Combined Treatment of Uterine Leiomyosarcoma with Gamma Secretase Inhibitor MK-0752 and Chemotherapeutic Agents Decreases Cellular Invasion and Increases Apoptosis.

Due to limited effective therapeutics for uterine leiomyosarcoma (uLMS), the impact of the gamma secretase inhibitor (GSI) MK-0752 with common chemotherapeutics was explored in uLMS. MTT assays were performed on two human uLMS cell lines, SK-UT-1B and SK-LMS-1, using MK-0752, docetaxel, doxorubicin, and gemcitabine, individually and in combination, to determine cell viability after treatment. Synergistic combinations were used in transwell invasion assays, cell cycle flow cytometry, proliferation assays, and RNA sequencing.

S309-CAR-NK cells bind the Omicron variants and reduce SARS-CoV-2 viral loads in humanized ACE2-NSG mice.

Unlabelled: Recent progress on chimeric antigen receptor (CAR)-NK cells has shown promising results in treating CD19-positive lymphoid tumors with minimal toxicities [including graft versus host disease (GvHD) and cytokine release syndrome (CRS) in clinical trials. Nevertheless, the use of CAR-NK cells in combating viral infections has not yet been fully explored. Previous studies have shown that CAR-NK cells expressing S309 single-chain fragment variable (scFv), hereinafter S309-CAR-NK cells, can bind to SARS-CoV-2 wildtype pseudotyped virus (PV) and effectively kill cells expressing wild-type spike protein .

To kill a tachyzoite: assault and battery.

Polymeric guanylate-binding proteins (GBPs) physically dismember the vacuole membrane formed by Toxoplasma gondii while nitric oxide (NO) poisons and inhibits parasite replication within interferon (IFN)-γ activated macrophages. Zhao et al. report a novel mechanism for synergy between these classical microbicidal and microbistatic effectors in cell-autonomous immunity to the intracellular parasites.

A Dose-Response Study on Functional and Transcriptomic Effects of FSH on Ex Vivo Mouse Folliculogenesis.

Follicle-stimulating hormone (FSH) binds to its membrane receptor (FSHR) in granulosa cells to activate various signal transduction pathways and drive the gonadotropin-dependent phase of folliculogenesis. Both FSH insufficiency (due to genetic or nongenetic factors) and FSH excess (as encountered with ovarian stimulation in assisted reproductive technology [ART]) can cause poor female reproductive outcomes, but the underlying molecular mechanisms remain elusive. Herein, we conducted single-follicle and single-oocyte RNA sequencing analysis along with other approaches in an ex vivo mouse folliculogenesis and oogenesis system to investigate the effects of different concentrations of FSH on key follicular events.

A novel microporous biomaterial vaccine platform for long-lasting antibody mediated immunity against viral infection.

Current antigen delivery platforms, such as alum and nanoparticles, are not readily tunable, thus may not generate optimal adaptive immune responses. We created an antigen delivery platform by loading lyophilized Microporous Annealed Particle (MAP) with aqueous solution containing target antigens. Upon administration of antigen loaded MAP (VaxMAP), the biomaterial reconstitution forms an instant antigen-loaded porous scaffold area with a sustained release profile to maximize humoral immunity.

Quorum-sensing system of primes gene expression for protection from lethal oxidative stress.

The quorum-sensing system links metabolism to virulence, in part by increasing bacterial survival during exposure to lethal concentrations of HO, a crucial host defense against . We now report that protection by surprisingly extends beyond post-exponential growth to the exit from stationary phase when the system is no longer turned on. Thus, can be considered a constitutive protective factor.

Regulation of Mertk Surface Expression via ADAM17 and γ-Secretase Proteolytic Processing.

Mertk, a type I receptor tyrosine kinase and member of the TAM family of receptors, has important functions in promoting efferocytosis and resolving inflammation under physiological conditions. In recent years, Mertk has also been linked to pathophysiological roles in cancer, whereby, in several cancer types, including solid cancers and leukemia/lymphomas. Mertk contributes to oncogenic features of proliferation and cell survival as an oncogenic tyrosine kinase.

The impact of ovarian stimulation on the human endometrial microenvironment.

Study Question: How does ovarian stimulation (OS), which is used to mature multiple oocytes for ART procedures, impact the principal cellular compartments and transcriptome of the human endometrium in the periovulatory and mid-secretory phases?

Summary Answer: During the mid-secretory window of implantation, OS alters the abundance of endometrial immune cells, whereas during the periovulatory period, OS substantially changes the endometrial transcriptome and impacts both endometrial glandular and immune cells.

What Is Known Already: Pregnancies conceived in an OS cycle are at risk of complications reflective of abnormal placentation and placental function. OS can alter endometrial gene expression and immune cell populations.

Sensitization with Fungal Protease Allergen Establishes Long-Lived, Allergenic Th Cell Memory in the Lung.

Allergic asthma is a chronic inflammatory disease that affects millions of individuals worldwide. Exposure to allergens produced by a variety of otherwise harmless microbes, including fungi, predisposes individuals to immunopathologic disease upon subsequent encounters with allergen. We developed a mouse model that employs a purified protease produced by Aspergillus (Asp f 13) to investigate the contributions of CD4+ Th cells to recurrent lung inflammation.

TNFR1 signaling converging on FGF14 controls neuronal hyperactivity and sickness behavior in experimental cerebral malaria.

Background: Excess tumor necrosis factor (TNF) is implicated in the pathogenesis of hyperinflammatory experimental cerebral malaria (eCM), including gliosis, increased levels of fibrin(ogen) in the brain, behavioral changes, and mortality. However, the role of TNF in eCM within the brain parenchyma, particularly directly on neurons, remains underdefined. Here, we investigate electrophysiological consequences of eCM on neuronal excitability and cell signaling mechanisms that contribute to observed phenotypes.

"AHR-ming" host defense against cryptosporidiosis.

Globally, cryptosporidiosis is a leading cause of childhood diarrheal disease and is a major risk factor for malnutrition and impairment of growth and cognitive development. In this issue of Cell Host & Microbe, Maradana et al. identify a target for dietary enhancement of innate immune defenses against cryptosporidiosis.

Rapid activation of IL-2 receptor signaling by CD301b DC-derived IL-2 dictates the outcome of helper T cell differentiation.

Effector T helper (Th) cell differentiation is fundamental to functional adaptive immunity. Different subsets of dendritic cells (DCs) preferentially induce different types of Th cells, but the fate instruction mechanism for Th type 2 (Th2) differentiation remains enigmatic, as the critical DC-derived cue has not been clearly identified. Here, we show that CD301b DCs, a major Th2-inducing DC subset, drive Th2 differentiation through cognate interaction by 'kick-starting' IL-2 receptor signaling in CD4T cells.

Dynamic intravital imaging reveals reactive vessel-associated microglia play a protective role in cerebral malaria coagulopathy.

Vascular congestion and coagulopathy have been shown to play a role in human and experimental cerebral malaria (eCM), but little is known about the role of microglia, or microglia-vascular interactions and hypercoagulation during disease progression in this fatal infection. Recent studies show microglia bind to fibrinogen, a glycoprotein involved in thrombosis. An eCM model of Plasmodium chabaudi infection in mice deficient in the regulatory cytokine IL-10 manifests neuropathology, including hypercoagulation with extensive fibrin(ogen) deposition and neuroinflammation.

Salmonella engages CDC42 effector protein 1 for intracellular invasion.

Human enterocytes are primary targets of infection by invasive bacterium Salmonella Typhimurium, and studies using nonintestinal epithelial cells established that S. Typhimurium activates Rho family GTPases, primarily CDC42, to modulate the actin cytoskeletal network for invasion. The host intracellular protein network that engages CDC42 and influences the pathogen's invasive capacity are relatively unclear.

CD4 T Cell Responses to Are a Double-Edged Sword.

CD4 T cells have been found to play critical roles in the control of both acute and chronic infection. Previous studies identified a protective role for the CD4 T cell-eliciting peptide AS15 (AVEIHRPVPGTAPPS) in C57BL/6J mice. Herein, we found that immunizing mice with AS15 combined with GLA-SE, a TLR-4 agonist in emulsion adjuvant, can be either helpful in protecting male and female mice at early stages against Type I and Type II parasites or harmful (lethal with intestinal, hepatic, and spleen pathology associated with a storm of IL6).

Improved Humoral Immunity and Protection against Influenza Virus Infection with a 3d Porous Biomaterial Vaccine.

New vaccine platforms that activate humoral immunity and generate neutralizing antibodies are required to combat emerging pathogens, including influenza virus. A slurry of antigen-loaded hydrogel microparticles that anneal to form a porous scaffold with high surface area for antigen uptake by infiltrating immune cells as the biomaterial degrades is demonstrated to enhance humoral immunity. Antigen-loaded-microgels elicited a robust cellular humoral immune response, with increased CD4 T follicular helper (Tfh) cells and prolonged germinal center (GC) B cells comparable to the commonly used adjuvant, aluminum hydroxide (Alum).

Infection and inflammation stimulate expansion of a CD74 Paneth cell subset to regulate disease progression.

Paneth cells (PCs), a specialized secretory cell type in the small intestine, are increasingly recognized as having an essential role in host responses to microbiome and environmental stresses. Whether and how commensal and pathogenic microbes modify PC composition to modulate inflammation remain unclear. Using newly developed PC-reporter mice under conventional and gnotobiotic conditions, we determined PC transcriptomic heterogeneity in response to commensal and invasive microbes at single cell level.

Targeting helminths: The expanding world of type 2 immune effector mechanisms.

In this new review, Rick Maizels and Bill Gause summarize how type 2 immune responses combat helminth parasites through novel mechanisms, coordinating multiple innate and adaptive cell and molecular players that can eliminate infection and repair-resultant tissue damage.

Impact of the pentose phosphate pathway on metabolism and pathogenesis of Staphylococcus aureus.

Staphylococcus aureus is an important pathogen that leads to significant disease through multiple routes of infection. We recently published a transposon sequencing (Tn-seq) screen in a mouse acute pneumonia model and identified a hypothetical gene (SAUSA300_1902, pgl) with similarity to a lactonase of Escherichia coli involved in the pentose phosphate pathway (PPP) that was conditionally essential. Limited studies have investigated the role of the PPP in physiology and pathogenesis of S.

Vascular changes in the cycling and early pregnant uterus.

Uterine vascular remodeling is intrinsic to the cycling and early pregnant endometrium. Maternal regulatory factors such as ovarian hormones, VEGF, angiopoietins, Notch, and uterine natural killer cells significantly mediate these vascular changes. In the absence of pregnancy, changes in uterine vessel morphology and function correlate with different stages of the human menstrual cycle.