Antibody-mediated immunological memory correlates with long-term Lyme veterinary vaccine protection in mice.

Lyme disease, caused by the bacterium Borrelia burgdorferi, is the most common tick-borne illness in the United States. Despite the rise in Lyme disease incidence, there is no vaccine against B. burgdorferi approved for human use. Little is known about the immune correlates of protection needed to prevent Lyme disease. In this work, a mouse model was used to characterize the immune response and compare the protection provided by two USDA-approved vaccines for use in canines: Duramune (bacterin vaccine) and Vanguard crLyme (subunit vaccine composed of two outer surface proteins, OspA and OspC). C3H/HeNCrl mice were immunized with two doses of either Duramune or Vanguard, and immune responses and protection against B. burgdorferi were assessed in short (35 days) and long-term (120 days) studies. Flow cytometry, ELISPOT detection of antibody-producing cells, and antibody affinity studies were performed to identify correlates of vaccine-mediated protection. Both vaccines induced humoral responses, with high IgG titers against B. burgdorferi. However, the levels of anti-B. burgdorferi antibodies decayed over time in Vanguard-vaccinated mice. While both vaccines triggered the production of antibodies against both OspA and OspC, antibody levels against these proteins were also lower in Vanguard-vaccinated mice 120 days post-vaccination. Both vaccines only provided partial protection against B. burgdorferi at the dose used in this model. The protection provided by Duramune was superior to Vanguard 120 days post-vaccination, and was characterized by higher antibody titers, higher abundance of long-lived plasma cells, and higher avidity antibodies than Vanguard. Overall, these studies provide insights into the importance of the humoral memory response to veterinary vaccines against Lyme disease and will help inform the development of future human vaccines.

Advancing Heteroanionicity in Zintl Phases: Crystal Structures, Thermoelectric and Magnetic Properties of Two Quaternary Semiconducting Arsenide Oxides, Eu8Zn2As6O and Eu14Zn5As12O.

Two novel quaternary oxyarsenides, Eu8Zn2As6O and Eu14Zn5As12O, were synthesized through metal flux reactions, and their crystal structures were established by single-crystal X-ray diffraction methods. Eu8Zn2As6O crystallizes in the orthorhombic space group Pbca, featuring polyanionic ribbons composed of corner-shared triangular [ZnAs3] units, running along the [100] direction. The structure of Eu14Zn5As12O crystallizes in the monoclinic space group P2/m and its anionic substructure can be described as an infinite "ribbonlike" chain comprised of [ZnAs3] trigonal-planar units, although the structural complexity here is greater and also amplified by disorder on multiple crystallographic positions. In both structures, the O2- anion occupies an octahedral void with six neighboring Eu2+ cations. Formal electron counting, electronic structure calculations, and transport properties reveal the charge-balanced semiconducting nature of these heteroanionic Zintl phases. High-temperature thermoelectric transport properties measurements on Eu14Zn5As12O reveal relatively high resistivity (ρ500K = 8 Ω·cm) and Seebeck coefficient values (S500K = 220 µV K-1), along with a low concentration and mobility of holes as the dominant charge-carriers (n500K = 8.0 × 1017 cm-3, µ500K = 6.4 cm2/V s). Magnetic studies indicate the presence of divalent Eu2+ species in Eu14Zn5As12O and complex magnetic ordering, with two transitions observed at T1 = 21.6 K and T2 = 9 K.

ESR1 and p53 interactome alteration defines mechanisms of tamoxifen response in luminal breast cancer.

The canonical mechanism behind tamoxifen's therapeutic effect on estrogen receptor α/ESR1+ breast cancers is inhibition of ESR1-dependent estrogen signaling. Although ESR1+ tumors expressing wild-type p53 were reported to be more responsive to tamoxifen (Tam) therapy, p53 has not been factored into choice of this therapy and the mechanism underlying the role of p53 in Tam response remains unclear. In a window-of-opportunity trial on patients with newly diagnosed stage I-III ESR1+/HER2/wild-type p53 breast cancer who were randomized to arms with or without Tam prior to surgery, we reveal that the ESR1-p53 interaction in tumors was inhibited by Tam. This resulted in functional reactivation of p53 leading to transcriptional reprogramming that favors tumor-suppressive signaling, as well as downregulation of oncogenic pathways. These findings illustrating the convergence of ESR1 and p53 signaling during Tam therapy enrich mechanistic understanding of the impact of p53 on the response to Tam therapy.

Multifactoral immune modulation potentiates durable remission in multiple models of aggressive malignancy.

Tumors typically lack canonical danger signals required to activate adaptive immunity and also frequently employ substantial immunomodulatory mechanisms that downregulate adaptive responses and contribute to escape from immune surveillance. Given the variety of mechanisms involved in shielding tumors from immune recognition, it is not surprising that single-agent immunomodulatory approaches have been largely unsuccessful in generating durable antitumor responses. Here we report a unique combination of immunomodulatory and cytostatic agents that recondition the tumor microenvironment and eliminate complex and/or poor-prognosis tumor types including the non-immunogenic 4T-1 model of TNBC, the aggressive MOC-2 model of HNSCC, and the high-risk MYCN-amplified model of neuroblastoma. A course of therapy optimized for TNBC cured a majority of tumors in both ectopic and orthotopic settings and eliminated metastatic spread in all animals tested at the highest doses. Immune responses were transferable between therapeutic donor and naïve recipient through adoptive transfer, and a sizeable abscopal effect on distant, untreated lesions could be demonstrated experimentally. Similar results were observed in HNSCC and neuroblastoma models, with characteristic remodeling of the tumor microenvironment documented in all model systems. scRNA-seq analysis implicated upregulation of innate immune responses and antigen presentation in tumor cells and the myeloid cell compartment as critical early events. This analysis also highlighted the potential importance of the autonomic nervous system in the governance of inflammatory processes. The data indicate that the targeting of multiple pathways and mechanisms of action can result in substantial synergistic antitumor effects and suggest follow-up in the neoadjuvant setting may be warranted.

Critical care outcomes in decompensated cirrhosis: a United States national inpatient sample cross-sectional study.

BACKGROUND: Prior assessments of critical care outcomes in patients with cirrhosis have shown conflicting results. We aimed to provide nationwide generalizable results of critical care outcomes in patients with decompensated cirrhosis. METHODS: This is a retrospective study using the National Inpatient Sample from 2016 to 2019. Adults with cirrhosis who required respiratory intubation, central venous catheter placement or both (n = 12,945) with principal diagnoses including: esophageal variceal hemorrhage (EVH, 24%), hepatic encephalopathy (58%), hepatorenal syndrome (HRS, 14%) or spontaneous bacterial peritonitis (4%) were included. A comparison cohort of patients without cirrhosis requiring intubation or central line placement for any principal diagnosis was included. RESULTS: Those with cirrhosis were younger (mean 58 vs. 63 years, p < 0.001) and more likely to be male (62% vs. 54%, p < 0.001). In-hospital mortality was higher in the cirrhosis cohort (33.1% vs. 26.6%, p < 0.001) and ranged from 26.7% in EVH to 50.6% HRS. Mortality when renal replacement therapy was utilized (n = 1580, 12.2%) was 46.5% in the cirrhosis cohort, compared to 32.3% in other hospitalizations (p < 0.001), and was lowest in EVH (25.7%) and highest in HRS (51.5%). Mortality when cardiopulmonary resuscitation was used was increased in the cirrhosis cohort (88.0% vs. 72.1%, p < 0.001) and highest in HRS (95.7%). CONCLUSIONS: One-third of patients with cirrhosis requiring critical care did not survive to discharge in this U.S. nationwide assessment. While outcomes were worse than in patients without cirrhosis, the results do suggest better outcomes compared to previous studies.

Non-invasive biomarkers for detecting progression toward hypovolemic cardiovascular instability in a lower body negative pressure model.

Occult hemorrhages after trauma can be present insidiously, and if not detected early enough can result in patient death. This study evaluated a hemorrhage model on 18 human subjects, comparing the performance of traditional vital signs to multiple off-the-shelf non-invasive biomarkers. A validated lower body negative pressure (LBNP) model was used to induce progression towards hypovolemic cardiovascular instability. Traditional vital signs included mean arterial pressure (MAP), electrocardiography (ECG), plethysmography (Pleth), and the test systems utilized electrical impedance via commercial electrical impedance tomography (EIT) and multifrequency electrical impedance spectroscopy (EIS) devices. Absolute and relative metrics were used to evaluate the performance in addition to machine learning-based modeling. Relative EIT-based metrics measured on the thorax outperformed vital sign metrics (MAP, ECG, and Pleth) achieving an area-under-the-curve (AUC) of 0.99 (CI 0.95-1.00, 100% sensitivity, 87.5% specificity) at the smallest LBNP change (0-15 mmHg). The best vital sign metric (MAP) at this LBNP change yielded an AUC of 0.6 (CI 0.38-0.79, 100% sensitivity, 25% specificity). Out-of-sample predictive performance from machine learning models were strong, especially when combining signals from multiple technologies simultaneously. EIT, alone or in machine learning-based combination, appears promising as a technology for early detection of progression toward hemodynamic instability.

Peri-Operative Impact of Cannabis Use in Conjunction With Elective Primary Breast Augmentation in a Private Practice.

Background The consumption of recreational and medicinal cannabis in the United States continues to increase. Understanding the effects of cannabis in patients undergoing elective primary breast augmentation (EPBA) is of paramount importance with the expanding rates of reported cannabis consumption. Objectives This study aims to analyze the peri-operative impact of cannabis use in conjunction with EPBA in a single-surgeon practice in San Francisco, California. Methods A retrospective chart review was performed of 134 adult female patients undergoing EPBA from August 2018 to January 2022 within a single-surgeon practice plastic surgery office. Cannabis use was self-reported as current use or former use. Cohorts were grouped as cannabis users and cannabis non-users. Results Of the 134 patient charts identified for analysis, 58 (43.3%) reported cannabis use. Cannabis users were significantly younger than cannabis non-users (26.8 years versus 31.5 years, P<0.001). No significant differences were found between groups among intra-operative blood loss, post-operative complication rates, post-operative narcotic use, or intra-operative anesthetic requirements. The incidence of adverse events, including wound breakdown, skin necrosis, and capsular contracture requiring reoperation, did not differ significantly between cannabis users and cannabis non-user groups. Ninety-six percent of patients had their implants placed subpectorally, and all procedures were done using a Keller funnel. Eighty-three percent of patients had Sientra implants, and 96% of all implants were silicone gel implants. All procedures were done under general anesthesia. Patients were followed for up to two years. Discussion This review found no significant differences in peri-operative and post-operative outcomes between cannabis users and cannabis non-users.

Race-specific coregulatory and transcriptomic profiles associated with DNA methylation and androgen receptor in prostate cancer.

BACKGROUND: Prostate cancer is a significant health concern, particularly among African American (AA) men who exhibit higher incidence and mortality compared to European American (EA) men. Understanding the molecular mechanisms underlying these disparities is imperative for enhancing clinical management and achieving better outcomes. METHODS: Employing a multi-omics approach, we analyzed prostate cancer in both AA and EA men. Using Illumina methylation arrays and RNA sequencing, we investigated DNA methylation and gene expression in tumor and non-tumor prostate tissues. Additionally, Boolean analysis was utilized to unravel complex networks contributing to racial disparities in prostate cancer. RESULTS: When comparing tumor and adjacent non-tumor prostate tissues, we found that DNA hypermethylated regions are enriched for PRC2/H3K27me3 pathways and EZH2/SUZ12 cofactors. Olfactory/ribosomal pathways and distinct cofactors, including CTCF and KMT2A, were enriched in DNA hypomethylated regions in prostate tumors from AA men. We identified race-specific inverse associations of DNA methylation with expression of several androgen receptor (AR) associated genes, including the GATA family of transcription factors and TRIM63. This suggests that race-specific dysregulation of the AR signaling pathway exists in prostate cancer. To investigate the effect of AR inhibition on race-specific gene expression changes, we generated in-silico patient-specific prostate cancer Boolean networks. Our simulations revealed prolonged AR inhibition causes significant dysregulation of TGF-ß, IDH1, and cell cycle pathways specifically in AA prostate cancer. We further quantified global gene expression changes, which revealed differential expression of genes related to microtubules, immune function, and TMPRSS2-fusion pathways, specifically in prostate tumors of AA men. Enrichment of these pathways significantly correlated with an altered risk of disease progression in a race-specific manner. CONCLUSIONS: Our study reveals unique signaling networks underlying prostate cancer biology in AA and EA men, offering potential insights for clinical management strategies tailored to specific racial groups. Targeting AR and associated pathways could be particularly beneficial in addressing the disparities observed in prostate cancer outcomes in the context of AA and EA men. Further investigation into these identified pathways may lead to the development of personalized therapeutic approaches to improve outcomes for prostate cancer patients across different racial backgrounds.

Aryl hydrocarbon receptor suppresses STING-mediated type I IFN expression in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is one of the most aggressive types of cancer. Despite decades of intense investigation, treatment options remain limited, and rapid recurrence with distant metastases remains a significant challenge. Cancer cell-intrinsic production of cytokines such as type I interferons (IFN-I) is a known potent modulator of response to therapy in many cancers, including TNBC, and can influence therapeutic outcome. Here, we report that, in TNBC systems, the aryl hydrocarbon receptor (AhR) suppresses IFN-I expression via inhibition of STImulator of Interferon Genes (STING), a key mediator of interferon production. Intratumoral STING activity is essential in mediating the efficacy of PARP inhibitors (PARPi) which are used in the treatment of cancers harboring BRCA1 deficiency. We find that, in TNBC cells, PARPi treatment activates AhR in a BRCA1 deficiency-dependent manner, thus suggesting the presence of a negative feedback loop aimed at modulating PARPi efficacy. Importantly, our results indicate that the combined inhibition of PARP and AhR is superior in elevating IFN-I expression as compared to PARPi-alone. Thus, AhR inhibition may allow for enhanced IFN-I production upon PARPi in BRCA1-deficient breast cancers, most of which are of TNBC origin, and may represent a therapeutically viable strategy to enhance PARPi efficacy.

New Perspectives on Foot Segment Forces and Joint Kinetics-Integrating Plantar Shear Stresses and Pressures with Multi-segment Foot Modeling.

The role of the many small foot articulations and plantar tissues in gait is not well understood. While kinematic multi-segment foot models have increased our knowledge of foot segmental motions, the integration of kinetics with these models could further advance our understanding of foot mechanics and energetics. However, capturing and effectively utilizing segmental ground reaction forces remains challenging. The purposes of this study were to (1) develop methodology to integrate plantar pressures and shear stresses with a multi-segment foot model, and (2) generate and concisely display key normative data from this combined system. Twenty-six young healthy adults walked barefoot (1.3 m/s) across a pressure/shear sensor with markers matching a published 4-segment foot model. A novel anatomical/geometric template-based masking method was developed that successfully separated regions aligned with model segmentation. Directional shear force plots were created to summarize complex plantar shear distributions, showing opposing shear forces both between and within segments. Segment centers of pressure (CoPs) were shown to be primarily stationary within each segment, suggesting that forward progression in healthy gait arises primarily from redistributing weight across relatively fixed contact points as opposed to CoP movement within a segment. Inverse dynamics-based normative foot joint moments and power were presented in the context of these CoPs to aid in interpretation of tissue stresses. Overall, this work represents a successful integration of motion capture with direct plantar pressure and shear measurements for multi-segment foot kinetics. The presented tools are versatile enough to be used with other models and contexts, while the presented normative database may be useful as a baseline comparison for clinical work in gait energetics and efficiency, balance, and motor control. We hope that this work will aid in the advancement and availability of kinetic MSF modeling, increase our knowledge of foot mechanics, and eventually lead to improved clinical diagnosis, rehabilitation, and treatment.

Novel ternary Zintl phosphide halides Ba3P5X (X = Cl, Br) with 1D helical phosphorus chains: synthesis, crystal and electronic structure.

Black single crystals of two novel ternary phosphide halides, Ba3P5Cl and Ba3P5Br, were grown using molten metal Pb-flux high-temperature reactions. These compounds were structurally characterized with the aid of the single-crystal X-ray diffraction (SCXRD) method at 100(2) K. The SCXRD shows that both compounds are isostructural and adopt a new structure type (space group R3̄c, No. 167, Z = 6) with unit cell parameters a = 14.9481(16) Å, c = 7.3954(11) Å and a = 15.045(4) Å, c = 7.537(3) Å for Ba3P5Cl and Ba3P5Br, respectively. Cl- and Br- anions are octahedrally coordinated by Ba2+ cations, thus composing a face-sharing 1D infinite chain 1∞[XBa3]5+ running along the [001] direction. Moreover, the crystal structures feature peculiar one-dimensional disordered infinite helical chains of 1∞P-, composed of partially occupied phosphorous atoms, each being a superposition of three symmetrical copies of the ordered phosphorus chain, with continuity along the c-axis. Ba3P5X (X = Cl, Br) compounds are charge-balanced heteroanionic Zintl phases according to the charge-partitioning scheme (Ba2+)3[P-]5X-. The presumed semiconducting behavior of both compounds corroborates well with the results of the electronic structure calculations performed with the aid of the TB-LMTO-ASA code.

BODIPY Chemisorbed on SnO2 and TiO2 Surfaces for Photoelectrochemical Applications.

Advancement toward dye-sensitized photoelectrochemical cells to produce solar fuels by solar-driven water splitting requires a photosensitizer that is firmly attached to the semiconducting photoelectrodes. Covalent binding enhances the efficiency of electron injection from the photoexcited dye into the metal oxide. Optimization of charge transfer, efficient electron injection, and minimal electron-hole recombination are mandatory for achieving high efficiencies. Here, a BODIPY-based dye exploiting a novel surface-anchoring mode via boron is compared to a similar dye bound by a traditional carboxylic acid anchoring group. Through terahertz and transient absorption spectroscopic studies, along with interfacial electron transfer simulations, we find that, when compared to the traditional carboxylic acid anchoring group, electron injection of boron-bound BODIPY is faster into both TiO2 and SnO2. Although the surface coverage is low compared with carboxylic acids, the binding stability is improved over a wide range of pH. Subsequent photoelectrochemical studies using a sacrificial electron donor showed that this combined dye and anchoring group maintained photocurrent with good stability over long-time irradiation. This recently discovered binding mode of BODIPY shows excellent electron injection and good stability over time, making it promising for future investigations.

Downregulation of IRF8 in alveolar macrophages by G-CSF promotes metastatic tumor progression.

Tissue-resident macrophages (TRMs) are abundant immune cells within pre-metastatic sites, yet their functional contributions to metastasis remain incompletely understood. Here, we show that alveolar macrophages (AMs), the main TRMs of the lung, are susceptible to downregulation of the immune stimulatory transcription factor IRF8, impairing anti-metastatic activity in models of metastatic breast cancer. G-CSF is a key tumor-associated factor (TAF) that acts upon AMs to reduce IRF8 levels and facilitate metastasis. Translational relevance of IRF8 downregulation was observed among macrophage precursors in breast cancer and a CD68hiIRF8loG-CSFhi gene signature suggests poorer prognosis in triple-negative breast cancer (TNBC), a G-CSF-expressing subtype. Our data highlight the underappreciated, pro-metastatic roles of AMs in response to G-CSF and identify the contribution of IRF8-deficient AMs to metastatic burden. AMs are an attractive target of local neoadjuvant G-CSF blockade to recover anti-metastatic activity.

Use of hare bone for the manufacture of a Clovis bead.

A tubular bone bead dating to ~ 12,940 BP was recovered from a hearth-centered activity area at the La Prele Mammoth site in Converse County, Wyoming, USA. This is the oldest known bead from the Western Hemisphere. To determine the taxonomic origin of the bead, we extracted collagen for zooarchaeology by mass spectrometry (ZooMS). We also used micro-CT scanning for morphological analysis to determine likely skeletal elements used for its production. We conclude that the bead was made from a metapodial or proximal phalanx of a hare (Lepus sp.). This find represents the first secure evidence for the use of hares during the Clovis period. While the use of hare bone for the manufacture of beads was a common practice in western North America during the Holocene, its origins can now be traced back to at least the terminal Pleistocene.

Outcomes of Liver Transplant Recipients Hospitalized With COVID-19: A Nationwide Analysis From the United States.

Introduction: Currently available data regarding the impact of liver transplantation on the outcomes of patients hospitalized with COVID-19 is conflicting. This study aims to compare the outcomes and resource utilization between patients with and without a history of liver transplant hospitalized with COVID-19. Methods and materials: This is a retrospective study using the National Inpatient Sample. All adults hospitalized with COVID-19 in the year 2020 were included. Mortality was the primary outcome, while endotracheal intubation, length of hospital stay, and total hospital charges were the secondary outcomes. Results: Out of 1,050,720 adults admitted with COVID-19 as the primary diagnosis, 1,455 had a secondary diagnosis of liver transplant. Mortality was not significantly increased in transplant recipients (OR adjusted = 0.69, 95% CI: 0.46-1.03, P = 0.07). Intubation rates and total hospital charges did not differ significantly between liver transplant recipients and patients without a history of liver transplant receipt. LOS was shorter by a coefficient of almost two days in patients with a history of LT (P < 0.001). Conclusion: Liver transplant recipients do not appear to be at increased risk of severe COVID-19 and COVID-19 mortality.

Outcome metrics utilized in evaluations of programs and interventions for combat and operational stress: A review of psychometric properties.

The Department of Defense has mandated combat and operational stress control (COSC) efforts for the Services since 1999. Although several COSC-related programs have been implemented, few have undergone evaluation, and no standardized metrics have been established to assess their effectiveness and utility. The purpose of this review was to characterize the content and psychometrics of measures that have been utilized as outcome metrics in evaluations of COSC-related programs and interventions. Systematic literature searches were conducted for publications that: a) evaluated at least one measure from U.S. service members who participated in a program or intervention to prevent or reduce the adverse effects of combat and operational stress; and b) reported U.S. data on the internal consistency, test-retest reliability, convergent validity, and sensitivity/specificity of the identified measures. This process identified 15 measures for which psychometric properties were reviewed for acceptability based on recommended criteria. Identified measures varied from well-validated measures to newer instruments for which more data is needed on one or more of the target psychometric properties. Aside from internal consistency, psychometric data from U.S. military samples were sparse. Results further suggested that some measures might have reduced sensitivity in service members under certain conditions, such as large-scale screening. Additional studies are needed to validate COSC-relevant measures in service members. Future evaluations of programs and interventions for combat and operational stress should select measures that will increase the consistency of the literature, allow comparisons across studies, and ensure alignment with the objectives of identified programs.

Dual-Hit Strategy for Therapeutic Targeting of Pancreatic Cancer in Patient-Derived Xenograft Tumors.

PURPOSE: Paracrine activation of pro-fibrotic hedgehog (HH) signaling in pancreatic ductal adenocarcinoma (PDAC) results in stromal amplification that compromises tumor drug delivery, efficacy, and patient survival. Interdiction of HH-mediated tumor-stroma crosstalk with smoothened (SMO) inhibitors (SHHi) "primes" PDAC patient-derived xenograft (PDX) tumors for increased drug delivery by transiently increasing vascular patency/permeability, and thereby macromolecule delivery. However, patient tumor isolates vary in their responsiveness, and responders show co-induction of epithelial-mesenchymal transition (EMT). We aimed to identify the signal derangements responsible for EMT induction and reverse them and devise approaches to stratify SHHi-responsive tumors noninvasively based on clinically-quantifiable parameters. EXPERIMENTAL DESIGN: Animals underwent diffusion-weighted magnetic resonance (DW-MR) imaging for measurement of intratumor diffusivity. In parallel, tissue-level deposition of nanoparticle probes was quantified as a marker of vascular permeability/perfusion. Transcriptomic and bioinformatic analysis was employed to investigate SHHi-induced gene reprogramming and identify key "nodes" responsible for EMT induction. RESULTS: Multiple patient tumor isolates responded to short-term SHH inhibitor exposure with increased vascular patency and permeability, with proportionate increases in tumor diffusivity. Nonresponding PDXs did not. SHHi-treated tumors showed elevated FGF drive and distinctly higher nuclear localization of fibroblast growth factor receptor (FGFR1) in EMT-polarized tumor cells. Pan-FGFR inhibitor NVP-BGJ398 (Infigratinib) reversed the SHHi-induced EMT marker expression and nuclear FGFR1 accumulation without compromising the enhanced permeability effect. CONCLUSIONS: This dual-hit strategy of SMO and FGFR inhibition provides a clinically-translatable approach to compromise the profound impermeability of PDAC tumors. Furthermore, clinical deployment of DW-MR imaging could fulfill the essential clinical-translational requirement for patient stratification.

Revaccination for Hepatitis B in Previous Nonresponders Following Hepatitis C Eradication.

BACKGROUND: Patients with chronic hepatitis C virus (HCV) do not respond to hepatitis B virus (HBV) vaccination as efficiently as the general population. We assessed if revaccination after HCV treatment resulted in improved response. METHODS: Previous HBV vaccine nonresponders were prospectively recruited for revaccination after HCV eradication. Hepatitis B surface antibody (HBsAb) testing was performed 1 month after series completion. RESULTS: Follow-up HBsAb testing was performed in 31 of 34 enrolled patients with 21 (67.7%) reactive results. There were no significant differences in HBsAb reactivity based on age, sex, race, or advanced fibrosis presence. CONCLUSIONS: HBV vaccine nonresponders should be considered for revaccination following HCV cure.

A Translational Regulatory Mechanism Mediated by Hypusinated Eukaryotic Initiation Factor 5A Facilitates ß-Cell Identity and Function.

As professional secretory cells, ß-cells require adaptable mRNA translation to facilitate a rapid synthesis of proteins, including insulin, in response to changing metabolic cues. Specialized mRNA translation programs are essential drivers of cellular development and differentiation. However, in the pancreatic ß-cell, the majority of factors identified to promote growth and development function primarily at the level of transcription. Therefore, despite its importance, the regulatory role of mRNA translation in the formation and maintenance of functional ß-cells is not well defined. In this study, we have identified a translational regulatory mechanism mediated by the specialized mRNA translation factor eukaryotic initiation factor 5A (eIF5A), which facilitates the maintenance of ß-cell identity and function. The mRNA translation function of eIF5A is only active when it is posttranslationally modified ("hypusinated") by the enzyme deoxyhypusine synthase (DHPS). We have discovered that the absence of ß-cell DHPS in mice reduces the synthesis of proteins critical to ß-cell identity and function at the stage of ß-cell maturation, leading to a rapid and reproducible onset of diabetes. Therefore, our work has revealed a gatekeeper of specialized mRNA translation that permits the ß-cell, a metabolically responsive secretory cell, to maintain the integrity of protein synthesis necessary during times of induced or increased demand.

Pathways linking nutrient enrichment, habitat structure, and parasitism to host-resource interactions.

Human activities simultaneously alter nutrient levels, habitat structure, and levels of parasitism. These activities likely have individual and joint impacts on food webs. Furthermore, there is particular concern that nutrient additions and changes to habitat structure might exacerbate the size of epidemics and impacts on host density. We used a well-studied zooplankton-fungus host-parasite system and experimental whole water column enclosures to factorially manipulate nutrient levels, habitat structure (specifically: mixing), and presence of parasites. Nutrient addition increased infection prevalence, density of infected hosts, and total host density. We hypothesized that nutrients, mixing, and parasitism were linked in multiple ways, including via their combined effects on phytoplankton (resource) abundance, and we used structural equation modeling to disentangle these pathways. In the absence of the parasite, both nutrients and mixing increased abundance of phytoplankton, whereas host density was negatively related to phytoplankton abundance, suggesting a mixture of bottom-up and top-down control of phytoplankton. In the presence of the parasite, nutrients still increased phytoplankton abundance but mixing no longer did, and there was no longer a significant relationship between host density and phytoplankton. This decoupling of host-resource dynamics may have resulted from reduced grazing due to illness-mediated changes in feeding behavior. Overall, our results show that the impact of one human activity (e.g., altered habitat structure) might depend on other human impacts (e.g., parasite introduction). Fortunately, carefully designed experiments and analyses can help tease apart these multifaceted relationships, allowing us to understand how human activities alter food webs, including interactions between hosts and their parasites and resources.