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Purpose – The purpose of this paper is to study the behavior of negative stiffness beams when arranged in a honeycomb configuration and to compare the energy absorption capacity of these negative stiffness honeycombs with regular honeycombs of equivalent relative densities. Design/methodology/approach – A negative stiffness honeycomb is fabricated in nylon 11 using selective laser sintering. Its force-displacement behavior is simulated with finite element analysis and experimentally evaluated under quasi-static displacement loading. Similarly, a hexagonal honeycomb of equivalent relative density is also fabricated and tested. The energy absorbed for both specimens is computed from the resulting force-displacement curves. The beam geometry of the negative stiffness honeycomb is optimized for maximum energy absorption per unit mass of material. Findings – Negative stiffness honeycombs exhibit relatively large positive stiffness, followed by a region of plateau stress as the cell walls buckle, similar to regular hexagonal honeycombs, but unlike regular honeycombs, they demonstrate full recovery after compression. Representative specimens are found to absorb about 65 per cent of the energy incident on them. Optimizing the negative stiffness beam geometry can result in energy-absorbing capacities comparable to regular honeycombs of similar relative densities. Research limitations/implications – The honeycombs were subject to quasi-static displacement loading. To study shock isolation under impact loads, force-controlled loading is desirable. However, the energy absorption performance of the negative stiffness honeycombs is expected to improve under force-controlled conditions. Additional experimentation is needed to investigate the rate sensitivity of the force-displacement behavior of the negative stiffness honeycombs, and specimens with various geometries should be investigated. Originality/value – The findings of this study indicate that recoverable energy absorption is possible using negative stiffness honeycombs without sacrificing the high energy-absorbing capacity of regular honeycombs. The honeycombs can find usefulness in a number of unique applications requiring recoverable shock isolation, such as bumpers, helmets and other personal protection devices. A patent application has been filed for the negative stiffness honeycomb design.

Background In the absence of sex and recombination, genomes are expected to accumulate deleterious mutations via an irreversible process known as Muller’s ratchet, especially in the case of polyploidy. In contrast, no genome-wide mutation accumulation was detected in a transcriptome of facultative apomictic, hexaploid plants of the Ranunculus auricomus complex. We hypothesize that mutations cannot accumulate in flowering plants with facultative sexuality because sexual and asexual development concurrently occurs within the same generation. We assume a strong effect of purging selection on reduced gametophytes in the sexual developmental pathway because previously masked recessive deleterious mutations would be exposed to selection. Results We test this hypothesis by modeling mutation elimination using apomictic hexaploid plants of the R. auricomus complex. To estimate mean recombination rates, the mean number of recombinants per generation was calculated by genotyping three F1 progeny arrays with six microsatellite markers and character incompatibility analyses. We estimated the strength of purging selection in gametophytes by calculating abortion rates of sexual versus apomictic development at the female gametophyte, seed and offspring stage. Accordingly, we applied three selection coefficients by considering effects of purging selection against mutations on (1) male and female gametophytes in the sexual pathway (additive, s  = 1.000), (2) female gametophytes only ( s  = 0.520), and (3) on adult plants only (sporophytes, s  = 0.212). We implemented recombination rates into a mathematical model considering the three different selection coefficients, and a genomic mutation rate calculated from genome size of our plants and plant-specific mutation rates. We revealed a mean of 6.05% recombinants per generation. This recombination rate eliminates mutations after 138, 204 or 246 generations, depending on the respective selection coefficients ( s  = 1.000, 0.520, and 0.212). Conclusions Our results confirm that the empirically observed frequencies of facultative recombination suffice to prevent accumulation of deleterious mutations via Muller’s ratchet even in a polyploid genome. The efficiency of selection is in flowering plants strongly increased by acting on the haplontic (reduced) gametophyte stage.

Purpose This study aimed to assess the feasibility, acceptability, and satisfaction associated with the MyInspiration intervention, a digital spiritual support tool for patients undergoing cancer surgery. Additionally, we evaluated changes in spiritual well-being and the ability to find meaning in their experience with cancer before and after the intervention. Methods This was a prospective, single-arm pilot study. Feasibility and acceptability were assessed by ratio of participants who completed all assessments among individuals who had signed consent forms. Satisfaction was assessed with 5 Likert-style questions around user experience. Patient spiritual well-being and finding meaning in their experience with cancer were measured at baseline and post-intervention. Results Forty patients were enrolled, the majority of whom were female (80.0%) and diagnosed with breast cancer (52.5%), with an average age of 54.4 years (SD = 13.7, range 29.0–82.0). Regarding feasibility and acceptability, 76.9% of patients who consented to participate completed the full study protocol. In assessing satisfaction, 59% of patients were satisfied with the overall experience of MyInspiration. There was no difference in spiritual well-being pre-/post-intervention. There was a difference in pre ( M  = 1.95, SD = .95) and post ( M  = 2.23, SD = .86) scores relative to “finding meaning in the cancer experience” with a mean difference of 0.28 ( p  = 0.008). Conclusion MyInspiration was feasible and acceptable to patients, and the majority were satisfied with the tool. The intervention was associated with changes in patients’ ability to find meaning within their cancer experience. A randomized control trial is needed to evaluate the efficacy of the tool in a broader population of patients with cancer.

Reconstructing the evolutionary origins of Mycobacterium tuberculosis , the causative agent of human tuberculosis, has helped identify bacterial factors that have led to the tubercle bacillus becoming such a formidable human pathogen. Here we report the discovery and detailed characterization of an exceedingly slow growing mycobacterium that is closely related to M . tuberculosis for which we have proposed the species name Mycobacterium spongiae sp. nov., (strain ID: FSD4b-SM). The bacterium was isolated from a marine sponge, taken from the waters of the Great Barrier Reef in Queensland, Australia. Comparative genomics revealed that, after the opportunistic human pathogen Mycobacterium decipiens , M . spongiae is the most closely related species to the M . tuberculosis complex reported to date, with 80% shared average nucleotide identity and extensive conservation of key M . tuberculosis virulence factors, including intact ESX secretion systems and associated effectors. Proteomic and lipidomic analyses showed that these conserved systems are functional in FSD4b-SM, but that it also produces cell wall lipids not previously reported in mycobacteria. We investigated the virulence potential of FSD4b-SM in mice and found that, while the bacteria persist in lungs for 56 days after intranasal infection, no overt pathology was detected. The similarities with M . tuberculosis , together with its lack of virulence, motivated us to investigate the potential of FSD4b-SM as a vaccine strain and as a genetic donor of the ESX-1 genetic locus to improve BCG immunogenicity. However, neither of these approaches resulted in superior protection against M . tuberculosis challenge compared to BCG vaccination alone. The discovery of M . spongiae adds to our understanding of the emergence of the M . tuberculosis complex and it will be another useful resource to refine our understanding of the factors that shaped the evolution and pathogenesis of M . tuberculosis .

Among the 16 two-component systems in the opportunistic human pathogen Staphylococcus aureus , only WalKR is essential. Like the orthologous systems in other Bacillota, S. aureus WalKR controls autolysins involved in peptidoglycan remodeling and is therefore intimately involved in cell division. However, despite the importance of WalKR in S. aureus , the basis for its essentiality is not understood and the regulon is poorly defined. Here, we defined a consensus WalR DNA-binding motif and the direct WalKR regulon by using functional genomics, including chromatin immunoprecipitation sequencing, with a panel of isogenic walKR mutants that had a spectrum of altered activities. Consistent with prior findings, the direct regulon includes multiple autolysin genes. However, this work also revealed that WalR directly regulates at least five essential genes involved in lipoteichoic acid synthesis ( ltaS ): translation ( rplK ), DNA compaction ( hup ), initiation of DNA replication ( dnaA , hup ) and purine nucleotide metabolism ( prs ). Thus, WalKR in S. aureus serves as a polyfunctional regulator that contributes to fundamental control over critical cell processes by coordinately linking cell wall homeostasis with purine biosynthesis, protein biosynthesis, and DNA replication. Our findings further address the essentiality of this locus and highlight the importance of WalKR as a bona fide target for novel anti-staphylococcal therapeutics. The opportunistic human pathogen Staphylococcus aureus uses an array of protein sensing systems called two-component systems (TCS) to sense environmental signals and adapt its physiology in response by regulating different genes. This sensory network is key to S. aureus versatility and success as a pathogen. Here, we reveal for the first time the full extent of the regulatory network of WalKR, the only staphylococcal TCS that is indispensable for survival under laboratory conditions. We found that WalKR is a master regulator of cell growth, coordinating the expression of genes from multiple, fundamental S. aureus cellular processes, including those involved in maintaining cell wall metabolism, protein biosynthesis, nucleotide metabolism, and the initiation of DNA replication.

BACKGROUNDNK cell function is impaired in people with HIV (PWH), hindering their potential to reduce the lymphoid tissue (LT) reservoir. The IL-15 superagonist N-803 has been shown to enhance NK and T cell function and thus may reduce viral reservoirs.METHODSTo determine the impact of N-803 on LTs, we conducted a clinical trial where 10 PWH on effective antiretroviral therapy (ART) were given 3 subcutaneous 6 mcg/kg doses of N-803. We obtained PBMCs and lymph node (LN) and gut biopsies at baseline and after the last N-803 dose.RESULTSWe found a nonstatistically significant approximately 0.50 median log reduction in the frequency of viral RNA+ (vRNA+) and vDNA+ cells/g in the 6 participants with baseline and posttreatment LN biopsies. In the ileum, we observed reductions of vRNA+ cells in 8/10 participants and vDNA+ cells in all participants. We also found significant inverse correlations between NK cell proliferation and the frequency of vRNA+ cells and between NKG2A expression on NK cells and the frequency of vRNA+ cells.CONCLUSIONOur findings suggest N-803 may reduce the HIV reservoir in LTs of PWH on ART, an effect likely mediated by enhanced NK cell function. Controlled studies assessing the impact of NK cell therapy on HIV LTs are needed.TRIAL REGISTRATIONClinicalTrials.gov NCT04808908.FUNDINGNIH grants 5UM1AI126611, UL1TR002494, R01 AI147912, R35 CA283892, and UM1AI164561.

•A retrospective economic evaluation of worksite CAM interventions was conducted.•A propensity matched score generated a viable control group on salient variables.•Pharmaceutical cost and use by intervention groups was higher than controls.•CAM interventions generated overall cost savings over 5 years compared to controls. To compare healthcare costs and utilization among participants in a study of two active lifestyle interventions implemented in the workplace and designed to foster awareness of and attention to health with a propensity score matched control group. We retrospectively compared changes in healthcare (HC) utilization among participants in the mindfulness intervention (n=84) and the diet/exercise intervention (n=86) to a retrospectively matched control group (n=258) drawn for this study. The control group was matched from the non-participant population on age, gender, relative risk score, and HC expenditures in the 9 month preceding the study. Measures included number of primary care visits, number and cost of pharmacy prescriptions, number of hospital admissions, and overall healthcare costs tracked for 5 years after the intervention. Significantly fewer primary care visits (p<.001) for both intervention groups as compared to controls, with a non-significant trend towards lower overall HC utilization (4,300.00 actual dollar differences) and hospital admissions for the intervention groups after five years. Pharmacy costs and number of prescriptions were significantly higher for the two intervention groups compared to controls over the five years (p<0.05), yet still resulted in less HC utilization costs, potentially indicating greater self-management of care. This study provides valuable information as to the cost savings and value of providing workplace lifestyle interventions that focus on awareness of one’s body and health. Health economic studies validate the scale of personal and organization health cost savings that such programs can generate.

N-803, an IL-15 superagonist, is currently being studied in clinical trials as a treatment to reverse HIV latency. However, its effects on the gut microbiome are not well understood. In this longitudinal metagenomic study, we analyzed fecal microbiomes from ART-suppressed people with HIV at four different timepoints before, during, and after N-803 treatment. Overall taxonomic and functional diversity did not change significantly, yet beneficial microbial taxa and pathways were enriched after N-803. Specifically, the relative abundance of increased significantly after N-803, whereas histidine degradation pathways, often associated with pro-inflammatory mucosal state, decreased. A higher baseline microbial diversity correlated with stronger CD8 and natural killer (NK) cells activation and reduced frequency of rectal HIV RNA cells. analyses further associated short-chain fatty acid (SCFA)-producing taxa and pathways with increased immune activation markers. These results indicate that gut microbiome diversity prior to immunotherapy influences host response and suggest that microbiome-based strategies could improve efforts to cure HIV.

Despite effective antiretroviral therapy (ART), many people with HIV (PWH) exhibit persistent immune activation (IA) and suffer metabolic comorbidities. We investigated whether residual HIV production in lymphoid tissues drives IA. Among 20 ART-suppressed PWH, HIV RNA cells were detected in lymph nodes and correlated directly with markers of pyroptosis, assessed via cleaved gasdermin D positivity, but not with most plasma cytokines or IA markers. Notably, glucagon-like peptide 1 (GLP-1), an enteroendocrine hormone with anti-inflammatory roles, was upregulated in the ileum of PWH and correlated directly with systemic cytokines but inversely with lymph node pyroptosis. These findings suggest that chronic occult inflammation in people with successfully suppressed HIV infection is mediated by persistent virus production in lymph nodes leading to pyroptosis, which may trigger compensatory anti-inflammatory enteroendocrine activation that may dampen pyroptosis. Targeting pyroptosis or enhancing GLP-1 signaling represent potential therapeutic strategies for modulating IA and managing metabolic comorbidities in PWH.