bluuebunny/crossref_metadata_2025 huggingface dataset:
Waning of vaccine effectiveness against moderate and severe covid-19 among adults in the US from the VISION network: test negative, case-control study
Authors: Ferdinands Jill M , Rao Suchitra , Dixon Brian E , Mitchell Patrick K , DeSilva Malini B , Irving Stephanie A , Lewis Ned , Natarajan Karthik , Stenehjem Edward , Grannis Shaun J , Han Jungmi , McEvoy Charlene , Ong Toan C , Naleway Allison L , Reese Sarah E , Embi Peter J , Dascomb Kristin , Klein Nicola P , Griggs Eric P , Liao I-Chia , Yang Duck-Hye , Fadel William F , Grisel Nancy , Goddard Kristin , Patel Palak , Murthy Kempapura , Birch Rebecca , Valvi Nimish R , Arndorfer Julie , Zerbo Ousseny , Dickerson Monica , Raiyani Chandni , Williams Jeremiah , Bozio Catherine H , Blanton Lenee , Link-Gelles Ruth , Barron Michelle A , Gaglani Manjusha , Thompson Mark G , Fireman Bruce
Published: October 2022

Objective

To estimate the effectiveness of mRNA vaccines against moderate and severe covid-19 in adults by time since second, third, or fourth doses, and by age and immunocompromised status.

Design

Test negative case-control study.

Setting

Hospitals, emergency departments, and urgent care clinics in 10 US states, 17 January 2021 to 12 July 2022.

Participants

893 461 adults (≥18 years) admitted to one of 261 hospitals or to one of 272 emergency department or 119 urgent care centers for covid-like illness tested for SARS-CoV-2.

Main outcome measures

The main outcome was waning of vaccine effectiveness with BNT162b2 (Pfizer-BioNTech) or mRNA-1273 (Moderna) vaccine during the omicron and delta periods, and the period before delta was dominant using logistic regression conditioned on calendar week and geographic area while adjusting for age, race, ethnicity, local virus circulation, immunocompromised status, and likelihood of being vaccinated.

Results

45 903 people admitted to hospital with covid-19 (cases) were compared with 213 103 people with covid-like illness who tested negative for SARS-CoV-2 (controls), and 103 287 people admitted to emergency department or urgent care with covid-19 (cases) were compared with 531 168 people with covid-like illness who tested negative for SARS-CoV-2. In the omicron period, vaccine effectiveness against covid-19 requiring admission to hospital was 89% (95% confidence interval 88% to 90%) within two months after dose 3 but waned to 66% (63% to 68%) by four to five months. Vaccine effectiveness of three doses against emergency department or urgent care visits was 83% (82% to 84%) initially but waned to 46% (44% to 49%) by four to five months. Waning was evident in all subgroups, including young adults and individuals who were not immunocompromised; although waning was morein people who were immunocompromised. Vaccine effectiveness increased among most groups after a fourth dose in whom this booster was recommended.

Conclusions

Effectiveness of mRNA vaccines against moderate and severe covid-19 waned with time after vaccination. The findings support recommendations for a booster dose after a primary series and consideration of additional booster doses.
A framework for managing health research capacity strengthening consortia: addressing tensions and enhancing capacity outcomes
Authors: Tagoe Nadia , Pulford Justin , Kinyanjui Sam , Molyneux Sassy
Published: October 2022

There has been a steady increase in health research capacity strengthening (HRCS) consortia and programmes. However, their structures and management practices and the effect on the capacity strengthening outcomes have been underexamined. We conducted a case study involving three HRCS consortia where we critically examined the consortia’s decision-making processes, strategies for resolving management tensions and the potential implications for consortia outcomes. We conducted 44 in-depth interviews with a range of consortia members and employed the framework method to analyse the data. We assessed the extent to which consortia’s management practices and strategies enabled or hindered research capacity strengthening using a capacity development lens. At the heart of consortium management is how tensions are navigated and the resolution strategies adopted. This study demonstrates that the management strategies adopted by consortia have capacity strengthening consequences. When deciding on tension management strategies, trade-offs often occur, sometimes to the detriment of capacity strengthening aims. When management strategies align with capacity development principles, consortium management processes become capacity strengthening mechanisms for participating individuals and institutions. Such alignment enhances programme effectiveness and value for money. Drawing on these findings, we propose an evidence-informed management framework that consortia leaders can use in practice to support decision-making to optimise research capacity gains. Considering the increasing investment in HRCS consortia, leveraging all consortium processes towards capacity strengthening will maximise the returns on investments made.
Metabolic syndrome and its components are associated with non-arteritic anterior ischaemic optic neuropathy
Authors: Kohli Darrell , Wu Kristi Y , White Launia J , Hodge David O , Chen John J , Roddy Gavin W
Published: October 2022

Purpose

To determine whether metabolic syndrome (MetS) is a risk factor for various forms of optic neuropathy including non-arteritic anterior ischaemic optic neuropathy (NAION).

Methods

This population-based analysis identified patients ≥40 years of age in Olmsted County, Minnesota, USA using the Rochester Epidemiology Project 2005–2018. Patients with MetS were identified if three or more of the five standard criteria for diagnosing MetS were present: systemic hypertension, hyperglycaemia, hypertriglyceridaemia, reduced high-density lipoprotein cholesterol (hypoalphalipoproteinaemia) and central adiposity defined by increased body mass index. Charts of patients identified as having an optic neuropathy were reviewed to record specific diagnoses and compared with patients without ocular pathology other than cataract. The odds ratio (OR) of association with MetS was calculated and adjusted for age, sex and race with multivariate analysis for the various optic neuropathies.

Results

Patients with MetS were more likely to have an optic neuropathy than those without (OR 2.2, p<0.001). After adjusting for age, sex and race, the only optic neuropathy found to be significantly associated with MetS was NAION (OR 6.17, p=0.002). For patients with NAION, though each individual component of MetS was individually significantly associated with MetS, further analysis suggested that hypertriglyceridaemia, hypoalphalipoproteinaemia and hyperglycaemia were likely the key drivers in the overall significance between NAION and MetS.

Conclusion

Patients with MetS were more likely to have NAION. Further studies are needed to determine whether MetS is a modifiable risk factor for NAION.
Population-wide cohort study of statin use for the secondary cardiovascular disease prevention in Scotland in 2009–2017
Authors: Thalmann Inna , Preiss David , Schlackow Iryna , Gray Alastair , Mihaylova Borislava
Published: October 2022

Objective

To estimate the extent of suboptimal statin use for the secondary prevention of atherosclerotic cardiovascular disease (ASCVD) at different stages of the treatment pathway and identify patient groups at risk of suboptimal treatment.

Methods

National retrospective cohort study using linked National Health Service Scotland administrative data of adults hospitalised for an ASCVD event (n=167 978) from 2009 to 2017. Proportions of patients initiating, adhering to, discontinuing and reinitiating statins were calculated. We separately examined treatment following myocardial infarction (MI), ischaemic stroke and peripheral arterial disease (PAD) hospitalisations. Multivariable logistic regression and Cox proportional hazards models were used to assess the roles of patient characteristics in the likelihood of initiating and discontinuing statins.

Results

Of patients hospitalised with ASCVD, only 81% initiated statin therapy, 40% of whom used high-intensity statin. Characteristics associated with lower odds of initiation included female sex (28% less likely than men), age below 50 years or above 70 years (<50 year-olds 26% less likely, and 70–79, 80–89 and ≥90 year-olds 22%, 49% and 77% less likely, respectively, than 60–69 year-olds), living in the most deprived areas and history of mental health-related hospital admission. Following MI, 88% of patients initiated therapy compared with 81% following ischaemic stroke and 75% following PAD events. Of statin-treated individuals, 24% discontinued treatment. Characteristics associated with discontinuation were similar to those related to non-initiation.

Conclusions

Statin use remains suboptimal for the secondary ASCVD prevention, particularly in women and older patients, and following ischaemic stroke and PAD hospitalisations. Improving this would offer substantial benefits to population health at low cost.
Local TLR4 stimulation augments in situ vaccination induced via local radiation and anti-CTLA-4 checkpoint blockade through induction of CD8 T-cell independent Th1 polarization
Authors: Jagodinsky Justin C , Bates Amber M , Clark Paul A , Sriramaneni Raghava N , Havighurst Thomas C , Chakravarty Ishan , Nystuen Erin J , Kim KyungMann , Sondel Paul M , Jin Won Jong , Morris Zachary S
Published: October 2022

Background

Radiation therapy (RT) has been demonstrated to generate an in situ vaccination (ISV) effect in murine models and in patients with cancer; however, this has not routinely translated into enhanced clinical response to immune checkpoint inhibition (ICI). We investigated whether the commonly used vaccine adjuvant, monophosphoryl lipid A (MPL) could augment the ISV regimen consisting of combination RT and ICI.

Materials/methods

We used syngeneic murine models of melanoma (B78) and prostate cancer (Myc-CaP). Tumor-bearing mice received either RT (12 Gy, day 1), RT+anti-CTLA-4 (C4, day 3, 6, 9), MPL (20 µg IT injection days 5, 7, 9), RT+C4+MPL, or PBS control. To evaluate the effect of MPL on the irradiated tumor microenvironment, primary tumor with tumor draining lymph nodes were harvested for immune cell infiltration analysis and cytokine profiling, and serum was collected for analysis of antitumor antibody populations.

Results

Combination RT+C4+MPL significantly reduced tumor growth, increased survival and complete response rate compared with RT+C4 in both B78 and Myc-CaP models. MPL favorably reprogrammed the irradiated tumor-immune microenvironment toward M1 macrophage and Th1 TBET+CD4+T cell polarization. Furthermore, MPL significantly increased intratumoral expression of several Th1-associated and M1-associated proinflammatory cytokines. In co-culture models, MPL-stimulated macrophages directly activated CD8 T cells and polarized CD4 cells toward Th1 phenotype. MPL treatment significantly increased production of Th1-associated, IgG2c antitumor antibodies, which were required for and predictive of antitumor response to RT+C4+MPL, and enabled macrophage-mediated antibody-dependent direct tumor cell killing by MPL-stimulated macrophages. Macrophage-mediated tumor cell killing was dependent on FcγR expression. In metastatic models, RT and MPL generated a systemic antitumor immune response that augmented response to ICIs. This was dependent on macrophages and CD4+but not CD8+T cells.

Conclusions

We report the potential for MPL to augment the ISV effect of combination RT+C4 through FcγR, macrophage, and TBET+CD4+Th1 cell dependent mechanisms. To our knowledge, this is the first report describing generation of a CD8+T cell-independent, Th1 polarized, systemic antitumor immune response with subsequent generation of immunologic memory. These findings support the potential for vaccine adjuvants to enhance the efficacy of in situ tumor vaccine approaches.
Association between operator volume and mortality in primary percutaneous coronary intervention
Authors: Krishnamurthy Arvindra , Keeble Claire M , Anderson Michelle , Burton-Wood Natalie , Somers Kathryn , Harland Charlotte , Baxter Paul D , McLenachan Jim M , Blaxill Jonathan M , Blackman Daniel J , Malkin Christopher J , Wheatcroft Stephen B , Greenwood John P
Published: October 2022

Background

There is a paucity of real-world data assessing the association of operator volumes and mortality specific to primary percutaneous coronary intervention (PPCI).

Methods

Demographic, clinical and outcome data for all patients undergoing PPCI in Leeds General Infirmary, UK, between 1 January 2009 and 31 December 2011, and 1 January 2013 and 31 December 2013, were obtained prospectively. Operator volumes were analysed according to annual operator PPCI volume (low volume: 1–54 PPCI per year; intermediate volume: 55–109 PPCI per year; high volume: ≥110 PPCI per year). Cox proportional hazards regression analyses were undertaken to investigate 30-day and 12-month all-cause mortality, adjusting for confounding factors.

Results

During this period, 4056 patients underwent PPCI, 3703 (91.3%) of whom were followed up for a minimum of 12 months. PPCI by low-volume operators was associated with significantly higher adjusted 30-day mortality (HR 1.48 (95% CI 1.05 to 2.08); p=0.02) compared with PPCI performed by high-volume operators, with no significant difference in adjusted 12-month mortality (HR 1.26 (95% CI 0.96 to 1.65); p=0.09). Comparisons between low-volume and intermediate-volume operators, and between intermediate and high-volume operators, showed no significant differences in 30-day and 12-month mortality.

Conclusions

Low operator volume is independently associated with higher probability of 30-day mortality compared with high operator volume, suggesting a volume–outcome relationship in PPCI at a threshold higher than current recommendations.
Integrating trawl and longline surveys across British Columbia improves groundfish distribution predictions
Authors: Thompson Patrick L. , Anderson Sean C. , Nephin Jessica , Robb Carolyn K. , Proudfoot Beatrice , Park Ashley E. , Haggarty Dana R. , Rubidge Emily M.
Published: October 2022

Predictions of the distribution of groundfish species are needed to support ongoing marine spatial planning initiatives in Canadian Pacific waters. Data to inform species distribution models are available from several fishery-independent surveys. However, no single survey covers the entire region and different gear types are required to survey the range of relevant habitat. Here, we demonstrated a method for integrating presence–absence data across surveys and gear types that allows us to predict the coastwide distributions of 65 groundfish species in British Columbia. Our model leverages data from multiple surveys to estimate how species respond to environmental gradients while accounting for differences in survey catchability. We find that this method has two main benefits: (1) it increases the accuracy of predictions in data-limited surveys and regions while having negligible impacts on accuracy when data are already sufficient, and (2) it reduces uncertainty, resulting in tighter confidence intervals on predicted occurrences. These benefits are particularly relevant in areas of our coast where our understanding of habitat suitability is limited due to a lack of spatially comprehensive long-term groundfish surveys.
Performance analysis of vibration characteristics on VCR engine using hybrid honeycomb structure
Authors: Senthilkumar C. , Vasudevan D.
Published: October 2022

There are a number of techniques available to reduce the engine vibration, and vibration isolation is one among those techniques. Such vibrations can be isolated using hybrid engine mounts that absorb the forces caused by vibration. Consequently, the present work proposes a hybrid aluminium mount filled with silica gel to isolate the engine vibration. Experiments were carried out on the variable compression ratio engine mounted on the hybrid honeycomb structure, and the free, forced vibrations, and frequency domains were analysed. The test results portrayed that the performance of the engine with a hybrid mount is found to be better than the conventional rubber mount. The hybrid sandwich panel with a honeycomb structure crowded with silica gel as fibrous material was utilized to isolate the engine vibrations. Compared with conventional mount (1.502 m/s2), high amount of vibration was reduced by honeycomb structured mount (0.814 m/s2) using different load conditions and fuel input pressure of 150 bar. Vibration in conventional mount for blower closing condition was 1.546 m/s2 and that in honeycomb structured mount was 1.4 m/s2.
Dead men still tell tales: bivalve death assemblages record dynamics and consequences of recent biological invasions in Kingston Harbour, Jamaica
Authors: Kokesh Broc S. , Stemann Thomas A.
Published: October 2022

Short-lived biological invasions may leave lasting impacts on ecosystems well after they have concluded, yet the nature of such events is difficult to elucidate in the absence of monitoring efforts. Here, the ability for surficial death assemblages to recount such invasion events and their ecological legacies was tested using mangrove-dwelling bivalves from Kingston Harbour, Jamaica, where the Asian green mussel (
Perna viridis
) was introduced
c.
20 years ago. While rare in Kingston Harbour today, relative densities of dead
P. viridis
shells mapped well to historical surveys from early into the invasion and thus help reconstruct spatial variations in invasion intensity. Live–dead discordance for the bivalve community further indicated that species have not returned to pre-invasion relative abundance distributions such that the economically-important mangrove oyster (
Crassostrea rhizophorae
) declined while the flat tree oyster (
Isognomon alatus
) rose to dominance. Finally, we report the presence of the charru mussel (
Mytella strigata
) in Kingston Harbour, a newly introduced species that has not yet been significantly incorporated into the subfossil record. This case study exemplifies the utility of underexploited sources of geohistorical data for informing the growing problem of human-assisted biological invasion.
Biodiversity change and extinction risk in Plio-Pleistocene Mediterranean bivalves: the families Veneridae, Pectinidae and Lucinidae
Authors: Danise Silvia , Dominici Stefano
Published: October 2022

Understanding species vulnerability to extinction is one of the goals of conservation. Here we analyse a dataset of Plio-Pleistocene Mediterranean bivalve occurrences (families Veneridae, Pectinidae and Lucinidae), to reconstruct biodiversity change through time, and to test whether species occurrence frequency, geographical range and habitat specialization explained species survival or extinction. We found that biodiversity loss started soon after the mid-Piacenzian warming Period, at
c.
3.0 Ma, and continued as climate progressively cooled, up to the Gelasian. It was more gradual than expected, as some species found a temporary
refugium
in the warmer, eastern Mediterranean. Extinction was more intense for the epifaunal, mobile pectinids, compared to the infaunal, siphonate venerids and lucinids. Occurrence frequency, geographical range and habitat specialization were good predictors of species extinction for the Veneridae and the Lucinidae. For the Pectinidae habitat specialization was a good predictor of extinction, but not occurrence frequency and geographical range, as also some common and geographical widespread Pliocene species became extinct. In this family, extinction risk was better predicted by latitudinal range than geographical range. Habitat loss due to the fragmentation of carbonate palaeoenvironments and high metabolic rates related to large body size also played a role in pectinid extinction.
Contextual Path Retrieval: A Contextual Entity Relation Embedding-based Approach
Authors: Lo Pei-Chi , Lim Ee-Peng
Published: October 2022

Contextual path retrieval
(CPR) refers to the task of finding contextual path(s) between a pair of entities in a knowledge graph that explains the connection between them in a given context. For this novel retrieval task, we propose the Embedding-based Contextual Path Retrieval (ECPR) framework. ECPR is based on a three-component structure that includes a context encoder and path encoder that encode query context and path, respectively, and a path ranker that assigns a ranking score to each candidate path to determine the one that should be the contextual path. For context encoding, we propose two novel context encoding methods, i.e., context-fused entity embeddings and contextualized embeddings. For path encoding, we propose PathVAE, an inductive embedding approach to generate path representations. Finally, we explore two path-ranking approaches. In our evaluation, we construct a synthetic dataset from Wikipedia and two real datasets of Wikinews articles constructed through crowdsourcing. Our experiments show that methods based on ECPR framework outperform baseline methods, and that our two proposed context encoders yield significantly better performance than baselines. We also analyze a few case studies to show the distinct features of ECPR-based methods.
A Fast and Flexible FPGA-based Accelerator for Natural Language Processing Neural Networks
Authors: Hur Suyeon , Na Seongmin , Kwon Dongup , Kim Joonsung , Boutros Andrew , Nurvitadhi Eriko , Kim Jangwoo
Published: October 2022

Deep neural networks (DNNs) have become key solutions in the natural language processing (NLP) domain. However, the existing accelerators customized for their narrow target models cannot support diverse NLP models. Therefore, naively running complex NLP models on the existing accelerators often leads to very marginal performance improvements. For these reasons, architects are now in dire need of a new accelerator that can run various NLP models while taking its full performance potential. In this article, we propose FlexRun, an FPGA-based modular accelerator to efficiently support diverse and complex NLP models. First, we identify key components commonly used by NLP models and implement them on top of a current state-of-the-art FPGA-based accelerator. Next, FlexRun conducts an in-depth design space exploration to find the best accelerator architecture for a target NLP model. Last, FlexRun automatically reconfigures the accelerator based on the exploration results. Our FlexRun design outperforms the current state-of-the-art FPGA-based accelerator by 1.21×–2.73× and 1.15×–1.50× for BERT and GPT2, respectively. Compared to Nvidia’s V100 GPU, FlexRun achieves 2.69× higher performance on average for various BERT and GPT2 models.
Worst-case Power Integrity Prediction Using Convolutional Neural Network
Authors: Dong Xiao , Chen Yufei , Chen Jun , Wang Yucheng , Li Ji , Ni Tianming , Shi Zhiguo , Yin Xunzhao , Zhuo Cheng
Published: October 2022

Power integrity analysis is an essential step in power distribution network (PDN) sign-off to ensure the performance and reliability of chips. However, with the growing PDN size and increasing scenarios to be validated, it becomes very time- and resource-consuming to conduct full-stack PDN simulation to check the power integrity for different test vectors. Recently, various works have proposed machine learning–based methods for PDN power integrity prediction, many of which still suffer from large training overhead, inefficiency, or non-scalability. Thus, this article proposed an efficient and scalable framework for the worst-case power integrity prediction, which can handle general tasks including dynamic noise prediction and bump current prediction. The framework first reduces the spatial and temporal redundancy in the PDN and input current vector and then employs efficient feature extraction as well as a novel convolutional neural network architecture to predict the worst-case power integrity. Experimental results show that the proposed framework consistently outperforms the commercial tool and the state-of-the-art machine learning method with only 0.63–1.02% mean relative error and 25–69× speedup for noise prediction and 0.22–1.06% mean relative error and 24–64× speedup for bump current prediction.
Game Theory–Based Parameter Tuning for Energy-Efficient Path Planning on Modern UAVs
Authors: Moolchandani Diksha , Yadav Kishore , Kulathunga Geesara , Afanasyev Ilya , Kumar Anshul , Mazzara Manuel , Sarangi Smruti
Published: October 2022

Present-day path planning algorithms for UAVs rely on various parameters that need to be tuned at runtime to be able to plan the best possible route. For example, for a sampling-based algorithm, the number of samples plays a crucial role. The dimension of the space that is being searched to plan the path, the minimum distance for extending a path in a direction, and the minimum distance that the drone should maintain with respect to obstacles while traversing the planned path are all important variables. Along with this, we have a choice of vision algorithms, their parameters, and platforms.

Finding a suitable configuration for all these parameters at runtime is very challenging because we need to solve a complicated optimization problem, and that too within tens of milliseconds. The area of theoretical exploration of the optimization problems that arise in such settings is dominated by traditional approaches that use regular nonlinear optimization techniques often enhanced with AI-based techniques such as genetic algorithms. These techniques are sadly rather slow, have convergence issues, and are typically not suitable for use at runtime. In this article, we leverage recent and promising research results that propose to solve complex optimization problems by converting them into approximately equivalent game-theoretic problems. The computed equilibrium strategies can then be mapped to the optimal values of the tunable parameters. With simulation studies in virtual worlds, we show that our solutions are 5-21% better than those produced by traditional methods, and our approach is 10× faster.
Distribution of Copper Electrochemical Nucleation Activities on Glassy Carbon: A New Perspective Based on Local Electrochemistry
Authors: Torres Daniel , Bernal Miguel , Demaude Annaëlle , Hussain Sajid , Bar Laure , Losada-Pérez Patricia , Reniers François , Ustarroz Jon
Published: October 2022

The electrochemical nucleation and growth (EN&G) on active surface sites has been a concept of fundamental and technological interest for several decades. Here, we have studied the EN&G of Cu on glassy carbon with a new perspective using the Scanning Electrochemical Cell Microscopy (SECCM), in combination with scanning electron microscopy, atomic force microscopy, and X‐ray photo-electron spectroscopy. Unlike the conventional macroscopic approach, we leveraged the spatial resolution of the SECCM to probe individual sites on the same surface, independently from each other, revealing regions with different energy barriers for nucleation and a distribution of activities for EN&G at the microscopic scale. This site-dependent activity can be modified with common surface pretreatments (i.e., polishing and preanodization). We addressed the electrochemical diversity through multiple descriptors and used them to conduct statistical analysis, supported by surface characterization techniques, bringing forward information that is simply unavailable with the conventional macroscopic approach. This work serves as a departure point to conceive new analysis strategies and address the real nature of active sites for nucleation.
COOH-terminal fragment of APP interacts with p62, forms an aggregate, and induces autophagic degradation in Alzheimer’s cell model
Authors: Tanaka Keigo , Kuramoto Kohei , Nakagawa Tadashi , Nomura Yasuyuki , Ozawa Koichiro , Hosoi Toru
Published: October 2022

Alzheimer’s disease is an intractable disease, and the accumulation of amyloid β in the brain is thought to be involved in the onset of the disease. Additionally, abnormal protein accumulation due to autophagic deficiency may also be involved in disease progression. Autophagy involves a mechanism called selective autophagy. However, the relationship between selective autophagy and the amyloid precursor protein (APP) remains unclear. In the present study, we analyzed the interaction between p62, an adapter protein, and an APP-related molecule and found that p62 interacted with the COOH-terminal fragment of APP (C60). When C60 and p62 are overexpressed, aggregates are formed and C60 is degraded by autophagy. These aggregates cannot be easily degraded, even with a reducing agent. We also found that autophagosome- and lysosome marker-positive vesicles were formed in the C60- and p62-expressing cells. Superresolution technology also revealed that p62-C60-positive autophagosomes were formed in the cells. Overall, these results suggest that p62 may bind with C60 to form aggregates and induce autophagy in autophagosomes. These results reveal one of the mechanisms underlying the progression of Alzheimer’s disease, in which selective autophagy may be involved.
Breast cancers co-opt normal mechanisms of tolerance to promote immune evasion and metastasis
Authors: Crump Lyndsey S. , Kines Kelsey T. , Richer Jennifer K. , Lyons Traci R.
Published: October 2022

Normal developmental processes, such as those seen during embryonic development and postpartum mammary gland involution, can be reactivated by cancer cells to promote immune suppression, tumor growth, and metastatic spread. In mammalian embryos, paternal-derived antigens are at risk of being recognized as foreign by the maternal immune system. Suppression of the maternal immune response toward the fetus, which is mediated in part by the trophoblast, is critical to ensure embryonic survival and development. The postpartum mammary microenvironment also exhibits immunosuppressive mechanisms accompanying the massive cell death and tissue remodeling that occurs during mammary gland involution. These normal immunosuppressive mechanisms are paralleled during malignant transformation, where tumors can develop neoantigens that may be recognized as foreign by the immune system. To circumvent this, tumors can dedifferentiate and co-opt immune-suppressive mechanisms normally utilized during fetal tolerance and postpartum mammary involution. In this review, we discuss those similarities and how they can inform our understanding of cancer progression and metastasis.
State-of-the-art techniques for imaging the vascular microenvironment in craniofacial bone tissue engineering applications
Authors: Ren Yunke , Senarathna Janaka , Grayson Warren L. , Pathak Arvind P.
Published: October 2022

Vascularization is a crucial step during musculoskeletal tissue regeneration via bioengineered constructs or grafts. Functional vasculature provides oxygen and nutrients to the graft microenvironment, facilitates wound healing, enhances graft integration with host tissue, and ensures the long-term survival of regenerating tissue. Therefore, imaging de novo vascularization (i.e., angiogenesis), changes in microvascular morphology, and the establishment and maintenance of perfusion within the graft site (i.e., vascular microenvironment or VME) can provide essential insights into engraftment, wound healing, as well as inform the design of tissue engineering (TE) constructs. In this review, we focus on state-of-the-art imaging approaches for monitoring the VME in craniofacial TE applications, as well as future advances in this field. We describe how cutting-edge in vivo and ex vivo imaging methods can yield invaluable information regarding VME parameters that can help characterize the effectiveness of different TE constructs and iteratively inform their design for enhanced craniofacial bone regeneration. Finally, we explicate how the integration of novel TE constructs, preclinical model systems, imaging techniques, and systems biology approaches could usher in an era of “image-based tissue engineering.”
Different modalities of host cell death and their impact on Mycobacterium tuberculosis infection
Authors: Nisa Annuurun , Kipper Franciele C. , Panigrahy Dipak , Tiwari Sangeeta , Kupz Andreas , Subbian Selvakumar
Published: October 2022

Mycobacterium tuberculosis ( Mtb) is the pathogen that causes tuberculosis (TB), a leading infectious disease of humans worldwide. One of the main histopathological hallmarks of TB is the formation of granulomas comprised of elaborately organized aggregates of immune cells containing the pathogen. Dissemination of Mtb from infected cells in the granulomas due to host and mycobacterial factors induces multiple cell death modalities in infected cells. Based on molecular mechanism, morphological characteristics, and signal dependency, there are two main categories of cell death: programmed and nonprogrammed. Programmed cell death (PCD), such as apoptosis and autophagy, is associated with a protective response to Mtb by keeping the bacteria encased within dead macrophages that can be readily phagocytosed by arriving in uninfected or neighboring cells. In contrast, non-PCD necrotic cell death favors the pathogen, resulting in bacterial release into the extracellular environment. Multiple types of cell death in the PCD category, including pyroptosis, necroptosis, ferroptosis, ETosis, parthanatos, and PANoptosis, may be involved in Mtb infection. Since PCD pathways are essential for host immunity to Mtb, therapeutic compounds targeting cell death signaling pathways have been experimentally tested for TB treatment. This review summarizes different modalities of Mtb-mediated host cell deaths, the molecular mechanisms underpinning host cell death during Mtb infection, and its potential implications for host immunity. In addition, targeting host cell death pathways as potential therapeutic and preventive approaches against Mtb infection is also discussed.
Downregulation of NHE-3 (SLC9A3) expression by MicroRNAs in intestinal epithelial cells
Authors: Anbazhagan Arivarasu N. , Priyamvada Shubha , Kumar Anoop , Jayawardena Dulari , Borthakur Alip , Gill Ravinder K. , Alrefai Waddah A. , Dudeja Pradeep K. , Saksena Seema
Published: October 2022

Na+/H+ exchanger-3 (NHE-3) is the major apical membrane transporter involved in vectorial Na+ absorption in the intestine. Dysregulation of NHE-3 expression and/or function has been implicated in pathophysiology of diarrhea associated with gut inflammation and infections. Therefore, it is critical to understand the mechanisms involved in the regulation of NHE-3 expression. MicroRNAs (miRNAs) are highly conserved small RNAs that can regulate gene expression at the posttranscriptional level. To date, however, very little is known about the regulation of NHE-3 expression by microRNAs. Therefore, current studies were undertaken to examine the potential miRNA candidates that can regulate the expression of NHE-3 in intestinal epithelial cells. In silico analysis, using different algorithms, predicted several miRNAs that target NHE-3. MicroRNAs with highest context and target score, miR-326, miR-744-5p, and miR-330-5p, were selected for the current study. Human NHE-3 gene 3′ untranslated region [3′UTR; 160 base pair (bp)] was cloned into pmirGLO vector upstream of luciferase reporter and transiently transfected with mimics of miR-326, miR-744-5p, and miR-330-5p into Caco-2, HT-29, and SK-CO15 cells. Cotransfection of NHE-3 3′ UTR with miR-326 and -miR-330-5p mimics resulted in a significant decrease in relative luciferase activity. Transfection of miR-326 and -330-5p mimics into SK-CO15 cells significantly decreased the NHE-3 protein expression, with no change in NHE-3 messenger ribonucleic acid (mRNA) levels. Our findings demonstrate a novel mechanism for posttranscriptional regulation of NHE-3 by miR-326 and -330-5p by translational repression. We speculate that miR-326 and -330-5p dependent pathways may be involved in modulating NHE-3 expression under physiological and pathophysiological conditions.
Activation of brain lactate receptor GPR81 aggravates exercise-induced central fatigue
Authors: Li Junxia , Xia Yiming , Xu Honghao , Xiong Renping , Zhao Yan , Li Ping , Yang Tian , Huang Qingyuan , Shan Fabo
Published: October 2022

Exercise-induced fatigue is a complex physiological phenomenon and is greatly influenced by central mechanisms in brain. As one of the most abundant circulating carbon metabolites, l-lactate in brain has been considered to be an important supplementary fuel during exercise; however, whether it plays a signaling role in fatigue remains largely obscure. In this study, our results initially revealed that brain l-lactate levels were increased after an exhaustive swimming session in several brain regions including motor cortex, hippocampus, and cerebellum. Then, we examined the specific role of brain lactate receptor, also known as hydroxycarboxylic acid receptor 1 (GPR81), in exercise-induced fatigue. We found that intracerebroventricular injection of either d-lactate (an enantiomer that could mediate activation of GPR81 as l-lactate) or a potent GPR81 agonist 3-chloro-5-hydroxybenzoic acid (CHBA), significantly decreased the swimming time to fatigue. After being subjected to the same weight-loaded swimming for 30 min, no obvious changes of blood lactate levels, gastrocnemius pAMPK/AMPK ratio, and glycogen contents were observed between intracerebroventricular CHBA-injected mice and vehicle-treated ones, which suggested a comparable degree of peripheral fatigue. Meanwhile, there were higher extracellular γ-aminobutyric acid (GABA) levels and lower extracellular glutamate levels and glutamate/GABA ratio in motor cortex of the intracerebroventricular CHBA-injected mice than that of vehicle-treated ones, indicating a greater extent of central fatigue in CHBA-injected mice than that in vehicle animals. Collectively, our results suggested that an increased level of brain l-lactate acts as a signaling molecule via activating GPR81, which in turn exacerbates central fatigue during exercise.
Assessing functional sympatholysis during rhythmic handgrip exercise using Doppler ultrasound and near-infrared spectroscopy: sex differences and test-retest reliability
Authors: Teixeira André L. , Garland Matthew , Lee Jordan B. , Nardone Massimo , Millar Philip J.
Published: October 2022

The effects of sympathetic activity on vasoconstriction are dampened in active skeletal muscle during exercise, a phenomenon termed functional sympatholysis. Limited work has examined the influence of sex on the magnitude of sympatholysis or the test-retest reliability of measurements. In 16 women and 15 men, forearm blood flow (FBF; Doppler ultrasound), muscle oxygenation (near-infrared spectroscopy, NIRS), and beat-to-beat mean arterial pressure (MAP; photoplethysmography) were measured during lower-body negative pressure (LBNP; −20 mmHg) at rest and simultaneously during rhythmic handgrip exercise (30% maximum contraction). Measures were taken twice within the same visit (separated by 15 min) and repeated on a second visit. Forearm vascular conductance (FVC) was calculated as FBF/MAP. The magnitude of sympatholysis was calculated as the difference of LBNP-induced changes between handgrip and rest. LBNP decreased FBF (Δ−45 ± 15%), FVC (Δ−45 ± 16%), and muscle oxygenation (Δ−14 ± 11%); however, these responses were attenuated when LBNP was applied during rhythmic handgrip exercise (Δ−7 ± 9%, Δ−9 ± 10%, and Δ−6 ± 9%, respectively). The magnitude of sympatholysis was not different between men and women (FBF: 40 ± 16% vs. 35 ± 9%, P = 0.37; FVC: 38 ± 16% vs. 35 ± 11%, P = 0.53; muscle oxygenation: 5 ± 9% vs. 11 ± 10%, P = 0.11). Furthermore, sympatholysis measurements demonstrated good to excellent intraday (intraclass-correlation coefficients; ICC ≥ 0.85) and interday (ICC ≥ 0.72) test-retest reliability (all P ≤ 0.01) in both sexes. The coefficients of variation were larger with NIRS (68–91%) than with Doppler ultrasound (16%−22%) assessments of functional sympatholysis. Collectively, these findings demonstrate that assessments of functional sympatholysis are not impacted by biological sex and that Doppler ultrasound-derived measures of sympatholysis have better within-subject reliability than NIRS-derived measures in young healthy adults.
Maternal exercise improves epithelial development of fetal intestine by enhancing apelin signaling and oxidative metabolism
Authors: Chae Song Ah , Son Jun Seok , de Avila Jeanene Marie , Du Min , Zhu Mei-Jun
Published: October 2022

Obesity in pregnancy is currently the leading cause of gestational complications for the mother and fetus worldwide. Maternal obesity (MO), common in western societies, impedes development of intestinal epithelium in the fetuses, which causes disorders in the nutrient absorption and intestine-related immune responses in offspring. Here, using a mouse model of maternal exercise (ME), we found that exercise during pregnancy protects the impairment of fetal intestinal morphometrical formation and epithelial development due to MO. MO decreased villus length and epithelial proliferation markers in E18.5 fetal small intestine, which was increased due to ME. The expression of the epithelial differentiation markers, Lyz1, Muc2, and Tff3, in fetal small intestine was decreased due to MO, but protected by ME. Consistently, the biomarkers related to mitochondrial biogenesis and oxidative metabolism were downregulated in MO fetal small intestine but recovered by ME. Apelin injection to dams partially mirrored the beneficial effects of ME. ME and apelin injection activated AMPK, the downstream target of apelin receptor signaling, which might mediate the improvement of fetal epithelial development and oxidative metabolism. These findings suggest that ME, a highly accessible intervention, is effective in improving fetal intestinal epithelium of obese dams. Apelin-AMPK-mitochondrial biogenesis axis provides amenable therapeutic targets to facilitate fetal intestinal development of obese mothers.
Epithelial sodium channels in macrophage migration and polarization: role of proinflammatory cytokines TNFα and IFNγ
Authors: Nemeth Zoltan , Hildebrandt Emily , Parsa Nicholas , Fleming Adam B. , Wasson Robert , Pittman Katarina , Bell Xavier , Granger Joey P. , Ryan Michael J. , Drummond Heather A.
Published: October 2022

Migration of monocytes-macrophages plays an important role in phagocytosis of pathogens and cellular debris in a variety of pathophysiological conditions. Although epithelial Na+ channels (ENaCs) are required for normal migratory responses in other cell types, their role in macrophage migration signaling is unknown. To address this possibility, we determined whether ENaC message is present in several peripheral blood monocyte cell populations and tissue-resident macrophages in healthy humans using the Human Protein Atlas database ( www.proteinatlas.org ) and the mouse monocyte cell line RAW 264.7 using RT-PCR. We then determined that selective ENaC inhibition with amiloride inhibited chemotactic migration (∼50%), but not phagocytosis, of the mouse monocyte-macrophage cell line RAW 264.7. Furthermore, we generated a cell line stably expressing an NH2-terminal truncated αENaC to interrupt normal channel trafficking and found it suppressed migration. Prolonged exposure (48 h) of RAW 264.7 cells to proinflammatory cytokines interferon γ (IFNγ) and/or tumor necrosis factor α (TNFα) inhibited RAW 264.7 migration and abolished the amiloride (1 µM)-sensitive component of migration, a finding consistent with ENaC downregulation. To determine if proinflammatory cytokines regulate αENaC protein expression, cells were exposed to proinflammatory cytokines IFNγ (10 ng/mL, last 48 h) and TNFα (10 ng/mL, last 24 h). By Western blot analysis, we found whole cell αENaC protein is reduced ≥50%. Immunofluorescence demonstrated heterogeneous αENaC inhibition. Finally, we found that overnight exposure to amiloride stimulated morphological changes and increased polarization marker expression. Our findings suggest that ENaC may be a critical molecule in macrophage migration and polarization.
Protective Mechanisms of Nootropic Herb Shankhpushpi (Convolvulus pluricaulis) against Dementia: Network Pharmacology and Computational Approach
Authors: Hannan Md. Abdul , Sultana Armin , Rahman Md. Hasanur , Al Mamun Sohag Abdullah , Dash Raju , Uddin Md Jamal , Hossen Muhammad Jahangir , Moon Il Soo
Published: October 2022

Convolvulus pluricaulis (CP), a Medhya Rasayana (nootropic) herb, is a major ingredient in Ayurvedic and Traditional Chinese formulae indicated for neurological conditions, namely, dementia, anxiety, depression, insanity, and epilepsy. Experimental evidence suggests various neuroactive potentials of CP such as memory-enhancing, neuroprotective, and antiepileptic. However, precise mechanisms underlying the neuropharmacological effects of CP remain unclear. The study, therefore, aimed at deciphering the molecular basis of neuroprotective effects of CP phytochemicals against the pathology of dementia disorders such as Alzheimer’s (AD) and Parkinson’s (PD) disease. The study exploited bioinformatics tools and resources, such as Cytoscape, DAVID (Database for annotation, visualization, and integrated discovery), NetworkAnalyst, and KEGG (Kyoto Encyclopedia of Genes and Genomes) database to investigate the interaction between CP compounds and molecular targets. An in silico analysis was also employed to screen druglike compounds and validate some selective interactions. ADME (absorption, distribution, metabolism, and excretion) analysis predicted a total of five druglike phytochemicals from CP constituents, namely, scopoletin, 4-hydroxycinnamic acid, kaempferol, quercetin, and ayapanin. In network analysis, these compounds were found to interact with some molecular targets such as prostaglandin G/H synthase 1 and 2 (PTGS1 and PTGS2), endothelial nitric oxide synthase (NOS3), insulin receptor (INSR), heme oxygenase 1 (HMOX1), acetylcholinesterase (ACHE), peroxisome proliferator-activated receptor-gamma (PPARG), and monoamine oxidase A and B (MAOA and MAOB) that are associated with neuronal growth, survival, and activity. Docking simulation further confirmed interaction patterns and binding affinity of selected CP compounds with those molecular targets. Notably, scopoletin showed the highest binding affinity with PTGS1, NOS3, PPARG, ACHE, MAOA, MAOB, and TRKB, quercetin with PTGS2, 4-hydroxycinnamic acid with INSR, and ayapanin with HMOX1. The findings indicate that scopoletin, kaempferol, quercetin, 4-hydroxycinnamic acid, and ayapanin are the main active constituents of CP which might account for its memory enhancement and neuroprotective effects and that target proteins such as PTGS1, PTGS2, NOS3, PPARG, ACHE, MAOA, MAOB, INSR, HMOX1, and TRKB could be druggable targets against dementia.