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Sialidases, or neuraminidases, are enzymes that catalyze the hydrolysis of sialic acid (Sia)-containing molecules, mostly removal of the terminal Sia (desialylation). By desialylation, sialidase can modulate the functionality of the target compound and is thus often involved in biological pathways. Inhibition of sialidases with inhibitors is an important approach for understanding sialidase function and the underlying mechanisms and could serve as a therapeutic approach as well. Transition-state analogues, such as anti-influenza drugs oseltamivir and zanamivir, are major sialidase inhibitors. In addition, difluoro-sialic acids were developed as mechanism-based sialidase inhibitors. Further, fluorinated quinone methide-based suicide substrates were reported. Sialidase product analogue inhibitors were also explored. Finally, natural products have shown competitive inhibiton against viral, bacterial, and human sialidases. This Perspective describes sialidase inhibitors with different mechanisms and their activities and future potential, which include transition-state analogue inhibitors, mechanism-based inhibitors, suicide substrate inhibitors, product analogue inhibitors, and natural product inhibitors.

Objectives. To test a tailored mobile health (i.e., mHealth) intervention for waterpipe tobacco cessation in young adults. Methods. From 2018 to 2020 at 2 US sites, we conducted a randomized trial with 349 waterpipe tobacco smokers aged 18 to 30 years randomized to control (no intervention), untailored, or tailored intervention arms. Intervention arms received a 6-week mHealth intervention conveying risks of waterpipe tobacco through text and images and strategies to enhance motivation and support quitting. The tailored intervention was personalized to baseline measures and intervention text message responses. Risk appraisals, motivation to quit, waterpipe smoking frequency, and cessation were assessed at 6 weeks, 3 months, and 6 months. Results. At 6 months, cessation was higher in the tailored (49%) than the control arm (29%; odds ratio = 2.4; 95% confidence interval = 1.3, 4.2) and smoking frequency was lower in the tailored (mean = 3.5 days) than the control arm (mean = 4.3 days; P = .006). At interim follow-ups, significant differences in other outcomes favored the tailored intervention. Conclusions. Tailored mobile messaging can help young adult waterpipe tobacco smokers quit. This scalable intervention is poised for population implementation.

In the central nervous system (CNS), execution of programmed cell death (PCD) is crucial for proper neurodevelopment. However, aberrant activation of these pathways in adult CNS leads to neurodegenerative diseases including amyotrophic lateral sclerosis (ALS). How a cell dies is critical, as it can drive local immune activation and tissue damage. Classical apoptosis engages several mechanisms to evoke "immunologically silent" responses, whereas other forms of programmed death such as pyroptosis, necroptosis, and ferroptosis release molecules that can potentiate immune responses and inflammation. In ALS, a fatal neuromuscular disorder marked by progressive death of lower and upper motor neurons, several cell types in the CNS express machinery for multiple PCD pathways. The specific cell types engaging PCD, and ultimate mechanisms by which neuronal death occurs in ALS are not well defined. Here, we provide an overview of different PCD pathways implicated in ALS. We also examine immune activation in ALS and differentiate apoptosis from necrotic mechanisms based on downstream immunological consequences. Lastly, we highlight therapeutic strategies that target cell death pathways in the treatment of neurodegeneration and inflammation in ALS.

Objective: We aimed to determine the prevalence of abnormal umbilical artery (UA), uterine artery (UtA), middle cerebral artery (MCA) and cerebroplacental ratio (CPR) Doppler, and their relationship with adverse perinatal outcomes in women undergoing routine antenatal care in the third trimester. Design: Prospective cohort. Setting: Kagadi Hospital, Uganda. Population: Non-anomalous singleton pregnancies. Methods: Women underwent an early dating ultrasound and a third-trimester Doppler scan between 32 and 40 weeks of gestation, from 2018 to 2020. We handled missing data using multiple imputation and analysed the data using descriptive methods and a binary logistic regression model. Main outcome measures: Composite adverse perinatal outcome (CAPO), perinatal death and stillbirth. Results: We included 995 women. The mean gestational age at Doppler scan was 36.9 weeks (SD 1.02 weeks) and 88.9% of the women gave birth in a health facility. About 4.4% and 5.6% of the UA pulsatility index (PI) and UtA PI were above the 95th percentile, whereas 16.4% and 10.4% of the MCA PI and CPR were below the fifth percentile, respectively. Low CPR was strongly associated with stillbirth (OR 4.82, 95% CI 1.09–21.30). CPR and MCA PI below the fifth percentile were independently associated with CAPO; the association with MCA PI was stronger in small-for-gestational-age neonates (OR 3.75, 95% CI 1.18–11.88). Conclusion: In late gestation, abnormal UA PI was rare. Fetuses with cerebral blood flow redistribution were at increased risk of stillbirth and perinatal complications. Further studies examining the predictive accuracy and effectiveness of antenatal Doppler ultrasound screening in reducing the risk of perinatal deaths in low- and middle-income countries are warranted. Tweetable abstract: Blood flow redistribution to the fetal brain is strongly associated with stillbirths in low-resource settings.

All Medicaid programs pay for fluoride varnish applications during medical visits for infants and toddlers, but receipt of care varies considerably across states. Using 2006–2014 Medicaid data from 22 states, this study examined the association between Medicaid payment and receipt of fluoride varnish during pediatric medical visits. Among 3,393,638 medical visits, fewer than one in 10 visits included fluoride varnish. Higher Medicaid payment was positively associated with receipt of fluoride varnish during pediatric medical visits. As policymakers consider strategies for increasing young children’s access to preventive oral health services, as well as consider strategies for balancing budgets, attention should be paid to the effects of provider payment on access to pediatric oral health services.

Bidirectional communication between the peripheral nervous system (PNS) and the immune system is a crucial part of an effective but balanced mammalian response to invading pathogens, tissue damage and inflammatory stimuli. Here, we review how somatosensory and autonomic neurons regulate immune cellular responses at barrier tissues and in peripheral organs. Immune cells express receptors for neuronal mediators, including neuropeptides and neurotransmitters, allowing neurons to influence their function in acute and chronic inflammatory diseases. Distinct subsets of peripheral sensory, sympathetic, parasympathetic and enteric neurons are able to signal to innate and adaptive immune cells to modulate their cellular functions. In this Review, we highlight recent studies defining the molecular mechanisms by which neuroimmune signalling mediates tissue homeostasis and pathology. Understanding the neural circuitry that regulates immune responses can offer novel targets for the treatment of a wide array of diseases.

Chronic progressive neurodegenerative diseases (NDD) cause mobility and cognitive impairments that disrupt quality of life. The learning of new motor skills, motor learning, is a critical component of rehabilitation efforts to counteract these chronic progressive impairments. In people with NDD, there are impairments in motor learning which appear to scale with the severity of impairment. Compensatory cortical activity plays a role in counteracting motor learning impairments in NDD. Yet, the functional and structural brain alterations associated with motor learning have not been synthesized in people with NDD. The purpose of this scoping review is to explore the neural alterations of motor learning in NDD. Thirty-five peer-reviewed original articles met the inclusion criteria. Participant demographics, motor learning results, and brain imaging results were extracted. Distinct motor learning associated compensatory processes were identified across NDD populations. Evidence from this review suggests the success of motor learning in NDD populations depends on the neural alterations and their interaction with motor learning networks, as well as the progression of disease.

Young adults who never engaged in waterpipe tobacco smoking (WTS) yet are open to trying it, that is, are susceptible, is a high-risk group for initiation WTS. Very few interventions dissuade this group from WTS. Thus, we explored how four short videos that varied themes of WTS harms influenced susceptible young adults' risk perceptions, risk beliefs, and susceptibility to future WTS. As part of online cross-sectional study, 208 participants aged 18-34 were randomized to watch or not a short video; each video focused on different themes of WTS risks: physical harms, myths about WTS, addiction, and harms to others. The main outcomes were perceived personal risks, risk beliefs, perceived harm of WTS compared to cigarettes, and susceptibility to future WTS. Watching any video increased beliefs of harm of WTS and lowered susceptibility to future WTS compared to not watching a video. The theme of physical harms was most effective at increasing risk beliefs and lowering susceptibility to future WTS. All four videos were rated as credible, engaging, personally relevant, producing negative affect toward WTS, and effective at dissuading WTS. These promising findings suggest further testing is needed to determine if effects persist and prevent WTS among adults susceptible to WTS.

The desire to engage in waterpipe tobacco smoking (WTS) may occur when smokers and nonsmokers conjure positive mental simulations of WTS. However, effects of these simulations on desire to smoke waterpipe tobacco and potential mediators are unexplored. This research addressed these effects among young adult waterpipe tobacco smokers and nonsmokers. Two online studies were conducted with adults ages 18-30. In Study 1, 200 smokers, 190 susceptible nonsmokers, and 182 nonsusceptible nonsmokers were randomized to mentally simulate or not WTS in the future. In Study 2, 234 smokers and 241 susceptible nonsmokers were randomized to four arms: no simulation or simulations that varied valence of experience (positive, negative or no valence provided). Main outcomes were immediate desire to smoke waterpipe tobacco, cognitive and affective attitudes, and perceived harms. In Study 1, mental simulations increased the desire to smoke waterpipe tobacco among smokers. In Study 2, asking participants to simulate WTS positively or with no valence instruction increased desire to smoke relative to negative valence instruction or no simulation. Negative simulations reduced perceived probability of smoking within a month compared to positive simulations. Effects on desire to engage in WTS were mediated by cognitive and affective attitudes among susceptible nonsmokers and by cognitive attitudes among smokers. These findings suggest that exploring when and how often mental simulations about WTS are evoked and their potency for promoting prevention and cessation of WTS merit further attention.

The liver is innervated by autonomic and sensory fibers of the sympathetic and parasympathetic nervous systems that regulate liver function, regeneration, and disease. Although the importance of the hepatic nervous system in maintaining and restoring liver homeostasis is increasingly appreciated, much remains unknown about the specific mechanisms by which hepatic nerves both influence and are influenced by liver diseases. While recent work has begun to illuminate the developmental mechanisms underlying recruitment of nerves to the liver, evolutionary differences contributing to species-specific patterns of hepatic innervation remain elusive. In this review, we summarize current knowledge on the development of the hepatic nervous system and its role in liver regeneration and disease. We also highlight areas in which further investigation would greatly enhance our understanding of the evolution and function of liver innervation.

Characterization of germinal center B and T cell responses yields critical insights into vaccine immunogenicity. Nonhuman primates are a key preclinical animal model for human vaccine development, allowing both lymph node (LN) and circulating immune responses to be longitudinally sampled for correlates of vaccine efficacy. However, patterns of vaccine Ag drainage via the lymphatics after i.m. immunization can be stochastic, driving uneven deposition between lymphoid sites and between individual LN within larger clusters. To improve the accurate isolation of Ag-exposed LN during biopsies and necropsies, we developed and validated a method for coformulating candidate vaccines with tattoo ink in both mice and pigtail macaques. This method allowed for direct visual identification of vaccine-draining LN and evaluation of relevant Ag-specific B and T cell responses by flow cytometry. This approach is a significant advancement in improving the assessment of vaccine-induced immunity in highly relevant nonhuman primate models.

Movement disorders 38(1), 45-56 (2023). doi:10.1002/mds.29261, Published by Wiley, New York, NY

The adoptive transfer of natural killer (NK) cells, which can recognize and obliterate cancer cells, provides a practical alternative to current treatment modalities to improve cancer patients' survival. However, translating NK cell therapies to treat solid tumors has proven challenging due to the tumor microenvironment (TME). Hypoxia in the TME induces immunosuppression that inhibits the cytotoxic function of NK cells. Thus, reversing hypoxia-induced immunosuppression is critical for effective adoptive NK cell immunotherapy. In this study, we use manganese dioxide nanoparticles (MnO2 NPs) to catalyze the degradation of tumor-produced hydrogen peroxide, thereby generating oxygen. For improved biocompatibility and modulation of oxygen production, the MnO2 NPs were encapsulated into poly(lactic-co-glycolic) to produce particles that are 116 nm in size and with a ζ-potential of +17 mV (PLGA-MnO2 NPs). The PLGA-MnO2 NPs showed first-order oxygen production and sustained high oxygen tension compared to equivalent amounts of bare MnO2 NPs in the presence of H2O2. The PLGA-MnO2 NPs were biocompatible, reduced hypoxia after penetration into the core of cancer spheroids, and decreased hypoxia-induced factor 1 α expression. Reducing hypoxia in the spheroid resulted in a decrease in the potent immunosuppressors, adenosine, and lactate, which was confirmed by electrospray ionization mass spectroscopy (ESI-MS). ESI-MS also showed a change in the metabolism of the amino acids aspartate, glutamine, and glutamate after hypoxia reduction in the cancer cells. Notably, the spheroids' microenvironment changes enhanced NK cells' cytotoxicity, which obliterated the spheroids. These results demonstrate that reducing hypoxia-induced immunosuppression in tumors is a potent strategy to increase the potency of cytotoxic immune cells in the TME. The developed NPs are promising new tools to improve adoptive NK cell therapy.

Periodontitis is induced by periodontal dysbiosis characterized by the predominance of anaerobic species. TLRs constitute the classical pathway for cell activation by infection. Interestingly, the Toll/IL-1 receptor homology domain adapters initiate signaling events, leading to the activation of the expression of the genes involved in the host immune response. The aim of this study was to evaluate the effects of Porphyromonas gingivalis on the expression and protein-protein interactions among five TIR adapters (MAL, MyD88, TRIF, TRAM and SARM) in gingival epithelial cells and endothelial cells. It was observed that P. gingivalis is able to modulate the signaling cascades activated through its recognition by TLR4/2 in gingival epithelial cells and endothelial cells. Indeed, MAL-MyD88 protein-protein interactions associated with TLR4 was the main pathway activated by P. gingivalis infection. When transient siRNA inhibition was performed, cell viability, inflammation, and cell death induced by infection decreased and such deleterious effects were almost absent when MAL or TRAM were targeted. This study emphasizes the role of such TIR adapter proteins in P. gingivalis elicited inflammation and the precise evaluation of TIR adapter protein interactions may pave the way for future therapeutics in both periodontitis and systemic disease with a P. gingivalis involvement, such as atherothrombosis.

Background Nearly 90,000 under-five children die from diarrhoea annually in Nigeria. Over 90% of the deaths can be prevented with oral rehydration salt (ORS) and zinc treatment but coverage nationally was less than 34% for ORS and 3% for zinc with wide inequities. A program was implemented in eight states to address critical barriers to the optimal functioning of the health care market to deliver these treatments. In this study, we examine changes in the inequities of coverage of ORS and zinc over the intervention period. Methods Baseline and endline household surveys were used to measure ORS and zinc coverage and household assets. Principal component analysis was used to construct wealth quintiles. We used multi-level logistic regression models to estimate predictive coverage of ORS and zinc by wealth and urbanicity at each survey period. Simple measures of disparity and concentration indices and curves were used to evaluate changes in ORS and zinc coverage inequities. Results At baseline, 28% (95% CI: 22–35%) of children with diarrhoea from the poorest wealth quintile received ORS compared to 50% (95% CI: 52–58%) from the richest. This inequality reduced at endline as ORS coverage increased by 21%-points (P P Conclusion The results show a pro-rural improvement in coverage and a reduction in coverage inequities across wealth quintiles from baseline to endline. This gives an indication that initiatives focused on shaping healthcare market systems may be effective in reducing health coverage gaps without detracting from equity as a health policy objective.

Over the last 2 decades, many African countries have undergone dietary and nutrition transitions fueled by globalization, rapid urbanization, and development. These changes have altered African food environments and, subsequently, dietary behaviors, including food acquisition and consumption. Dietary patterns associated with the nutrition transition have contributed to Africa's complex burden of malnutrition - obesity and other diet-related noncommunicable diseases (DR-NCDs) - along with persistent food insecurity and undernutrition. Available evidence links unhealthy or obesogenic food environments (including those that market and offer energy-dense, nutrient-poor foods and beverages) with suboptimal diets and associated adverse health outcomes. Elsewhere, governments have responded with policies to improve food environments. However, in Africa, the necessary research and policy action have received insufficient attention. Contextual evidence to motivate, enable, and create supportive food environments in Africa for better population health is urgently needed. In November 2020, the Measurement, Evaluation, Accountability, and Leadership Support for Noncommunicable Diseases Prevention Project (MEALS4NCDs) convened the first Africa Food Environment Research Network Meeting (FERN2020). This 3-d virtual meeting brought researchers from around the world to deliberate on future directions and research priorities related to improving food environments and nutrition across the African continent. The stakeholders shared experiences, best practices, challenges, and opportunities for improving the healthfulness of food environments and related policies in low- and middle-income countries. In this article, we summarize the proceedings and research priorities identified in the meeting to advance the food environment research agenda in Africa, and thus contribute to the promotion of healthier food environments to prevent DR-NCDs, and other forms of malnutrition.

Significance Although the overwhelming majority of COVID-19-related deaths are due to respiratory failure, little is known about the host response to SARS-CoV-2 in lung parenchyma. By profiling the lung and colon transcriptome and lung proteome of nine patients who died of COVID-19 during the first wave of the pandemic in Wuhan, China, we obtained molecular insights into the host response to severe SARS-CoV-2 infection. Interestingly, all samples had a low viral burden, a finding that suggests the patients’ deaths may be due to uncontrolled host inflammatory processes rather than an active viral infection. Taken together, our findings shed light on COVID-19 pathophysiology and offer potential therapeutic targets for severe COVID-19 disease., Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, has resulted thus far in greater than 933,000 deaths worldwide; yet disease pathogenesis remains unclear. Clinical and immunological features of patients with COVID-19 have highlighted a potential role for changes in immune activity in regulating disease severity. However, little is known about the responses in human lung tissue, the primary site of infection. Here we show that pathways related to neutrophil activation and pulmonary fibrosis are among the major up-regulated transcriptional signatures in lung tissue obtained from patients who died of COVID-19 in Wuhan, China. Strikingly, the viral burden was low in all samples, which suggests that the patient deaths may be related to the host response rather than an active fulminant infection. Examination of the colonic transcriptome of these patients suggested that SARS-CoV-2 impacted host responses even at a site with no obvious pathogenesis. Further proteomics analysis validated our transcriptome findings and identified several key proteins, such as the SARS-CoV-2 entry-associated protease cathepsins B and L and the inflammatory response modulator S100A8/A9, that are highly expressed in fatal cases, revealing potential drug targets for COVID-19.

INTRODUCTION Abnormal gene expression patterns may contribute to the onset and progression of late-onset Alzheimer's disease (LOAD). METHODS We performed transcriptome-wide meta-analysis (N = 1440) of blood-based microarray gene expression profiles as well as neuroimaging and cerebrospinal fluid (CSF) endophenotype analysis. RESULTS We identified and replicated five genes (CREB5, CD46, TMBIM6, IRAK3, and RPAIN) as significantly dysregulated in LOAD. The most significantly altered gene, CREB5, was also associated with brain atrophy and increased amyloid beta (Aβ) accumulation, especially in the entorhinal cortex region. cis-expression quantitative trait loci mapping analysis of CREB5 detected five significant associations (P < 5 × 10-8 ), where rs56388170 (most significant) was also significantly associated with global cortical Aβ deposition measured by [18 F]Florbetapir positron emission tomography and CSF Aβ1-42 . DISCUSSION RNA from peripheral blood indicated a differential gene expression pattern in LOAD. Genes identified have been implicated in biological processes relevant to Alzheimer's disease. CREB, in particular, plays a key role in nervous system development, cell survival, plasticity, and learning and memory.

Neuroinflammation is a key pathologic hallmark of numerous neurologic diseases, however, its exact role in vivo is yet to be fully understood. PET imaging enables investigation, quantification, and tracking of different neuroinflammation biomarkers in living subjects longitudinally. One such biomarker that has been imaged extensively using PET is translocator protein 18 kDa (TSPO). Although imaging TSPO has yielded valuable clinical data linking neuroinflammation to various neurodegenerative diseases, considerable limitations of TSPO PET have prompted identification of other more cell-specific and functionally relevant biomarkers. This review analyzes the clinical potential of available and emerging PET biomarkers of innate and adaptive immune responses, with mention of exciting future directions for the field.

Visceral hypersensitivity of the lower gastrointestinal tract, defined as an increased response to colorectal distension, frequently prompts episodes of debilitating abdominal pain in irritable bowel syndrome (IBS). Although the pathophysiology of IBS is not yet fully elucidated, it is well known that stress is a major risk factor for development and acts as a trigger of pain sensation. Stress modulates both immune responses as well as the gut microbiota and vice versa. Additionally, either microbes themselves or through involvement of the immune system, activate or sensitize afferent nociceptors. In this paper, we review current knowledge on the influence of stress along the gut-brain-microbiota axis and exemplify relevant neuroimmune cross talk mechanisms in visceral hypersensitivity, working toward understanding how gut microbiota-neuroimmune cross talk contributes to visceral pain sensation in IBS patients.

Prenatal alcohol exposure (PAE) affects at least 10% of newborns globally and leads to the development of fetal alcohol spectrum disorders (FASDs). Despite its high incidence, there is no consensus on the implications of PAE on metabolic disease risk in adults. Here, we describe a cohort of adults with FASDs that had an increased incidence of metabolic abnormalities, including type 2 diabetes, low HDL, high triglycerides, and female-specific overweight and obesity. Using a zebrafish model for PAE, we performed population studies to elucidate the metabolic disease seen in the clinical cohort. Embryonic alcohol exposure (EAE) in male zebrafish increased the propensity for diet-induced obesity and fasting hyperglycemia in adulthood. We identified several consequences of EAE that may contribute to these phenotypes, including a reduction in adult locomotor activity, alterations in visceral adipose tissue and hepatic development, and persistent diet-responsive transcriptional changes. Taken together, our findings define metabolic vulnerabilities due to EAE and provide evidence that behavioral changes and primary organ dysfunction contribute to resultant metabolic abnormalities.

Purpose: To evaluate the characteristics of ocular injuries among elderly patients admitted to an urban level I trauma center because of major trauma from 2008 to 2015. Methods: A retrospective chart review was conducted of patients aged >65 years admitted with ocular injuries that were identified with ICD-9 codes. Tabulated data were analyzed using the Student’s paired t-test, the chi-squared test, and regression analysis using STATA/MP-12 software. Significance was set at p

Background. Waterpipe tobacco smoking is associated with many negative health outcomes due to toxicants produced by heating the tobacco using charcoal or electrical heaters. Little is known about how young adult waterpipe tobacco smokers perceive harms of these heating sources. Aims. To examine young adult waterpipe tobacco smokers’ perceived harms of electrical heaters and charcoal to heat waterpipe tobacco. Method. This online cross-sectional study enrolled 18- to 32-year-olds who smoked waterpipe tobacco within the past 30 days. Participants completed measures assessing, for each heating source, amount and knowledge of toxicants released (e.g., carbon monoxide, cancer-causing chemicals), perceived safety, worry about inhaling toxicants, perceived health risk, desire to quit, and intention to smoke in the next month. Question order for knowledge of and perceived harms was counterbalanced for each heating source. Results. Analyses were based on responses from 199 participants. Perceived harms for both heating sources were average to low. Despite some question order effects, participants viewed charcoal as more harmful than electrical heaters. Participants knew more about chemicals released from charcoal than electrical heaters. Greater knowledge of chemicals released by both heating sources correlated positively with perceived harms. Perceived harms were associated with a stronger desire to quit, yet unrelated with likelihood of smoking waterpipe during the next month. Discussion. Many young adult waterpipe tobacco smokers view charcoal as more harmful than electrical heaters, although knowledge about harms for each heating source is poor. Conclusion. Interventions are needed to inform the public about harms of waterpipe heating sources in order to curb use.

Chronic neuroinflammation and microglial dysfunction are key features of many neurological diseases, including Alzheimer's Disease and multiple sclerosis. While there is unfortunately a dearth of highly selective molecular imaging biomarkers/probes for studying microglia in vivo, P2Y12R has emerged as an attractive candidate PET biomarker being explored for this purpose. Importantly, P2Y12R is selectively expressed on microglia in the CNS and undergoes dynamic changes in expression according to inflammatory context (e.g., toxic versus beneficial/healing states), thus having the potential to reveal functional information about microglia in living subjects. Herein, we identified a high affinity, small molecule P2Y12R antagonist (AZD1283) to radiolabel and assess as a candidate radiotracer through in vitro assays and in vivo positron emission tomography (PET) imaging of both wild-type and total knockout mice and a non-human primate.First, we evaluated the metabolic stability and passive permeability of non-radioactive AZD1283 in vitro. Next, we radiolabeled [We determined the half-life of AZD1283 in mouse and human liver microsomes to be 37 and 160 min, respectively, and predicted passive CNS uptake with a small amount of active efflux, using a Caco-2 assay. Our radiolabeling efforts afforded [Despite our initial encouraging liver microsome and Caco-2 monolayer data, in addition to the observed high stability of [

Made available in DSpace on 2022-04-29T08:38:50Z (GMT). No. of bitstreams: 0 Previous issue date: 2022-02-01 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Heat Shock Protein 70s (HSP70s) are key molecular chaperones that are overexpressed in many cancers and often associated with metastasis and poor prognosis. It has proven difficult to develop ATP-competitive, drug-like small molecule inhibitors of HSP70s due to the flexible and hydrophilic nature of the HSP70 ATP-binding site and its high affinity for endogenous nucleotides. The aim of this study was to explore the potential for the inhibition of HSP70 through alternative binding sites using fragment-based approaches. A surface plasmon resonance (SPR) fragment screen designed to detect secondary binding sites in HSP70 led to the identification by X-ray crystallography of a cryptic binding site in the nucleotide-binding domain (NBD) of HSP70 adjacent to the ATP-binding site. Fragment binding was confirmed and characterized as ATP-competitive using SPR and ligand-observed NMR methods. Molecular dynamics simulations were applied to understand the interactions with the protein upon ligand binding, and local secondary structure changes consistent with interconversion between the observed crystal structures with and without the cryptic pocket were detected. A virtual high-throughput screen (vHTS) against the cryptic pocket was conducted, and five compounds with diverse chemical scaffolds were confirmed to bind to HSP70 with micromo-lar affinity by SPR. These results identified and characterized a new targetable site on HSP70. While targeting HSP70 remains challenging, the new site may provide opportunities to develop allosteric ATP-competitive inhibitors with differentiated physicochemical properties from current series. Cancer Research UK Cancer Therapeutics Unit The Institute of Cancer Research School of Pharmacy and Bioengineering Keele University Department of Biochemistry Albert Einstein College of Medicine School of Pharmacy Institute of Clinical Sciences College of Medical and Dental Sciences University of Birmingham, Edgbaston Departamento de Física Instituto de Biociências Letras e Ciências Exatas (IBILCE) UNESP, Rua Cristovão Colombo 2265 Departamento de Física Instituto de Biociências Letras e Ciências Exatas (IBILCE) UNESP, Rua Cristovão Colombo 2265 CAPES: 001

PLOS ONE 17(11), : e0269649 (2022). doi:10.1371/journal.pone.0269649, Published by PLOS, San Francisco, California, US

Bacterial products can act on neurons to alter signaling and function. Here, we find that dorsal root ganglia (DRG) sensory neurons are enriched for ANTXR2, the high-affinity receptor for anthrax toxins. Anthrax toxins are composed of protective antigen (PA), which binds to ANTXR2, and the protein cargoes Edema Factor (EF) and Lethal Factor (LF). Intrathecal administration of Edema Toxin (ET; PA+EF) targeted DRG neurons and induced analgesia in mice. ET inhibited mechanical and thermal sensation, and pain caused by formalin, carrageenan, and nerve injury. Analgesia depended on ANTXR2 expressed by Na(v)1.8(+) or Advillin(+) neurons. ET modulated PKA signaling in mouse sensory and human iPS-derived sensory neurons and attenuated spinal cord neurotransmission. We further engineered anthrax toxins to introduce exogenous protein cargoes, including botulinum toxin, into DRG neurons to silence pain. Our study highlights interactions between a bacterial toxin and nociceptors which may lead to the development of novel pain therapeutics.

Background Many of the world’s population, across all age groups and abilities, are not meeting or even aware of internationally recommended physical activity (PA) and sedentary behaviour (SB) guidelines. In order to enhance awareness and uptake, guidelines should be perceived positively by targeted users. The purpose of this study was to review the literature on end-user and stakeholder perceptions of PA and SB guidelines. Methods The electronic databases APA PsycInfo, CINAHL, MEDLINE, and SPORTDiscus, using EBSCOhost Research Platform, and Web of Science were searched from inception to June, 2021 with keyword synonyms for “perceptions”, “PA guidelines”, and “SB guidelines”. Studies of any design that collected stakeholder and/or end-user responses to a PA and/or SB guideline were included and assessed for risk of bias. The PA and/or SB guideline could be any type of official form (e.g., national documents, organizational guidelines, expert consensus statements, etc.) from any country, that targets individuals at the regional, provincial/statewide, national, or international level, and includes all types of guidelines (e.g., strength, aerobic, clinical, nonclinical, screen-time, sitting, etc.). Data were extracted and analyzed using thematic synthesis. Results After screening 1399 abstracts and applying citation screening, 304 full-texts were retrieved. A total of 31 articles met the inclusion criteria. End-users and stakeholders for PA guidelines across all age groups expressed the need for simplified language with more definitions, relatable examples and imagery, and quantification of PA behaviours. There was concern for the early years and child PA guidelines leading to guilt amongst parents and the SB guidelines, particularly the recommendations to limit screen-time, being unrealistic. General age group PA guidelines were not perceived as usable to populations with differing abilities, clinical conditions, and socioeconomic status. Guidelines that targeted clinical populations, such as persons with multiple sclerosis and persons with spinal cord injury, were well received. Conclusions There is a clear need to balance the evidence base with the pragmatic needs of translation and uptake so that the guidelines are not ignored or act as a barrier to actual engagement.

Inflammation early in life can prime the local immune milieu of peripheral tissues, which can cause lasting changes in immunological tone that confer disease protection or susceptibility1. The cellular and molecular mechanisms that prompt changes in immune tone in many nonlymphoid tissues remain largely unknown. Here we find that time-limited neonatal inflammation induced by a transient reduction in neonatal regulatory T cells causes a dysregulation of subcutaneous tissue in mouse skin. This is accompanied by the selective accumulation of type 2 helper T (TH2) cells within a distinct microanatomical niche. TH2 cells are maintained into adulthood through interactions with a fibroblast population in skin fascia that we refer to as TH2-interacting fascial fibroblasts (TIFFs), which expand in response to TH2 cytokines to form subcutaneous fibrous bands. Activation of the TH2–TIFF niche due to neonatal inflammation primes the skin for altered reparative responses to wounding. Furthermore, we identify fibroblasts in healthy human skin that express the TIFF transcriptional signature and detect these cells at high levels in eosinophilic fasciitis, an orphan disease characterized by inflammation and fibrosis of the skin fascia. Taken together, these data define a previously unidentified TH2 cell niche in skin and functionally characterize a disease-associated fibroblast population. The results also suggest a mechanism of immunological priming whereby inflammation early in life creates networks between adaptive immune cells and stromal cells to establish an immunological set-point in tissues that is maintained throughout life. Time-limited skin inflammation in neonatal mice promotes a reciprocal interaction between type 2 helper T cells and fascial fibroblasts that regulates wound repair in later life.

Neuroepithelial crosstalk is critical for gut physiology. However, the mechanisms by which sensory neurons communicate with epithelial cells to mediate gut barrier protection at homeostasis and during inflammation are not well understood. Here, we find that Nav1.8

Regulatory T cells (Tregs) reside in nonlymphoid tissues where they carry out unique functions. The molecular mechanisms responsible for Treg accumulation and maintenance in these tissues are relatively unknown. Using an unbiased discovery approach, we identified LAYN (layilin), a C-type lectin-like receptor, to be preferentially and highly expressed on a subset of activated Tregs in healthy and diseased human skin. Expression of layilin on Tregs was induced by TCR-mediated activation in the presence of IL-2 or TGF-β. Mice with a conditional deletion of layilin in Tregs had reduced accumulation of these cells in tumors. However, these animals somewhat paradoxically had enhanced immune regulation in the tumor microenvironment, resulting in increased tumor growth. Mechanistically, layilin expression on Tregs had a minimal effect on their activation and suppressive capacity in vitro. However, expression of this molecule resulted in a cumulative anchoring effect on Treg dynamic motility in vivo. Taken together, our results suggest a model whereby layilin facilitates Treg adhesion in skin and, in doing so, limits their suppressive capacity. These findings uncover a unique mechanism whereby reduced Treg motility acts to limit immune regulation in nonlymphoid organs and may help guide strategies to exploit this phenomenon for therapeutic benefit.

This study characterized the health risks due to the consumption of mycotoxin-contaminated foods and assessed the consumer awareness level of mycotoxins in households in two north-central Nigerian states during the harvest and storage seasons of 2018. Twenty-six mycotoxins and 121 other microbial and plant metabolites were quantified by LC-MS/MS in 250 samples of cereals, nuts and legumes. Aflatoxins were detected in all food types (cowpea, maize, peanut and sorghum) except in millet. Aflatoxin B1 was the most prevalent mycotoxin in peanut (64%) and rice (57%), while fumonisin B1 occurred most in maize (93%) and beauvericin in sorghum (71%). The total aflatoxin concentration was highest in peanut (max: 8422 µg/kg, mean: 1281 µg/kg) and rice (max: 955 µg/kg, mean: 94 µg/kg), whereas the totals of the B-type fumonisins and citrinin were highest in maize (max: 68,204 µg/kg, mean: 2988 µg/kg) and sorghum (max: 1335 µg/kg, mean: 186 µg/kg), respectively. Citrinin levels also reached 51,195 µg/kg (mean: 2343 µg/kg) in maize. Aflatoxin and citrinin concentrations in maize were significantly (p &lt, 0.05) higher during storage than at harvest. The estimated chronic exposures to aflatoxins, citrinin and fumonisins were high, resulting in as much as 247 new liver cancer cases/year/100,000 population and risks of nephrotoxicity and esophageal cancer, respectively. Children who consumed the foods were the most vulnerable. Mycotoxin co-occurrence was evident, which could increase the health risk of the outcomes. Awareness of mycotoxin issues was generally low among the households.

Background. Hookah is one of the most commonly used tobacco products among U.S. young adults due in part to widespread misperceptions that it is not harmful or addictive. There is growing evidence that hookah tobacco is associated with health harms and can lead to addiction. Research on interventions to address these misperceptions by communicating the harms and addictiveness of hookah use is needed. Aims. This study developed and pretested mobile multimedia message service (MMS) message content communicating the risks of hookah tobacco use to young adult hookah smokers. Method. Message content, delivery, and pretesting were tailored to participants’ risk beliefs, hookah use frequency, and responses to simulated text message prompts. Participants viewed 4 of 12 core MMS messages randomized within-subjects and completed postexposure measures of message receptivity and emotional response (e.g., worry). Results. The sample included 156 young adult (age 18-30 years) hookah smokers; 31% smoked hookah monthly and 69% weekly/daily. Prior to viewing messages, a majority endorsed beliefs reflecting misperceptions about the risks of hookah tobacco. Postexposure measures showed participants were receptive to the messages and the messages evoked emotional response. As anticipated, messages produced similar receptivity and there were few differences in emotional response between the messages tested. Discussion. Young adult hookah tobacco smokers were receptive to tailored mobile MMS messages and messages evoked emotional response, two critical precursors to behavior change. Conclusion. Findings indicate that research testing the efficacy of tailored MMS messaging as a strategy for reducing hookah tobacco use in young adults is warranted.

The purpose of this study was to evaluate a new scale to measure multiple aspects of partner support for quitting smoking relevant to dual-smoker couples, called the Partner Support for Quitting Scale. The best model fit ( N = 238 individuals in 119 couples) considers the frequency of, confidence in, and perceived usefulness of partner support behaviors. Path analysis revealed that the Partner Support for Quitting Scale factors were uniquely predicted by relationship commitment and nicotine dependence and, in turn, predicted self-efficacy for smoking cessation and desire to quit. Preliminary support was found for the Partner Support for Quitting Scales’ value as an assessment tool for measuring partner support for smoking cessation among dual-smoker couples.

Background: It is unclear whether overweight and obesity in older age reduces or increases the risk of incident dementia.\ud Objective: To assess the impacts of overweight and obesity in older age on incident dementia.\ud Methods: We searched cohort studies reporting body weight measured in older age and dementia through PubMed, Embase,\ud Medline, PyschInfo, and Cochrane library until July 2016. Sixteen articles were identified for the review. We pooled data from them and a new unpublished study from China, to calculate relative risk (RR) of incident dementia in relation to body mass index (BMI) and waist circumference (WC).\ud Results: All 16 cohort studies were undertaken in high income countries, with follow-up periods ranging between 3 to 18 years. Thirteen studies showed an inverse association between BMI and dementia, and three studies demonstrated a positive association. Pooled RR of dementia in relation to continuous BMI from 14 studied populations, including the new Chinese data, was 0.97 (95%CI 0.95–1.00); in those followed up

The nervous and immune systems are classically studied as two separate entities. However, their interactions are crucial for maintaining barrier functions at tissues constantly exposed to the external environment. We focus here on the role of neuronal signaling in regulating the immune system at two major barriers: the skin and respiratory tract. Barrier tissues are heavily innervated by sensory and autonomic nerves, and are densely populated by resident immune cells, allowing rapid, coordinated responses to noxious stimuli, as well as to bacterial and fungal pathogens. Neural release of neurotransmitters and neuropeptides allows fast communication with immune cells and their recruitment. In addition to maintaining homeostasis and fighting infections, neuroimmune interactions are also implicated in several chronic inflammatory conditions such as atopic dermatitis (AD), chronic obstructive pulmonary disease (COPD), and asthma.

Providing adults tailored risk estimates of getting colorectal cancer (CRC) can increase screening. A concern is that receipt of lower risk estimates will demotivate screening; this effect may be curbed by matching level of risk with message framing. Theoretically, pairing lower risk estimates with gain-frame messages, and higher risk estimates with loss-frame messages, should increase screening and screening intentions more than pairing lower risk estimates with loss-frame messages/higher risk estimates with gain-frame messages. These effects may be mediated by how screening is construed (e.g., to find health problems vs. to reaffirm one is healthy). These predictions were tested experimentally among 560 men and women ages 50–75 who have never screened. Participants at baseline received online a tailored comparative risk estimate with gain- or loss-frame information on screening. Screening was assessed six months later. Among the 400 reached at six months, 9.5% reported screening. There were no main effects or interactions between risk feedback and framing predicting construals, screening intentions, or screening. Worry about getting CRC and screening intentions predicted screening. While hypothesized interactions were not found, future research should explore further mechanisms through which online interventions utilizing risk feedback and framing motivate screening among adults who have never screened.

Strategies that control the differentiation of mesenchymal stem cells (MSC) and enable image-guided cell implantation and longitudinal monitoring could advance MSC-based therapies for bone defects and injuries. Here we demonstrate a multifunctional nanoparticle system that delivers resveratrol (RESV) intracellularly to improve osteogenesis and enables photoacoustic imaging of MSCs. RESV-loaded nanoparticles (RESV-NPs), formulated from poly (lactic-co-glycolic) acid and iron oxide, enhanced the stability of RESV by 18-fold and served as photoacoustic tomography (PAT) contrast for MSCs. Pre-loading MSCs with RESV-NP upregulated RUNX2 expression with a resultant increase in mineralization by 27% and 45% compared to supplementation with RESV-NP and free RESV, respectively, in 2-dimensional cultures. When grown in polyethylene glycol-based hydrogels, MSCs pre-loaded with RESV-NPs increased the overall level and homogeneity of mineralization compared to those supplemented with free RESV or RESV-NP. The PAT detected RESV-NP-loaded MSCs with a resolution of 1500 cells/μL, which ensured imaging of MSCs upon encapsulation in a PEG-based hydrogel and implantation within the rodent cranium. Significantly, RESV-NP-loaded MSCs in hydrogels did not show PAT signal dilution over time or a reduction in signal upon osteogenic differentiation. This multifunctional NP platform has the potential to advance translation of stem cell-based therapies, by improving stem cell function and consistency via intracellular drug delivery, and enabling the use of a promising emerging technology to monitor cells in a clinically relevant manner.