Revolutionizing Brain Tumor Care: Emerging Technologies and Strategies.

Glioblastoma multiforme (GBM) is one of the most aggressive forms of brain tumor, characterized by a daunting prognosis with a life expectancy hovering around 12-16 months. Despite a century of relentless research, only a select few drugs have received approval for brain tumor treatment, largely due to the formidable barrier posed by the blood-brain barrier. The current standard of care involves a multifaceted approach combining surgery, irradiation, and chemotherapy. However, recurrence often occurs within months despite these interventions. The formidable challenges of drug delivery to the brain and overcoming therapeutic resistance have become focal points in the treatment of brain tumors and are deemed essential to overcoming tumor recurrence. In recent years, a promising wave of advanced treatments has emerged, offering a glimpse of hope to overcome the limitations of existing therapies. This review aims to highlight cutting-edge technologies in the current and ongoing stages of development, providing patients with valuable insights to guide their choices in brain tumor treatment.

The Neurodegenerative Disease Knowledge Portal: Propelling Discovery Through the Sharing of Neurodegenerative Disease Genomic Resources.

Although large-scale genetic association studies have proven opportunistic for the delineation of neurodegenerative disease processes, we still lack a full understanding of the pathological mechanisms of these diseases, resulting in few appropriate treatment options and diagnostic challenges. To mitigate these gaps, the Neurodegenerative Disease Knowledge Portal (NDKP) was created as an open-science initiative with the aim to aggregate, enable analysis, and display all available genomic datasets of neurodegenerative disease, while protecting the integrity and confidentiality of the underlying datasets. The portal contains 218 genomic datasets, including genotyping and sequencing studies, of individuals across ten different phenotypic groups, including neurological conditions such as Alzheimer's disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson's disease. In addition to securely hosting large genomic datasets, the NDKP provides accessible workflows and tools to effectively utilize the datasets and assist in the facilitation of customized genomic analyses. Here, we summarize the genomic datasets currently included within the portal, the bioinformatics processing of the datasets, and the variety of phenotypes captured. We also present example use-cases of the various user interfaces and integrated analytic tools to demonstrate their extensive utility in enabling the extraction of high-quality results at the source, for both genomics experts and those in other disciplines. Overall, the NDKP promotes open-science and collaboration, maximizing the potential for discovery from the large-scale datasets researchers and consortia are expending immense resources to produce and resulting in reproducible conclusions to improve diagnostic and therapeutic care for neurodegenerative disease patients.

Unraveling reproductive and maternal health challenges of women living with HIV/AIDS in Vietnam: a qualitative study.

BACKGROUND: Human Immunodeficiency Virus (HIV) remains a significant public health concern worldwide. Women living with HIV/AIDS (WLHA) have the additional and unique need to seek sexual and reproductive health services. WLHA's maternal health journeys can be shaped by the cultural norms and resources that exist in their society. This study sought to understand if and how WLHA's family planning, pregnancy, and motherhood experiences could be influenced by the patriarchal culture, gender roles, and HIV stigma in Vietnam, specifically. METHODS: Between December 2021 and March 2022, 30 WLHA with diverse socioeconomic backgrounds and childbirth experiences were interviewed in Hanoi, Vietnam. These semi-structured interviews covered topics including HIV stigma, gender norms, pregnancy experiences, and child-rearing challenges. Interviews were audio recorded, transcribed, and analysed using ATLAS.ti. RESULTS: Qualitative analyses of participant quotes revealed how limited information on one's health prospects and reproductive options posed a significant challenge to family planning. Societal and familial expectations as well as economic circumstances also influenced reproductive decision-making. WLHA often encountered substandard healthcare during pregnancy, labor, and delivery. Stigma and lack of provider attentiveness resulted in cases where women were denied pain relief and other medical services. Communication breakdowns resulted in failure to administer antiretroviral therapy for newborns. Motherhood for WLHA was shadowed by concerns for not only their own health, but also the wellbeing of their children, as HIV stigma affected their children at school and in society as well. Many WLHA highlighted the constructive or destructive role that family members could play in their childbirth decision-making and care-giving experiences. CONCLUSIONS: Overall, this study underscores the complex ways that cultural expectations, family support, and stigma in healthcare impact WLHA. Efforts to educate and engage families and healthcare providers are warranted to better understand and address the needs of WLHA, ultimately improving their reproductive and maternal health.

HIV-related stigma and discrimination have consequential impacts on health and quality of life for women living with HIV (WLHA). WLHA in Vietnam must navigate the additional challenges of a traditionally patriarchal and hierarchical society. Women typically face less educational and occupational opportunities and are often expected to defer to expectations of family and virtue. Stigma among family members, friends, employers, and healthcare providers poses a significant challenge to WLHA autonomy, especially as it relates to their reproductive health decision-making and maternal health experiences. This study aims to better understand the experiences of WLHA throughout family planning, pregnancy, and motherhood. The findings will hopefully shed light on strategies to empower WLHA and to combat HIV- and gender-based stigma not only in Vietnam, but also globally.

Viral reprogramming of host transcription initiation.

Viruses are master remodelers of the host cell environment in support of infection and virus production. For example, viruses typically regulate cell gene expression through modulating canonical cell promoter activity. Here, we show that Epstein Barr virus (EBV) replication causes 'de novo' transcription initiation at 29674 new transcription start sites throughout the cell genome. De novo transcription initiation is facilitated in part by the unique properties of the viral pre-initiation complex (vPIC) that binds a TATT[T/A]AA, TATA box-like sequence and activates transcription with minimal support by additional transcription factors. Other de novo promoters are driven by the viral transcription factors, Zta and Rta and are influenced by directional proximity to existing canonical cell promoters, a configuration that fosters transcription through existing promoters and transcriptional interference. These studies reveal a new way that viruses interact with the host transcriptome to inhibit host gene expression and they shed light on primal features driving eukaryotic promoter function.

Direct observations of microbial community succession on sinking marine particles.

Microbial community dynamics on sinking particles control the amount of carbon that reaches the deep ocean and the length of time that carbon is stored, with potentially profound impacts on Earth's climate. A mechanistic understanding of the controls on sinking particle distributions has been hindered by limited depth- and time-resolved sampling and methods that cannot distinguish individual particles. Here, we analyze microbial communities on nearly 400 individual sinking particles in conjunction with more conventional composite particle samples to determine how particle colonization and community assembly might control carbon sequestration in the deep ocean. We observed community succession with corresponding changes in microbial metabolic potential on the larger sinking particles transporting a significant fraction of carbon to the deep sea. Microbial community richness decreased as particles aged and sank; however, richness increased with particle size and the attenuation of carbon export. This suggests that the theory of island biogeography applies to sinking marine particles. Changes in POC flux attenuation with time and microbial community composition with depth were reproduced in a mechanistic ecosystem model that reflected a range of POC labilities and microbial growth rates. Our results highlight microbial community dynamics and processes on individual sinking particles, the isolation of which is necessary to improve mechanistic models of ocean carbon uptake.

Phenome- and genome-wide analyses of retinal optical coherence tomography images identify links between ocular and systemic health.

The human retina is a multilayered tissue that offers a unique window into systemic health. Optical coherence tomography (OCT) is widely used in eye care and allows the noninvasive, rapid capture of retinal anatomy in exquisite detail. We conducted genotypic and phenotypic analyses of retinal layer thicknesses using macular OCT images from 44,823 UK Biobank participants. We performed OCT layer cross-phenotype association analyses (OCT-XWAS), associating retinal thicknesses with 1866 incident conditions (median 10-year follow-up) and 88 quantitative traits and blood biomarkers. We performed genome-wide association studies (GWASs), identifying inherited genetic markers that influence retinal layer thicknesses and replicated our associations among the LIFE-Adult Study (N = 6313). Last, we performed a comparative analysis of phenome- and genome-wide associations to identify putative causal links between retinal layer thicknesses and both ocular and systemic conditions. Independent associations with incident mortality were detected for thinner photoreceptor segments (PSs) and, separately, ganglion cell complex layers. Phenotypic associations were detected between thinner retinal layers and ocular, neuropsychiatric, cardiometabolic, and pulmonary conditions. A GWAS of retinal layer thicknesses yielded 259 unique loci. Consistency between epidemiologic and genetic associations suggested links between a thinner retinal nerve fiber layer with glaucoma, thinner PS with age-related macular degeneration, and poor cardiometabolic and pulmonary function with a thinner PS. In conclusion, we identified multiple inherited genetic loci and acquired systemic cardio-metabolic-pulmonary conditions associated with thinner retinal layers and identify retinal layers wherein thinning is predictive of future ocular and systemic conditions.

Desilification of phytolith exacerbates the release of arsenic from rice straw.

Arsenic (As) turnover in rice paddy agro-ecosystems has received much attention because As can enter the food chain through its accumulation in rice, thereby affecting human health. Returning straw to soil is a common practice to retain nutrients for soil and crops, but it also cycles As within the rice paddy field ecosystems. However, there is still a lack of detailed understanding of the fate of As in rice straw, and how or to what extent it is recycled back into the soil environment. This study aims to elucidate the relationship between the microstructure of rice straw and the release of As during rice straw decomposition. The microstructure of rice straw was found to comprise both organic and silica (phytolith) components. These two constituents are inter-embedded to form a composite-like structure that contains up to 6.48 mg As Kg-1. The 30-day batch experiments revealed that the biochemical release of As simultaneously depends upon the decomposition of the organic component and the desilicification of the silica component. Accompanying the release of As was the release of other elements such as Fe, Al, P and S. These elements can further interact with As to form less mobile compounds. The introduction of either Trichoderma harzianum or Bacillus velezensis was expected to accelerate the decomposition of rice straw, and enhance the silica dissolution, hence contributing to an increase in the As release. Despite these expectations, our observations showed the opposite effects. Microorganisms presumably have facilitated the change in solution chemistry or the inclusion of As into the newly-formed precipitates. The biochemical decomposition process can reduce straw particle size, while the negatively-charge surface will involve microsized straw particles in the electrostatic interaction, thereby favoring the dispersibility state. Therefore, the co-transport of micro-sized straw particles with As under field conditions should not be neglected.

Ab initio kinetics of the CH3NH + NO2 reaction: formation of nitramines and N-alkyl nitroxides.

This study provides a detailed understanding of how the reaction between CH3NH, one of the primary products of the CH3NH2 + OH/Cl reactions, and NOx occurs in the atmosphere since the reaction is expected to be a dominant sink for the tropospheric CH3NH radical. First, we focus on the reaction of the aminyl radical CH3NH with NO2, complementing the known reaction between CH3NH and NO, to provide the overall picture of the CH3NH + NOx system. The reaction was meticulously examined across the extended range of temperature (298-2000 K) and pressure (0.76-76 000 torr) using quantum chemistry calculations and kinetic modeling based on the framework of the Rice-Ramsperger-Kassel-Marcus (RRKM)-based master equation. Highly correlated electronic structure calculations unveil that the intricate reaction mechanism of the CH3NH + NO2 reaction, which can proceed through O-addition or N-addition to form NO2, encompasses numerous steps, channels, and various intermediates and products. The temperature-/pressure-dependent kinetic behaviors and product distribution of the CH3NH + NO2 reaction are revealed under atmospheric and combustion conditions. The main products under atmospheric conditions are found to be CH3NHO and NO, as well as CH3NHNO2, while under combustion conditions, the primary products are only CH3NHO and NO. Given its stability under ambient conditions, CH3NHNO2, a nitramine, is believed to have the potential to induce DNA damage, which can ultimately result in severe cancers. Secondly, by building upon prior research on the CH3NH + NO system, this study shows that the reaction of CH3NH with NOx holds greater importance in urban areas with elevated NOx emissions than other oxidants like O2. Furthermore, this reaction occurs swiftly and results in the creation of various compounds, such as the carcinogenic nitrosamine (CH3NHNO), carcinogenic nitramine (CH3NHNO2), CH3NNOH, (CH3NN + H2O) and (CH3NHO + NO).

The interplay of membrane fluidity, acyl chain order and area per lipid on the partitioning of two antidepressants paroxetine and sertraline.

Selective serotonin reuptake inhibitors (SSRIs) are among the popular drugs for treating depression and mental disorders. Membrane fluidity has previously been considered as the main factor in modulating the membrane partitioning of SSRIs, while other biophysical properties, such as the acyl chain order and area per lipid, were often neglected. Varying the lipid membrane composition and temperature can significantly modify the physical phase and, in turn, affect its fluidity, acyl chain order and area per lipid. Here, we investigate the role of membrane fluidity, acyl chain order and area per lipid in the partitioning of two SSRIs, paroxetine (PAX) and sertraline (SER). The model membranes were either POPC : SM (1 : 1 mol ratio) or POPC : SM : Chol (1 : 1 : 1 mol ratio) and studied in the temperature range of 25-45 °C. The order parameters and area per lipid in the two lipid mixtures were calculated using molecular dynamics simulations. The membrane partitioning of PAX and SER was determined via second derivative spectrophotometry. In a lower temperature range (25-32 °C), membrane fluidity favors the SSRI partitioning into Lo/Ld POPC:SM:Chol. In a higher temperature range (37-45 °C), the interplay between membrane fluidity, acyl chain order and area per lipid favors drug partitioning into Ld POPC:SM. The findings offer indication for the inconsistent distribution of SSRIs in tissues as well as the possible interaction of SSRIs with lipid domains and membrane-bound proteins.

OH-initiated oxidation of vinyl butyrate: ab initio insights.

The widespread use of vinyl butyrate (CH2CHOC(O)CH2CH2CH3 or VB) in the polymer industry and daily-life materials inevitably results in its emission into the atmosphere. Therefore, understanding the mechanism and kinetics of the VB conversion is critical for evaluating its fate and environmental impacts. Herein, we theoretically investigate the chemical transformation of VB initiated by OH radicals in the atmosphere using the stochastic Rice-Ramsperger-Kassel-Marcus (RRKM)-based master equation kinetic model on the potential energy surface explored at the M06-2X/aug-cc-pVTZ level of theory. Showing excellent agreement with limited experimental kinetic data, the VB + OH kinetic model reveals that H-abstraction from Cß (i.e., -CßH2CH3) prevails over the OH-addition to the double bond (CC), even at low temperatures. The detailed analyses, including those of the time-resolved species profiles, reaction rate, and reaction flux, reveal the reaction mechanism shift with temperature (causing the U-shaped temperature dependence of k(T, P)) and the noticeable pressure dependence of k(T, P) at low temperatures. The secondary chemistry under atmospheric conditions (namely, the reaction of the main product with O2 and its subsequent reactions with NO) was then characterized within the same framework to reveal the detailed kinetic mechanism (e.g., [4-(ethenyloxy)-4-oxobutan-2-yl]oxidanyl (IM12) + NO2 is the dominant channel under atmospheric conditions), suggesting VB is not a persistent organic pollutant and a new environmental concern regarding the formed NO2. Also, the kinetic behaviors of vinyl butyrate and its oxidation products were extended from atmospheric to combustion conditions for further applications. Moreover, through TD-DFT calculations, it is shown that several related important species (i.e., 1-(ethenyloxy)-1-oxobutan-2-yl (P4), [4-(ethenyloxy)-4-oxobutan-2-yl]dioxidanyl (IM7), and IM12) can potentially undergo photolysis in the atmosphere.

Stimulation of ectopically expressed muscarinic receptors induces IFN-γ but suppresses IL-2 production by inhibiting activation of pAKT pathways in primary T cells.

T cell antigen receptor stimulation induces tyrosine phosphorylation of downstream signaling molecules and the phosphatidylinositol, Ras, MAPK, and PI3 kinase pathways, leading to T cell activation. Previously, we reported that the G-protein-coupled human muscarinic receptor could bypass tyrosine kinases to activate the phosphatidylinositol pathway and induce interleukin-2 production in Jurkat leukemic T cells. Here, we demonstrate that stimulating G-protein-coupled muscarinic receptors (M1 and synthetic hM3Dq) can activate primary mouse T cells if PLCß1 is coexpressed. Resting peripheral hM3Dq+PLCß1 (hM3Dq/ß1) T cells did not respond to clozapine, an hM3Dq agonist, unless they were preactivated by TCR and CD28 stimulation which increased hM3Dq and PLCß1 expression. This permitted large calcium and phosphorylated ERK responses to clozapine. Clozapine treatment induced high IFN-γ, CD69, and CD25 expression, but surprisingly did not induce substantial IL-2 in hM3Dq/ß1 T cells. Importantly, costimulation of both muscarinic receptors plus the TCR even led to reduced IL-2 expression, suggesting a selective inhibitory effect of muscarinic receptor costimulation. Stimulation of muscarinic receptors induced strong nuclear translocation of NFAT and NFκB and activated AP-1. However, stimulation of hM3Dq led to reduced IL-2 mRNA stability which correlated with an effect on the IL-2 3'UTR activity. Interestingly, stimulation of hM3Dq resulted in reduced pAKT and its downstream pathway. This may explain the inhibitory impact on IL-2 production in hM3Dq/ß1T cells. Moreover, an inhibitor of PI3K reduced IL-2 production in TCR-stimulated hM3Dq/ß1 CD4 T cells, suggesting that activating the pAKT pathway is critical for IL-2 production in T cells.

Earthworms can mobilize soil arsenic through their casts.

The mobilization of arsenic (As) in paddy soil has received much attention because it might accelerate the transfer of As from soil to rice. This study aims to elucidate whether earthworms can mobilize As through their casts. Cast samples were collected from 23 different paddy fields in the Red River delta. We first analysed different forms of As through fractionation and then performed batch experiments under reducing conditions to identify factors that govern the mobility of As in casts. Because the dissociation of casts may induce colloids that carry As, the colloidal properties of cast suspensions were also examined. The median value of As in casts (obtained from aqua regia digestion) was 5.11 mg kg-1, which was lower than that in the surrounding soil (6.7 mg kg-1). Compared with the surrounding soil, casts contain less As, possibly because cast As is more labile and more easily lost due to leaching. Various processes, including the reductive dissolution of Fe oxides, decomposition of organic matter, and sorption competition of soluble anionic substances, such as P, Si and DOC, were found to strongly correlate with the release of As from casts. We propose that earthworms, via their casts, may accelerate the As cycle in paddy soils, potentially intensifying As exposure to human health. The dissociation of cast could release colloids containing As; therefore, the cotransport of As with cast-induced colloids should also be considered in future works.

Dietary restriction of cysteine and methionine sensitizes gliomas to ferroptosis and induces alterations in energetic metabolism.

Ferroptosis is mediated by lipid peroxidation of phospholipids containing polyunsaturated fatty acyl moieties. Glutathione, the key cellular antioxidant capable of inhibiting lipid peroxidation via the activity of the enzyme glutathione peroxidase 4 (GPX-4), is generated directly from the sulfur-containing amino acid cysteine, and indirectly from methionine via the transsulfuration pathway. Herein we show that cysteine and methionine deprivation (CMD) can synergize with the GPX4 inhibitor RSL3 to increase ferroptotic cell death and lipid peroxidation in both murine and human glioma cell lines and in ex vivo organotypic slice cultures. We also show that a cysteine-depleted, methionine-restricted diet can improve therapeutic response to RSL3 and prolong survival in a syngeneic orthotopic murine glioma model. Finally, this CMD diet leads to profound in vivo metabolomic, proteomic and lipidomic alterations, highlighting the potential for improving the efficacy of ferroptotic therapies in glioma treatment with a non-invasive dietary modification.

A cell state specific metabolic vulnerability to GPX4-dependent ferroptosis in glioblastoma.

Glioma cells hijack developmental transcriptional programs to control cell state. During neural development, lineage trajectories rely on specialized metabolic pathways. However, the link between tumor cell state and metabolic programs is poorly understood in glioma. Here we uncover a glioma cell state-specific metabolic liability that can be leveraged therapeutically. To model cell state diversity, we generated genetically engineered murine gliomas, induced by deletion of p53 alone (p53) or with constitutively active Notch signaling (N1IC), a pathway critical in controlling cellular fate. N1IC tumors harbored quiescent astrocyte-like transformed cell states while p53 tumors were predominantly comprised of proliferating progenitor-like cell states. N1IC cells exhibit distinct metabolic alterations, with mitochondrial uncoupling and increased ROS production rendering them more sensitive to inhibition of the lipid hydroperoxidase GPX4 and induction of ferroptosis. Importantly, treating patient-derived organotypic slices with a GPX4 inhibitor induced selective depletion of quiescent astrocyte-like glioma cell populations with similar metabolic profiles.

Therapeutic Drug-Induced Metabolic Reprogramming in Glioblastoma.

Glioblastoma WHO IV (GBM), the most common primary brain tumor in adults, is a heterogenous malignancy that displays a reprogrammed metabolism with various fuel sources at its disposal. Tumor cells primarily appear to consume glucose to entertain their anabolic and catabolic metabolism. While less effective for energy production, aerobic glycolysis (Warburg effect) is an effective means to drive biosynthesis of critical molecules required for relentless growth and resistance to cell death. Targeting the Warburg effect may be an effective venue for cancer treatment. However, past and recent evidence highlight that this approach may be limited in scope because GBM cells possess metabolic plasticity that allows them to harness other substrates, which include but are not limited to, fatty acids, amino acids, lactate, and acetate. Here, we review recent key findings in the literature that highlight that GBM cells substantially reprogram their metabolism upon therapy. These studies suggest that blocking glycolysis will yield a concomitant reactivation of oxidative energy pathways and most dominantly beta-oxidation of fatty acids.

A systemic cell stress signal confers neuronal resilience toward oxidative stress in a Hedgehog-dependent manner.

Cells possess several conserved adaptive mechanisms to respond to stress. Stress signaling is initiated to reestablish cellular homeostasis, but its effects on the tissue or systemic levels are far less understood. We report that the secreted luminal domain of the endoplasmic reticulum (ER) stress transducer CREB3L2 (which we name TAILS [transmissible activator of increased cell livability under stress]) is an endogenous, cell non-autonomous activator of neuronal resilience. In response to oxidative insults, neurons secrete TAILS, which potentiates hedgehog signaling through direct interaction with Sonic hedgehog (SHH) and its receptor PTCH1, leading to improved antioxidant signaling and mitochondrial function in neighboring neurons. In an in vivo model of ischemic brain injury, administration of TAILS enables survival of CNS neurons and fully preserves cognitive function in behavioral tests. Our findings reveal an SHH-mediated, cell non-autonomous branch of cellular stress signaling that confers resilience to oxidative stress in the mature brain, providing protection from ischemic neurodegeneration.

Genetic Characterization of African Swine Fever Virus in Various Outbreaks in Central and Southern Vietnam During 2019-2021.

This study aimed to identify potential genetic diversity among African swine fever virus (ASFV) strains circulating in central and southern Vietnam. Thirty ASFV strains were collected from domestic pigs and convalescent pigs with ASFV-infected clinical signs from 19 different provinces of central and southern Vietnam during 2019-2021. A portion of the B646L (p72) gene and the entire E183L (p54), CP204L (p30), and B602L (CVR) genes were amplified, purified, and sequenced. Web-based BLAST and MEGA X software were used for sequence analysis. Analysis of the partial B646L (p72) gene, the full-length E183L (p54) and CP204L (p30) genes, and the central hypervariable region (CVR) of the B602L gene sequence showed that all 30 ASFV isolates belonged to genotype II and were 100% identical to the previously identified strains in Vietnam and China. Analysis of the p72, p54, and p30 regions did not indicate any change in the nucleotide and amino acid sequences among these strains in 3 years of research. No novel variant was found in the CVR within the B602L gene. Analysis of the CVR showed that these ASFV strains belong to subgroup XXXII. The results of this study revealed that these ASFVs shared high similarity with ASFV isolates detected previously in northern Vietnam and China. Taken together, the results of this study and a previous study in Vietnam showed high stability and no genetic diversity in the ASFV genome.

Brucella Phagocytosis Mediated by Pathogen-Host Interactions and Their Intracellular Survival.

The Brucella species is the causative agent of brucellosis in humans and animals. So far, brucellosis has caused considerable economic losses and serious public health threats. Furthermore, Brucella is classified as a category B bioterrorism agent. Although the mortality of brucellosis is low, the pathogens are persistent in mammalian hosts and result in chronic infection. Brucella is a facultative intracellular bacterium; hence, it has to invade different professional and non-professional phagocytes through the host phagocytosis mechanism to establish its lifecycle. The phagocytosis of Brucella into the host cells undergoes several phases including Brucella detection, formation of Brucella-containing vacuoles, and Brucella survival via intracellular growth or being killed by host-specific bactericidal activities. Different host surface receptors contribute effectively to recognize Brucella including non-opsonic receptors (toll-like receptors and scavenger receptor A) or opsonic receptors (Fc receptors and complement system receptors). Brucella lacks classical virulence factors such as exotoxin, spores, cytolysins, exoenzymes, virulence plasmid, and capsules. However, once internalized, Brucella expresses various virulence factors to avoid phagolysosome fusion, bypass harsh environments, and establish a replicative niche. This review provides general and updated information regarding Brucella phagocytosis mediated by pathogen-host interactions and their intracellular survival in host cells.

Formation of lipid raft nanodomains in homogeneous ternary lipid mixture of POPC/DPSM/cholesterol: Theoretical insights.

Lipid rafts, in biological membranes, are cholesterol-rich nanodomains that regulate many protein activities and cellular processes. Understanding the formation of the lipid-raft nanodomains helps us elucidate many complex interactions in the cell. In this study, the formation of lipid-raft nanodomains in a ternary palmitoyl-oleoyl-phosphatidylcholine/stearoyl-sphingomyelin/cholesterol (POPC/DPSM/Chol) lipid mixture, the most realistic surrogate model for biological membranes, has been successfully observed for the first time in-silico using microsecond timescale molecular dynamics simulations. The model reveals the formation of cholesterol-induced nanodomains with raft-like characteristics and their underlying mechanism: the cholesterol molecules segregate themselves into cholesterol nanodomains and then enrich the cholesterol-rich domain with sphingomyelin molecules to form a lipid raft thanks to the weak bonding of cholesterol with sphingomyelin. Besides, it is found that the increase in cholesterol concentration enhances the biophysical properties (e.g., bilayer thickness, area per lipid headgroup, and order parameter) of the lipid raft nanodomains. Such findings suggest that the POPC/DPSM/Chol bilayer is a suitable model to fundamentally extend the nanodomain evolution to investigate their lifetime and kinetics as well as to study protein-lipid interaction, protein-protein interaction, and selection of therapeutic molecules in the presence of lipid rafts.

Dissecting the treatment-naive ecosystem of human melanoma brain metastasis.

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macrophages and dysfunctional TOX+CD8+ T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.