Multiple Mechanisms Research Articles

SIMILARITY IN HEALTH-RELATED BEHAVIORS WITHIN OLDER ADULTS’ CLOSE SOCIAL RELATIONSHIPS

Abstract Health-related behaviors are socially contagious, spreading through social networks via multiple mechanisms. It remains unclear though which mechanisms are most salient among older adults. Guided by Social Contagion Theory and the Convoy Model of Social Relations we examine similarity in health-related behaviors (exercise, smoking, alcohol consumption) between older adults and their closest social network members and investigate associations with multiple social factors (homophily, network structure, relationship quality). Data are from Wave 3 of the Detroit-based Social Relations Study collected in 2015. Panel respondents nominated people who were close and important in their lives, and up to the first three nominated were interviewed. Analyses were conducted at the dyad-level, and we selected dyads in which at least one member was age 60 or older (n=247 dyads). Generalized estimating equations were used due to some panel respondents being in multiple dyads. Greater homophily was found to be associated with similarity in both exercise frequency and number of alcoholic drinks consumed per week. Specifically, pairs of close social network members who were more similar in self-rated health were significantly more similar in exercise frequency, and those of the same gender and more similar in age were significantly more similar in alcohol consumption. Network structure, specifically greater contact frequency, was associated with significantly more similarity in alcohol consumption, but less similarity in exercise frequency. Findings suggest the salience of multiple aspects of older adults’ close social relationships that can be incorporated into behavior change interventions and leveraged to encourage healthy lifestyles in later life.

CHANGES IN TECH USE PREDICTING SOCIAL WELL-BEING FOR INTERGENERATIONAL PROGRAM PARTICIPANTS

Abstract Previous research has shown that technology-based interventions show promise for reducing social isolation and loneliness. Less research has examined quality of life outcomes for these programs or interconnectedness of these outcomes when examining pre/post-change. This study examined the connections between technology use and knowledge with loneliness, social isolation, and quality of life before and after participation in the program. The final sample (N=324) was rather diverse regarding work and living status (for example, 67.5% retired; 67.8% lived alone; 70.1% had less than $30,000 income; 40.2% had a high school education or less). Using structural equation modeling, this study examined pre- and post-data to identify to what extent technology usage and knowledge (frequency of iPad use, digital competence) predicted an individual’s change in loneliness, social isolation, and quality of life. This final model showed excellent model fit (𝜒2(148, N=324)=247.01 p<.05 with CFI = .95, TLI = .93, RMSEA = .05, CMIN/df = 1.67). Within this model, findings showed that digital competence improvements predicted quality of life, social isolation, and loneliness (Ad. R. Square = 0.17); the frequency of iPad use influenced social isolation and quality of life (Adj. R Square = 0.29); and loneliness influenced quality of life and social isolation (Adj. R Square = 0.81). There are multiple possible mechanisms through which older participants’ lives can be impacted by intergenerational technology programs. Understanding the complex interplay of factors helps us understand the potential benefits of these programs on quality of life.

PATHOGEN APATHY RESULTING FROM SKN-1 ACTIVATION: A MARK OF RESILIENCE OR A RATTLED GUT FEELING?

Abstract Innate immunity is a key driver in promoting survival against xenobiotic stressors and hostile environments and an appropriate immune response is essential to organismal health across lifespan. Caenorhabditis elegans encounter pathogens in their natural environment and initiate cytoprotective and immune responses that can have long-lasting effects on health, even after the pathogen has been neutralized. Pseudomonas aeruginosa (PA14) is an opportunistic pathogen that is lethal to C. elegans with prolonged exposure. C. elegans employ multiple defense mechanisms to ensure survival upon exposure to pathogens to defend against the current infection and to avoid continued exposure, including activation of the key cytoprotective transcription factor SKN-1 (mammalian homologue Nrf2). Although wild type C. elegans quickly learn to avoid pathogens, our current work documents a peculiar apathy to pathogen in animals with constitutive activation of SKN-1. The outcome is surprising as the role of SKN-1 is to protect an animal from intracellular and environmental insults. This behavior is mediated by tissue specific actions of SKN-1 that initiate cell non-autonomous responses for pathogen avoidance, survival, and metabolic adaptation. Based on transcriptional signature of animals with SKN-1 activation upon exposure to PA14 we observed that the apathy behavior is independent of somatic lipid depletion, thus uncoupling these two exceptional physiological responses. Further, we define the role of neurosignalling molecules in the gut-brain axis that drive the apathy response to pathogens. Our work reveals new insights into how animals perceive pathogens in the environment and subsequently alter behavior and cellular programs to promote survival.

Molecular Basis of Müllerian Agenesis Causing Congenital Uterine Factor Infertility-A Systematic Review.

Infertility affects around 1 in 5 couples in the world. Congenital absence of the uterus results in absolute infertility in females. Müllerian agenesis is the nondevelopment of the uterus. Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome is a condition of uterovaginal agenesis in the presence of normal ovaries and the 46 XX Karyotype. With advancements in reproductive techniques, women with MA having biological offspring is possible. The exact etiology of MA is unknown, although several genes and mechanisms affect the development of Müllerian ducts. Through this systematic review of the available literature, we searched for the genetic basis of MA. The aims included identification of the genes, chromosomal locations, changes responsible for MA, and fertility options, in order to offer proper management and counseling to these women with MA. A total of 85 studies were identified through searches. Most of the studies identified multiple genes at various locations, although the commonest involved chromosomes 1, 17, and 22. There is also conflicting evidence of the involvement of various candidate genes in the studies. The etiology of MA seems to be multifactorial and complex, involving multiple genes and mechanisms including various mutations and mosaicism.

RESIDENTIAL SEGREGATION AND DEPRESSIVE SYMPTOMS IN OLDER CHINESE IMMIGRANTS: MEDIATING ROLE OF SOCIAL PROCESSES

Abstract Older Chinese immigrants are particularly at risk for depression due to acculturative stress and language barriers. Residential segregation with respect to language use may play an important role in mental health of historically marginalized immigrant populations. Previous research provided mixed evidence about the segregation effect among older Latino and Asian immigrants. Guided by a model of social processes, we examined the direct and indirect effects of residential segregation on depressive symptoms via multiple mechanisms of acculturation, discrimination, social network, social support, social strain, and social engagement. Four waves of depressive symptoms were assessed in the Population Study of Chinese Elderly (2011-2019, N=1,970), and linked to the 2010-2014 American Community Survey estimates of neighborhood context. Residential segregation was measured by the Index of Concentrations at the Extremes that simultaneously assesses Chinese and English language use within a given census tract. Latent growth curve models with adjusted cluster robust standard errors were estimated after controlling for individual-level factors. Residents of segregated Chinese-speaking neighborhoods had fewer baseline depressive symptoms but a slower decline rate than those living in segregated toward English-only speaking neighborhoods. Racial discrimination, social strain, and social engagement partially mediated the association between segregation and initial level; social strain and social engagement also partially mediated the association with decline in depressive symptoms. This study demonstrates the importance of residential segregation and social processes in shaping mental well-being among older Chinese immigrants and suggests potential mechanisms to alleviate mental health risks.

HISTORICAL CHANGES IN COLLEGE EDUCATION AND EMPLOYMENT: GENDER EFFECTS ON LATE-LIFE COGNITIVE STATUS

Abstract Early-life education and gender are well-known predictors of cognitive status in old age but multiple mechanisms underlie these associations. Recent US research on late-life cognition and dementia prevalence has highlighted the roles of age-cohort and racial/ethnic differences K-12 education. Less attention has been given to historical increases since the 1970s in the completion of college degrees by women and their subsequent employment histories. We examined new data for two cohorts (N = 9926; 50% born before 1948 vs. Baby Boomers, born 1948-1959) in the Health and Retirement Study (HRS) about the quantity (years, degree types) and content (field of study) of their college degrees. College information and employment histories were collected in a Life History Mail Survey (2015-2017). Cognitive status based on the Langa-Weir algorithm was defined as normal, cognitive impairment not dementia or dementia (CIND/D). Compared to men, women were less likely to have post-high school education (p < .002) or to have worked after their education. Cognitive status was predicted by degree type and work history. Gender by degree and gender by work interactions (for Baby Boomers only) revealed that having a BA/BS degree provided more protection against cognitive impairment for women than for men with the same degree, and women who worked had lower odds ratio of having CIND/D (0.36 [CI 0.17-0.77], p < .01). College majors were gendered and significantly accounted for variance in late-life cognitive status among the college educated. These findings provide new insight into the gendered life histories related to late-life cognition.

STATE-LEVEL DESCRIPTION OF MEDICAID POLICY AND ACCESS TO LICENSED ASSISTED LIVING CARE FOR LOW-INCOME ADULTS

Abstract A growing proportion of Medicaid funds are allocated to care in assisted living (AL) settings. However, a state must have a state plan amendment or waiver to utilize these funds. States issue levels of licensure for AL communities, which govern the care and oversight that can be provided and may determine whether ALs can accept Medicaid funding. However, until now, Medicaid coverage for AL has been analyzed at the state level and is not well-documented for license types. Using Medicaid state plans and waiver applications, we describe the types of Medicaid funding mechanisms that states use to finance care in AL and identify the demographics and health characteristics of residents in Medicaid-eligible ALs. We find that five states do not utilize Medicaid to finance care in AL. Among the 45 states and DC with Medicaid-financed AL, 12 states limit Medicaid funding to specific licenses, whereas 34 states provide access to Medicaid-funded care for all AL license types. Among identified ALs, 86% are licensed to accept Medicaid funds. Although the modal funding mechanism is through 1915c waivers, the largest percentage (40%) of ALs licensed to accept Medicaid funding are in states that utilize multiple mechanisms. In states that fund AL through state plan amendments, 88% of Medicare beneficiaries reside in covered ALs; conversely, in states that use 1115 demonstration waivers, 99% of Medicare beneficiaries reside in covered ALs. This work will benefit future research and policymaking aiming to use Medicaid funding to increase access to appropriate, high-quality care in licensed ALs.

A Mechanistic Review on How Berberine Use Combats Diabetes and Related Complications: Molecular, Cellular, and Metabolic Effects.

Berberine (BBR) is an isoquinoline alkaloid that can be extracted from herbs such as Coptis, Phellodendron, and Berberis. BBR has been widely used as a folk medicine to treat various disorders. It is a multi-target drug with multiple mechanisms. Studies have shown that it has antioxidant and anti-inflammatory properties and can also adjust intestinal microbial flora. This review focused on the promising antidiabetic effects of BBR in several cellular, animal, and clinical studies. Based on previous research, BBR significantly reduced levels of fasting blood glucose, hemoglobin A1C, inflammatory cytokines, and oxidative stress markers. Furthermore, BBR stimulated insulin secretion and improved insulin resistance through different pathways, including up-regulation of protein expression of proliferator-activated receptor (PPAR)-γ, glucose transporter (GLUT) 4, PI3K/AKT, and AMP-activated protein kinase (AMPK) activation. Interestingly, it was demonstrated that BBR has protective effects against diabetes complications, such as diabetic-induced hepatic damage, cardiovascular disorders, nephropathy, and neuropathy. Furthermore, multiple clinical trial studies have emphasized the ameliorative effects of BBR in type 2 diabetic patients.

Drivers controlling black carbon temporal variability in the lower troposphere of the European Arctic

Abstract. Black carbon (BC) is a short-lived climate forcer affecting the Arctic climate through multiple mechanisms, which vary substantially from winter to summer. Several models still fail in reproducing BC seasonal variability, limiting the ability to fully describe BC climate implications. This study aims at gaining insights into the mechanisms controlling BC transport from lower latitudes to the Arctic lower troposphere. Here we investigate the drivers controlling black carbon daily and seasonal variability in the Arctic using generalized additive models (GAMs). We analysed equivalent black carbon (eBC) concentrations measured at the Gruvebadet Atmospheric Laboratory (GAL – Svalbard archipelago) from March 2018 to December 2021. The eBC showed a marked seasonality with higher values in winter and early spring. The eBC concentration averaged 22 ± 20 ng m−3 in the cold season (November–April) and 11 ± 11 ng m−3 in the warm season (May–October). The seasonal and interannual variability was mainly modulated by the efficiency of wet scavenging removal during transport towards higher latitudes. Conversely, the short-term variability was controlled by boundary layer dynamics as well as local-scale and synoptic-scale circulation patterns. During both the cold and warm seasons, the transport of air masses from Europe and northern Russia was an effective pathway for the transport of pollution to the European Arctic. Finally, in the warm season we observed a link between the intrusion of warm air from lower latitudes and the increase in eBC concentration. Changes in the synoptic-scale circulation system and precipitation rate in the Northern Hemisphere, linked to climate change, are expected to modify the BC burden in the Arctic.

Association between triclosan and obesity using NHANES 2007-2016: Overall and stratified population

Studies have shown that triclosan is able to exert estrogenic activity and may affect energy metabolism through multiple mechanisms, which in turn is associated with obesity and overweight. However, insufficient research has been done to confirm its connection to obesity in the general population. This study's aim was to explore the relationship between triclosan and obesity in American adults (aged 20). The association was further explored in populations stratified by sex, age, race, education level, and socioeconomic status. In the general population, there was a connection between triclosan and obesity that was detrimental. (OR: 0.97, 95% CI: 0.95-0.99, p value: 0.017).In the other race group, triclosan and obesity were found to be dramatically negatively correlated (including multi-racial) when stratified by race (OR: 0.89, 95% CI: 0.8-0.98, p value: 0.019). When stratified by socioeconomic class, there was a substantial relationship between triclosan and obesity in the above poverty group. (OR: 0.97, 95% CI: 0.94-1, p value: 0.023). Finally, when dividing the population according to education level, we had a more novel finding in the graduate or above group: it was discovered that triclosan lowers the likelihood of obesity (OR: 0.92, 95% CI: 0.88-0.98, p value: 0.005) while increasing odds of overweight (OR: 1.06, 95% CI: 1.01-1.11, p value: 0.027).

Construction of MOFs@COFs composite material as stationary phase for efficient separation of diverse organic compounds

BackgroundThe development of efficent chromatographic stationary phases (SP) with mixed-mode or multiple interactions in high-performance liquid chromatography (HPLC) for the separation of complex samples is a challenging task. Metal organic frameworks (MOFs)-based SP can provide desired multiple interactions and enable the separation of a diverse range of solutes, but have limitations of low column efficiency and poor stability. ResultsHerein, the hybrid MOFs@Covalent organic frameworks (COFs) materials were used as SP in HPLC due to their synergistic structural features. The SiO2@NH2-UiO-66@CTF SP was synthesized by integration of NH2-UiO-66 and covalent triazine framework (CTF) onto silica surface. Due to the unique structure of SiO2@NH2-UiO-66@CTF with hierarchical-pores, this column showed higher column efficiency (up to 49,369 plates m−1 for alkylbenzenes) than the reported columns packed with MOFs-based SP. Owing to the Zr4+-N coordination bonding between CTF and NH2-UiO-66, the structural stability of SiO2@NH2-UiO-66@CTF can be improved. Furthermore, this new column exhibited remarkable column stability with relative standard deviation of retention time of <0.40% after 400 injections. With the combined advantages of multifunctional properties, high column efficiency, and good stability, SiO2@NH2-UiO-66@CTF SP showed excellent selectivity for the separation of a variety of hydrophobic, aromatic, heteroatomic, and hydrophilic analytes. Significance and noveltyThis work not only offers a promising SP with multiple retention mechanisms for HPLC, but also provides an efficient strategy for development of high column efficiency MOFs-based SP with good stability. Moreover, the MOFs@COFs hybrid materials were expanded in application area through this study, and the research results can also afford the foundation for further explore its structural characteristics.

An efficient diagnostic strategy for intermittent faults in electronic circuit systems by enhancing and locating local features of faults

Due to their short duration, concealability, and random occurrence, intermittent faults have become the most dangerous hazard in electronic circuit systems. However, existing intelligent diagnostic methods often struggle to provide substantial effectiveness for such objects. This article proposes a scheme to enhance the output signal of electronic circuits to make the features more intuitive and facilitate fault feature mining, and designs a scheme to mine tiny fault features from global signals. First, the circuit’s output signal undergoes an S-transform to obtain its time-frequency domain characteristics. Next, a sequence and excitation networks attention module is employed to allocate weights to different channels. Finally, the aforementioned output is used as input to the Swin transformer framework to thoroughly explore fault features. Three electronic circuits are used as experimental circuits to test the proposed method. The experiment shows that the proposed diagnostic method is fast and has an accuracy of over 97%. Therefore, the effectiveness of the designed strategy that includes multiple attention mechanisms in mining intermittent fault features in electronic circuit systems has been demonstrated.

A Emergência da Família Chaple à Elite Liberal: Advogados e Mobilidade Socialna Cuba de Meados do Século XIX

As migrant families relocated to Cuba during the second half of the eighteenth century, new generations of creoles were born during the economic and demographic expansion of the island. Some of these Cubans, inspired on early liberal ideas, found the ways to amass a fortune, and started climbing the social ladder by procuring positions in the local bureaucracy. A legal degree, however, was essential to obtain a high ranked public office, and many new students of law enrolled at the University of Havana. As a result, the number of lawyers on the island multiplied and started occupying posts in the local judiciary and the administration, as well as the academia, to legitimize themselves in the Cuban society. This study thus uses the Chaple family to examine a case of social mobility in early nineteenth century Cuba tied to the increase of the number of legal professionals, and their multiple mechanisms to gain participation and control of the public sphere. As the family Chaple illustrates, legal professionals, with their growing connections, created a complex social, political, and familiar network that included many individuals who held key judicial and administrative positions on the island. These lawyers, who came from humble origins, transformed the colonial society by breaking traditional barriers to the legal education and practice. Consequently, creoles with law degrees, who increasingly participated in local public affairs, emerged as a first generation of Cuban liberal elites during the nineteenth century.

Enhancing strength and ductility in the nugget zone of friction stir welded 7Mn steel via tailoring austenitic stability

The martensite often appears in the nugget zone (NZ) of friction stir welding (FSW) 7 wt.% Mn steel due to low austenite stability, deteriorating ductility and toughness. In this work, a 7 wt.% Mn steel was subjected to FSW, and preheating was used to tailor the austenitic stability to greatly improve the strength–ductility combination of the NZ. The austenitic deformation behavior and strain hardening mechanism in the NZ were systematically investigated. The microstructure of the as-welded NZ was composed of ultrafine blocky ferrite, austenite, and small amounts of martensite, whereas the as-preheated NZ contained ultrafine blocky ferrite and austenite, and the concentration of Mn in austenite was increased from 8.4 wt.% to 10.7 wt.%. This enhanced the austenitic stability, resulting in a significant increase in the volume fraction of austenite in the as-preheated NZ from 37.3% to 66.4%. The product of strength and elongation (PSE) in the as-preheated NZ increased dramatically from 42.6 GPa% to 67.1 GPa%, depending on a persistent high strain hardening rate (SHR). Multiple strain-hardening mechanisms were revealed. The austenite with enhanced stability can provoke sustained transformation-induced plasticity (TRIP) and twinning-induced plasticity (TWIP) effects, and massive dislocation multiplication occurs during tension, resulting in strong strain hardening.

Suprathermal Population Associated with Stream Interaction Regions Observed by STEREO-A: New Insights

Abstract Stream interaction regions (SIRs) are often thought to be responsible for the generation of suprathermal population in the interplanetary medium. Even though the source is the same, wide variations in the spectral indices of suprathermal populations are observed at 1 au during SIRs. This poses a significant uncertainty in understanding the generation of suprathermal ion populations by SIRs and indicates an interplay of multiple source mechanisms. By analyzing variations in suprathermal 4He, O, and Fe for 20 SIR events recorded by STEREO-A during 2007–2014, we find that the spectral indices of these elements vary in the range of 2.06–4.08, 1.85–4.56, and 2.11–4.04 for 19 events. However, in one special case, all three suprathermal elements show nearly identical (∼1.5) spectral indices. We describe possible mechanisms that might cause significant variations in the spectral indices of suprathermal particles. More importantly, we show the possible role of merging and/or contraction of small-scale magnetic islands near 1 au in producing nearly identical spectral indices for three different elements with different first ionization potentials and mass-to-charge ratios. The occurrence of these magnetic islands near 1 au also supports the minimal modulation in the spectral indices of these particles. We also suggest that a possible solar flare may have played a role in generating these magnetic islands near the heliospheric current sheet.

Dual functional roles of nutritional additives in nutritional fortification and safety of thermally processed food: Potential, limitations, and perspectives.

The Maillard reaction (MR) has been established to be a paramount contributor to the characteristic sensory property of thermally processed food products. Meanwhile, MR also gives rise to myriads of harmful byproducts (HMPs) (e.g., advanced glycation end products (AGEs) and acrylamide). Nutritional additives have attracted increasing attention in recent years owing to their potential to simultaneously improve nutritional quality and attenuate HMP formation. In this manuscript, a brief overview of various nutritional additives (vitamins, minerals, fatty acids, amino acids, dietary fibers, and miscellaneous micronutrients) in heat-processed food is provided, followed by a summary of the formation mechanisms of AGEs and acrylamide highlighting the potential crosstalk between them. The main body of the manuscript is on the capability of nutritional additives to modulate AGE and acrylamide formation besides their traditional roles as nutritional enhancers. Finally, limitations/concerns associated with their use to attenuate dietary exposure to HMPs and future perspectives are discussed. Literature data support that through careful control of the addition levels, certain nutritional additives possess promising potential for simultaneous improvement of nutritional value and reduction of AGE and acrylamide content via multiple action mechanisms. Nonetheless, there are some major concerns that may limit their wide applications for achieving such dual functions, including influence on sensory properties of food products, potential overestimation of nutrition enhancement, and introduction of hazardous alternative reaction products or derivatives. These could be overcome through comprehensive assay of dose-response relationships and systematic evaluation of the diverse combinations from the same and/or different categories of nutritional additives to establish synergistic mixtures.

Effect of steady-state strength of medium to dense sand on the performance of sheet pile wall as identified through centrifuge tests and Type-B and C simulations

This study focuses on five centrifuge experiments of a sheet pile wall performed by three institutions, which cover relative densities ranging from 55 % to 66 %. A strain space multiple mechanism model incorporated in the computer program FLIP is used for the simulation. In the Type-B simulation performed before the centrifuge test data release, the steady-state strength Sus is not considered, i.e., Sus is assumed to be infinity (Sus=∞), and only cyclic resistance is considered. In the Type-C simulation performed after the release of the centrifuge test data, Sus and cyclic resistance are considered. When Sus=∞, the computed displacements of the sheet pile wall are consistent with or unconservative by a factor of one-half of the measured displacements. However, when Sus ranges from 1500 to 7500 kPa evaluated for clean sands, the computed displacements are generally consistent with the measured displacements, or slightly conservative. When Sus ranges from 100 to 400 kPa evaluated for sands with fines content of 5 %, or when Sus ranges from 20 to 50 kPa inferred from cyclic laboratory tests, the computed displacements are conservative by a factor of one and a half or two of the measured displacements. The steady-state strength of medium to dense sand is identified as a significant factor influencing the performance of a sheet pile wall.

Implications of oral dysbiosis and HPV infection in head and neck cancer: from molecular and cellular mechanisms to early diagnosis and therapy.

Head and neck cancer (HNC) is the sixth most common type of cancer, with more than half a million new cases annually. This review focuses on the role of oral dysbiosis and HPV infection in HNCs, presenting the involved taxons, molecular effectors and pathways, as well as the HPV-associated particularities of genetic and epigenetic changes and of the tumor microenvironment occurred in different stages of tumor development. Oral dysbiosis is associated with the evolution of HNCs, through multiple mechanisms such as inflammation, genotoxins release, modulation of the innate and acquired immune response, carcinogens and anticarcinogens production, generation of oxidative stress, induction of mutations. Thus, novel microbiome-derived biomarkers and interventions could significantly contribute to achieving the desideratum of personalized management of oncologic patients, regarding both early diagnosis and treatment. The results reported by different studies are not always congruent regarding the variations in the abundance of different taxons in HNCs. However, there is a consistent reporting of a higher abundance of Gram-negative species such as Fusobacterium, Leptotrichia, Treponema, Porphyromonas gingivalis, Prevotella, Bacteroidetes, Haemophilus, Veillonella, Pseudomonas, Enterobacterales, which are probably responsible of chronic inflammation and modulation of tumor microenvironment. Candida albicans is the dominant fungi found in oral carcinoma being also associated with shorter survival rate. Specific microbial signatures (e.g., F. nucleatum, Bacteroidetes and Peptostreptococcus) have been associated with later stages and larger tumor, suggesting their potential to be used as biomarkers for tumor stratification and prognosis. On the other hand, increased abundance of Corynebacterium, Kingella, Abiotrophia is associated with a reduced risk of HNC. Microbiome could also provide biomarkers for differentiating between oropharyngeal and hypopharyngeal cancers as well as between HPV-positive and HPV-negative tumors. Ongoing clinical trials aim to validate non-invasive tests for microbiome-derived biomarkers detection in oral and throat cancers, especially within high-risk populations. Oro-pharyngeal dysbiosis could also impact the HNCs therapy and associated side-effects of radiotherapy, chemotherapy, and immunotherapy. HPV-positive tumors harbor fewer mutations, as well as different DNA methylation pattern and tumor microenvironment. Therefore, elucidation of the molecular mechanisms by which oral microbiota and HPV infection influence the HNC initiation and progression, screening for HPV infection and vaccination against HPV, adopting a good oral hygiene, and preventing oral dysbiosis are important tools for advancing in the battle with this public health global challenge.

Development of Integrated Bioorthogonal Self-Catalyzed NO Donor/Platinum(IV) Prodrugs for Synergistical Intervention against Triple-Negative Breast Cancer.

The platinum(IV) prodrug strategy is attractive for the synergistic antitumor effect. High levels (>400 nM) of nitric oxide (NO) exert promising cancer inhibition effects via multiple mechanisms. Herein, we designed and synthesized a new group of integrated bioorthogonal self-catalyzed NO donor/Pt(IV) prodrugs bearing long alkyl chains to enhance the stability in circulation, while the cytoplasmic reductants trigger cascade activation to release Pt and NO in tumor cells. Specifically, compound 10c exhibited an improved stability, favorable pharmacokinetic properties (AUC(0-t) of 2210.10 h*ng/mL), potent anti-triple-negative breast cancer (TNBC) effects (71.08% tumor growth inhibition (TGI) against the MDA-MB-231 xenograft model), potent in vivo anti-TNBC lung metastasis activity, and acceptable low toxicity. Importantly, NO released from 10c leads to the S-nitrosation of metal transporters Atox1&ATP7a in TNBC cells, which increases the Pt retention and inhibits lysyl oxidase, generating synergistic tumoricidal and antimetastatic activity. These results may inspire further study on the synergistical therapy of Pt and NO for the treatment of TNBC.

An impact evaluation of conservation investments targeting long-distance migratory species.

We evaluated the impact of a philanthropic program investing in the conservation of sites along the Pacific Americas Flyway, which spans >16,000km of coastline and is used by millions of shorebirds. Using a quasi-experimental, mixed methods approach, we estimated what would have happened to shorebird populations at 17 wintering sites without the sustained and additional investment they received. We modeled shorebird populations across the entire flyway and at sites with and without investment. Combining shorebird abundance estimates with a land-cover classification model, we used the synthetic control method to create counterfactuals for shorebird trends at the treatment sites. We found no evidence of an overall effect across three outcome variables. Species- and site-level treatment effects were heterogeneous, with a few cases showing evidence of a positive effect, including a site with a high level of overall investment. Results suggest six shorebirds declined across the entire flyway, including at many Latin American sites. However, the percentage of flyway populations present at the sites remained stable, and the percentage at the treatment sites was higher (i.e., investment sites) than at control sites. Multiple mechanisms behind our results are possible, including that investments have yet to mitigate impacts and negative impacts at other sites are driving declines at the treatment sites. A limitation of our evaluation is the sole focus on shorebird abundance and the lack of data that prohibits the inclusion of other outcome variables. Monitoring infrastructure is now in place to design a more robust and a priori shorebird evaluation framework across the entire flyway. With this framework, it will prove easier to prioritize limited dollars to result in the most positive conservation outcomes.