A dietary commensal microbe enhances antitumor immunity by activating tumor macrophages to sequester iron.

Innate immune cells generate a multifaceted antitumor immune response, including the conservation of essential nutrients such as iron. These cells can be modulated by commensal bacteria; however, identifying and understanding how this occurs is a challenge. Here we show that the food commensal Lactiplantibacillus plantarum IMB19 augments antitumor immunity in syngeneic and xenograft mouse tumor models. Its capsular heteropolysaccharide is the major effector molecule, functioning as a ligand for TLR2. In a two-pronged manner, it skews tumor-associated macrophages to a classically active phenotype, leading to generation of a sustained CD8+ T cell response, and triggers macrophage 'nutritional immunity' to deploy the high-affinity iron transporter lipocalin-2 for capturing and sequestering iron in the tumor microenvironment. This process induces a cycle of tumor cell death, epitope expansion and subsequent tumor clearance. Together these data indicate that food commensals might be identified and developed into 'oncobiotics' for a multi-layered approach to cancer therapy.

Race/ethnicity and the measurement of cognition in NSHAP: Recommendations for robustness.

OBJECTIVES: In this study, we examine the measurement of cognition in different racial/ethnic groups to move towards a less biased and more inclusive set of measures for capturing cognitive change and decline in older adulthood. METHODS: We use data from Round 2 (N=3377) and Round 3 (N=4777) of the National Social Life, Health, and Aging Project (NSHAP) and examine the study's Survey Adjusted version of the Montreal Cognitive Assessment (MoCA-SA). We employ exploratory factor analyses to explore configural invariance by racial/ethnic group. Using modification indexes, two-parameter item response theory models, and split-sample testing, we identify items that seem robust to bias by race. We test the predictive validity of the full (18-item) and short (4-item) MoCA-SAs using self-reported dementia diagnosis, instrumental activities of daily living (IADLs), proxy reports of dementia, proxy reports of dementia-related death, and National Death Index reports of dementia-related death. RESULTS: We found that four measures out of the 18 used in NSHAP's MoCA-SA formed a scale that was more robust to racial bias. The shortened form predicted consequential outcomes as well as NSHAP's full MoCA-SA. The short form was also moderately correlated with the full form. DISCUSSION: Although sophisticated structural equation modeling techniques would be preferrable for assuaging measurement invariance by race in NSHAP, the shortened form of the MoCA-SA provides a quick way for researchers to carry out robustness checks and to see if the disparities and associations by race they document are "real" or the product of artifactual bias.

Hip joint center lateralization minimally affects the biomechanics of patient-specific flanged acetabular components: A computational model.

Patient-specific flanged acetabular components are utilized to treat failed total hip arthroplasties with large acetabular defects. Previous clinical studies from our institution showed that these implants tend to lateralize the acetabular center of rotation. However, the clinical impact of lateralization on implant survivorship is debated. Our goal was to develop a finite element model to quantify how lateralization of the native hip center affects periprosthetic strain and implant-bone micromotion distributions in a static level gait loading condition. To build the model, we computationally created a superomedial acetabular defect in a computed tomography 3D reconstruction of a native pelvis and designed a flanged acetabular implant to address this simulated bone defect. We modeled two implants, one with ~1 cm and a second with ~2 cm of hip center lateralization. We applied the maximum hip contact force and corresponding abductor force observed during level gait. The resulting strains were compared to bone fatigue strength (0.3% strain) and the micromotions were compared to the threshold for bone ingrowth (20 µm). Overall, the model demonstrated that the additional lateralization only slightly increased the area of bone at risk of failure and decreased the areas compatible with bone ingrowth. This computational study of patient-specific acetabular implants establishes the utility of our modeling approach. Further refinement will yield a model that can explore a multitude of variables and could be used to develop a biomechanically-based acetabular bone loss classification system to guide the development of patient-specific implants in the treatment of large acetabular bone defects.

Probiotic Consortium Confers Synergistic Anti-Inflammatory Effects in Inflammatory Disorders.

The composition and diversity of gut microbiota significantly influence the immune system and are linked to various diseases, including inflammatory and allergy disorders. While considerable research has focused on exploring single bacterial species or consortia, the optimal strategies for microbiota-based therapeutics remain underexplored. Specifically, the comparative effectiveness of bacterial consortia versus individual species warrants further investigation. In our study, we assessed the impact of the bacterial consortium MPRO, comprising Lactiplantibacillus plantarum HY7712, Bifidobacterium animalis ssp. lactis HY8002, and Lacticaseibacillus casei HY2782, in comparison to its individual components. The administration of MPRO demonstrated enhanced therapeutic efficacy in experimental models of atopic dermatitis and inflammatory colitis when compared to single strains. MPRO exhibited the ability to dampen inflammatory responses and alter the gut microbial landscape significantly. Notably, MPRO administration led to an increase in intestinal CD103+CD11b+ dendritic cells, promoting the induction of regulatory T cells and the robust suppression of inflammation in experimental disease settings. Our findings advocate the preference for bacterial consortia over single strains in the treatment of inflammatory disorders, carrying potential clinical relevance.

Childhood Adversity and Passive Suicidal Ideation in Later Life in the United States: Does Religious Attendance Matter?

This study examines whether adverse childhood experiences are associated with passive suicidal ideation in later life and whether religious attendance moderates this association among U.S. older adults. To this end, logistic regression analyses were conducted using data from the 2016 Health and Retirement Study. The results show that poor childhood health, lack of parental affection, and childhood trauma are all positively associated with passive suicidal ideation in later life. However, religious attendance modifies the association between childhood health and passive suicidal ideation. For instance, poor childhood health is associated with greater odds of passive suicidal ideation only for older adults who never attend religious services, while this is not the case for those who attend religious services. Yet, the associations of parental affection and childhood trauma with passive suicidal ideation do not appear to differ by religious attendance. We discuss the theoretical implications of these findings for views about childhood adversity, religion, and suicide risk in later life.

Cumulative exposure to extreme heat and trajectories of cognitive decline among older adults in the USA.

BACKGROUND: The projected increase in extreme heat days is a growing public health concern. While exposure to extreme heat has been shown to negatively affect mortality and physical health, very little is known about its long-term consequences for late-life cognitive function. We examined whether extreme heat exposure is associated with cognitive decline among older adults and whether this association differs by race/ethnicity and neighbourhood socioeconomic status. METHODS: Data were drawn from seven waves of the Health and Retirement Study (2006-2018) merged with historical temperature data. We used growth curve models to assess the role of extreme heat exposure on trajectories of cognitive function among US adults aged 52 years and older. RESULTS: We found that high exposure to extreme heat was associated with faster cognitive decline for blacks and residents of poor neighbourhoods, but not for whites, Hispanics or residents of wealthier neighbourhoods. CONCLUSION: Extreme heat exposure can disproportionately undermine cognitive health in later life for socially vulnerable populations. Our findings underscore the need for policy actions to identify and support high-risk communities for increasingly warming temperatures.

Living Alone, Environmental Hazards, and Falls Among U.S. Older Adults.

Background and Objectives: Physical conditions of living environments can affect the incidence of falls; however, prior work has focused typically on 1 domain at a time-either neighborhood or home, capturing limited environmental boundaries of older adults. We examined how neighborhood together with the home environment affect the incidence of falls over time and whether living arrangement modifies the influence of the environmental risks on falls. Research Design and Methods: Using the 2012-2020 waves of the Health and Retirement Study (HRS; N = 1,893), we fitted logistic regression to estimate the incidence of falls over an 8-year study period. We used the neighborhood and housing data that are collected systematically by trained observers in the HRS to assess environmental hazards. Sidewalk quality, neighborhood disorder, and the presence of green space were measured to capture outdoor environmental hazards. Indoor environmental hazards included the presence of housing decay and poorly maintained stairways. All models were stratified by living arrangement. Results: Neighborhood and housing environment were independently associated with the odds of falls net of demographic characteristics and preexisting health conditions, and effects were significant for people living alone only. The presence of green space and poorly maintained stairways were associated with greater odds of falling, net of covariates during 8 years of follow-up (odds ratios = 2.10 and 2.65, p < .05, respectively). None of the environmental risk factors were significant for those living with others. Discussion and Implications: Falls in old age may be determined in part by a combination of outdoor and indoor risk factors. More research is needed to understand pathways that lead to greater vulnerability among older adults living alone to environmental hazards.

Ability of a selfish B chromosome to evade genome elimination in the jewel wasp, Nasonia vitripennis.

B chromosomes are non-essential, extra chromosomes that can exhibit transmission-enhancing behaviors, including meiotic drive, mitotic drive, and induction of genome elimination, in plants and animals. A fundamental but poorly understood question is what characteristics allow B chromosomes to exhibit these extraordinary behaviors. The jewel wasp, Nasonia vitripennis, harbors a heterochromatic, paternally transmitted B chromosome known as paternal sex ratio (PSR), which causes complete elimination of the sperm-contributed half of the genome during the first mitotic division of fertilized embryos. This genome elimination event may result from specific, previously observed alterations of the paternal chromatin. Due to the haplo-diploid reproduction of the wasp, genome elimination by PSR causes female-destined embryos to develop as haploid males that transmit PSR. PSR does not undergo self-elimination despite its presence with the paternal chromatin until the elimination event. Here we performed fluorescence microscopic analyses aimed at understanding this unexplained property. Our results show that PSR, like the rest of the genome, participates in the histone-to-protamine transition, arguing that PSR does not avoid this transition to escape self-elimination. In addition, PSR partially escapes the chromatin-altering activity of the intracellular bacterium, Wolbachia, demonstrating that this ability to evade chromatin alteration is not limited to PSR's own activity. Finally, we observed that the rDNA locus and other unidentified heterochromatic regions of the wasp's genome also seem to evade chromatin disruption by PSR, suggesting that PSR's genome-eliminating activity does not affect heterochromatin. Thus, PSR may target an aspect of euchromatin to cause genome elimination.

Marchf6 E3 ubiquitin ligase critically regulates endoplasmic reticulum stress, ferroptosis, and metabolic homeostasis in POMC neurons.

The metabolic prohormone pro-opiomelanocortin (POMC) is generally translocated into the endoplasmic reticulum (ER) for entry into the secretory pathway. Patients with mutations within the signal peptide (SP) of POMC or its adjoining segment develop metabolic disorders. However, the existence, metabolic fate, and functional outcomes of cytosol-retained POMC remain unclear. Here, we show that SP-uncleaved POMC is produced in the cytosol of POMC neuronal cells, thus inducing ER stress and ferroptotic cell death. Mechanistically, the cytosol-retained POMC sequesters the chaperone Hspa5 and subsequently accelerates degradation of the glutathione peroxidase Gpx4, a core regulator of ferroptosis, via the chaperone-mediated autophagy. We also show that the Marchf6 E3 ubiquitin ligase mediates the degradation of cytosol-retained POMC, thereby preventing ER stress and ferroptosis. Furthermore, POMC-Cre-mediated Marchf6-deficient mice exhibit hyperphagia, reduced energy expenditure, and weight gain. These findings suggest that Marchf6 is a critical regulator of ER stress, ferroptosis, and metabolic homeostasis in POMC neurons.

Prophylactic cable prevents tapered titanium stem subsidence with 2 cm of stem-cortical engagement in a cadaveric model.

Aims: When performing revision total hip arthroplasty using diaphyseal-engaging titanium tapered stems (TTS), the recommended 3 to 4 cm of stem-cortical diaphyseal contact may not be available. In challenging cases such as these with only 2 cm of contact, can sufficient axial stability be achieved and what is the benefit of a prophylactic cable? This study sought to determine, first, whether a prophylactic cable allows for sufficient axial stability when the contact length is 2 cm, and second, if differing TTS taper angles (2° vs 3.5°) impact these results. Methods: A biomechanical matched-pair cadaveric study was designed using six matched pairs of human fresh cadaveric femora prepared so that 2 cm of diaphyseal bone engaged with 2° (right femora) or 3.5° (left femora) TTS. Before impaction, three matched pairs received a single 100 lb-tensioned prophylactic beaded cable; the remaining three matched pairs received no cable adjuncts. Specimens underwent stepwise axial loading to 2600 N or until failure, defined as stem subsidence > 5 mm. Results: All specimens without cable adjuncts (6/6 femora) failed during axial testing, while all specimens with a prophylactic cable (6/6) successfully resisted axial load, regardless of taper angle. In total, four of the failed specimens experienced proximal longitudinal fractures, three of which occurred with the higher 3.5° TTS. One fracture occurred in a 3.5° TTS with a prophylactic cable yet passed axial testing, subsiding < 5 mm. Among specimens with a prophylactic cable, the 3.5° TTS resulted in lower mean subsidence (0.5 mm (SD 0.8)) compared with the 2° TTS (2.4 mm (SD 1.8)). Conclusion: A single prophylactic beaded cable dramatically improved initial axial stability when stem-cortex contact length was 2 cm. All implants failed secondary to fracture or subsidence > 5 mm when a prophylactic cable was not used. A higher taper angle appears to decrease the magnitude of subsidence but increased the fracture risk. The fracture risk was mitigated by the use of a prophylactic cable.

Guided Autotransplantation of Impacted Canines Using a CAD/CAM Surgical Template.

Autotransplantation is a potential treatment alternative when orthodontic traction of an impacted tooth is difficult. In this article, we describe two cases of guided autotransplantation of an impacted canine using a computer-aided designed and manufactured surgical template. The impacted canine was segmented on preoperative cone-beam computed tomography images to ensure a sufficient periodontal ligament space and placement of the donor tooth with the least pressure on it. The canine was virtually transposed using a simulation program considering the adjacent teeth. The surgical template, which was connected to the occlusal stop on adjacent teeth, was designed and 3D-printed with polymer resin. The recipient site was prepared using the surgical template, followed by immediate transplantation of the surgically extracted canine into the socket. The transplanted donor tooth was positioned in planned infra-occlusion to prevent occlusal interference. It was then splinted with the adjacent teeth for initial stabilization. During follow-up, one transplanted tooth showed pulp canal obliteration and the other had suspected pulp necrosis; endodontic treatment was performed. One year after the procedure, the periradicular condition of both teeth was favorable.

Microbial Components and Effector Molecules in T Helper Cell Differentiation and Function.

The mammalian intestines harbor trillions of commensal microorganisms composed of thousands of species that are collectively called gut microbiota. Among the microbiota, bacteria are the predominant microorganism, with viruses, protozoa, and fungi (mycobiota) making up a relatively smaller population. The microbial communities play fundamental roles in the maturation and orchestration of the immune landscape in health and disease. Primarily, the gut microbiota modulates the immune system to maintain homeostasis and plays a crucial role in regulating the pathogenesis and pathophysiology of inflammatory, neuronal, and metabolic disorders. The microbiota modulates the host immune system through direct interactions with immune cells or indirect mechanisms such as producing short-chain acids and diverse metabolites. Numerous researchers have put extensive efforts into investigating the role of microbes in immune regulation, discovering novel immunomodulatory microbial species, identifying key effector molecules, and demonstrating how microbes and their key effector molecules mechanistically impact the host immune system. Consequently, recent studies suggest that several microbial species and their immunomodulatory molecules have therapeutic applicability in preclinical settings of multiple disorders. Nonetheless, it is still unclear why and how a handful of microorganisms and their key molecules affect the host immunity in diverse diseases. This review mainly discusses the role of microbes and their metabolites in T helper cell differentiation, immunomodulatory function, and their modes of action.

Synthesis of 1,4-Dialkoxynaphthalene-Based Imidazolium Salts and Their Cytotoxicity in Cancer Cell Lines.

In this study, we designed and synthesized novel 1,4-dialkoxynaphthalene-2-alkyl imidazolium salt (IMS) derivatives containing both 1,4-dialkoxynaphthalene and imidazole, which are well known as pharmacophores. The cytotoxicities of these newly synthesized IMS derivatives were investigated in order to explore the possibility of using them to develop anticancer drugs. It was found that some of the new IMS derivatives showed good cytotoxic activities. In addition, an initial, qualitative structure-activity relationship is presented on the basis of observations of activity changes corresponding to structural changes.

Childhood lead exposure is associated with lower cognitive functioning at older ages.

The Flint, Michigan water crisis renewed concern about lead toxicity in drinking water. While lead in drinking water has been shown to negatively affect cognition among children, much less is known about its long-term consequences for late-life cognition. Using a nationally representative sample of U.S. older adults linked to historical administrative data from 1940, we find that older adults who lived as children in cities with lead pipes and acidic or alkaline water-the conditions required for lead to leach into drinking water-had worse cognitive functioning but not steeper cognitive decline. About a quarter of the association between lead and late-life cognition was accounted for by educational attainment. Within the next 10 years, American children exposed to high levels of lead during the 1970s will enter older ages. Our evidence highlights the need for stronger actions to identify interventions to mitigate long-term damage among people at high risk.

Do social determinants of health explain racial/ethnic disparities in COVID-19 infection?

Racial/ethnic minorities have experienced higher COVID-19 infection rates than whites, but it is unclear how individual-level housing, occupational, behavioral, and socioeconomic conditions contribute to these disparities in a nationally representative sample. In this study, we assess the extent to which social determinants of health contribute to racial/ethnic differences in COVID-19 infection. Data are from the Understanding America Study's Understanding Coronavirus in America survey (UAS COVID-19 waves 7-29). UAS COVID-19 is one of the only nationally representative longitudinal data sources that collects information on household, work, and social behavioral context during the pandemic. We analyze onset of COVID-19 cases, defined as a positive test or a diagnosis of COVID-19 from a healthcare provider since the previous survey wave, over a year of follow-up (June 2020-July 2021). We consider educational attainment, economic resources, work arrangements, household size, and social distancing as key social factors that may be structured by racism. Cox hazard models indicate that Hispanic people have 48% higher risk of experiencing a COVID-19 infection than whites after adjustment for age, sex, local infection rate, and comorbidities, but we do not observe a higher risk of COVID-19 among Black respondents. Controlling for engagement in any large or small social gathering increases the hazard ratio for Hispanics by 9%, suggesting that had Hispanics had the same social engagement patterns as whites, they may have had even higher risk of COVID-19. Other social determinants-lower educational attainment, working away from home, and number of coresidents-all independently predict higher risk of COVID-19, but do not explain why Hispanic Americans have higher COVID-19 infection risk than whites.

Effect of childhood proximity to lead mining on late life cognition.

INTRODUCTION: Lead exposure negatively affects cognitive functioning among children. However, there is limited evidence about whether exposure to lead in early life impairs later life cognitive functioning. METHODS: Participants in the prospective Wisconsin Longitudinal Study cohort (N = 8583) were linked to the 1940 Census, which was taken when they were young children. We estimated the effect of living near a lead mine in childhood on late life memory/attention and language/executive function in 2004 (mean age 64) and 2011 (mean age 71). RESULTS: Lead-exposed children had significantly steeper memory/attention decline between 2004 and 2011 and worse language/executive function at baseline in late life. These long-term effects of lead were not mediated through adolescent IQ or late life SES and health factors. DISCUSSION: Proximity to lead mining in childhood had long-term effects on late life memory/attention decline and language/executive function, reflecting a possible latent influence of lead exposure. More research is needed to understand behavioral and biological pathways underlying this relationship.

Disorder, networks, and cognition: do social networks buffer the influence of neighborhood and household disorder on cognitive functioning?

OBJECTIVES: To examine whether neighborhood and household disorder matter for cognitive functioning among middle-aged and older adults and whether the disorder-cognition link is moderated by social network resources. METHOD: Data are drawn from National Social Life, Health, and Aging Project (NSHAP) Wave 2 (N = 3198). Both neighborhood and household were considered as key residential contexts that shape one's social life and health. Exposure to neighborhood and household disorder was measured using interviewer assessments of signs of disorder and decay, including the presence of disrepair, trash, noise, and unpleasant smells such as air pollution, in the buildings and streets in which the respondent lives. Cognitive function was measured using the survey-adapted Montreal Cognitive Assessment (MoCA-SA). Network size, network range, and frequency of interaction among network members were assessed as moderators. RESULTS: Neighborhood and household disorder were independently associated with cognitive function. However, disorder in the household appeared to have more direct associations with cognitive function than did the neighborhood when both were present. The association between household disorder and cognitive function was mitigated by network size, such that poor housing conditions were associated with lower cognitive function only for those with small social networks. CONCLUSION: This study suggests a larger network may play a role in minimizing the negative influence of household disorder on cognitive function for middle-aged and older adults. Social policy and intervention aimed at promoting network ties may help reduce further disparities in cognitive function, especially for those vulnerable groups living in a poor-quality household.

Adherence to Social-Distancing and Personal Hygiene Behavior Guidelines and Risk of COVID-19 Diagnosis: Evidence From the Understanding America Study.

Objectives. To assess the association between individual-level adherence to social-distancing and personal hygiene behaviors recommended by public health experts and subsequent risk of COVID-19 diagnosis in the United States. Methods. Data are from waves 7 through 26 (June 10, 2020-April 26, 2021) of the Understanding America Study COVID-19 survey. We used Cox models to assess the relationship between engaging in behaviors considered high risk and risk of COVID-19 diagnosis. Results. Individuals engaging in behaviors indicating lack of adherence to social-distancing guidelines, especially those related to large gatherings or public interactions, had a significantly higher risk of COVID-19 diagnosis than did those who did not engage in these behaviors. Each additional risk behavior was associated with a 9% higher risk of COVID-19 diagnosis (hazard ratio [HR] = 1.09; 95% confidence interval [CI] = 1.05, 1.13). Results were similar after adjustment for sociodemographic characteristics and local infection rates. Conclusions. Personal mitigation behaviors appear to influence the risk of COVID-19, even in the presence of social factors related to infection risk. Public Health Implications. Our findings emphasize the importance of individual behaviors for preventing COVID-19, which may be relevant in contexts with low vaccination. (Am J Public Health. 2022;112(1):169-178. https://doi.org/10.2105/AJPH.2021.306565).

Childhood Background Measures and Their Associations With Later-Life Physical, Mental, and Social Health in the National Social Life, Health, and Aging Project.

OBJECTIVE: We describe each childhood background measure available in the National Social Life, Health, and Aging Project (NSHAP), report preliminary population estimates for each measure by age and gender, and validate the childhood measures by showing that the associations between the NSHAP childhood measures and later-life health outcomes are consistent with previous studies on this topic. METHOD: Childhood background measures included family life happiness, family structure, parental educational attainment, perceived financial situation, experience of violence, witness of violence, childhood health, and place of birth. We measured self-rated health, depressive symptoms, and social support to assess later-life physical, mental, and social health. Logistic and linear regression models were used for the binary and continuous outcome variables, respectively. RESULTS: Older age groups were more likely than those in younger age groups to report a poor financial situation in childhood, lower parental education, and intact family structure and were less likely to have experienced or witnessed a violent event as a child. Growing up in a happy and well-educated family was associated with better physical, mental, and social health in older ages. DISCUSSION: NSHAP childhood data included a variety of measures assessing the family social environment during childhood, providing a valuable resource for the study of early-life determinants of health and well-being over the life course.

Suppressing mosquito populations with precision guided sterile males.

The mosquito Aedes aegypti is the principal vector for arboviruses including dengue/yellow fever, chikungunya, and Zika virus, infecting hundreds of millions of people annually. Unfortunately, traditional control methodologies are insufficient, so innovative control methods are needed. To complement existing measures, here we develop a molecular genetic control system termed precision-guided sterile insect technique (pgSIT) in Aedes aegypti. PgSIT uses a simple CRISPR-based approach to generate flightless females and sterile males that are deployable at any life stage. Supported by mathematical models, we empirically demonstrate that released pgSIT males can compete, suppress, and even eliminate mosquito populations. This platform technology could be used in the field, and adapted to many vectors, for controlling wild populations to curtail disease in a safe, confinable, and reversible manner.