The effects of probiotics administration during pregnancy on preeclampsia and associated maternal, fetal, and newborn outcomes: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to synthesize the available evidence on probiotic administration during pregnancy for the prevention of preeclampsia and its effects on related maternal, fetal, and newborn outcomes. DATA SOURCES: Six databases were systematically searched for eligible studies, namely Ovid MEDLINE, Embase, CINAHL, Cochrane, Global Index Medicus, and the Maternity and Infant Care Database, from inception to August 2, 2023. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials that evaluated the effects of probiotic administration on women during any stage of pregnancy were eligible for inclusion. METHODS: The protocol was registered with the International Prospective Register of Systematic Reviews under identifier CRD42023421613. Evaluating study eligibility, extracting data, assessing risk of bias (ROB-2 tool), and rating certainty (Grading of Recommendations, Assessment, Development and Evaluations) were conducted independently by 2 authors. The primary outcomes were incidence of preeclampsia, eclampsia, and maternal mortality. A meta-analysis was performed, and the results were reported as risk ratios with 95% confidence intervals. RESULTS: A total of 29 trials (7735 pregnant women) met the eligibility criteria. There was heterogeneity across the trials in the population of enrolled women and the type of probiotic tested (20 different strains), although most used oral administration. Probiotics may make no difference to the risk of preeclampsia (risk ratio, 1.14; 95% confidence interval, 0.84-1.53; 11 trials; 2401 women; low certainty evidence), preterm birth at <37 weeks' gestation (risk ratio, 0.93; 95% confidence interval, 0.66-1.30; 18 trials, 4016 women; low certainty evidence), or gestational age at delivery (mean difference, -0.03 weeks [≈0.2 days]; 95% confidence interval, -0.16 to 0.10 weeks [≈ -1.1 to 0.7 days]; 13 trials, 2194 women; low certainty evidence). It is difficult to assess the effects of probiotics on other secondary outcomes because the evidence was of very low certainty, however, no benefits or harms were observed. CONCLUSION: Limited evidence suggests that probiotic supplementation does not affect the risk for preeclampsia. Further high-quality trials are needed to definitively assess the benefits and possible harms of probiotic supplementation during pregnancy. There is also a lack of data from trials that included women who were undernourished or who experienced microbial dysbiosis and for whom probiotic supplementation might be useful.

The effect of selenium supplementation in pregnant women on maternal, fetal, and newborn outcomes: a systematic review and meta-analysis.

OBJECTIVE: Low maternal selenium status has been associated with poor pregnancy outcomes, including preterm birth. This study aimed to evaluate available evidence of the effects of selenium supplementation during pregnancy on preterm birth and related maternal, fetal, and newborn outcomes. DATA SOURCES: MEDLINE, Embase, CINAHL, Global Index Medicus, and the Cochrane Library were systematically searched on June 23, 2022, without language or time restrictions. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials and nonrandomized interventional studies were included if they compared the effects of selenium supplementation with placebo or no treatment among pregnant women. The review protocol was registered in the International Prospective Register of Systematic Reviews (identification number: CRD42022383669). METHODS: For outcomes reported by ≥1 study, a meta-analysis was conducted. Because of the small number of studies and high clinical heterogeneity between populations, random-effects models were used. The Risk of Bias 2 and Risk Of Bias In Non-randomized Studies - of Interventions tools were used to assess study quality, and Grading of Recommendations Assessment, Development, and Evaluation analysis was used to determine the certainty of evidence for each outcome. RESULTS: Literature searches identified 5105 unique records, and 32 studies met the eligibility criteria. Of note, 11 reports were not included for analysis following research integrity assessments. Moreover, 10 trials and 3 observational studies met the inclusion criteria; however, only 8 trials (1851 women) and 1 prospective cohort study (71,728 women) reported on at least 1 review outcome. Our results could not determine the effect of selenium supplementation on preterm birth at <37 weeks of gestation (relative risk, 0.65; 95% confidence interval, 0.26-1.63; very low certainty evidence) and <34 weeks of gestation (relative risk, 1.05; 95% confidence interval, 0.59-1.44; very low certainty evidence). CONCLUSION: There is limited evidence on the effects of selenium supplementation during pregnancy. Further trials, with larger sample sizes, more representative populations, and reliable assessment of maternal selenium status at trial entry, are required.

Evaluation of an Online Training Program on COVID-19 for Health Workers in Papua New Guinea.

BACKGROUND: Health worker training is an important component of a holistic outbreak response, and travel restrictions resulting from the COVID-19 pandemic have highlighted the potential of virtual training. Evaluation of training activities is essential for understanding the effectiveness of a training program on knowledge and clinical practice. We conducted an evaluation of the online COVID-19 Healthcare E-Learning Platform (CoHELP) in Papua New Guinea (PNG) to assess its effectiveness, measure engagement and completion rates, and determine barriers and enablers to implementation, in order to inform policy and practice for future training in resource-limited settings. METHODS: The evaluation team conducted a mixed methods evaluation consisting of pre- and post-knowledge quizzes; quantification of engagement with the online platform; post-training surveys; qualitative interviews with training participants, non-participants, and key informants; and audits of six health facilities. RESULTS: A total of 364 participants from PNG signed up to participate in the CoHELP online training platform, with 41% (147/360) completing at least one module. Of the 24 participants who completed the post-training survey, 92% (22/24) would recommend the program to others and 79% (19/24) had used the knowledge or skills gained through CoHELP in their clinical practice. Qualitative interviews found that a lack of time and infrastructural challenges were common barriers to accessing online training, and participants appreciated the flexibility of online, self-paced learning. CONCLUSIONS: Initially high registration numbers did not translate to ongoing engagement with the CoHELP online platform, particularly for completion of evaluation activities. Overall, the CoHELP program received positive feedback from participants involved in the evaluation, highlighting the potential for further online training courses in PNG.

Current methods and limitations for longitudinal fMRI analysis across development.

The human brain is remarkably plastic. The brain changes dramatically across development, with ongoing functional development continuing well into the third decade of life and substantial changes occurring again in older age. Dynamic changes in brain function are thought to underlie the innumerable changes in cognition, emotion, and behavior that occur across development. The brain also changes in response to experience, which raises important questions about how the environment influences the developing brain. Longitudinal functional magnetic resonance imaging (fMRI) studies are an essential means of understanding these developmental changes and their cognitive, emotional, and behavioral correlates. This paper provides an overview of common statistical models of longitudinal change applicable to developmental cognitive neuroscience, and a review of the functionality provided by major software packages for longitudinal fMRI analysis. We demonstrate that there are important developmental questions that cannot be answered using available software. We propose alternative approaches for addressing problems that are commonly faced in modeling developmental change with fMRI data.

Wnt ligand presentation and reception: from the stem cell niche to tissue engineering.

Stem cells reside in niches where spatially restricted signals maintain a delicate balance between stem cell self-renewal and differentiation. Wnt family proteins are particularly suited for this role as they are modified by lipids, which constrain and spatially regulate their signalling range. In recent years, Wnt/ß-catenin signalling has been shown to be essential for the self-renewal of a variety of mammalian stem cells. In this review, we discuss Wnt-responsive stem cells in their niche, and mechanisms by which Wnt ligands are presented to responsive cells. We also highlight recent progress in molecular visualization that has allowed for the monitoring of Wnt signalling within the stem cell compartment and new approaches to recapitulate this niche signalling in vitro Indeed, new technologies that present Wnt in a localized manner and mimic the three-dimensional microenvironment of stem cells will advance our understanding of Wnt signalling in the stem cell niche. These advances will expand current horizons to exploit Wnt ligands in the rapidly evolving fields of tissue engineering and regenerative medicine.

Phase I/IIa clinical trial of a novel hTERT peptide vaccine in men with metastatic hormone-naive prostate cancer.

In newly diagnosed metastatic hormone-naive prostate cancer (mPC), telomerase-based immunotherapy with the novel hTERT peptide vaccine UV1 can induce immune responses with potential clinical benefit. This phase I dose escalation study of UV1 evaluated safety, immune response, effects on prostate-specific antigen (PSA) levels, and preliminary clinical outcome. Twenty-two patients with newly diagnosed metastatic hormone-naïve PC (mPC) were enrolled; all had started androgen deprivation therapy and had no visceral metastases. Bone metastases were present in 17 (77%) patients and 16 (73%) patients had affected lymph nodes. Three dose levels of UV1 were given as intradermal injections combined with GM-CSF (Leukine®). Twenty-one patients in the intention-to-treat population (95%) received conformal radiotherapy. Adverse events reported were predominantly grade 1, most frequently injection site pruritus (86.4%). Serious adverse events considered possibly related to UV1 and/or GM-CSF included anaphylactic reaction in two patients and thrombocytopenia in one patient. Immune responses against UV1 peptides were confirmed in 18/21 evaluable patients (85.7%), PSA declined to <0.5 ng/mL in 14 (64%) patients and in ten patients (45%) no evidence of persisting tumour was seen on MRI in the prostatic gland. At the end of the nine-month reporting period for the study, 17 patients had clinically stable disease. Treatment with UV1 and GM-CSF gave few adverse events and induced specific immune responses in a large proportion of patients unselected for HLA type. The intermediate dose of 0.3 mg UV1 resulted in the highest proportion of, and most rapid UV1-specific immune responses with an acceptable safety profile. These results warrant further clinical studies in mPC.

Tankyrase Inhibitors Stimulate the Ability of Tankyrases to Bind Axin and Drive Assembly of ß-Catenin Degradation-Competent Axin Puncta.

Activation of the wnt signaling pathway is a major cause of colon cancer development. Tankyrase inhibitors (TNKSi) have recently been developed to block the wnt pathway by increasing axin levels to promote degradation of the wnt-regulator ß-catenin. TNKSi bind to the PARP (poly(ADP)ribose polymerase) catalytic region of tankyrases (TNKS), preventing the PARylation of TNKS and axin that normally control axin levels through ubiquitination and degradation. TNKSi treatment of APC-mutant SW480 colorectal cancer cells can induce axin puncta which act as sites for assembly of ß-catenin degradation complexes, however this process is poorly understood. Using this model system, we found that siRNA knockdown of TNKSs 1 and 2 actually blocked the ability of TNKSi drugs to induce axin puncta, revealing that puncta formation requires both the expression and the inactivation of TNKS. Immunoprecipitation assays showed that treatment of cells with TNKSi caused a strong increase in the formation of axin-TNKS complexes, correlating with an increase in insoluble or aggregated forms of TNKS/axin. The efficacy of TNKSi was antagonized by proteasome inhibitors, which stabilized the PARylated form of TNKS1 and reduced TNKSi-mediated assembly of axin-TNKS complexes and puncta. We hypothesise that TNKSi act to stimulate TNKS oligomerization and assembly of the TNKS-axin scaffold that form puncta. These new insights may help in optimising the future application of TNKSi in anticancer drug design.

Characterization of a beta-catenin nuclear localization defect in MCF-7 breast cancer cells.

Beta-catenin plays a key role in transducing Wnt signals from the plasma membrane to the nucleus. Here we characterize an unusual subcellular distribution of beta-catenin in MCF-7 breast cancer cells, wherein beta-catenin localizes to the cytoplasm and membrane but atypically did not relocate to the nucleus after Wnt treatment. The inability of Wnt or the Wnt agonist LiCl to induce nuclear localization of beta-catenin was not due to defective nuclear transport, as the transport machinery was intact and ectopic GFP-beta-catenin displayed rapid nuclear entry in living cells. The mislocalization is explained by a shift in the retention of beta-catenin from nucleus to cytoplasm. The reduced nuclear retention is caused by unusually low expression of lymphoid enhancer factor/T-cell factor (LEF/TCF) transcription factors. The reconstitution of LEF-1 or TCF4 expression rescued nuclear localization of beta-catenin in Wnt treated cells. In the cytoplasm, beta-catenin accumulated in recycling endosomes, golgi and beta-COP-positive coatomer complexes. The peripheral association with endosomes diminished after Wnt treatment, potentially releasing ß-catenin into the cytoplasm for nuclear entry. We propose that in MCF-7 and perhaps other breast cancer cells, beta-catenin may contribute to cytoplasmic functions such as ER-golgi transport, in addition to its transactivation role in the nucleus.

A systematic review of adolescent physiological development and its relationship with health-related behaviour: a protocol.

BACKGROUND: At any one time, there are one billion people worldwide who are in the second decade of their life, and 1.8 billion in the 10-24 age range. Whilst a great deal of focus has been placed on healthy early years development, the adolescent years are also a unique period of opportunity: exposure to health-influencing behaviours such as alcohol consumption or cigarette smoking, may serve to establish patterns that have significant health consequences in later life. Although there is often an emphasis on risk-taking and detrimental health behaviours during adolescence, these years also provide significant opportunities for behaviour to be shaped in positive ways that may improve longer term health outcomes. However, it is firstly important to understand the complex physiological changes that are taking place within the human body during this period and their relationship with health-related behaviour. Such knowledge can help to inform health policy and intervention development. AIM: The aim of this study is to gain a comprehensive understanding of the relationship between physiological development and health-related behaviours in adolescence. METHODS: The principles of an integrative review will be used. Such reviews are of use where research has emerged in different fields, to combine existing knowledge and produce a more extensive understanding. Studies from a range of different methodological approaches, published or unpublished, will be included. A range of databases and literature depositories will be searched using a pre-defined search strategy. The review will include studies that focus on adolescents (nominally, those aged 10-24 years). We will seek papers that focus on both physiological development and health behaviour, or papers focusing solely on physiological development if there are clear implications for health behaviour. Studies with a focus on participants with specific health conditions will be excluded. Two reviewers will independently screen potential studies for eligibility and quality; members of the project team will act as third reviewers in the case of uncertainty or discrepancy. Further analyses (e.g. meta-analysis, meta-synthesis, meta-summary) will be decided upon, and sub-set analyses carried out. Finally, an integrative summation will be produced, giving a critical analysis of the results and providing conclusions and recommendations.

APC binds the Miro/Milton motor complex to stimulate transport of mitochondria to the plasma membrane.

Mutations in adenomatous polyposis coli (APC) disrupt regulation of Wnt signaling, mitosis, and the cytoskeleton. We describe a new role for APC in the transport of mitochondria. Silencing of wild-type APC by small interfering RNA caused mitochondria to redistribute from the cell periphery to the perinuclear region. We identified novel APC interactions with the mitochondrial kinesin-motor complex Miro/Milton that were mediated by the APC C-terminus. Truncating mutations in APC abolished its ability to bind Miro/Milton and reduced formation of the Miro/Milton complex, correlating with disrupted mitochondrial distribution in colorectal cancer cells that could be recovered by reconstitution of wild-type APC. Using proximity ligation assays, we identified endogenous APC-Miro/Milton complexes at mitochondria, and live-cell imaging showed that loss of APC slowed the frequency of anterograde mitochondrial transport to the membrane. We propose that APC helps drive mitochondria to the membrane to supply energy for cellular processes such as directed cell migration, a process disrupted by cancer mutations.

The BARD1 BRCT domain contributes to p53 binding, cytoplasmic and mitochondrial localization, and apoptotic function.

BARD1 is a breast cancer tumor suppressor with multiple domains and functions. BARD1 comprises a tandem BRCT domain at the C-terminus, and this sequence has been reported to target BARD1 to distinct subcellular locations such as nuclear DNA breakage sites and the centrosome through binding to regulatory proteins such as HP1 and OLA1, respectively. We now identify the BRCT domain as a binding site for p53. We first confirmed previous reports that endogenous BARD1 binds to p53 by immunoprecipitation assay, and further show that BARD1/p53 complexes locate at mitochondria suggesting a cellular location for p53 regulation of BARD1 apoptotic activity. We used a proximity ligation assay to map three distinct p53 binding sequences in human BARD1, ranging from weak (425-525) and modest (525-567) to strong (551-777 comprising BRCT domains). Deletion of the BRCT sequence caused major defects in the ability of BARD1 to (1) bind p53, (2) localize to the cytoplasm and mitochondria, and (3) induce Bax oligomerization and apoptosis. Our data suggest that BARD1 can move to mitochondria independent of p53, but subsequently associates with p53 to induce Bax clustering in part by decreasing mitochondrial Bcl-2 levels. We therefore identify a role for the BRCT domain in stimulating BARD1 nuclear export and mitochondrial localization, and in assembling mitochondrial BARD1/p53 complexes to regulate specific activities such as apoptotic function.

APC as a mobile scaffold: regulation and function at the nucleus, centrosomes, and mitochondria.

Genetic mutations of adenomatous polyposis coli (APC) predispose to high risk of human colon cancer. APC is a large tumor suppressor protein and truncating mutations disrupt its normal roles in regulating cell migration, DNA replication/repair, mitosis, apoptosis, and turnover of oncogenic ß-catenin. APC is targeted to multiple subcellular sites, and here we discuss recent evidence implicating novel protein interactions and functions of APC in the nucleus and at centrosomes and mitochondria. The ability of APC to shuttle between these and other cell locations is hypothesized to be integral to its cellular function.

Nuclear export and centrosome targeting of the protein phosphatase 2A subunit B56alpha: role of B56alpha in nuclear export of the catalytic subunit.

Protein phosphatase (PP) 2A is a heterotrimeric enzyme regulated by specific subunits. The B56 (or B'/PR61/PPP2R5) class of B-subunits direct PP2A or its substrates to different cellular locations, and the B56alpha, -beta, and -epsilon isoforms are known to localize primarily in the cytoplasm. Here we studied the pathways that regulate B56alpha subcellular localization. We detected B56alpha in the cytoplasm and nucleus, and at the nuclear envelope and centrosomes, and show that cytoplasmic localization is dependent on CRM1-mediated nuclear export. The inactivation of CRM1 by leptomycin B or by siRNA knockdown caused nuclear accumulation of ectopic and endogenous B56alpha. Conversely, CRM1 overexpression shifted B56alpha to the cytoplasm. We identified a functional nuclear export signal at the C terminus (NES; amino acids 451-469), and site-directed mutagenesis of the NES (L461A) caused nuclear retention of full-length B56alpha. Active NESs were identified at similar positions in the cytoplasmic B56-beta and epsilon isoforms, but not in the nuclear-localized B56-delta or gamma isoforms. The transient expression of B56alpha induced nuclear export of the PP2A catalytic (C) subunit, and this was blocked by the L461A NES mutation. In addition, B56alpha co-located with the PP2A active (A) subunit at centrosomes, and its centrosome targeting involved sequences that bind to the A-subunit. Fluorescence Recovery after Photobleaching (FRAP) assays revealed dynamic and immobile pools of B56alpha-GFP, which was rapidly exported from the nucleus and subject to retention at centrosomes. We propose that B56alpha can act as a PP2A C-subunit chaperone and regulates PP2A activity at diverse subcellular locations.