Proteomimetic Polymers Trigger Potent Antigen-Specific T Cell Responses to Limit Tumor Growth.

Elicitation of effective antitumor immunity following cancer vaccination requires the selective activation of distinct effector cell populations and pathways. Here we report a therapeutic approach for generating potent T cell responses using a modular vaccination platform technology capable of inducing directed immune activation, termed the Protein-like Polymer (PLP). PLPs demonstrate increased proteolytic resistance, high uptake by antigen-presenting cells (APCs), and enhanced payload-specific T cell responses. Key design parameters, namely payload linkage chemistry, degree of polymerization, and side chain composition, were varied to optimize vaccine formulations. Linking antigens to the polymer backbone using an intracellularly cleaved disulfide bond copolymerized with a diluent amount of oligo(ethylene glycol) (OEG) resulted in the highest payload-specific potentiation of antigen immunogenicity, enhancing dendritic cell (DC) activation and antigen-specific T cell responses. Vaccination with PLPs carrying either gp100, E7, or adpgk peptides significantly increased the survival of mice inoculated with B16F10, TC-1, or MC38 tumors, respectively, without the need for adjuvants. B16F10-bearing mice immunized with gp100-carrying PLPs showed increased antitumor CD8+ T cell immunity, suppressed tumor growth, and treatment synergy when paired with two distinct stimulator of interferon gene (STING) agonists. In a human papillomavirus-associated TC-1 model, combination therapy with PLP and 2'3'-cGAMP resulted in 40% of mice completely eliminating implanted tumors while also displaying curative protection from rechallenge, consistent with conferment of lasting immunological memory. Finally, PLPs can be stored long-term in a lyophilized state and are highly tunable, underscoring the unique properties of the platform for use as generalizable cancer vaccines.

A potential novel treatment for cirrhosis-related ascites: Empagliflozin is safe and tolerable in advanced chronic liver disease.

AIMS: Advanced chronic liver disease and advanced chronic liver disease-related ascites have a high mortality. The pharmacological treatment of ascites and fluid overload has changed little over time. Empagliflozin, a sodium-glucose cotransporter type 2 inhibitor is an untested potential novel treatment in cirrhosis, as it has survival benefits in heart failure, which has similar pathophysiological fluid overload mechanisms. Before investigating empagliflozin's potential benefit in cirrhosis, its safety must be addressed. METHODS: Ten participants (five each with compensated or decompensated advanced chronic liver disease, based on Child-Pugh class) received empagliflozin 10 mg orally daily for 4 weeks with 2 weeks follow-up. Empagliflozin safety, pharmacokinetics and pharmacodynamics were investigated. RESULTS: In total, eight patients (80%) reported an adverse event, and three patients (30%) experienced a serious adverse event, one of which was attributed to empagliflozin. Overall, the frequency of adverse events was similar to previous phase 3 trials of gliflozins. Higher plasma empagliflozin concentrations did not significantly increase the risk of adverse events. CONCLUSIONS: Four-week treatment with empagliflozin was safe and well tolerated in patients with advanced chronic liver disease. These preliminary data support assessment of long-term treatment on disease-related and mortality outcomes in patients with cirrhosis through randomized control trials.

Analysis of Female Participant Representation in Registered Oncology Clinical Trials in the United States from 2008 to 2020.

BACKGROUND: Female underrepresentation in oncology clinical trials can result in outcome disparities. We evaluated female participant representation in US oncology trials by intervention type, cancer site, and funding. MATERIALS AND METHODS: Data were extracted from the publicly available Aggregate Analysis of ClinicalTrials.gov database. Initially, 270,172 studies were identified. Following the exclusion of trials using Medical Subject Heading terms, manual review, those with incomplete status, non-US location, sex-specific organ cancers, or lacking participant sex data, 1650 trials consisting of 240,776 participants remained. The primary outcome was participation to prevalence ratio (PPR): percent females among trial participants divided by percent females in the disease population per US Surveillance, Epidemiology, and End Results Program data. PPRs of 0.8-1.2 reflect proportional female representation. RESULTS: Females represented 46.9% of participants (95% CI, 45.4-48.4); mean PPR for all trials was 0.912. Females were underrepresented in surgical (PPR 0.74) and other invasive (PPR 0.69) oncology trials. Among cancer sites, females were underrepresented in bladder (odds ratio [OR] 0.48, 95% CI 0.26-0.91, P = .02), head/neck (OR 0.44, 95% CI 0.29-0.68, P < .01), stomach (OR 0.40, 95% CI 0.23-0.70, P < .01), and esophageal (OR 0.40 95% CI 0.22-0.74, P < .01) trials. Hematologic (OR 1.78, 95% CI 1.09-1.82, P < .01) and pancreatic (OR 2.18, 95% CI 1.46-3.26, P < .01) trials had higher odds of proportional female representation. Industry-funded trials had greater odds of proportional female representation (OR 1.41, 95% CI 1.09-1.82, P = .01) than US government and academic-funded trials. CONCLUSIONS: Stakeholders should look to hematologic, pancreatic, and industry-funded cancer trials as exemplars of female participant representation and consider female representation when interpreting trial results.

Selective use of Molecular Testing Based on Sonographic Features of Cytologically Indeterminate Thyroid Nodules: A Decision Analysis.

BACKGROUND: Molecular diagnostics can allow some patients with indeterminate thyroid nodule cytopathology to avoid diagnostic hemithyroidectomy; however, the testing is costly. We hypothesized that molecular testing with the intention of preventing unnecessary diagnostic hemithyroidectomy would be cost-effective if this test was applied selectively based on sonographic risk of malignancy. METHODS: A Markov model was constructed depicting a 40-year-old patient with a cytologically indeterminate thyroid nodule. Molecular testing of fine needle aspiration material was compared to a strategy of immediate diagnostic hemithyroidectomy. Data from a single tertiary-referral health system were reviewed to estimate the outcomes of molecular testing of indeterminate nodules stratified by the American Thyroid Association sonographic classification system. Other outcome probabilities and their utilities were derived from literature review. Costs were estimated with Medicare reimbursement data. A $100,000/QALY threshold for cost-effectiveness was applied. Sensitivity analysis was employed to examine uncertainty in the model's assumptions. RESULTS: Of 123 patients who underwent molecular testing for indeterminate cytology, 12 (9.8%) were classified as high sonographic suspicion, 49 (40%) were intermediate suspicion, and 62 (50%) were low or very low suspicion. Molecular testing was only cost-effective when the pretest probability of a negative test was greater than 31%. The model was most sensitive to the cost of molecular testing and the quality adjustment factor for hypothyroidism. CONCLUSIONS: In hypothetical modeling, molecular testing is only cost-effective for cytologically indeterminate thyroid nodules with sonographic features that are intermediate or low suspicion for malignancy. In nodules with high sonographic suspicion, molecular testing is rarely negative and appears to add minimal value.

Biomolecular Densely Grafted Brush Polymers: Oligonucleotides, Oligosaccharides and Oligopeptides.

In this Minireview, we describe synthetic polymers densely functionalized with sequence-defined biomolecular sidechains. We focus on synthetic brush polymers of oligonucleotides, oligosaccharides, and oligopeptides, prepared via graft-through polymerization from biomolecule functionalized monomers. The resulting structures are brush polymers wherein a biomolecular graft is positioned at each monomer backbone unit. We describe key synthetic milestones, identify synthetic opportunities, and highlight recent advances in the field, including biological applications.

Hyperglycaemia attenuates in vivo reprogramming of pancreatic exocrine cells to beta cells in mice.

AIMS/HYPOTHESIS: Reprogramming of pancreatic exocrine to insulin-producing cells by viral delivery of the genes encoding transcription factors neurogenin-3 (Ngn3), pancreas/duodenum homeobox protein 1 (Pdx1) and MafA is an efficient method for reversing diabetes in murine models. The variables that modulate reprogramming success are currently ill-defined. METHODS: Here, we assess the impact of glycaemia on in vivo reprogramming in a mouse model of streptozotocin-induced beta cell ablation, using subsequent islet transplantation or insulin pellet implantation for creation of groups with differing levels of glycaemia before viral delivery of transcription factors. RESULTS: We observed that hyperglycaemia significantly impaired reprogramming of exocrine to insulin-producing cells in their quantity, differentiation status and function. With hyperglycaemia, the reprogramming of acinar towards beta cells was less complete. Moreover, inflammatory tissue changes within the exocrine pancreas including macrophage accumulation were found, which may represent the tissue's response to clear the pancreas from insufficiently reprogrammed cells. CONCLUSIONS/INTERPRETATION: Our findings shed light on normoglycaemia as a prerequisite for optimal reprogramming success in a diabetes model, which might be important in other tissue engineering approaches and disease models, potentially facilitating their translational applications.

Inhibitory interneuron progenitor transplantation restores normal learning and memory in ApoE4 knock-in mice without or with Aß accumulation.

Excitatory and inhibitory balance of neuronal network activity is essential for normal brain function and may be of particular importance to memory. Apolipoprotein (apo) E4 and amyloid-ß (Aß) peptides, two major players in Alzheimer's disease (AD), cause inhibitory interneuron impairments and aberrant neuronal activity in the hippocampal dentate gyrus in AD-related mouse models and humans, leading to learning and memory deficits. To determine whether replacing the lost or impaired interneurons rescues neuronal signaling and behavioral deficits, we transplanted embryonic interneuron progenitors into the hippocampal hilus of aged apoE4 knock-in mice without or with Aß accumulation. In both conditions, the transplanted cells developed into mature interneurons, functionally integrated into the hippocampal circuitry, and restored normal learning and memory. Thus, restricted hilar transplantation of inhibitory interneurons restores normal cognitive function in two widely used AD-related mouse models, highlighting the importance of interneuron impairments in AD pathogenesis and the potential of cell replacement therapy for AD. More broadly, it demonstrates that excitatory and inhibitory balance are crucial for learning and memory, and suggests an avenue for investigating the processes of learning and memory and their alterations in healthy aging and diseases.

Can we manipulate brain connectivity? A systematic review of cortico-cortical paired associative stimulation effects.

OBJECTIVE: Cortico-cortical paired associative stimulation (ccPAS) is a form of dual-site transcranial magnetic stimulation (TMS) entailing a series of single-TMS pulses paired at specific interstimulus intervals (ISI) delivered to distant cortical areas. The goal of this article is to systematically review its efficacy in inducing plasticity in humans focusing on stimulation parameters and hypotheses of underlying neurophysiology. METHODS: A systematic review of the literature from 2009-2023 was undertaken to identify all articles utilizing ccPAS to study brain plasticity and connectivity. Six electronic databases were searched and included. RESULTS: 32 studies were identified. The studies targeted connections within the same hemisphere or between hemispheres. 28 ccPAS studies were in healthy participants, 1 study in schizophrenia, and 1 in Alzheimer's disease (AD) patients. 2 additional studies used cortico-cortical repetitive paired associative stimulation (cc-rPAS) in generalized anxiety disorder (GAD) patients. Outcome measures include electromyography (EMG), behavioral measures, electroencephalography (EEG), and functional magnetic resonance imaging (fMRI). ccPAS seems to be able to modulate brain connectivity depending on the ISI. CONCLUSIONS: ccPAS can be used to modulate corticospinal excitability, brain activity, and behavior. Although the stimulation parameters used across studies reviewed in this paper are varied, ccPAS is a promising approach for basic research and potential clinical applications. SIGNIFICANCE: Recent advances in neuroscience have caused a shift of interest from the study of single areas to a more complex approach focusing on networks of areas that orchestrate brain activity. Consequently, the TMS community is also witnessing a change, with a growing interest in targeting multiple brain areas rather than a single locus, as evidenced by an increasing number of papers using ccPAS. In light of this new enthusiasm for brain connectivity, this review summarizes existing literature and stimulation parameters that have proven effective in changing electrophysiological, behavioral, or neuroimaging-derived measures.

Safety, Pharmacokinetics and Preliminary Efficacy of IL4-Rα Monoclonal Antibody AK120 in Both Healthy and Atopic Dermatitis Subjects: A Phase I, Randomized, Two-Part, Double-Blind, Placebo-Controlled, Dose-Escalation, First-In-Human Clinical Study.

INTRODUCTION: Interleukin-4 (IL-4) and interleukin-13 (IL-13) are two essential cytokines involved in the T helper 2 (Th2)-mediated inflammatory response to diseases, such as atopic dermatitis (AD). AK120 is a humanized immunoglobulin G subclass 4 (IgG4) monoclonal antibody (mAb) directed against the IL-4 receptor alpha (IL-4Rα) subunit shared by the IL-4 and IL-13 receptor complexes. This mAb inhibits the signaling of the IL-4 and IL-13 cytokines. METHODS: The study consisted of two parts. Part 1 was a single ascending dose (SAD) study with five cohorts (receiving 15, 50, 150, 300 or 600 mg of AK120, respectively) of healthy subjects; part 2 was a multiple ascending dose (MAD) study with four cohorts (receiving AK120 at doses of 300 mg once every 2 weeks [Q2W], 300 mg once weekly [QW], 150 mg QW or 75 mg QW) of subjects with AD. A total of 81 subjects (40 in part 1, 41 in part 2) were enrolled in the study. RESULTS: The compound was safe and well tolerated in both a SAD up to 600 mg in healthy subjects and in a MAD from 75 to 600 mg in subjects with AD. The exposure of AK120 increased in an approximately dose-dependent manner upon subcutaneous dosing. The levels of the biomarkers serum thymus and activation-regulated chemokine ligand 17 (TARC/CCL17) and immunoglobulin E decreased from baseline after AK120 administration, indicating the inhibition of the IL-4/IL-13 signaling pathways. AK120 showed improved Eczema Area and Severity Index (EASI) scores, and the proportion of subjects with Investigator Global Assessment (IGA) score 0/1 increased after AK120 treatment. CONCLUSIONS: AK120 exhibited an acceptable safety profile in healthy and AD subjects, and showed preliminary efficacy. These findings support the continued investigation of AK120 for treating AD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identification number: NCT04256174.

Leveraging Open Electronic Health Record Data and Environmental Exposures Data to Derive Insights Into Rare Pulmonary Disease.

Research on rare diseases has received increasing attention, in part due to the realized profitability of orphan drugs. Biomedical informatics holds promise in accelerating translational research on rare disease, yet challenges remain, including the lack of diagnostic codes for rare diseases and privacy concerns that prevent research access to electronic health records when few patients exist. The Integrated Clinical and Environmental Exposures Service (ICEES) provides regulatory-compliant open access to electronic health record data that have been integrated with environmental exposures data, as well as analytic tools to explore the integrated data. We describe a proof-of-concept application of ICEES to examine demographics, clinical characteristics, environmental exposures, and health outcomes among a cohort of patients enriched for phenotypes associated with cystic fibrosis (CF), idiopathic bronchiectasis (IB), and primary ciliary dyskinesia (PCD). We then focus on a subset of patients with CF, leveraging the availability of a diagnostic code for CF and serving as a benchmark for our development work. We use ICEES to examine select demographics, co-diagnoses, and environmental exposures that may contribute to poor health outcomes among patients with CF, defined as emergency department or inpatient visits for respiratory issues. We replicate current understanding of the pathogenesis and clinical manifestations of CF by identifying co-diagnoses of asthma, chronic nasal congestion, cough, middle ear disease, and pneumonia as factors that differentiate patients with poor health outcomes from those with better health outcomes. We conclude by discussing our preliminary findings in relation to other published work, the strengths and limitations of our approach, and our future directions.

Penpulimab, an Fc-Engineered IgG1 Anti-PD-1 Antibody, With Improved Efficacy and Low Incidence of Immune-Related Adverse Events.

Background: IgG4 anbibodies are deficient in stability and may contribute to tumor-associated escape from immune surveillance. We developed an IgG1 backbone anti-programmed cell death protein-1 (PD-1) antibody, penpulimab, which is designed to remove crystallizable fragment (Fc) gamma receptor (FcγR) binding that mediates antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and proinflammatory cytokine release. Methods: Aggregation of different anti-PD-1 antibodies was tested by size exclusion chromatography, and melting temperature midpoint (Tm) and aggregation temperature onset (Tagg) were also determined. The affinity constants of penpulimab for PD-1 and human FcγRs were measured by surface plasmon resonance and biolayer interferometry. ADCC and ADCP were determined in cellular assays and antibody-dependent cytokine release (ADCR) from human macrophages was detected by ELISA. Binding kinetics of penpulimab to human PD-1 was determined by Biacore, and epitope/paratope mapping of PD-1/penpulimab was investigated using x-ray crystallography. Additionally, patients from six ongoing trials were included for analysis of immune-related adverse events (irAEs). Results: Penpulimab demonstrated better stability and a lower level of host-cell protein residue compared with IgG4 backbone anti-PD-1 antibodies. As expected, penpulimab exhibited no apparent binding to FcγRIa, FcγRIIa_H131, FcγRIIIa_V158 and FcγRIIIa_F158, elicited no apparent ADCC and ADCP activities, and induced no remarkable IL-6 and IL-8 release by activated macrophages in vitro. Penpulimab was shown in the co-crystal study to bind to human PD-1 N-glycosylation site at N58 and had a slower off-rate from PD-1 versus nivolumab or pembrolizumab. Four hundred sixty-five patients were analyzed for irAEs. Fifteen (3.2%) patients had grade 3 or above irAEs. No death from irAEs was reported. Conclusions: IgG1 backbone anti-PD1 antibody penpulimab has a good stability and reduced host cell protein residue, as well as potent binding to the antigen. Fc engineering has eliminated Fc-mediated effector functions of penpulimab including ADCC, ADCP and reduced ADCR, which may contribute to its more favorable safety profile. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: AK105-101: NCT03352531, AK105-201: NCT03722147, AK105-301: NCT03866980, AK105-202:NCT03866967, AK105-203: NCT04172571, AK105-204: NCT04172506.

On-demand electrochemically controlled compound release from an ultrasonically powered implant.

On-demand drug delivery systems are promising for a wide range of therapeutic applications. When combined with wireless implants for controlled drug delivery, they can reduce overall dosage and side effects. Here, we demonstrate release of fluorescein from a novel on-demand release system for negatively charged compounds. The release system is based on a modified electroresponsive polypyrrole nanoparticulate film designed to minimize ion exchange with the stored compound - a major passive leakage mechanism. We further designed an ultrasonically powered mm-sized implant to electronically control the on-demand drug delivery system in vivo. Release kinetics are characterized both in vitro and in vivo in mice using fluorescein as a model drug, demonstrating the feasibility of wireless, controllable drug release using an ultrasonically powered implant.

Effects of variability in manually contoured spinal cord masks on fMRI co-registration and interpretation.

Functional magnetic resonance imaging (fMRI) of the human spinal cord (SC) is a unique non-invasive method for characterizing neurovascular responses to stimuli. Group-analysis of SC fMRI data involves co-registration of subject-level data to standard space, which requires manual masking of the cord and may result in bias of group-level SC fMRI results. To test this, we examined variability in SC masks drawn in fMRI data from 21 healthy participants from a completed study mapping responses to sensory stimuli of the C7 dermatome. Masks were drawn on temporal mean functional image by eight raters with varying levels of neuroimaging experience, and the rater from the original study acted as a reference. Spatial agreement between rater and reference masks was measured using the Dice Similarity Coefficient, and the influence of rater and dataset was examined using ANOVA. Each rater's masks were used to register functional data to the PAM50 template. Gray matter-white matter signal contrast of registered functional data was used to evaluate the spatial normalization accuracy across raters. Subject- and group-level analyses of activation during left- and right-sided sensory stimuli were performed for each rater's co-registered data. Agreement with the reference SC mask was associated with both rater (F(7, 140) = 32.12, P < 2 × 10-16, η2 = 0.29) and dataset (F(20, 140) = 20.58, P < 2 × 10-16, η2 = 0.53). Dataset variations may reflect image quality metrics: the ratio between the signal intensity of spinal cord voxels and surrounding cerebrospinal fluid was correlated with DSC results (p < 0.001). As predicted, variability in the manually-drawn masks influenced spatial normalization, and GM:WM contrast in the registered data showed significant effects of rater and dataset (rater: F(8, 160) = 23.57, P < 2 × 10-16, η2 = 0.24; dataset: F(20, 160) = 22.00, P < 2 × 10-16, η2 = 0.56). Registration differences propagated into subject-level activation maps which showed rater-dependent agreement with the reference. Although group-level activation maps differed between raters, no systematic bias was identified. Increasing consistency in manual contouring of spinal cord fMRI data improved co-registration and inter-rater agreement in activation mapping, however our results suggest that improvements in image acquisition and post-processing are also critical to address.

Population pharmacokinetic/pharmacodynamic analysis of AK111, an IL-17A monoclonal antibody, in subjects with moderate-to-severe plaque psoriasis.

AK111 is an innovative IL-17A antibody, presenting high affinity to IL-17A and showing similar pharmacokinetic (PK) characteristics to those of typical immunoglobulin (Ig) G1 antibodies. To optimize the dosage regimen for phase 2/3 clinical trials, PK and pharmacodynamics (PD) of AK111 were first characterized in Chinese moderate-to-severe plaque psoriasis patients in a phase 1b study. AK111 PK serum sample and Psoriasis Area and Severity Index (PASI) score data were collected from 48 moderate-to-severe psoriasis patients in this study. Non-linear mixed-effects modeling was used for the population PK/PD analysis. A one-compartment model with a first-order absorption and a first-order elimination best described the PK behavior of AK111. The apparent systemic clearance was 0.182 L/day, and the central volume was 6.65 L. The exposure-response relationship was characterized using an indirect response model. The pharmacological effect of AK111 was described in the form of inhibiting the formation of psoriatic plaque, whereas placebo was quantified in the form of promoting the degradation of psoriatic skin lesions. The maximum effect of drug effect (Imax) and placebo effect (PLBmax) was 1 and 0.429, respectively. The rate constant for psoriatic plaque production (Kin) was 0.474 PASI/day and psoriatic plaque loss (Kout) was 0.024 day-1. The body surface area (BSA) affected by psoriasis was identified as a significant covariate on K o u t . The simulation results confirmed that all of the predicted PASI90 response rates at week 12 were higher than 60% at 150 and 300 mg dose levels with different regimens and could reach higher than 80% at week 24. We hope this first PK/PD study of AK111 in Chinese moderate-to-severe plaque psoriasis patients will be of help in the further clinical development of AK111 and provide a reference to the dosage optimization for similar antibodies with a long half-life.

Multi-Access Networking with Wireless Ultrasound-Powered Implants.

Multi-access networking with miniaturized wireless implantable devices can enable and advance closed-loop medical applications to deliver precise diagnosis and treatment. Using ultrasound (US) for wireless implant systems is an advantageous approach as US can beamform with high spatial resolution to efficiently power and address multiple implants in the network. To demonstrate these capabilities, we use wirelessly powered mm-sized implants with bidirectional communication links; uplink data communication measurements are performed using time, spatial, and frequency-division multiplexing schemes in tissue phantom. A 32-channel linear transmitter array and an external receiver are used as a base station to network with two implants that are placed 6.5 cm deep and spaced less than 1 cm apart. Successful wireless powering and uplink data communication around 100 kbps with a measured bit error rate below 10-4 are demonstrated for all three networking schemes, validating the multi-access networking feasibility of US wireless implant systems.

Ultrasonic Implant Localization for Wireless Power Transfer: Active Uplink and Harmonic Backscatter.

Efficient ultrasonic power transfer to implantable devices requires precise transmitter beamforming to the receiver and can quickly degrade with small changes in implant location. Ultrasound localization can be used to find and track implants in the body to maintain an efficient link. We present a framework to calculate localization accuracy showing that sub-mm accuracy is obtainable using only three receive channels. A harmonic backscatter approach, which passively provides contrast in the frequency domain without active load modulation is compared to active uplink from the implant. The localization accuracy using both active uplink and harmonic backscatter from the implant power receiver is characterized using a linear array probe. The measured location standard deviation is nearly two orders of magnitude smaller than the half-power beamwidth of the array focal spot. Finally, beamforming using the measured location information increases the available power by over 20 × compared to an unfocused beam.

Low expression Macrophage Migration Inhibitory Factor (MIF) alleles and tuberculosis in HIV infected South Africans.

Host immunity is crucial for controlling M. tuberculosis infection. Functional polymorphisms in the cytokine macrophage migration inhibitory factor (MIF) show global population stratification, with the highest prevalence of low expression MIF alleles found in sub-Saharan Africans, which is a population with the greatest confluence of both TB and HIV infection and disease. We investigated the association between MIF alleles and tuberculosis (TB) and HIV in South Africa. We acquired clinical information and determined the frequency of two MIF promoter variants: a functional -794 CATT5-8 microsatellite and an associated -173 G/C SNP in two HIV-positive cohorts of patients with active laboratory-confirmed TB and in controls without active TB who were all HIV positive. We found a greater frequency of low expression MIF promoter variants (-794 CATT5,6) among TB disease cases compared to controls (OR = 2.03, p = 0.023), supporting a contribution of genetic low MIF expression to the high prevalence of TB in South Africa. Among those with HIV, circulating MIF levels also were associated with lower CD4 cell counts irrespective of TB status (p = 0.016), suggesting an influence of HIV immunosuppression on MIF expression.

Design of Tunable Ultrasonic Receivers for Efficient Powering of Implantable Medical Devices With Reconfigurable Power Loads.

Miniaturized ultrasonic receivers are designed for efficient powering of implantable medical devices with reconfigurable power loads. Design parameters that affect the efficiency of these receivers under highly variable load conditions, including piezoelectric material, geometry, and operation frequency, are investigated. Measurements were performed to characterize electrical impedance and acoustic-to-electrical efficiency of ultrasonic receivers for off-resonance operation. Finally, we propose, analyze, and demonstrate adaptive matching and frequency tuning techniques using two different reconfigurable matching networks for typical implant loads from 10 [Formula: see text] to 1 mW. Both simulations and measurements show a significant increase in total implant efficiency (up to 50 percentage points) over this load power range when operating off-resonance with the proposed matching networks.

Astrocytic adenosine receptor A2A and Gs-coupled signaling regulate memory.

Astrocytes express a variety of G protein-coupled receptors and might influence cognitive functions, such as learning and memory. However, the roles of astrocytic Gs-coupled receptors in cognitive function are not known. We found that humans with Alzheimer's disease (AD) had increased levels of the Gs-coupled adenosine receptor A2A in astrocytes. Conditional genetic removal of these receptors enhanced long-term memory in young and aging mice and increased the levels of Arc (also known as Arg3.1), an immediate-early gene that is required for long-term memory. Chemogenetic activation of astrocytic Gs-coupled signaling reduced long-term memory in mice without affecting learning. Like humans with AD, aging mice expressing human amyloid precursor protein (hAPP) showed increased levels of astrocytic A2A receptors. Conditional genetic removal of these receptors enhanced memory in aging hAPP mice. Together, these findings establish a regulatory role for astrocytic Gs-coupled receptors in memory and suggest that AD-linked increases in astrocytic A2A receptor levels contribute to memory loss.

Comparison of the impact of the I27L polymorphism of the hepatocyte nuclear factor-1alpha on estimated and measured beta cell indices.

OBJECTIVE: We investigated the impact of the I27L polymorphism of the hepatocyte nuclear factor-1alpha gene on measured and estimated beta cell indices. We also examined the conservation of this amino acid among different species. DESIGN AND METHODS: Estimated first and second phase insulin responses (1stPH(S) and 2ndPH(S)) were estimated from oral glucose tolerance tests in 78 glucose tolerant subjects. Among these subjects, first and second phase insulin responses (1stIR and 2ndIR) were measured in 60 subjects. The I27L genotypes were determined from genomic DNA. We also reviewed the published peptide sequence data on this polymorphism. RESULTS: The estimated beta cell indices correlated well with the measured indices. Although the impact of this polymorphism was noted in the measured indices (P<0.01 for 1stIR and P=0.04 for 2ndIR) from 60 subjects, the differences in the estimated indices were only noted in the extended sample set with 78 subjects (P=0.05 for 1stPH(S) and P=0.04 for 2ndPH(S)). This polymorphism occurs in the dimerization domain, which is completely conserved within human, rat, mouse and hamster. This amino acid is also conserved in chicken and zebrafish, but not in the frog. This conservation suggests a possible biological importance of this amino acid. CONCLUSIONS: By increasing the sample size, we demonstrated the role of the I27L polymorphism in the pathogenesis of type 2 diabetes by using estimated beta cell indices. The conservation among species suggests a possible biological importance of this amino acid. Analysis of the published data confirms a modest role of this polymorphism in type 2 diabetes.