild respiratory SARS-CoV-2 infection can cause considerable neuroinflammation with microglial and macrophage reactivity. Such changes could also be gleaned by measuring chemokines and cytokines in the circulating blood. Moreover, neuroinflammation caused by mild SARS-CoV-2 infection can also impair hippocampal neurogenesis, deplete oligodendrocytes, and decrease myelinated axons. All these changes likely contribute to cognitive deficits in long-COVID syndrome. Therefore, strategies capable of restraining neuroinflammation, maintaining better hippocampal neurogenesis, and preserving oligodendrocyte lineage differentiation and maturation may prevent or reduce the incidence of long-COVID after SARS-CoV-2 respiratory infection.

Complications of COVID-19 on the Central Nervous System: Mechanisms and Potential Treatment for Easing Long COVID.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) invades human cells by binding to the angiotensin-converting-enzyme-2 (ACE-2) using a spike protein and leads to Coronavirus disease-2019 (COVID-19). COVID-19 primarily causes a respiratory infection that can lead to severe systemic inflammation. It is also common for some patients to develop significant neurological and psychiatric symptoms. The spread of SARS-CoV-2 to the CNS likely occurs through several pathways. Once spread in the CNS, many acute symptoms emerge, and such infections could also transpire into severe neurological complications, including encephalitis or ischemic stroke. After recovery from the acute infection, a significant percentage of patients develop "long COVID," a condition in which several symptoms of COVID-19 persist for prolonged periods. This review aims to discuss acute and chronic neurological problems after SARS-CoV-2 infection. The potential mechanisms by which SARS-CoV-2 enters the CNS and causes neuroinflammation, neuropathological changes observed in post-mortem brains of COVID-19 patients, and cognitive and mood problems in COVID-19 survivors are discussed in the initial part. The later part of the review deliberates the causes of long COVID, approaches for noninvasive tracking of neuroinflammation in long COVID patients, and the potential therapeutic strategies that could ease enduring CNS symptoms observed in long COVID.

Determinants of infant behavior and growth in breastfed late preterm and early term infants: a secondary data analysis.

BACKGROUND: Late preterm and early term infants are at increased risk of poor growth, behavioral problems, and developmental delays. This study aimed to investigate the impact of maternal and infant characteristics, feeding practices, and breastmilk composition on infant behavior following late preterm and early term delivery, and to evaluate the association between infant behavior and growth. METHODS: Data from 52 Chinese mothers and their late preterm/early term infants participating in the Breastfeed a Better Youngster study were used. Maternal and infant characteristics were collected using questionnaires at 1 week postpartum. Breastmilk macronutrient content was measured using a human milk analyzer, and infant behavior was assessed using a 3-day infant behavior diary at 8 weeks postpartum. Feeding practices were collected at both time points using questionnaires. Multivariate models were used to assess associations between potential predictors and infant behavior and between infant behavior and growth. RESULTS: Exclusive breastfeeding was associated with greater sleep duration (P = 0.02) and shorter crying duration (P = 0.01). Mothers with a vocational education reported greater distress duration (P = 0.006). Greater colic duration was associated with higher maternal annual income (P = 0.004). There was no significant association between infant behavior and growth (all P > 0.05). CONCLUSIONS: Exclusive breastfeeding might promote more favorable infant behaviors in late preterm/early term infants, while the development of infant distress behaviors was associated with some maternal characteristics (maternal education and annual income). However, due to the limitations of diary methods, determinants of infant behavior should ideally be assessed using more objective measures in larger samples.

Effects of relaxation therapy on maternal psychological status and infant growth following late preterm and early-term delivery: a randomized controlled trial.

BACKGROUND: Maternal stress is one modifiable variable that could influence mother-infant signaling and negatively affect breastfeeding and infant growth. OBJECTIVES: This study aimed to test the hypothesis that relaxation therapy would reduce maternal stress and improve infant growth, behavior, and breastfeeding outcomes after late preterm (LP) and early-term (ET) delivery. METHODS: A single-blind randomized controlled trial was conducted in healthy Chinese primiparous mother-infant pairs after LP or ET delivery (34+0-37+6 gestation weeks). Mothers were randomly assigned to the intervention group (IG, listening to relaxation meditation at least once a day) or control group (CG, normal care). Primary outcomes-changes in maternal stress (perceived stress scale), anxiety (Beck Anxiety Inventory), and infant weight and length standard deviation score-were assessed at 1 wk and 8 wks postpartum. Secondary outcomes-breast milk energy and macronutrient composition, maternal breastfeeding attitudes, infant behaviors (3-d diary), and 24-hour milk intake-were assessed at 8 wks. RESULTS: In total, 96 mother-infant pairs were recruited. There was a significantly greater reduction in maternal perceived stress (Perceived Stress Scale score) (mean difference [MD] = 2.65; 95% CI: 0.8, 4.5) and significantly greater infant weight standard deviation score gain (MD = 0.51; 95% CI: 0.2, 0.9) from 1 wk to 8 wks in the IG than those in the CG. Exploratory analyses showed a significant interaction between intervention and sex, with greater effects on weight gain in female infants. Mothers of female infants used the intervention more frequently with significantly higher milk energy observed at 8 wks. CONCLUSIONS: The relaxation meditation tape is a simple, effective practical tool that could easily be used in clinical settings to support breastfeeding mothers after LP and ET delivery. The findings need confirmation in larger groups and in other populations.

Three-dimensional structured illumination microscopy with enhanced axial resolution.

The axial resolution of three-dimensional structured illumination microscopy (3D SIM) is limited to ∼300 nm. Here we present two distinct, complementary methods to improve axial resolution in 3D SIM with minimal or no modification to the optical system. We show that placing a mirror directly opposite the sample enables four-beam interference with higher spatial frequency content than 3D SIM illumination, offering near-isotropic imaging with ∼120-nm lateral and 160-nm axial resolution. We also developed a deep learning method achieving ∼120-nm isotropic resolution. This method can be combined with denoising to facilitate volumetric imaging spanning dozens of timepoints. We demonstrate the potential of these advances by imaging a variety of cellular samples, delineating the nanoscale distribution of vimentin and microtubule filaments, observing the relative positions of caveolar coat proteins and lysosomal markers and visualizing cytoskeletal dynamics within T cells in the early stages of immune synapse formation.

Diagnosis, treatment, and prevention of monkeypox in children: an experts' consensus statement.

Monkeypox is a zoonotic disease. Since the first human monkeypox case was detected in 1970, it has been prevalent in some countries in central and western Africa. Since May 2022, monkeypox cases have been reported in more than 96 non-endemic countries and regions worldwide. As of September 14, 2022, there have been more than 58,200 human monkeypox cases, and there is community transmission. The cessation of smallpox vaccination in 1980, which had some cross-protection with monkeypox, resulted in a general lack of immunity to monkeypox, which caused global concern and vigilance. As of September 14, 2022, there are four monkeypox cases in China, including three in Taiwan province and one in Hong Kong city. Previous foreign studies have shown that children are vulnerable to monkeypox and are also at high risk for severe disease or complications. In order to improve pediatricians' understanding of monkeypox and achieve early detection, early diagnosis, early treatment,  and early disposal, we have organized national authoritative experts in pediatric infection, respiratory, dermatology, critical care medicine, infectious diseases, and public health and others to formulate this expert consensus, on the basis of the latest "Clinical management and infection prevention and control for monkeypox" released by The World Health Organization, the "guidelines for diagnosis and treatment of monkeypox (version 2022)" issued by National Health Commission of the People's Republic of China and other relevant documents. During the development of this consensus, multidisciplinary experts have repeatedly demonstrated the etiology, epidemiology, transmission, clinical manifestations, laboratory examinations, diagnosis, differential diagnosis, treatment, discharge criteria, prevention, disposal process, and key points of prevention and control of suspected and confirmed cases.

A compendium of co-regulated mitoribosomal proteins in pan-cancer uncovers collateral defective events in tumor malignancy.

Mitochondria are major organelles responsible for cellular energy and metabolism, and their dysfunction is tightly linked to cancer. The mitochondrial ribosome (mitoribosome) is a protein complex consisting of 82 mitoribosomal proteins (MRPs) encoded by nuclear genes and is essential for mitochondrial protein synthesis. However, their roles in tumorigenesis remain poorly understood. We performed pan-cancer analyses of 18,177 tumors representing 28 cancer types to determine somatic alterations of MRP genes as a genetic basis for tumorigenesis. We identified a set of 20 altered MRPs known to be involved in early assembly of the mitoribosome complex. We found that tumors with affected MRPs were associated with impaired mitochondrial functions and TP53 mutations accompanied by increased genomic instability and intra-tumor heterogeneity. MRP deletions were associated with poor survival. Our results reveal a key role for mitochondrial ribosome biogenesis in tumor malignancy across cancer types.

Tumor-infiltrated activated B cells suppress liver metastasis of colorectal cancers.

More than 40% of patients with late-stage colorectal cancer (CRC) develop liver metastasis (LM). Which immune cells play important roles in CRC-LM and contribute to the difference between left-sided CRC (LCC) and right-sided CRC (RCC) remain unclear. By single-cell RNA sequencing (scRNA-seq), we not only find that activated B cells are significantly depleted in CRC with LM, but also find a subtype of B cells developed from activated B cells, namely immature plasma cell population alpha (iMPA), highly correlated with metastasis. Mechanistically, inhibition of the Wnt and transforming growth factor ß (TGF-ß) pathways in cancer cell promotes activated B cell migration via the SDF-1-CXCR4 axis. This study reveals that B cell subpopulations in the tumor immune microenvironment (TIME) play a key role in CRC-LM as well as in LCC and RCC. The preventive effects of modulating B cell subpopulations in CRC may provide a rationale for subsequent drug development and CRC-LM management.

Monogenic basis of young-onset cryptogenic stroke: a multicenter study.

Background: The prevalence of stroke in young adults is increasing. We investigated the monogenic basis of young adult cryptogenic stroke patients. Methods: This multicenter study enrolled cryptogenic stroke patients under 55 years old, and individuals with nonstroke diseases were included as controls. Targeted next-generation sequencing (NGS) was applied with a custom-designed gene panel that included 551 genes. Rare variants were classified into 2 groups: pathogenic variants and variants of unknown significance. Results: A total of 153 individuals, including 30 (21 males, 70%; mean age 36.1±10.2 years) in the disease group and 123 (59 males, 48.0%; mean age 40.4±13.1 years) in the control group, were recruited. In the disease group, 32 rare variants were identified. Among these individuals, 18 pathogenic variants in 16 patients were detected, with a 53.3% (16/30) diagnostic yield of monogenic causes for cryptogenic stroke. None of these mutations were observed in the control group. Among the mutant genes, the most prevalent were Notch receptor 3 (NOTCH3), protein kinase AMP-activated noncatalytic subunit gamma 2 (PRKAG2), and ryanodine receptor 2 (RYR2). Genes associated with cardiogenic diseases showed the highest mutation frequency (10/18, 55.6%) followed by genes associated with small-vessel diseases (SVDs) and coagulation disorders. None of the patients with mutations had evident abnormalities in the heart or other systems checked by routine tests. For the imaging phenotype-genotype association analysis, infarctions in both the anterior and posterior cerebral circulation were only observed in patients with genes related to cardiogenic disease. Conclusions: In this study, pathogenic variants were identified in nearly half of the young-onset cryptogenic stroke patients, with genes related to cardiogenic diseases being the most frequently mutated. This may have implications for future clinical decision-making, including the development of finer and more sensitive examinations.

Can mild cognitive impairment and Alzheimer's disease be diagnosed by monitoring a miRNA triad in the blood?

Objectively diagnosing age-related cognitive impairment (ACI), mild cognitive impairment (MCI), and early-stage Alzheimer's disease (AD) is a difficult task, as most cognitive impairment is clinically established via questionnaires, history, and physical examinations. A recent study has suggested that monitoring a miRNA triad, miR-181a-5p, miR-146a-5p, and miR-148a-3p can identify ACI and its progression to MCI and AD (Islam et al., EMBO Mol Med. 13: e14997, 2021). This commentary deliberates findings from this article, such as elevated levels of the miRNA triad in the brain impairing neural plasticity and cognitive function, the efficiency of measuring the miRNA triad in the circulating blood diagnosing MCI and AD, and the promise for improving cognitive function in MCI and AD by inhibiting this miRNA triad. Additional studies required prior to employing this miRNA triad in clinical practice are also discussed.

The impact of the Covid-19 pandemic on maternal delivery experiences and breastfeeding practices in China: data from a cross-sectional study.

BACKGROUND: The COVID-2019 pandemic has placed extensive pressure on health systems and posed a severe public health challenge worldwide. Lockdown measures implemented in many countries have delayed virus spread. However, a considerable number of people have faced unprecedented pressure, especially pregnant and breast-feeding women, because face-to-face professional support has been reduced during the lockdown in many countries. OBJECTIVES: To compare the delivery and infant feeding experiences of women who delivered before (BL) versus during (DL) the Covid-19 pandemic in Beijing, China and to investigate predictors of breastfeeding at 6-months. METHODS: Women aged ≥18 years with an infant ≤18 months of age completed an anonymous survey. Information/links were shared online and via local clinics in Beijing. Logistic regression was performed to assess predictors of breastfeeding during the first 6-months. RESULTS: One thousand eight hundred seven women provided data; BL 1231 (68.1%), DL 576 (31.9%). Significantly more mothers in DL group reported the lockdown had moderate to high impact to their household income (p = 0.013) and the convenience of purchasing daily necessities(p = 0.014). Compared to BL mothers, significantly more mothers in the DL groups thought their birth location and breastfeeding intention had been effected by the COVID-19 (p < 0.001, p = 0.036 respectively). Mostly breastfeeding (MBF, mainly breastfeeding with few non-formula fluids added) at 6 months was predicted by delivery during the lockdown period (OR1.43, 95% confidence interval (CI) 1.08, 1.90), younger maternal age (OR 0.96, 95%CI 0.93, 0.99), getting support from friends or relatives (OR 1.95, 95%CI 1.06, 3.59), and discussing health issues in online groups > four times a week (OR 1.66, 95%CI 1.09, 2.53). CONCLUSION: The COVID-19 pandemic and lockdown measures influenced mothers' planned birth location and breastfeeding intention. However, breastfeeding practice was maintained during the pandemic. Our results highlight the importance of feeding support as well as potential beneficial effects of increased mother-infant contact during the lockdown period which is relevant even under normal circumstances.

Limitations in activities of daily living increase the risk of stroke in older Chinese adults: a population-based longitudinal study.

It remains unclear whether limitations in activities of daily living (ADL) increase the risk of stroke in older Chinese adults. This longitudinal study used data from the Chinese Longitudinal Healthy Longevity Survey to investigate the effects of limitations in ADL on the incidence of stroke in older adults. Between 2002 and 2011, 46,728 participants from 22 provinces in China were included in this study. Of participants, 11,241 developed limitations in ADL at baseline. A 3-year follow-up was performed to determine the incidence of stroke. During the 3-year follow-up, 929 participants (8.26%) and 2434 participants (6.86%) experienced stroke in the ADL limitations group and non-ADL limitations group, respectively. Logistic regression was used to analyze the effect of ADL limitations on the risk of stroke. The results showed that after adjusting for the confounding factors gender, age, weight, hypertension, diabetes, heart disease, natural teeth, hearing impairment, visual impairment, smoking, alcohol abuse, exercise, ethnicity, literacy, residential area, and poverty, the ADL limitations group had a 77% higher risk of developing stroke than the non-ADL limitations group. After propensity score matching, the ADL limitations group still had a 33% higher risk of developing stroke than the non-ADL limitations group (OR = 1.326, 95% CI: 1.174-1.497). These findings suggest that limitations in ADL are a stroke risk factor.

Plant casein kinases phosphorylate and destabilize a cyclin-dependent kinase inhibitor to promote cell division.

Cell cycle is one of the most fundamentally conserved biological processes of plants and mammals. Casein kinase1s (CK1s) are critical for cell proliferation in mammalian cells; however, how CK1s coordinate cell division in plants remains unknown. Through genetic and biochemical studies, here we demonstrated that plant CK1, Arabidopsis (Arabidopsis thaliana) EL1-like (AELs), regulate cell cycle/division by modulating the stability and inhibitory effects of Kip-related protein6 (KRP6) through phosphorylation. Cytological analysis showed that AELs deficiency results in suppressed cell-cycle progression mainly due to the decreased DNA replication rate at S phase and increased period of G2 phase. AELs interact with and phosphorylate KRP6 at serines 75 and 109 to stimulate KRP6's interaction with E3 ligases, thus facilitating the KRP6 degradation through the proteasome. These results demonstrate the crucial roles of CK1s/AELs in regulating cell division through modulating cell-cycle rates and elucidate how CK1s/AELs regulate cell division by destabilizing the stability of cyclin-dependent kinase inhibitor KRP6 through phosphorylation, providing insights into the plant cell-cycle regulation through CK1s-mediated posttranslational modification.

Inhibition of BCL9 Modulates the Cellular Landscape of Tumor-Associated Macrophages in the Tumor Immune Microenvironment of Colorectal Cancer.

Tumor-associated macrophages (TAMs) are an indispensable part of the tumor microenvironment (TME), and they likely play a negative rather than positive role in cancer treatment. However, the cellular landscape and transcriptional profile regulation of TAMs in the case of tumor gene inactivation or chemical interference remains unclear. The B-cell lymphoma 9/B-cell lymphoma 9-like (BCL9/BCL9L) is a critical transcription co-factor of ß-catenin. Suppression of Bcl9 inhibits tumor growth in mouse models of colorectal cancer (CRC). Here, we studied the TAMs of CRC by single-cell sequencing. Bcl9 depletion caused macrophage polarization inhibition from M0 to M2 and changed the CRC TME, which further interferes with the inflammation of M0 and M1. The transcription factor regulating these processes may be related to the Wnt signaling pathway from multiple levels. Furthermore, we also found that the cells delineated from monocyte to NK-like non-functioning cells were significantly different in the BCL9-deprived population. Combining these data, we proposed a TAM-to-NK score to evaluate the dynamic balance in TME of monocyte/TAM cells and NK-like non-functioning cells in The Cancer Genome Atlas (TCGA) clinical samples to verify the clinical significance. We demonstrated that the cell type balance and transcription differences of TAMs regulated by BCL9-driven Wnt signaling affected immune surveillance and inflammation of cancer, ultimately affecting patients' prognosis. We thereby highlighted the potential of targeting Wnt signaling pathway through cancer immunotherapy.

BCL9 regulates CD226 and CD96 checkpoints in CD8+ T cells to improve PD-1 response in cancer.

To date, the overall response rate of PD-1 blockade remains unsatisfactory, partially due to limited understanding of tumor immune microenvironment (TIME). B-cell lymphoma 9 (BCL9), a key transcription co-activator of the Wnt pathway, is highly expressed in cancers. By genetic depletion and pharmacological inhibition of BCL9 in tumors, we found that BCL9 suppression reduced tumor growth, promoted CD8+ T cell tumor infiltration, and enhanced response to anti-PD-1 treatment in mouse colon cancer models. To determine the underlying mechanism of BCL9's role in TIME regulation, single-cell RNA-seq was applied to reveal cellular landscape and transcription differences in the tumor immune microenvironment upon BCL9 inhibition. CD155-CD226 and CD155-CD96 checkpoints play key roles in cancer cell/CD8+ T cell interaction. BCL9 suppression induces phosphorylation of VAV1 in CD8+ T cells and increases GLI1 and PATCH expression to promote CD155 expression in cancer cells. In The Cancer Genome Atlas database analysis, we found that BCL9 expression is positively associated with CD155 and negatively associated with CD226 expression. BCL9 is also linked to adenomatous polyposis coli (APC) mutation involved in patient survival following anti-PD-1 treatment. This study points to cellular diversity within the tumor immune microenvironment affected by BCL9 inhibition and provides new insights into the role of BCL9 in regulating CD226 and CD96 checkpoints.

Maternal mental health and well-being during the COVID-19 pandemic in Beijing, China.

BACKGROUND: The aim of this study is to evaluate the impact of the coronavirus disease 2019 (COVID-19) pandemic on breastfeeding women and to identify predictors of maternal mental health and coping. METHODS: Mothers aged ≥ 18 years with a breast-fed infant ≤ 18 months of age during the COVID-19 pandemic in Beijing, China, completed a questionnaire. Descriptive analysis of lockdown consequences was performed and predictors of these outcomes were examined using stepwise linear regression. RESULTS: Of 2233 participants, 29.9%, 20.0% and 34.7% felt down, lonely, and worried, respectively, during the lockdown; however, 85.3% felt able to cope. Poorer maternal mental health was predicted by maternal (younger age, higher education) and infant (older age, lower gestation) characteristics, and social circumstances (husband unemployed or working from home, receiving advice from family, having enough space for the baby, living close to a park or green space). Conversely, better maternal mental health was predicted by higher income, employment requiring higher qualifications, more personal space at home, shopping or walking > once/week and lack of impact of COVID-19 on job or income. Mothers with higher education, more bedrooms, fair division of household chores and attending an online mother and baby group > once/week reported better coping. CONCLUSION: The findings highlight maternal characteristics and circumstances that predict poorer mental health and reduced coping which could be used to target interventions in any future public health emergencies requiring social restrictions.