Case Report: I feel like a mother to other babies: experiences and perspectives on bereavement and breastmilk donation from Vietnam

There is a growing recognition globally that care regarding lactation following a perinatal death needs to potentially offer the opportunity for maternal donation. This article discusses this experience and perspectives from a human milk bank (HMB) in Vietnam. This is a descriptive exploratory case study that has a long tradition in both the social and health sciences. Triangulated data collection involved a review of video data, interview data with the donor, and data review for the Da Nang HMB, a Center for Excellence in Breastfeeding. We found that although it is common for mothers in Vietnam to donate breastmilk to HMBs, it is less common for this to occur following perinatal loss. We offer a descriptive case study of the maternal loss of twins and a subsequent choice to donate for approximately 1 month to the Da Nang HMB, the first HMB in Vietnam. We discuss four reasons derived from this case regarding donation following perinatal loss. (1) A strong motivation to donate breastmilk when aware of the service, (2) donating breastmilk helped her deal with grief, (3) family members supported her through this tough time and supported her decision, and (4) health staff supported her decision. While human milk sharing (e.g., wet nursing) has been practiced in Vietnam, breastmilk donation from bereaved mothers has neither been discussed nor well-researched. Because maternal grief is complex and individual, deciding to donate breastmilk is a personal decision that needs to be supported, without creating guilt for those who do not wish to donate

Replicating Adenovirus-SIV Immunization of Rhesus Macaques Induces Mucosal Dendritic Cell Activation and Function Leading to Rectal Immune Responses

Inducing strong mucosal immune responses by vaccination is important for providing protection against simian immunodeficiency virus (SIV). A replicating adenovirus type 5 host range mutant vector (Ad5hr) expressing SIV proteins induced mucosal immune responses in rectal tissue associated with delayed SIV acquisition in female rhesus macaques, but the initial mechanisms leading to the induced immunity have not been elucidated. As dendritic cells (DCs) are known to orchestrate both innate and adaptive effector immune cell responses, we investigated their role here. Rhesus macaques were immunized twice mucosally with a replicating Ad5hr expressing SIV Env, Gag, and Nef (Ad-SIV) or empty Ad5hr vector (Ad-Empty). DC subsets and their activation were examined in rectal tissue, blood, and LNs at 3 timepoints after each immunization. Plasmacytoid DCs, myeloid DCs, and Langerhans cells were significantly increased in the rectal mucosa, but only myeloid DCs were significantly increased in blood post-immunizations. All rectal DC subsets showed increased frequencies of cells expressing activation markers and cytokines post-immunization, blood DCs showed mixed results, and LN DCs showed few changes. Rectal DCs responded strongly to the vector rather than expressed SIV antigens, but rectal DC frequencies positively correlated with induced rectal antigen-specific memory T and B cells. These correlations were confirmed by in vitro co-cultures showing that rectal Ad-SIV DCs induced proliferation and antigen-specific cytokine production by autologous naïve T cells. Our results highlight the rapid response of DCs to Ad immunization and their role in mucosal immune activation and identify initial cellular mechanisms of the replicating Ad-SIV vaccine in the rhesus macaque model

Protection from COVID-19 disease in hamsters vaccinated with subunit SARS-CoV-2 S1 mucosal vaccines adjuvanted with different adjuvants

IntroductionAdjuvant plays an important role in directing the immune responses induced by vaccines. In previous studies, we have shown that a mucosal SARS-CoV-2 S1 subunit vaccine adjuvanted with a combination of CpG, Poly I:C and IL-15 (named CP15) induced effective mucosal and systemic immunity and conferred nearly sterile protection against SARS-CoV-2 viral replication in macaque models.MethodsIn this study, we used a hamster model, which mimics the human scenario and reliably exhibits severe SARS-CoV-2 disease similar to hospitalized patients, to investigate the protection efficacy of the vaccines against COVID-19 disease. We compared the weight loss, viral loads (VLs), and clinical observation scores of three different vaccine regimens. All three regimens consisted of priming/boosting with S1 subunit vaccines, but adjuvanted with alum and/or CP15 administrated by either intramuscular (IM) or intranasal (IN) routes: Group 1 was adjuvanted with alum/alum administrated IM/IM; Group 2 was alum-IM/CP15-IN; and Group 3 was CP15-IM/CP15-IN.ResultsAfter challenge with SARS-CoV-2 WA strain, we found that the alum/CP15 group showed best protection against weight loss, while the CP15 group demonstrated best reduction of oral SARS-CoV-2 VLs, suggesting that the protection profiles were different. Sex differences for VL and clinical scores were observed. Humoral immunity was induced but not correlated with protection. Moreover, S1-specific binding antibody titers against beta, omicron BA.1, and BA.2 variants showed 2.6-, 4.9- and 2.8- fold reduction, respectively, compared to the Wuhan strain.DiscussionOverall, the data suggested that adjuvants in subunit vaccines determine the protection profiles after SARS-CoV-2 infection and that nasal/oral mucosal immunization can protect against systemic COVID-19 disease

Past rainfall patterns in Southeast Asia revealed by microanalysis of δ18O values in human teeth

Funding Information: Technical assistance was provided by Kamil Sokolowski and Brian Tse at the Preclinical Imaging Core Facility at the Translational Research Institute, funding support for which came from Therapeutic Innovation Australia, under the National Collaborative Research Infrastructure Strategy. Histological preparation and SHRIMP analyses were funded by the Australian Academy of Sciences Regional Collaborations Program; Project ‘Tracing Ancient Environments During the Peopling of Southeast Asia’ (BCC 2017/2305974; Co-PIS: TM Smith, IS Williams, HR Buckley, DR Green) and the Australian Research Council (Future Fellowship FT200100390, PI: TM Smith). The excavation of the Pain Haka site was funded by a grant from the Research Institute for Development, UMR Paloc, and by additional funding from the French Embassy in Indonesia and a University of Otago Research Grant. Regarding the Napa material we thank Mr Ermilando Napa; Captain Leopoldo Quindoza of Barangay Tuhian and the Barangay council; the Sitio Buhangin community; and Jeremy Barns and Angel Bautista of the National Museum of the Philippines. With respect to the Con Co Ngua material grant sponsors included the Australian Research Council DP110101097, FT120100299, FT100100527, and Japan Society for the Promotion of Science 16H02527. Two living tooth donors and their families are also acknowledged with gratitude for their contributions.Peer reviewedPublisher PD

Dual-targeting GroEL/ES chaperonin and protein tyrosine phosphatase B (PtpB) inhibitors: A polypharmacology strategy for treating Mycobacterium tuberculosis infections

Current treatments for Mycobacterium tuberculosis infections require long and complicated regimens that can lead to patient non-compliance, increasing incidences of antibiotic-resistant strains, and lack of efficacy against latent stages of disease. Thus, new therapeutics are needed to improve tuberculosis standard of care. One strategy is to target protein homeostasis pathways by inhibiting molecular chaperones such as GroEL/ES (HSP60/10) chaperonin systems. M. tuberculosis has two GroEL homologs: GroEL1 is not essential but is important for cytokine-dependent granuloma formation, while GroEL2 is essential for survival and likely functions as the canonical housekeeping chaperonin for folding proteins. Another strategy is to target the protein tyrosine phosphatase B (PtpB) virulence factor that M. tuberculosis secretes into host cells to help evade immune responses. In the present study, we have identified a series of GroEL/ES inhibitors that inhibit M. tuberculosis growth in liquid culture and biochemical function of PtpB in vitro. With further optimization, such dual-targeting GroEL/ES and PtpB inhibitors could be effective against all stages of tuberculosis – actively replicating bacteria, bacteria evading host cell immune responses, and granuloma formation in latent disease – which would be a significant advance to augment current therapeutics that primarily target actively replicating bacteria

A Pathogenic Role for Splenic B1 Cells in SIV Disease Progression in Rhesus Macaques

B1 cells spontaneously produce protective natural antibodies which provide the first line of defense against a variety of pathogens. Although these natural antibodies share similar autoreactive features with several HIV-1 broadly neutralizing antibodies, the role of B1 cells in HIV/SIV disease progression is unknown. We report the presence of human-like B1 cells in rhesus macaques. During chronic SIV infection, we found that the frequency of splenic CD11b+ B1 cells positively correlated with plasma SIV viral load and exhausted T cells. Mechanistically, we discovered that splenic CD11b+ B1 cells express PD-L2 and IL-10, and were able to induce PD-1 upregulation on CD4+ T cells in vitro. These findings suggest that splenic CD11b+ B1 cells may contribute to the regulation of SIV plasma viral load by enhancing T cell exhaustion. Therefore, understanding the mechanisms that govern their function in rhesus macaques may lead to novel therapeutic strategies for impeding HIV/SIV disease progression

Regulatory Feedback Loop of Two phz Gene Clusters through 5′-Untranslated Regions in Pseudomonas sp. M18

BACKGROUND: Phenazines are important compounds produced by pseudomonads and other bacteria. Two phz gene clusters called phzA1-G1 and phzA2-G2, respectively, were found in the genome of Pseudomonas sp. M18, an effective biocontrol agent, which is highly homologous to the opportunistic human pathogen P. aeruginosa PAO1, however little is known about the correlation between the expressions of two phz gene clusters. METHODOLOGY/PRINCIPAL FINDINGS: Two chromosomal insertion inactivated mutants for the two gene clusters were constructed respectively and the correlation between the expressions of two phz gene clusters was investigated in strain M18. Phenazine-1-carboxylic acid (PCA) molecules produced from phzA2-G2 gene cluster are able to auto-regulate expression itself and activate the expression of phzA1-G1 gene cluster in a circulated amplification pattern. However, the post-transcriptional expression of phzA1-G1 transcript was blocked principally through 5'-untranslated region (UTR). In contrast, the phzA2-G2 gene cluster was transcribed to a lesser extent and translated efficiently and was negatively regulated by the GacA signal transduction pathway, mainly at a post-transcriptional level. CONCLUSIONS/SIGNIFICANCE: A single molecule, PCA, produced in different quantities by the two phz gene clusters acted as the functional mediator and the two phz gene clusters developed a specific regulatory mechanism which acts through 5'-UTR to transfer a single, but complex bacterial signaling event in Pseudomonas sp. strain M18

Visual-somatosensory integration (VSI) as a novel marker of Alzheimer’s disease: A comprehensive overview of the VSI study

Identification of novel, non-invasive, non-cognitive based markers of Alzheimer’s disease (AD) and related dementias are a global priority. Growing evidence suggests that Alzheimer’s pathology manifests in sensory association areas well before appearing in neural regions involved in higher-order cognitive functions, such as memory. Previous investigations have not comprehensively examined the interplay of sensory, cognitive, and motor dysfunction with relation to AD progression. The ability to successfully integrate multisensory information across multiple sensory modalities is a vital aspect of everyday functioning and mobility. Our research suggests that multisensory integration, specifically visual-somatosensory integration (VSI), could be used as a novel marker for preclinical AD given previously reported associations with important motor (balance, gait, and falls) and cognitive (attention) outcomes in aging. While the adverse effect of dementia and cognitive impairment on the relationship between multisensory functioning and motor outcomes has been highlighted, the underlying functional and neuroanatomical networks are still unknown. In what follows we detail the protocol for our study, named The VSI Study, which is strategically designed to determine whether preclinical AD is associated with neural disruptions in subcortical and cortical areas that concurrently modulate multisensory, cognitive, and motor functions resulting in mobility decline. In this longitudinal observational study, a total of 208 community-dwelling older adults with and without preclinical AD will be recruited and monitored yearly. Our experimental design affords assessment of multisensory integration as a new behavioral marker for preclinical AD; identification of functional neural networks involved in the intersection of sensory, motor, and cognitive functioning; and determination of the impact of early AD on future mobility declines, including incident falls. Results of The VSI Study will guide future development of innovative multisensory-based interventions aimed at preventing disability and optimizing independence in pathological aging

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: a genotypic analysis.

Background: Molecular diagnostics are considered the most promising route to achievement of rapid, universal drug susceptibility testing for Mycobacterium tuberculosis complex (MTBC). We aimed to generate a WHO-endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction. Methods: In this systematic analysis, we used a candidate gene approach to identify mutations associated with resistance or consistent with susceptibility for 13 WHO-endorsed antituberculosis drugs. We collected existing worldwide MTBC whole-genome sequencing data and phenotypic data from academic groups and consortia, reference laboratories, public health organisations, and published literature. We categorised phenotypes as follows: methods and critical concentrations currently endorsed by WHO (category 1); critical concentrations previously endorsed by WHO for those methods (category 2); methods or critical concentrations not currently endorsed by WHO (category 3). For each mutation, we used a contingency table of binary phenotypes and presence or absence of the mutation to compute positive predictive value, and we used Fisher's exact tests to generate odds ratios and Benjamini-Hochberg corrected p values. Mutations were graded as associated with resistance if present in at least five isolates, if the odds ratio was more than 1 with a statistically significant corrected p value, and if the lower bound of the 95% CI on the positive predictive value for phenotypic resistance was greater than 25%. A series of expert rules were applied for final confidence grading of each mutation. Findings: We analysed 41 137 MTBC isolates with phenotypic and whole-genome sequencing data from 45 countries. 38 215 MTBC isolates passed quality control steps and were included in the final analysis. 15 667 associations were computed for 13 211 unique mutations linked to one or more drugs. 1149 (7·3%) of 15 667 mutations were classified as associated with phenotypic resistance and 107 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was more than 80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were identified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs. Interpretation: We present the first WHO-endorsed catalogue of molecular targets for MTBC drug susceptibility testing, which is intended to provide a global standard for resistance interpretation. The existence of this catalogue should encourage the implementation of molecular diagnostics by national tuberculosis programmes. Funding: Unitaid, Wellcome Trust, UK Medical Research Council, and Bill and Melinda Gates Foundation