Common human genetic variants of APOE impact murine COVID-19 mortality.

Clinical outcomes of severe acute respiratory syndrome 2 (SARS-CoV-2) infection are highly heterogeneous, ranging from asymptomatic infection to lethal coronavirus disease 2019 (COVID-19). The factors underlying this heterogeneity remain insufficiently understood. Genetic association studies have suggested that genetic variants contribute to the heterogeneity of COVID-19 outcomes, but the underlying potential causal mechanisms are insufficiently understood. Here we show that common variants of the apolipoprotein E (APOE) gene, homozygous in approximately 3% of the world's population1 and associated with Alzheimer's disease, atherosclerosis and anti-tumour immunity2-5, affect COVID-19 outcome in a mouse model that recapitulates increased susceptibility conferred by male sex and advanced age. Mice bearing the APOE2 or APOE4 variant exhibited rapid disease progression and poor survival outcomes relative to mice bearing the most prevalent APOE3 allele. APOE2 and APOE4 mice exhibited increased viral loads as well as suppressed adaptive immune responses early after infection. In vitro assays demonstrated increased infection in the presence of APOE2 and APOE4 relative to APOE3, indicating that differential outcomes are mediated by differential effects of APOE variants on both viral infection and antiviral immunity. Consistent with these in vivo findings in mice, our results also show that APOE genotype is associated with survival in patients infected with SARS-CoV-2 in the UK Biobank (candidate variant analysis, P = 2.6 × 10-7). Our findings suggest APOE genotype to partially explain the heterogeneity of COVID-19 outcomes and warrant prospective studies to assess APOE genotyping as a means of identifying patients at high risk for adverse outcomes.

Dicke State Generation and Extreme Spin Squeezing via Rapid Adiabatic Passage.

Considering the unique energy level structure of the one-axis twisting Hamiltonian in combination with standard rotations, we propose the implementation of a rapid adiabatic passage scheme on the Dicke state basis. The method permits to drive Dicke states of the many-atom system into entangled states with maximum quantum Fisher information. The designed states allow us to overcome the classical limit of phase sensitivity in quantum metrology and sensing. We show how to generate superpositions of Dicke states, which maximize metrological gain for a Ramsey interferometric measurement. The proposed scheme is remarkably robust to variations of the driving field and has favorable time scaling, especially for a small to moderate (∼1000) number of atoms, where the total time does not depend on the number of atoms.

Chlamydia muridarum infection causes bronchointerstitial pneumonia in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice.

The murine bacterial pathogen Chlamydia muridarum (Cm) has been used to study human Chlamydia infections in various mouse models. CD4+ T-cells, natural killer cells, and interferon-gamma (IFN-γ)-mediated immunity are important to control experimentally induced Cm infections. Despite its experimental use, natural infection by Cm has not been documented in laboratory mice since the 1940s. In 2022, the authors reported the discovery of natural Cm infections in numerous academic institutional laboratory mouse colonies around the globe. To evaluate the impact of Cm infection in severely immunocompromised mice, 19 NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice were cohoused with Cm shedding, naturally infected immunocompetent mice and/or their soiled bedding for 4 weeks and subsequently euthanized. Clinical disease, characterized by lethargy, dyspnea, and weight loss, was observed in 11/19 NSG mice, and 16/18 NSG mice had neutrophilia. All mice exhibited multifocal to coalescing histiocytic and neutrophilic bronchointerstitial pneumonia (17/19) or bronchiolitis (2/19) with intraepithelial chlamydial inclusions (CIs). Immunofluorescence showed CIs were often associated with bronchiolar epithelium. CIs were frequently detected by immunohistochemistry in tracheal and bronchiolar epithelium (19/19), as well as throughout the small and large intestinal epithelium without lesions (19/19). In a subset of cases, Cm colonized the surface epithelium in the nasopharynx (16/19), nasal cavity (7/19), and middle ear canal (5/19). Endometritis and salpingitis with intraepithelial CI were identified in a single mouse. These findings demonstrate that Cm infection acquired through direct contact or soiled bedding causes significant pulmonary pathology and widespread intestinal colonization in NSG mice.

Subcutaneous choriocarcinomas in captive Amargosa voles (Microtus californicus scirpensis).

Spontaneous choriocarcinomas are rare, highly vascular, malignant trophoblastic tumors that occur in humans and animals. This report describes the unusual spontaneous presentation of 4 choriocarcinomas within the subcutaneous tissues of 4, multiparous but nongravid, Amargosa voles (Microtus californicus scirpensis) from a captive breeding colony. Two subcutaneous neoplasms were composed of multifocal discohesive and infiltrative aggregates of medium to large trophoblasts and cytotrophoblasts within a fibrovascular stroma. Neoplastic cells were associated with variably sized thrombi and cavitary areas of hemorrhage and necrosis. Two subcutaneous tumors were predominantly composed of expansile, blood-filled, cystic spaces lined by neoplastic cytotrophoblasts and occasionally contained medium to large trophoblasts. Trophoblasts and cytotrophoblasts were positive for pancytokeratin and cytokeratin 8/18, negative for alpha-fetoprotein, and contained intracytoplasmic Periodic acid-Schiff (PAS)-positive glycogen in all 4 tumors. In species with hemochorial placentation, migration of trophoblasts into maternal circulation with embolization to distant nonreproductive tissues occurs and may explain the unusual subcutaneous distribution of these 4 tumors. The 2 multiloculated paucicellular tumors may represent an early stage of neoplastic transformation. To the authors' knowledge, this is the first report characterizing choriocarcinomas in extrareproductive sites in rodents.

Circularly polarized light-induced potentials and the demise of excited states.

In the presence of strong electric fields, the excited states of single-electron molecules and molecules with large transient dipoles become unstable because of anti-alignment, the rotation of the molecular axis perpendicular to the field vector, where bond hardening is not possible. We show how to overcome this problem by using circularly polarized electromagnetic fields. Using a full quantum description of the electronic, vibrational, and rotational degrees of freedom, we characterize the excited electronic state dressed by the field and analyze its dependence on the bond length and angle and the stability of its vibro-rotational eigenstates. Although the dynamics is metastable, most of the population remains trapped in this excited state for hundreds of femtoseconds, allowing quantum control. Contrary to what happens with linearly polarized fields, the photodissociation occurs along the initial molecular axis, not perpendicular to it.

Anti-alignment driven dynamics in the excited states of molecules under strong fields.

We develop two novel models of the H2+ molecule and its isotopes from which we assess quantum-mechanically and semi-classically whether the molecule anti-aligns with the field in the first excited electronic state. The results from both models allow us to predict anti-alignment dynamics even for the HD+ isotope, which possesses a permanent dipole moment. The molecule dissociates at angles perpendicular to the field polarization in both the excited and the ground electronic state, as the population is exchanged through a conical intersection. The quantum mechanical dispersion of the initial state is sufficient to cause full dissociation. We conclude that the stabilization of these molecules in the excited state through bond-hardening under a strong field is highly unlikely.

Simulations suggest that navigation software may not be as efficient as expected for city traffic.

We suggest a theoretical framework to study the dynamics of an open city, with cars entering at a certain rate and leaving as they reach their destinations. In particular, we assess through simulations some unexpected consequences of the massive use of GPS (global positioning system) navigation systems in the overall dynamics. One of our main interest is to identify what type of measurements would be the most relevant for an experimental study of this system, specifically, the ones useful for city traffic administrators. To do so, we solve the microdynamics using a cellular automaton model considering three different navigation strategies based on the minimization of the individual paths (unweighted strategy) or travel times (weighted strategies). Although the system is inherently stochastic, we found in our simulations an equivalent saddle-node bifurcation for all strategies where the input rate acts as a bifurcation parameter. There is also evidence of additional bifurcations for travel time minimization based strategies. Although we found that weighted strategies are more efficient in terms of car motion, there is a destabilization phenomenon that makes, in an unexpected way, a variation of the unweighted strategy more optimal at certain densities from the fuel efficiency of the overall city traffic point of view. These results bring new insight into the intrinsic dynamics of cities and the perturbations that individual traffic routing can produce on the city as a whole.

An Analytical Approach to Flow-Guided Nanocommunication Networks.

Continuous progress of nanocommunications and nano-networking is opening the door to the development of innovative yet unimaginable services, with a special focus on medical applications. Among several nano-network topologies, flow-guided nanocommunication networks have recently emerged as a promising solution to monitoring, gathering information, and data communication inside the human body. In particular, flow-guided nano-networks display a number of specific characteristics, such as the type of nodes comprising the network or the ability of a nano-node to transmit successfully, which significantly differentiates them from other types of networks, both at the nano and larger scales. This paper presents the first analytical study on the behavior of these networks, with the objective of evaluating their metrics mathematically. To this end, a theoretical framework of the flow-guided nano-networks is developed and an analytical model derived. The main results reveal that, due to frame collisions, there is an optimal number of nano-nodes for any flow-guided network, which, as a consequence, limits the maximum achievable throughput. Finally, the analytical results obtained are validated through simulations and are further discussed.

Anaplastic nephroblastoma with peritoneal metastasis in an adult female Sprague Dawley rat.

Spontaneous nephroblastomas are uncommon tumors of laboratory rats. This report describes a spontaneous nephroblastoma with peritoneal metastasis in an 11-month-old, female Sprague Dawley rat. The rat was part of a breeding program and presented 15 days post parturition with clinical signs including tachypnea, dyspnea and abdominal distension. At necropsy, the right kidney was markedly enlarged by an expansile pale-tan to white multinodular mass with extension into the retroperitoneal space, with multifocal variably sized nodules involving the mesentery, and surface of pancreas, liver, uterus, and ovarian bursa. The rat also had severe bicavitary effusion. Histologically, the renal parenchyma of the affected kidney was replaced by a moderately cellular, poorly-demarcated, non-encapsulated, multilobulated mass that appeared to compress the adjacent renal outer medulla and cortex. Three distinct neoplastic cell populations were identified in this renal tumor: epithelial cells (convoluted and dilated tubules / rare primitive glomeruloid structures), mesenchymal (neoplastic spindle cells in connective tissue), and blastemal cells (primitive neoplastic cells). The extrarenal nodular masses were predominantly composed of neoplastic mesenchymal and pleomorphic blastemal cells. Immunohistochemically, neoplastic epithelial cells in the renal mass were positive for pancytokeratin, and blastemal cells in both renal and extrarenal masses were positive for Wilms' tumor 1 protein (WT1) and vimentin. Neoplastic mesenchymal elements in both renal and extrarenal masses were positive for vimentin. The neoplasm was negative for chromogranin A and S100. The tumor was classified as an anaplastic nephroblastoma with metastasis to the mesentery and peritoneal organs.

Traumatic phacocele in an American Miniature Horse.

An 18-year-old American Miniature Horse mare was presented with a complaint of a scleral swelling affecting the right eye and a history of suspected trauma 6 weeks prior to evaluation. Clinical findings included severe blepharospasm, a bulbous swelling of the dorsotemporal bulbar conjunctiva, and phthisis bulbi. Ocular ultrasound was recommended but declined. Enucleation was elected for the blind, painful eye and was performed standing. Gross and histopathologic examinations of the globe were consistent with extrusion of the lens to the episcleral space, which is classified as a traumatic phacocele when associated with naturally occurring trauma. The location of lens entrapment suggested globe rupture occurred at the limbus, which is described as one of the weakest points of the equine globe. Subconjunctival dislocation of the lens and development of a traumatic phacocele should be considered as a differential diagnosis for horses presenting with subconjunctival masses, apparent aphakia, and historical trauma.

Positive and Negative Regulation of Glycerol Utilization by the c-di-GMP Binding Protein PlzA in Borrelia burgdorferi.

Borrelia burgdorferi, the causative agent of Lyme disease, encounters two disparate host environments during its enzootic life cycle, Ixodes ticks and mammalian hosts. B. burgdorferi has a small genome that encodes a streamlined cyclic dimeric GMP (c-di-GMP) signaling system comprising a single diguanylate cyclase, Rrp1, and two phosphodiesterases. This system is essential for spirochete survival in ticks, in part because it controls the expression of the glp operon involved in glycerol utilization. In this study, we showed that a B. burgdorferi c-di-GMP receptor, PlzA, functions as both a positive and a negative regulator for glp expression. Deletion of plzA or mutation in plzA that impaired c-di-GMP binding abolished glp expression. On the other hand, overexpression of plzA resulted in glp repression, which could be rescued by simultaneous overexpression of rrp1. plzA overexpression in the rrp1 mutant, which is devoid of c-di-GMP, or overexpression of a plzA mutant incapable of c-di-GMP binding further enhanced glp repression. Combined results suggest that c-di-GMP-bound PlzA functions as a positive regulator, whereas ligand-free PlzA acts as a negative regulator for glp expression. Thus, PlzA of B. burgdorferi with a streamlined c-di-GMP signaling system not only controls multiple targets, as previously envisioned, but has also evolved different modes of action.IMPORTANCE The Lyme disease pathogen, Borrelia burgdorferi, has a simple cyclic dimeric GMP (c-di-GMP) signaling system essential for adaptation of the pathogen to the complicated tick environment. The c-di-GMP effector of B. burgdorferi, PlzA, has been shown to regulate multiple cellular processes, including motility, osmolality sensing, and nutrient utilization. The findings of this study demonstrate that PlzA not only controls multiple targets but also has different functional modalities, allowing it to act as both positive and negative regulator of the glp operon expression. This work highlights how bacteria with a small genome can compensate for the limited regulatory repertoire by increasing the complexity of targets and modes of action in their regulatory proteins.

On the Nature of Energy-Feasible Wireless Nanosensor Networks.

Electromagnetic nanocommunications, understood as the communication between electronic nanoscale devices through electromagnetic waves in the terahertz band, has attracted increasing attention in recent years. In this regard, several solutions have already been proposed. However, many of them do not sufficiently capture the significance of the limitations in nanodevice energy-gathering and storing capacity. In this paper, we address key factors affecting the energy consumption of nanodevices, highlighting the effect of the communication scheme employed. Then, we also examine how nanodevices are powered, focusing on the main parameters governing the powering nanosystem. Different mathematical expressions are derived to analyze the impact of these parameters on its performance. Based on these expressions, the functionality of a nanogenerator is evaluated to gain insight into the conditions under which a wireless nanosensor network (WNSN) is viable from the energetic point of view. The results reveal that a micrometer-sized piezoelectric system in high-lossy environments (exceeding 100 dB/mm) becomes inoperative for transmission distances over 1.5 mm by its inability to harvest and store the amount of energy required to overcome the path loss.

Conceptual Design of a Nano-Networking Device.

Nanotechnology is an emerging scientific area whose advances, among many others, have a positive direct impact on the miniaturization of electronics. This unique technology enables the possibility to design and build electronic components as well as complete devices (called nanomachines or nanodevices) at the nano scale. A nanodevice is expected to be an essential element able to operate in a nanonetwork, where a huge number of them would coordinate to acquire data, process the information gathered, and wirelessly transmit those data to end-points providing innovative services in many key scenarios, such as the human body or the environment. This paper is aimed at studying the feasibility of this type of device by carefully examining their main component parts, namely the nanoprocessor, nanomemory, nanoantenna, and nanogenerator. To this end, a thorough state-of-the-art review is conveyed to discuss, substantiate, and select the most suitable current technology (commercial or pre-commercial) for each component. Then, we further contribute by developing a complete conceptual nanodevice layout taking into consideration its ultra-small size (similar to a blood cell) and its very restricted capabilities (e.g., processing, memory storage, telecommunication, and energy management). The required resources as well as the power consumption are realistically estimated.

Outer surface protein OspC is an antiphagocytic factor that protects Borrelia burgdorferi from phagocytosis by macrophages.

Outer surface protein C (OspC) is one of the major lipoproteins expressed on the surface of Borrelia burgdorferi during tick feeding and the early phase of mammalian infection. OspC is required for B. burgdorferi to establish infection in both immunocompetent and SCID mice and has been proposed to facilitate evasion of innate immune defenses. However, the exact biological function of OspC remains elusive. In this study, we showed that the ospC-deficient spirochete could not establish infection in NOD-scid IL2rγ(null) mice that lack B cells, T cells, NK cells, and lytic complement. The ospC mutant also could not establish infection in anti-Ly6G-treated SCID and C3H/HeN mice (depletion of neutrophils). However, depletion of mononuclear phagocytes at the skin site of inoculation in SCID and C3H/HeN mice allowed the ospC mutant to establish infection in vivo. In phagocyte-depleted mice, the ospC mutant was able to colonize the joints and triggered neutrophilia during dissemination. Furthermore, we found that phagocytosis of green fluorescent protein (GFP)-expressing ospC mutant spirochetes by murine peritoneal macrophages and human THP-1 macrophage-like cells, but not in PMN-HL60, was significantly higher than parental wild-type B. burgdorferi strains, suggesting that OspC has an antiphagocytic property. In addition, overproduction of OspC in spirochetes also decreased the uptake of spirochetes by murine peritoneal macrophages. Together, our findings provide evidence that mononuclear phagocytes play a key role in clearance of the ospC mutant and that OspC promotes spirochetes' evasion of macrophages during early Lyme borreliosis.

Enhancing Alginate Hydrogels as Possible Wound-Healing Patches: The Synergistic Impact of Reduced Graphene Oxide and Tannins on Mechanical and Adhesive Properties.

Hydrogels are three-dimensional crosslinked materials known for their ability to absorb water, exhibit high flexibility, their biodegradability and biocompatibility, and their ability to mimic properties of different tissues in the body. However, their application is limited by inherent deficiencies in their mechanical properties. To address this issue, reduced graphene oxide (rGO) and tannins (TA) were incorporated into alginate hydrogels (Alg) to evaluate the impact of the concentration of these nanomaterials on mechanical and adhesive, as well as cytotoxicity and wound-healing properties. Tensile mechanical tests demonstrated improvements in tensile strength, elastic modulus, and toughness upon the incorporation of rGO and TA. Additionally, the inclusion of these materials allowed for a greater energy dissipation during continuous charge-discharge cycles. However, the samples did not exhibit self-recovery under environmental conditions. Adhesion was evaluated on pig skin, revealing that higher concentrations of rGO led to enhanced adhesion, while the concentration of TA did not significantly affect this property. Moreover, adhesion remained consistent after 10 adhesion cycles, and the contact time before the separation between the material and the surface did not affect this property. The materials were not cytotoxic and promoted healing in human fibroblast-model cells. Thus, an Alg/rGO/TA hydrogel with enhanced mechanical, adhesive, and wound-healing properties was successfully developed.

Chlamydia muridarum Associated Pulmonary and Urogenital Disease and Pathology in a Colony of Enzootically Infected Il12rb2 Deficient and Stat1 Knockout Mice.

Chlamydia muridarum (Cm), an intracellular bacterium of historical importance, was recently rediscovered as moderately prevalent in research mouse colonies. Cm was first reported as a causative agent of severe pneumonia in mice about 80 y ago, and while it has been used experimentally to model Chlamydia trachomatis infection of humans, there have been no further reports of clinical disease associated with natural infection. We observed clinical disease and pathology in 2 genetically engi- neered mouse (GEM) strains, Il12rb2 KO and STAT1 KO, with impaired interferon-γ signaling and Th1 CD4+ T cell responses in a colony of various GEM strains known to be colonized with and shedding Cm. Clinical signs included poor condition, hunched posture, and poor fecundity. Histopathology revealed disseminated Cm with lesions in pulmonary, gastrointestinal, and urogenital tissues. The presence of Cm was confirmed using both immunohistochemistry for Cm major outer membrane protein-1 antigen and in situ hybridization using a target probe directed against select regions of Cm strain Nigg. Cm was also found in association with a urothelial papilloma in one mouse. These cases provide additional support for excluding Cm from research mouse colonies.

Assessment of Antimicrobial Therapy in Eradicating Chlamydia muridarum in Research Mice: Immune Status and its Impact on Outcomes.

Chlamydia muridarum (Cm) is a moderately prevalent, gram-negative, intracellular bacterium that affects laboratory mice, causing subclinical to severe disease, depending on the host's immune status. The effectiveness of various antibiotic regimens aimed at eradicating Cm in both immunodeficient and immunocompetent laboratory mice was evaluated. NSG mice were cohoused with Cm-shedding BALB/cJ mice for 14 days to simulate natural exposure. Four groups of 8 infected NSG mice were treated for 7 days with either 0.08% sulfamethoxazole and 0.016% trimethoprim (TMS) in water, 0.0625% doxycycline in feed, 0.124%/0.025% TMS in feed, or 0.12% amoxicillin in feed. A control group was provided standard water and feed. The impact of treatment on gastrointestinal microbiota (GM) was performed using next-generation shotgun sequencing on the last day of treatment. TMS and Amoxicillin had negligible effects on GM, while doxycycline had the largest effect. All antibiotic treated NSG mice exhibited clinical disease, including dehydration, hunched posture, >20% weight loss, and dyspnea, leading to euthanasia 21-40 days post-treatment (32.6 ± 4.2 days; mean ± SD). Untreated controls were euthanized 14-33 days post-exposure (23.75 ± 5.9 days). All mice were fecal PCR positive for Cm at euthanasia. Histological evaluation revealed multifocal histiocytic and neutrophilic bronchointerstitial pneumonia and/or bronchiolitis featuring prominent intralesional chlamydial inclusion bodies in all mice. Subsequently, groups of 8 C57BL/6J, BALB/cJ, NOD.SCID, and NSG mice infected with Cm were treated with 0.124%/0.025% TMS in feed for 7 (BALB/cJ and C57BL/6J) or 21 days (NSG and NOD.SCID). All immunocompetent and NOD.SCID mice were negative for Cm by PCR 14 days post-treatment, remained clinically normal and had no evidence of Cm infection at necropsy, all NSG mice remained Cm positive and were euthanized. While these findings highlight the difficulties in eradicating Cm from highly immunodeficient mice, eradication of Cm from immunocompetent or moderately immunocompromised mice with antibiotics is feasible.

Chlamydia muridarum Causes Persistent Subclinical Infection and Elicits Innate and Adaptive Immune Responses in C57BL/6J, BALB/cJ and J:ARC(S) Mice Following Exposure to Shedding Mice.

Chlamydia muridarum (Cm) has reemerged as a moderately prevalent infectious agent in research mouse colonies. Despite its' experimental use, few studies evaluate Cm's effects on immunocompetent mice following its natural route of infection. A Cm field isolate was administered (orogastric gavage) to 8-week-old female BALB/cJ (C) mice. After confirming shedding (through 95d), these mice were cohoused with naïve C57BL/6J (B6), C, and Swiss (J:ARC[S]) mice (n=28/strain) for 30 days. Cohoused mice (n=3-6 exposed and 1-6 control/strain) were evaluated 7, 14, 21, 63, 120, and 180 days post-cohousing (DPC) via hemograms, serum biochemistry analysis, fecal qPCR, histopathology, and Cm MOMP immunohistochemistry. Immunophenotyping was performed on spleen (B6, C, S; n=6/strain) and intestines (B6; n=6) at 14 and 63 DPC. Serum cytokine concentrations were measured (B6; n=6 exposed and 2 control) at 14 and 63 DPC. All B6 mice were shedding Cm by 3 through 180 DPI. One of 3 C and 1 of 6 S mice began shedding Cm at 3 and 14 DPC, respectively, with the remaining shedding thereafter. Clinical pathology was nonremarkable. Minimal-to-moderate enterotyphlocolitis and gastrointestinal associated lymphoid tissue (GALT) hyperplasia was observed in 15 and 47 of 76 Cm-infected mice, respectively. Cm antigen was frequently detected in GALT-associated surface intestinal epithelial cells. Splenic immunophenotyping revealed increased monocytes and shifts in T cell population subsets in all strains/timepoints. Gastrointestinal immunophenotyping (B6) revealed sustained increases in total inflammatory cells and elevated cytokine production in innate lymphoid cells and effector T cells (large intestine). Elevated concentrations of pro-inflammatory cytokines were detected in the serum (B6). Results demonstrate that while clinical disease was not appreciated, 3 commonly utilized strains of mice are susceptible to chronic enteric Cm infection which may alter various immune responses. Considering the widespread use of mice to model GI disease, institutions should consider excluding Cm from their colonies.

Diet induced insulin resistance is due to induction of PTEN expression.

Type 2 Diabetes (T2D) is a condition that is often associated with obesity and defined by reduced sensitivity of PI3K signaling to insulin (insulin resistance), hyperinsulinemia and hyperglycemia. Molecular causes and early signaling events underlying insulin resistance are not well understood. Insulin activation of PI3K signaling causes mTOR dependent induction of PTEN translation, a negative regulator of PI3K signaling. We speculated that insulin resistance is due to insulin dependent induction of PTEN protein that prevent further increases in PI3K signaling. Here we show that in a diet induced model of obesity and insulin resistance, PTEN levels are increased in fat, muscle and liver tissues. Onset of hyperinsulinemia and PTEN induction in tissue is followed by hyperglycemia, hepatic steatosis and severe glucose intolerance. Treatment with a PTEN phosphatase inhibitor prevents and reverses these phenotypes, whereas an mTORC1 kinase inhibitor reverses all but the hepatic steatosis. These data suggest that induction of PTEN by increasing levels of insulin elevates feedback inhibition of the pathway to a point where downstream PI3K signaling is reduced and hyperglycemia ensues. PTEN induction is thus necessary for insulin resistance and the type 2 diabetes phenotype and a potential therapeutic target.

Gastric coinfection with thiopeptide-positive Cutibacterium acnes decreases FOXM1 and pro-inflammatory biomarker expression in a murine model of Helicobacter pylori-induced gastric cancer.

IMPORTANCE: H. pylori infects half of the world population and is the leading cause of gastric cancer. We previously demonstrated that gastric cancer risk is associated with gastric microbiota. Specifically, gastric urease-positive Staphylococcus epidermidis and Streptococcus salivarius had contrasting effects on H. pylori-associated gastric pathology and immune responses in germ-free INS-GAS mice. As gastritis progresses to gastric cancer, the oncogenic transcription factor Foxm1 becomes increasingly expressed. In this study, we evaluated the gastric commensal C. acnes, certain strains of which produce thiopeptides that directly inhibit FOXM1. Thiopeptide-positive C. acnes was isolated from Nicaraguan patient gastric biopsies and inoculated into germ-free INS-GAS mice with H. pylori. We, therefore, asked whether coinfection with C. acnes expressing thiopeptide and H. pylori would decrease gastric Foxm1 expression and pro-inflammatory cytokine mRNA and protein levels. Our study supports the growing literature that specific non-H. pylori gastric bacteria affect inflammatory and cancer biomarkers in H. pylori pathogenesis.