Sialylated Milk Oligosaccharides Promote Microbiota-Dependent Growth in Models of Infant Undernutrition.

Identifying interventions that more effectively promote healthy growth of children with undernutrition is a pressing global health goal. Analysis of human milk oligosaccharides (HMOs) from 6-month-postpartum mothers in two Malawian birth cohorts revealed that sialylated HMOs are significantly less abundant in those with severely stunted infants. To explore this association, we colonized young germ-free mice with a consortium of bacterial strains cultured from the fecal microbiota of a 6-month-old stunted Malawian infant and fed recipient animals a prototypic Malawian diet with or without purified sialylated bovine milk oligosaccharides (S-BMO). S-BMO produced a microbiota-dependent augmentation of lean body mass gain, changed bone morphology, and altered liver, muscle, and brain metabolism in ways indicative of a greater ability to utilize nutrients for anabolism. These effects were also documented in gnotobiotic piglets using the same consortium and Malawian diet. These preclinical models indicate a causal, microbiota-dependent relationship between S-BMO and growth promotion.

Correction: TDP-43 and other hnRNPs regulate cryptic exon inclusion of a key ALS/FTD risk gene, UNC13A.

[This corrects the article DOI: 10.1371/journal.pbio.3002028.].

TDP-43 and other hnRNPs regulate cryptic exon inclusion of a key ALS/FTD risk gene, UNC13A.

A major function of TAR DNA-binding protein-43 (TDP-43) is to repress the inclusion of cryptic exons during RNA splicing. One of these cryptic exons is in UNC13A, a genetic risk factor for amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The accumulation of cryptic UNC13A in disease is heightened by the presence of a risk haplotype located within the cryptic exon itself. Here, we revealed that TDP-43 extreme N-terminus is important to repress UNC13A cryptic exon inclusion. Further, we found hnRNP L, hnRNP A1, and hnRNP A2B1 bind UNC13A RNA and repress cryptic exon inclusion, independently of TDP-43. Finally, higher levels of hnRNP L protein associate with lower burden of UNC13A cryptic RNA in ALS/FTD brains. Our findings suggest that while TDP-43 is the main repressor of UNC13A cryptic exon inclusion, other hnRNPs contribute to its regulation and may potentially function as disease modifiers.

Effect and mechanism of needleless transcutaneous neuromodulation on gastrointestinal function after pancreaticoduodenectomy.

BACKGROUND: Gastrointestinal motility disorders tend to develop after pancreaticoduodenectomy (PD). The objectives of this study were: (1) to investigate the impact of needleless transcutaneous neuromodulation (TN) on the postoperative recuperation following pancreaticoduodenectomy (PD), and (2) to explore the underlying mechanisms by which TN facilitates the recovery of gastrointestinal function after PD. METHODS: A total of 41 patients scheduled for PD were randomized into two groups: the TN group (n = 21) and the Sham-TN group (n = 20). TN was performed at acupoints ST-36 and PC-6 twice daily for 1 h from the postoperative day 1 (POD1) to day 7. Sham-TN was performed at non-acupoints. Subsequent assessments incorporated both heart rate variation and dynamic electrogastrography to quantify alterations in vagal activity (HF) and gastric pacing activity. RESULTS: 1)TN significantly decreased the duration of the first passage of flatus (p < 0.001) and defecation (p < 0.01) as well as the time required to resume diet (p < 0.001) when compared to sham-TN;2)Compared with sham-TN, TN increased the proportion of regular gastric pacing activity (p < 0.01);3) From POD1 to POD7, there was a discernible augmentation in HF induced by TN stimulation(p < 0.01);4) TN significantly decreased serum IL-6 levels from POD1 to POD7 (p < 0.001);5) TN was an independent predictor of shortened hospital stay(ß = - 0.349, p = 0.035). CONCLUSION: Needleless TN accelerates the recovery of gastrointestinal function and reduces the risk of delayed gastric emptying in patients after PD by enhancing vagal activity and controlling the inflammatory response.

Translation, cultural adaptation, and validation of the Chinese standardized outcomes in nephrology-hemodialysis fatigue (C-SONG-HD fatigue) scale: a study of Chinese patients undergoing hemodialysis.

OBJECTIVE: This study aimed to translate and culturally adapt the standardized outcomes in nephrology-hemodialysis fatigue (SONG-HD fatigue) scale and to assess the psychometric properties of the Chinese version of the SONG-HD fatigue (C-SONG-HD fatigue) scale. METHODS: Forward and back translations were used to translate the SONG-HD fatigue scale into Chinese. We used the C-SONG-HD fatigue scale to survey Chinese patients undergoing hemodialysis (HD) in China. We examined the distribution of responses and floor and ceiling effects. Cronbach's alpha and McDonald's omega coefficient, intraclass coefficients, and Spearman correlations were used to assess internal consistency reliability, test-retest reliability, and convergent validity, respectively. Responsiveness was also evaluated. RESULTS: In total, 489 participants across southeast China, northwest China, and central China completed the study. The C-SONG-HD fatigue scale had good internal consistency (Cronbach's alpha coefficient 0.861, omega coefficient 0.916), test-retest reliability (intraclass correlation coefficient 0.695), and convergent validity (Spearman correlation 0.691). The analysis of all first-time HD patients did not show notable responsiveness, and only patients with temporary vascular access had good responsiveness with an effect size (ES) of 0.54, a standardized response mean (SRM) of 0.85, and a standard error of measurement (SEM) of 0.77. CONCLUSION: The Chinese version of the SONG-HD fatigue scale showed satisfactory reliability and validity in patients undergoing hemodialysis (HD) in China. It could be used as a tool to measure the fatigue of Chinese HD patients.

Clinical features and prognosis of pediatric acute lymphocytic leukemia with JAK-STAT pathway genetic abnormalities: a case series.

The objective of this study is to explore the clinical features and outcomes of pediatric patients with acute lymphoblastic leukemia (ALL) harboring JAK-STAT signaling pathway genetic abnormalities. This retrospective case series examined the clinical data of pediatric patients diagnosed with ALL harboring JAK-STAT pathway genetic abnormality at the Children's Hospital of the Capital Institute of Pediatrics between January 2016 and January 2022. Bone marrow next-generation sequencing was used to reveal the JAK pathway abnormalities. Descriptive statistics were used. From 432 children with ALL during the study period, eight had JAK-STAT pathway genetic abnormalities. Regarding immunotyping, there were four patients with common-B cell types and one with pre-B cell type. The three patients with T-ALL had early T-cell precursor(ETP) type, pre-T cell type, and T cell type. Gene mutations were more common than fusion genes. There was no central nervous system involvement in eight patients. All patients were considered at least at intermediate risk before treatments. Four patients underwent hematopoietic stem cell transplantation (HSCT). One child had a comprehensive relapse and died. The child had a severe infection and could not tolerate high-intensity chemotherapy. Another child relapsed 2 years after HSCT and died. Disease-free survival was achieved in six children. JAK-STAT pathway genetic abnormalities in pediatric Ph-like ALL are rare. Special attention should be paid to treatment-related complications, such as infection and combination therapy (chemotherapy, small molecule targeted drugs, immunotherapy, etc.) to reduce treatment-related death and improve long-term quality of life.

Effect of dietary intervention on the prevalence of asymptomatic malaria among 6-18-month-old children in rural Malawi.

BACKGROUND: The complex interaction between malaria and undernutrition leads to increased mortality and morbidity rate among young children in malaria-endemic regions. Results from previous interventions suggest that improving nutritional status of young children may reduce the burden of malaria. This study tested a hypothesis that provision of lipid-based nutrient supplements (LNS) or corn-soy blend (CSB) supplementation to 6-18-month-old children in Malawi would reduce the prevalence of asymptomatic malaria among them. METHODS: A total of 840 6-month-old children were enrolled in a randomized trial. The participants received 12-month supplementation with three different daily dietary supplementations: CSB, soy-LNS, or milk-LNS, and one control group without supplementation. The prevalence rate of asymptomatic Plasmodium falciparum was determined by real-time PCR from the participant's dried blood spots (DBS) collected at the baseline and every 3 months. The global null hypothesis was tested using modified Poisson regression to estimate the prevalence ratio (PR) between the control group and three intervention groups at all ages combined. All the models were adjusted for malaria at baseline, season of DBS sample collection, site of enrolment, and household asset Z-score. RESULTS: All children combined, the prevalence of P. falciparum was 14.1% at enrollment, 8.7% at 9 months, 11.2% at 12 months, 13.0% at 15 months and 22.4% at 18 months of age. Among all samples that were taken after enrolment, the prevalence was 12.1% in control group, 12.2% in milk-LNS, 14.0% in soy-LNS, and 17.2% in CSB group. Compared to children in the control group the prevalence ratio of positive malaria tests was 1.19 (95% CI 0.81-1.74; P = 0.372) in the milk-LNS group, 1.32 (95% CI 0.88-1.96; P = 0.177) in the soy-LNS group and 1.72 (95% CI 1.19-2.49; P = 0.004) in the CSB group. CONCLUSION: The study findings do not support a hypothesis that LNS or CSB supplementation would reduce the prevalence of asymptomatic malaria among Malawian children. In contrast, there was a signal of a possible increase in malaria prevalence among children supplemented with CSB.

Design, synthesis and glycosidase inhibition of DAB derivatives with C-4 peptide and dipeptide branches.

A series of DAB-peptide and DAB-dipeptide derivatives were synthesized from D-tartrate-derived nitrone 18. The DAB peptides 16 are derivatives of trans,trans-3,4-dihydroxy-L-proline. Glycosidase inhibition assay found four of them to be weak and selective bovine liver ß-galactosidase inhibitors, and the C-2' methyl substituted compound 23b showed the most potent ß-galactosidase inhibition (IC50 = 0.66 µM). Molecular docking studies revealed different docking modes of compound 23b compared to those of other DAB-peptides, and partial similarity of compound 23b to DGJ.

Design and synthesis of iso-allo-DNJ and L-isoDALDP derivatives: pursuit of potent and selective inhibitors of α-glucosidase.

A series of iso-allo-DNJ and L-isoDALDP derivatives were synthesized from dithioacetal 16 with sequential and highly diastereoselective Ho and Henry reactions, and aziridinium intermediate-mediated ring rearrangement as key steps. Glycosidase inhibition assay found four of them as selective α-glucosidase inhibitors, and the less substituted compound 30 showed more potent α-glucosidase inhibition (IC50 = 9.3 µM) than the others. Molecular docking study revealed different docking modes of the iso-allo-DNJ and L-isoDALDP derivatives from their parent compounds, and also the similarity of compound 30 to isofagomine.

A Nucleus Accumbens Tac1 Neural Circuit Regulates Avoidance Responses to Aversive Stimuli.

Neural circuits that control aversion are essential for motivational regulation and survival in animals. The nucleus accumbens (NAc) plays an important role in predicting aversive events and translating motivations into actions. However, the NAc circuits that mediate aversive behaviors remain elusive. Here, we report that tachykinin precursor 1 (Tac1) neurons in the NAc medial shell regulate avoidance responses to aversive stimuli. We show that NAcTac1 neurons project to the lateral hypothalamic area (LH) and that the NAcTac1→LH pathway contributes to avoidance responses. Moreover, the medial prefrontal cortex (mPFC) sends excitatory inputs to the NAc, and this circuit is involved in the regulation of avoidance responses to aversive stimuli. Overall, our study reveals a discrete NAc Tac1 circuit that senses aversive stimuli and drives avoidance behaviors.

Comprehensive Analysis of PANoptosis-Related Gene Signature of Ulcerative Colitis.

Accumulating evidence shows that the abnormal increase in the mortality of intestinal epithelial cells (IECs) caused by apoptosis, pyroptosis, and necroptosis is closely related to the function of mucous membrane immunity and barrier function in patients with ulcerative colitis (UC). As a procedural death path that integrates the above-mentioned many deaths, the role of PANoptosis in UC has not been clarified. This study aims to explore the characterization of PANoptosis patterns and determine the potential biomarkers and therapeutic targets. We constructed a PANoptosis gene set and revealed significant activation of PANoptosis in UC patients based on multiple transcriptome profiles of intestinal mucosal biopsies from the GEO database. Comprehensive bioinformatics analysis revealed five key genes (ZBP1, AIM2, CASP1/8, IRF1) of PANoptosome with good diagnostic value and were highly correlated with an increase in pro-inflammatory immune cells and factors. In addition, we established a reliable ceRNA regulatory network of PANoptosis and predicted three potential small-molecule drugs sharing calcium channel blockers that were identified, among which flunarizine exhibited the highest correlation with a high binding affinity to the targets. Finally, we used the DSS-induced colitis model to validate our findings. This study identifies key genes of PANoptosis associated with UC development and hypothesizes that IRF1 as a TF promotes PANoptosome multicomponent expression, activates PANoptosis, and then induces IECs excessive death.

Association between asymptomatic infections and linear growth in 18-24-month-old Malawian children.

Inadequate diet and frequent symptomatic infections are considered major causes of growth stunting in low-income countries, but interventions targeting these risk factors have achieved limited success. Asymptomatic infections can restrict growth, but little is known about their role in global stunting prevalence. We investigated factors related to length-for-age Z-score (LAZ) at 24 months by constructing an interconnected network of various infections, biomarkers of inflammation (as assessed by alpha-1-acid glycoprotein [AGP]), and growth (insulin-like growth factor 1 [IGF-1] and collagen X biomarker [CXM]) at 18 months, as well as other children, maternal, and household level factors. Among 604 children, there was a continuous decline in mean LAZ and increased mean length deficit from birth to 24 months. At 18 months of age, the percentage of asymptomatic children who carried each pathogen was: 84.5% enterovirus, 15.5% parechovirus, 7.7% norovirus, 4.6% rhinovirus, 0.6% rotavirus, 69.6% Campylobacter, 53.8% Giardia lamblia, 11.9% malaria parasites, 10.2% Shigella, and 2.7% Cryptosporidium. The mean plasma IGF-1 concentration was 12.5 ng/ml and 68% of the children had systemic inflammation (plasma AGP concentration >1 g/L). Shigella infection was associated with lower LAZ at 24 months through both direct and indirect pathways, whereas enterovirus, norovirus, Campylobacter, Cryptosporidium, and malaria infections were associated with lower LAZ at 24 months indirectly, predominantly through increased systemic inflammation and reduced plasma IGF-1 and CXM concentration at 18 months.

[Chemical constituents from Paris rugosa rhizomes and their antimicrobial activities].

Paris rugosa(Melanthiaceae) only grows in Yunnan province of China at present, and its chemical constituents have not been systematically studied. In this study, nine compounds, including one new compound pariposide G(1) and eight known compounds of cerin(2), stigmast-4-en-3-one(3), ß-ecdysone(4), ophiopogonin C'(5), methyl protogracillin(6), gracillin(7), parissaponin H(8), and parisyunnanoside G(9), were isolated and identified from the ethanol extract of P. rugosa rhizomes by column chromatography methods and semi-preparative high-performance liquid chromatography(HPLC). Compounds 1-9 were isolated from this plant for the first time. The antibacterial and antifungal activities of all the compounds were evaluated. The results showed that ophiopogonin C' had strong inhibitory effects on Candida albicans [MIC_(90)=(4.68±0.01) µmol·L~(-1)] and the fluconazole-resistant strain of C. albicans [MIC_(90)=(4.66±0.02) µmol·L~(-1)].

Small-Quantity Lipid-Based Nutrient Supplements Increase Infants' Plasma Essential Fatty Acid Levels in Ghana and Malawi: A Secondary Outcome Analysis of the iLiNS-DYAD Randomized Trials.

INTRODUCTION: Small-quantity (SQ) lipid-based nutrient supplements (LNSs) may influence infants' plasma fatty acid (FA) profiles, which could be associated with short- and long-term outcomes. OBJECTIVES: We aimed to determine the impact of SQ-LNS consumption on infants' plasma FA profiles in Ghana and Malawi. METHODS: Ghanaian (n = 1320) and Malawian (n = 1391) women ≤20 weeks pregnant were assigned to consume 60 mg iron and 400 µg folic acid daily until delivery [iron and folic acid (IFA) group], multiple-micronutrient supplements (MMNs) until 6 months postpartum (MMN group), or SQ-LNSs (∼7.8 linoleic acid:α-linolenic acid ratio) until 6 months postpartum (LNS group). LNS group infants received SQ-LNS from 6 to 18 months of age. We compared infant plasma FAs by intervention group in subsamples (n = 379 in Ghana; n = 442 in Malawi) at 6 and 18 months using ANOVA and Poisson regression models. Main outcomes were mean percentage compositions (%Cs; percentage of FAs by weight) of α-linolenic acid (ALA), linoleic acid (LA), EPA, DHA, and arachidonic acid (AA). RESULTS: At 6 months, LNS infants had greater mean ± SD ALA %Cs in Ghana (0.23 ± 0.08; IFA, 0.21 ± 0.06; MMN, 0.21 ± 0.07; P = 0.034) and Malawi (0.42 ± 0.16; IFA, 0.38 ± 0.15; MMN, 0.38 ± 0.14; P = 0.034) and greater AA values in Ghana (6.25 ± 1.24; IFA, 6.12 ± 1.13; MMN, 5.89 ± 1.24; P = 0.049). At 18 months, LNS infants had a tendency towards greater ALA (0.32 ± 0.16; IFA, 0.24 ± 0.08; MMN, 0.24 ± 0.10; P = 0.06) and LA (27.8 ± 3.6; IFA, 26.9 ± 2.9; MMN, 27.0 ± 3.1; P = 0.06) in Ghana, and greater ALA (0.45 ± 0.18; IFA, 0.39 ± 0.18; MMN, 0.39 ± 0.18; P < 0.001) and LA (29.7 ± 3.5; IFA, 28.7 ± 3.3; MMN, 28.6 ± 3.4; P = 0.011) in Malawi. The prevalence of ALA below the population-specific 10th percentile was lower in the LNS group compared to the MMN group, but not the IFA group. Groups did not differ significantly in plasma EPA or DHA levels. CONCLUSIONS: SQ-LNS increased infants' plasma essential FA levels in Ghana and Malawi, which may have implications for health and developmental outcomes. These trials were registered at clinicaltrials.gov as NCT00970866 and NCT01239693.

Embryo morphologic quality in relation to the metabolic and cognitive development of singletons conceived by in vitro fertilization and intracytoplasmic sperm injection: a matched cohort study.

BACKGROUND: Embryos with higher morphologic quality grading may have a greater potential to achieve clinical pregnancy that leads to a live birth regardless of the type of cleavage-stage embryos or blastocysts. Few studies have investigated the impacts of embryo grading on the long-term health of the offspring. OBJECTIVE: This pilot study aimed to examine the associations between embryo morphologic quality and the physical, metabolic, and cognitive development of singletons conceived by in vitro fertilization and intracytoplasmic sperm injection at preschool age. STUDY DESIGN: This matched cohort study included singletons born to infertile couples who underwent fresh cleavage-stage embryo transfer cycles with good- or poor-quality embryos from 2014 to 2016 at the reproductive center of the Women's Hospital, School of Medicine, Zhejiang University. A total of 144 children, aged 4 to 6 years, participated in the follow-up assessment from 2020 to 2021, and the response rate of poor-quality embryo offspring was 39%. Singletons in the good-quality embryo group were matched with singletons in the poor-quality embryo group at a 2:1 ratio according to the fertilization method and the children's age (±1 year). We measured the offspring's height, weight, body mass index, blood pressure, thyroid hormone levels, and metabolic indicators. Neurodevelopmental assessments were performed using the Chinese version of the Wechsler Preschool and Primary Scale of Intelligence, Fourth Edition, and the Adaptive Behavior Assessment System, Second Edition. We also collected data from the medical records. A linear regression model was used to analyze the association between embryo morphologic quality and offspring health outcomes. RESULTS: A total of 48 singletons conceived with poor-quality embryo transfer and 96 matched singletons conceived with good-quality embryo transfer were included in the final analysis. Age, sex, height, weight, body mass index, blood pressure, thyroid function, and metabolic indicators were comparable between the 2 groups. After adjustment for potential risk factors by linear regression model 1 and model 2, poor-quality embryo offspring exhibited a tendency toward higher free thyroxine levels than offspring of good-quality embryo transfers (beta, 0.22; 95% confidence interval, 0.09-0.90; beta, 0.22; 95% confidence interval, 0.09-0.91, respectively), but this difference was not clinically significant. Regarding neurodevelopmental assessments, there was no difference in the full-scale intelligence quotient based on the Wechsler Preschool and Primary Scale of Intelligence (109.96±12.42 vs 109.60±14.46; P=.88) or the general adaptive index based on the Adaptive Behavior Assessment System (108.26±11.70 vs 108.08±13.44; P=.94) between the 2 groups. The subindices of the 2 tests were also comparable. These findings remained after linear regression analysis. CONCLUSION: At 4 to 6 years of age, singletons born from poor-quality embryo transfers have comparable metabolic and cognitive development as those born from good-quality embryo transfers using fresh cleavage-stage embryos. The results of this pilot study indicate that poor-quality embryos that can survive implantation and end in live birth are likely to have a developmental potential comparable to that of good-quality embryos.

Diastereoselective Synthesis, Glycosidase Inhibition, and Docking Study of C-7-Fluorinated Casuarine and Australine Derivatives.

C-7-fluorinated derivatives of two important polyhydroxylated pyrrolizidines, casuarine and australine, were synthesized with organocatalytic stereoselective α-fluorination of aldehydes as the key step. The strategy is extensively applicable to some synthetically challenging fluorinated iminosugars and carbohydrates. The docking studies indicated that the potent inhibitions of trehalase and amyloglucosidase by the fluorinated polyhydroxylated pyrrolizidines are due to the interaction modes dominated by fluorine atoms in these iminosugars with the amino acids' residues of the corresponding enzymes. Steady interactions were established between the C-7 fluoride and a hydrophobic pocket in amyloglucosidase by untypical anion-π interactions. These unexpected docking modes and related structure-activity relationship studies emphasize the value of fluorination in the design of polyhydroxylated pyrrolizidine glycosidase inhibitors.

A clinical prediction model to estimate the risk for coarctation of the aorta: From fetal to newborn life.

AIM: A prenatal diagnosis of coarctation of the aorta (CoA) is challenging. This study aimed to develop a coarctation probability model incorporating prenatal cardiac sonographic markers to estimate the probability of an antenatal diagnosis of CoA. METHODS: We reviewed 89 fetuses as an investigation cohort with prenatal suspicion for CoA and categorized them into three subgroups: severe CoA: symptomatic CoA and surgery within the first 3 months; mild CoA: surgery within 4 months to 1 year (29); and false-positive CoA: not requiring surgery (45). Logistic regression was used to create a multiparametric model, and a validation cohort of 86 fetuses with suspected CoA was used to validate the model. RESULTS: The prediction model had an optimal criterion >0.25 (sensitivity of 97.7%; specificity of 59.1%), and the area under the receiver operator curve was 0.85. The parameters and their cut-off values were as follows: left common carotid artery to left subclavian artery distance/distal transverse arch (LCCA-LSCA)/DT Index >1.77 (sensitivity 62%, specificity 88%, 95% confidence interval [CI]: 0.6-0.8), and z-score of AAo peak Doppler > -1.7 (sensitivity 77%, specificity 56%, 95% CI: 0.6-0.8). The risk assessment demonstrated that fetuses with a model probability >60% should have inpatient observation for a high risk of CoA, whereas fetuses with a model probability <15% should not undergo clinical follow-up. CONCLUSION: The probability model performs well in predicting CoA outcomes postnatally and can also improve the accuracy of risk assessment. The objectivity of its parameters may allow its implementation in multicenter studies of fetal cardiology.

Associations between Gut Microbiota and Intestinal Inflammation, Permeability and Damage in Young Malawian Children.

BACKGROUND: Environmental enteric dysfunction (EED) is common in low- and middle-income countries and associated with childhood undernutrition. The composition of gut microbiota has been implicated in the pathogenesis of EED. Our aim was to assess the associations between gut microbiota and EED biomarkers in rural Malawian children. We hypothesized that there would be an inverse association between microbiota maturity and diversity and fecal concentrations of EED biomarkers. METHODS: We used data from fecal samples collected at 6, 18 and 30 months from 611 children who were followed up during a nutrition intervention trial. The primary time point for analysis was 18 months. Microbiota data were obtained through 16S rRNA sequencing and variables included microbiota maturity and diversity, phylogenetic dissimilarity and relative abundances of individual taxa. EED biomarkers included calprotectin (marker of inflammation), alpha-1 antitrypsin (intestinal permeability) and REG1B (intestinal damage). RESULTS: There was an inverse association between microbiota maturity and diversity and fecal concentrations of all 3 EED biomarkers at 18 months (p≤0.001). The results were similar at 30 months, while at 6 months inverse associations were found only with calprotectin and alpha-1 antitrypsin concentrations. At 18 months, EED biomarkers were not associated with phylogenetic dissimilarity, but at 6 and 30 months several associations were observed. Individual taxa predicting EED biomarker concentrations at 18 months included several Bifidobacterium and Enterobacteriaceae taxa as well as potentially displaced oral taxa. CONCLUSIONS: Our findings support the hypothesis of an inverse association between microbiota maturity and diversity and EED in rural Malawian children.

Chronic childhood undernutrition is an important public health concern that affects about 150 million children, mostly in low- and middle-income countries. Undernutrition is caused by insufficient nutrient intake and frequent infections, but there are also other underlying factors. One of these is a condition called environmental enteric dysfunction (EED), which is characterized by intestinal inflammation and damage without apparent clinical symptoms. EED is thought to be caused by the ingestion of pathogenic bacteria that leads to changes in the intestine such as increased permeability and decreased absorptive capacity. This might make the intestinal wall vulnerable to bacterial invasion and reduce the absorption of nutrients. Besides potentially pathogenic bacteria, there are many commensal bacteria in the gastrointestinal tract that have beneficial functions and that interact with the immune system. The aim of our study was to assess the associations between all these bacteria, that is the intestinal microbiota and biomarkers of EED. We used data from fecal samples collected from young children participating in a nutrition intervention trial in rural Malawi. Our findings support an inverse association between the diversity and maturity of the intestinal microbiota and biomarkers of EED. Additionally, we identified the differences at the level of individual bacterial taxa (groups of bacteria defined by genetic similarity) between participants with different levels of EED biomarkers. Due to the type of study, we cannot determine whether the observed associations represent a causal relationship between the intestinal microbiota and EED. This as well as the exact mechanisms behind these associations should be assessed in further studies.

Protein intake and risk of inflammatory bowel disease: A meta-analysis.

BACKGROUND AND OBJECTIVES: Although the association between dietary protein intake and inflammatory bowel disease (IBD) risk has been investigated, the results are inconsistent. Therefore, we conducted a meta-analysis to reassess the relationship between dietary protein intake and IBD risk. METHODS AND STUDY DESIGN: The PubMed, Web of Knowledge, and Wanfang databases were searched for pertinent studies through January 31, 2020. Relative risks (RRs) with 95% confidence intervals (CIs) were derived using a random-effect model. Subgroup analyses according to disease type, geographic location, and sex; sensitivity analysis; and publication bias analysis were performed. RESULTS: The current report includes 8 articles consisting of 12 studies with 1069 cases and 330,676 participants. The pooled RR (95% CI) of the highest vs. the lowest categories of dietary protein intake for the IBD risk was 1.561 (0.384-6.347) in cohort studies and 1.060 (0.663-1.694) in case-control studies. Evidence of heterogeneity was found both in cohort studies (I2=86.4%, p=0.007) and in case-control studies (I2=49.0%, p=0.039). However, the association was significant among Asian populations (RR=1.675, 95% CI=1.096-2.559) but not in other populations. We did not find any relationship of dietary protein intake with the risk of either Crohn's disease or ulcerative colitis. CONCLUSIONS: Based on limited information, the highest dietary protein intakes among Asians may increase the risk of IBD, undifferentiated for ulcerative colitis or Crohn's disease. This may reflect dietary patterns for which protein is a marker rather than implicate protein itself.

Engineered Mesoporous Silica-Based Core-Shell Nanoarchitectures for Synergistic Chemo-Photodynamic Therapies.

Combinatorial therapies have garnered enormous interest from researchers in efficiently devastating malignant tumors through synergistic effects. To explore the combinatorial approach, multiple therapeutic agents are typically loaded in the delivery vehicles, controlling their release profiles and executing subsequent therapeutic purposes. Herein, we report the fabrication of core (silica)-shell (mesoporous silica nanoparticles, MSNs) architectures to deliver methylene blue (MB) and cupric doxorubicin (Dox) as model drugs for synergistic photodynamic therapy (PDT), chemotherapy, and chemodynamic therapy (CDT). MB, as the photosensitizer, is initially loaded and stabilized in the silica core for efficient singlet oxygen generation under light irradiation towards PDT. The most outside shell with imidazole silane-modified MSNs is immobilized with a chemotherapeutic agent of Dox molecules through the metal (Copper, Cu)-ligand coordination interactions, achieving the pH-sensitive release and triggering the production of intracellular hydrogen peroxide and subsequent Fenton-like reaction-assisted Cu-catalyzed free radicals for CDT. Further, the designed architectures are systematically characterized using various physicochemical characterization techniques and demonstrate the potent anti-cancer efficacy against skin melanoma. Together our results demonstrated that the MSNs-based core-shell nanoarchitectures have great potential as an effective strategy in synergistically ablating cancer through chemo-, chemodynamic, and photodynamic therapies.