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Abstract The study addressed a significant gap in the profiling and understanding of the gut microbiota’s influence on Malaysian Malay women with gestational diabetes mellitus (GDM). This prospective cohort study aimed to explore the intricate relationship between gut microbiota, dietary choices, and lifestyle factors among Malay women, both with and without GDM. The research specifically focused on participants during the second (T0) and third (T1) trimesters of pregnancy in Johor Bahru, Malaysia. In Part 1 of the study, a diverse pool of pregnant women at T0 was categorized into two groups: those diagnosed with GDM and those without GDM, with a total sample size of 105 individuals. The assessments encompassed demographic, clinical, lifestyle, and dietary factors at the T0 and T1 trimesters. Part 2 of the study delved into microbiome analysis, targeting a better understanding of the gut microbiota among the participants. Stool samples were randomly collected from 50% of the individuals in each group (GDM and non-GDM) at T0 and T1. The collected samples underwent processing, and 16s rRNA metagenomic analysis was employed to study the microbial composition. The results suggested an association between elevated body weight and glucose levels, poor sleep quality, lack of physical activity, greater intake of iron and meat, and reduced fruit consumption among women with GDM compared to non-GDM groups. The microbiome analysis revealed changes in microbial composition over time, with reduced diversity observed in the GDM group during the third trimester. The genera Lactiplantibacillus, Parvibacter, Prevotellaceae UCG001, and Vagococcus positively correlated with physical activity levels in GDM women in the second trimester. Similarly, the genus Victivallis exhibited a strong positive correlation with gravida and parity. On the contrary, the genus Bacteroides and Roseburia showed a negative correlation with omega-3 polyunsaturated fatty acids (PUFAs) in women without GDM in the third trimester. The study highlighted the multifaceted nature of GDM, involving a combination of lifestyle factors, dietary choices, and changes in gut microbiota composition. The findings emphasized the importance of considering these interconnected elements in understanding and managing gestational diabetes among Malaysian Malay women. Further exploration is essential to comprehend the mechanisms underlying this relationship and develop targeted interventions for effective GDM management.

The interleukin (IL)-12 family consists of pro- and anti-inflammatory cytokines that are able to signal the activation of host antiviral immunity while preventing over-reactive immune reactions due to active virus replication and viral clearance. Amongst others, IL-12 and IL-23 are produced and released by innate immune cells such as monocytes and macrophages to signal the proliferation of T cells and release of effector cytokines, which subsequently activate host defence against virus infections. Interestingly, the dualities of IL-27 and -35 are evidently shown in the course of virus infections; they regulate the synthesis of cytokines and antiviral molecules, proliferation of T cells, and viral antigen presentation in order to maximize virus clearance by the host immune system. In terms of anti-inflammatory reactions, IL-27 signals the formation of regulatory T cells (Treg) which in turn secrete IL-35 to control the scale of inflammatory response that takes place during virus infections. Given the multitasking of the IL-12 family in regards to the elimination of virus infections, its potential in antiviral therapy is unequivocally important. Thus, this work aims to delve deeper into the antiviral actions of the IL-12 family and their applications in antiviral therapies.

Zika virus (ZIKV) is a mosquito-borne, single-stranded RNA virus belonging to the genus Flavivirus. Although ZIKV infection is usually known to exhibit mild clinical symptoms, intrauterine ZIKV infections have been associated with severe neurological manifestations, including microcephaly and Guillain Barre syndrome (GBS). Therefore, it is imperative to understand the mechanisms of ZIKV entry into the central nervous system (CNS) and its effect on brain cells. Several routes of neuro-invasion have been identified, among which blood–brain barrier (BBB) disruption is the commonest mode of access. The molecular receptors involved in viral entry remain unknown; with various proposed molecular ZIKV-host interactions including potential non-receptor mediated cellular entry. As ZIKV invade neuronal cells, they trigger neurotoxic mechanisms via cell-autonomous and non-cell autonomous pathways, resulting in neurogenesis dysfunction, viral replication, and cell death, all of which eventually lead to microcephaly. Together, our understanding of the biological mechanisms of ZIKV exposure would aid in the development of anti-ZIKV therapies targeting host cellular and/or viral components to combat ZIKV infection and its neurological manifestations. In this present work, we review the current understanding of ZIKV entry mechanisms into the CNS and its implications on the brain. We also highlight the status of the drug repurposing approach for the development of potential antiviral drugs against ZIKV.

Zika virus (ZIKV), despite being discovered six decades earlier, became a major health concern only after an epidemic in French Polynesia and an increase in the number of microcephaly cases in Brazil. Substantial evidence has been found to support the link between ZIKV and neurological complications in infants. The virus targets various cells in the brain, including radial glial cells, neural progenitor cells (NPCs), astrocytes, microglial and glioblastoma stem cells. It affects the brain cells by exploiting different mechanisms, mainly through apoptosis and cell cycle dysregulation. The modulation of host immune response and the inflammatory process has also been demonstrated to play a critical role in ZIKV induced neurological complications. In addition to that, different ZIKV strains have exhibited specific neurotropism and unique molecular mechanisms. This review provides a comprehensive and up-to-date overview of ZIKV-induced neuroimmunopathogenesis by dissecting its main target cells in the brain, and the underlying cellular and molecular mechanisms. We highlighted the roles of the different ZIKV host factors and how they exploit specific host factors through various mechanisms. Overall, it covers key components for understanding the crosstalk between ZIKV and the brain.

General gut microbial dysbiosis in diabetes mellitus, including gestational diabetes mellitus (GDM), has been reported in a large body of literature. However, evidence investigating the association between specific taxonomic classes and GDM is lacking. Thus, we performed a systematic review of peer-reviewed observational studies and trials conducted among women with GDM within the last ten years using standard methodology. The National Institutes of Health (NIH) quality assessment tools were used to assess the quality of the included studies. Fourteen studies investigating microbial interactions with GDM were found to be relevant and included in this review. The synthesis of literature findings demonstrates that Bacteroidetes, Proteobacteria, Firmicutes, and Actinobacteria phyla, such as Desulfovibrio, Ruminococcaceae, P. distasonis, Enterobacteriaceae, Collinsella, and Prevotella, were positively associated with GDM. In contrast, Bifidobacterium and Faecalibacterium, which produce butyrate, are negatively associated with GDM. These bacteria were associated with inflammation, adiposity, and glucose intolerance in women with GDM. Lack of good diet management demonstrated the alteration of gut microbiota and its impact on GDM glucose homeostasis. The majority of the studies were of good quality. Therefore, there is great potential to incorporate personalized medicine targeting microbiome modulation through dietary intervention in the management of GDM.

The ability of self-replicating oncolytic viruses (OVs) to preferentially infect and lyse cancer cells while stimulating anti-tumor immunity of the host strongly indicates its value as a new field of cancer therapeutics to be further explored. The emergence of Zika virus (ZIKV) as a global health threat due to its recent outbreak in Brazil has caught the attention of the scientific community and led to the discovery of its oncolytic potential for the treatment of glioblastoma multiforme (GBM), the most common and fatal brain tumor with poor prognosis. Herein, we evaluate the neurotropism of ZIKV relative to the receptor tyrosine kinase AXL and its ligand Gas6 in viral entry and the RNA-binding protein Musashi-1 (MSI1) in replication which are also overexpressed in GBM, suggesting its potential for specific targeting of the tumor. Additionally, this review discusses genetic modifications performed to enhance safety and efficacy of ZIKV as well as speculates future directions for the OV therapy.

Aedes aegypti is a principal vector responsible for the transmission of dengue viruses (DENV). To date, vector control remains the key option for dengue disease management. To develop new vector control strategies, a more comprehensive understanding of the biological interactions between DENV and Ae. aegypti is required. In this study, a cDNA library derived from the midgut of female adult Ae. aegypti was used in yeast two-hybrid (Y2H) screenings against DENV2 envelope (E) protein. Among the many interacting proteins identified, carboxypeptidase B1 (CPB1) was selected, and its biological interaction with E protein in Ae. aegypti primary midgut cells was further validated. Our double immunofluorescent assay showed that CPB1-E interaction occurred in the endoplasmic reticulum (ER) of the Ae. aegypti primary midgut cells. Overexpression of CPB1 in mosquito cells resulted in intracellular DENV2 genomic RNA or virus particle accumulation, with a lower amount of virus release. Therefore, we postulated that in Ae. aegypti midgut cells, CPB1 binds to the E protein deposited on the ER intraluminal membranes and inhibits DENV2 RNA encapsulation, thus inhibiting budding from the ER, and may interfere with immature virus transportation to the trans-Golgi network.

Dengue virus (DENV) results in 100 million cases of infections and 22,000 deaths per year. Liver involvement, thrombocytopenia, haemorrhage and plasma leakage are characteristic manifestations of severe forms of DENV infection. However, the molecular pathways of DENV infection have not been comprehensively studied compared to the host immunological responses. We performed an in vivo study using the BALB/c mouse model with a modified mRNA differential display methodology (GeneFishingTM) using the annealing control primer (ACP) system to capture differentially expressed genes (DEGs) in mice liver upon primary infection with DENV1 and sequential heterologous infection with DENV2. Secondary heterologous infection with DENV2 was carried out at Immunoglobulin IgM and IgG peaks following the primary DENV1 infection with the hope of determining any potential effect antibodies IgM and IgG may have on sequential heterologous infection. 30 DEGs were identified and sequenced across all three treatment groups and they belong to a variety of important pathways such as apoptosis, innate immune response, inflammatory response, metabolic processes and oxidative stress. Analysis of differentially expressed genes in response to viral infection offers valuable knowledge about the dynamic and complex association between host cell and the virus. Furthermore, some DEGs identified support DENV induced liver damage.

Zika virus (ZIKV) is a mosquito borne flavivirus, which was a neglected tropical pathogen until it emerged and spread across the Pacific Area and the Americas, causing large human outbreaks associated with fetal abnormalities and neurological disease in adults. The factors that contributed to the emergence, spread and change in pathogenesis of ZIKV are not understood. We previously reported that ZIKV evades cellular antiviral responses by targeting STAT2 for degradation in human cells. In this study, we demonstrate that Stat2-/- mice are highly susceptible to ZIKV infection, recapitulate virus spread to the central nervous system (CNS), gonads and other visceral organs, and display neurological symptoms. Further, we exploit this model to compare ZIKV pathogenesis caused by a panel of ZIKV strains of a range of spatiotemporal history of isolation and representing African and Asian lineages. We observed that African ZIKV strains induce short episodes of severe neurological symptoms followed by lethality. In comparison, Asian strains manifest prolonged signs of neuronal malfunctions, occasionally causing death of the Stat2-/- mice. African ZIKV strains induced higher levels of inflammatory cytokines and markers associated with cellular infiltration in the infected brain in mice, which may explain exacerbated pathogenesis in comparison to those of the Asian lineage. Interestingly, viral RNA levels in different organs did not correlate with the pathogenicity of the different strains. Taken together, we have established a new murine model that supports ZIKV infection and demonstrate its utility in highlighting intrinsic differences in the inflammatory response induced by different ZIKV strains leading to severity of disease. This study paves the way for the future interrogation of strain-specific changes in the ZIKV genome and their contribution to viral pathogenesis.

We constructed a novel chicken (Gallus gallus) lung cDNA library fused inside yeast acting domain vector (pGADT7). Using yeast two-hybrid screening with highly pathogenic avian influenza (HPAI) nucleoprotein (NP) from the strain (A/chicken/Malaysia/5858/2004(H5N1)) as bait, and the Gallus gallus lung cDNA library as prey, a novel interaction between the Gallus gallus cellular RNA export adaptor protein Aly/REF and the viral NP was identified. This interaction was confirmed and validated with mammalian two hybrid studies and co-immunoprecipitation assay. Cellular localization studies using confocal microscopy showed that NP and Aly/REF co-localize primarily in the nucleus. Further investigations by mammalian two hybrid studies into the binding of NP of other subtypes of influenza virus such as the swine A/New Jersey/1976/H1N1 and pandemic A/Malaysia/854/2009(H1N1) to human Aly/REF, also showed that the NP of these viruses interacts with human Aly/REF. Our findings are also supported by docking studies which showed tight and favorable binding between H5N1 NP and human Aly/REF, using crystal structures from Protein Data Bank. siRNA knockdown of Aly/REF had little effect on the export of HPAI NP and other viral RNA as it showed no significant reduction in virus titer. However, UAP56, another component of the TREX complex, which recruits Aly/REF to mRNA was found to interact even better with H5N1 NP through molecular docking studies. Both these proteins also co-localizes in the nucleus at early infection similar to Aly/REF. Intriguingly, knockdown of UAP56 in A549 infected cells shows significant reduction in viral titer (close to 10 fold reduction). Conclusively, our study have opened new avenues for research of other cellular RNA export adaptors crucial in aiding viral RNA export such as the SRSF3, 9G8 and ASF/SF2 that may play role in influenza virus RNA nucleocytoplasmic transport.