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Cancer cells cannot proliferate without sufficient energy to generate biomass for rapid cell division, as well as to fuel their functions at baseline. For this reason, many recent observational and interventional studies have focused on increasing energy expenditure and/or reducing energy intake during and after cancer treatment. The impact of variance in diet composition and in exercise on cancer outcomes has been detailed extensively elsewhere and is not the primary focus of this review. Instead, in this translational, narrative review we examine studies of how energy balance impacts anticancer immune activation and outcomes in triple-negative breast cancer (TNBC). We discuss preclinical, clinical observational, and the few clinical interventional studies on energy balance in TNBC. We advocate for the implementation of clinical studies to examine how optimizing energy balance—through changes in diet and/or exercise—may optimize the response to immunotherapy in people with TNBC. It is our conviction that by taking a holistic approach that includes energy balance as a key factor to be considered during and after treatment, cancer care may be optimized, and the detrimental effects of cancer treatment and recovery on overall health may be minimized.

Introductory Paragraph / AbstractThe bloodstream represents a hostile environment that bacteria must overcome to cause bacteraemia. To understand how the major human pathogenStaphylococcus aureusmanages this we have utilised a functional genomics approach to identify a number of new loci that affect the ability of the bacteria to survive exposure to serum, the critical first step in the development of bacteraemia. The expression of one of these genes,tcaA,was found to be induced upon exposure to serum, and we show that it is involved in the elaboration of a critical virulence factor, the wall teichoic acids (WTA), within the cell envelope. The activity of the TcaA protein alters the sensitivity of the bacteria to cell wall attacking agents, including antimicrobial peptides, human defence fatty acids, and several antibiotics. This protein also affects the autolytic activity and lysostaphin sensitivity of the bacteria, suggesting that in addition to changing WTA abundance in the cell envelope, it also plays a role in peptidoglycan crosslinking. With TcaA rendering the bacteria more susceptible to serum killing, while simultaneously increasing the abundance of WTA in the cell envelope, it was unclear what effect this protein may have during infection. To explore this, we examined human data and performed murine experimental infections. Collectively, our data suggests that whilst mutations intcaAare selected for during bacteraemia, this protein positively contributes to the virulence ofS. aureusthrough its involvement in altering the cell wall architecture of the bacteria, a process that appears to play a key role in the development of bacteraemia.

1.ABSTRACTThe DASH diet is a dietary pattern designed to help treat or prevent hypertension. The diet includes foods rich in potassium, calcium, and magnesium while limiting foods high in sodium, saturated fat, and added sugars. The DASH diet’s relationship with hypertension in adults is well defined, but the effect of its variance in prevalence in nursing homes on seniors is not. We performed a mixed-methods observational study incorporating a survey collecting anonymized nursing home data regarding the number of servings of various food groups provided to senior residents per day. The data were analyzed using the Fung et al. DASH diet scoring method. We then conducted an interview with nursing home dieticians to investigate the public health effect of the DASH diet on hypertension in residents. Lastly, a content analysis was performed of nursing home menus to support the data from the surveys. In a pool of 11 nursing homes, 100% of the facilities incorporated some aspect of the DASH diet, and in a pool of five nursing homes, 60% achieved high adherence to the DASH diet. We additionally confirmed a previously observed negative relationship between red meat consumption in seniors to higher risk and poorer prognosis of hypertension. These analyses bolster the DASH diet’s potential role as a hypertension prevention mechanism in nursing homes, suggesting that future DASH diet interventions may hold promise.

1.AbstractCPT1A is a rate-limiting enzyme in fatty acid oxidation and is upregulated in high-risk breast cancer. Obesity and menopausal status’ relationship with breast cancer prognosis is well established, but its connection with fatty acid metabolism is not. We performed an observational study on anonymized RNA sequencing data in the Xena Functional Genomics Explorer, to explore CPT1A’s effect on breast cancer patients’ survival probability. Using [18F]-fluorothymidine positron emission tomography-computed tomography images from The Cancer Imaging Archive, we segmented these analyses by obesity and menopausal status. In 1214 patients, higher CPT1A expression is associated with lower breast cancer survivability. We confirmed a previously observed protective relationship between obesity and breast cancer in pre-menopausal patients and supported this data using two-sided Pearson correlations. Taken together, these analyses using open-access, deidentified databases bolster the potential role of CPT1A-dependent fatty acid metabolism as a pathogenic factor in breast cancer.

The onset of the pandemic saw shifts in messaging around the acceptability of alcohol consumption at different times and contexts. A psychometric analysis of responses to injunctive norms may reveal important differences in specific aspects of norms that were influenced by the pandemic. Study 1 used alignment analysis to evaluate measurement invariance in low- and high-risk injunctive norms across samples of Midwestern college students from 2019 to 2021. Study 2 used an alignment-within-confirmatory factor analysis (CFA) approach to replicate the solution from Study 1 in an independent longitudinal sample ( N = 1,148) who responded between 2019 and 2021. For Study 1, the latent mean for high-risk norms was significantly higher in 2021, and the endorsement of four specific norms also differed. In Study 2, increases in latent means for low- and high-risk norms were observed across 2020 and 2021, and differential endorsement emerged for one high-risk norm item. Examining scale-level changes in injunctive drinking norms provides insight into how college students’ perceptions changed in response to the COVID-19 pandemic.

Staphylococcal enterotoxin B (SEB), which is produced by the major human pathogen, Staphylococcus aureus, represents a powerful superantigenic toxin and is considered a bioweapon. However, the contribution of SEB to S. aureus pathogenesis has never been directly demonstrated with genetically defined mutants in clinically relevant strains. Many isolates of the predominant Asian community-associated methicillin-resistant S. aureus lineage sequence type (ST) 59 harbor seb, implying a significant role of SEB in the observed hypervirulence of this lineage. We created an isogenic seb mutant in a representative ST59 isolate and assessed its virulence potential in mouse infection models. We detected a significant contribution of seb to systemic ST59 infection that was associated with a cytokine storm. Our results directly demonstrate that seb contributes to S. aureus pathogenesis, suggesting the value of including SEB as a target in multipronged antistaphylococcal drug development strategies. Furthermore, they indicate that seb contributes to fatal exacerbation of community-associated methicillin-resistant S. aureus infection.

Previously either regarded as insignificant or feared as potential sources of infection, the bacteria living on our skin are increasingly recognized for their role in benefitting human health. Skin commensals modulate mucosal immune defenses and directly interfere with pathogens; however, their contribution to the skin's physical integrity is less understood. Here, we show that the abundant skin commensal Staphylococcus epidermidis contributes to skin barrier integrity. S. epidermidis secretes a sphingomyelinase that acquires essential nutrients for the bacteria and assists the host in producing ceramides, the main constituent of the epithelial barrier that averts skin dehydration and aging. In mouse models, S. epidermidis significantly increases skin ceramide levels and prevents water loss of damaged skin in a fashion entirely dependent on its sphingomyelinase. Our findings reveal a symbiotic mechanism that demonstrates an important role of the skin microbiota in the maintenance of the skin's protective barrier.

Quorum sensing contributes to systemic Enterococcus infection in mice and is inhibited by oral administration of Bacillus spores.

Whether and how probiotics promote human health is a controversial issue. Their claimed benefit for counteracting gastrointestinal infection is linked predominantly to reducing pathogen abundance within the intestinal microbiota. Less understood mechanistically is the reported value that probiotics could have in reducing systemic infections.

Many scientific conferences employ a two-phase paper review process, where some papers are assigned additional reviewers after the initial reviews are submitted. Many conferences also design and run experiments on their paper review process, where some papers are assigned reviewers who provide reviews under an experimental condition. In this paper, we consider the question: how should reviewers be divided between phases or conditions in order to maximize total assignment similarity? We make several contributions towards answering this question. First, we prove that when the set of papers requiring additional review is unknown, a simplified variant of this problem is NP-hard. Second, we empirically show that across several datasets pertaining to real conference data, dividing reviewers between phases/conditions uniformly at random allows an assignment that is nearly as good as the oracle optimal assignment. This uniformly random choice is practical for both the two-phase and conference experiment design settings. Third, we provide explanations of this phenomenon by providing theoretical bounds on the suboptimality of this random strategy under certain natural conditions. From these easily-interpretable conditions, we provide actionable insights to conference program chairs about whether a random reviewer split is suitable for their conference.

Virtual dolphin-assisted therapy (DAT) can be used to treat children with autism spectrum disorder (ASD), where interactions with virtual dolphins can be enabled by Virtual Reality (VR) technology. With the aid of VR, it is possible to reproduce an immersive environment with virtual objects to replicate the real-world DAT interactions. Using VR to create human–virtual dolphin interactions in an immersive setting allows DAT to be carried out virtually, protecting both participants, children and dolphins, from any harm or infections. The aim of recreating a DAT VR environment is also to make the treatment cheaper and more readily accessible to the masses of children with ASD. It can control the treatment environment and ensure the safety of the participants and those parties involved. A VR serious game, 3D Virtual Pink Dolphin is developed in Nanyang Technological University, which is running on both PC with single display screen and a 3D immersive room with 320-degree curved screens. The experiment has been conducted with children from a special needs school in Singapore.

Water-pipe smoking (WPS) is becoming the most popular form of tobacco use among the youth, especially in the Middle East, replacing cigarettes rapidly and becoming a major risk of tobacco addiction worldwide. Smoke from WPS contains similar toxins as those present in cigarette smoke and is linked directly with different types of cancers including lung and head and neck (HN) carcinomas. However, the underlying molecular pathways and/or target genes responsible for the carcinogenic process are still unknown. In this study, human normal oral epithelial (HNOE) cells, NanoString PanCancer Pathways panel of 770 gene transcripts and quantitative real-time polymerase chain reaction (qRT-PCR) analysis were applied to discover differentially expressed genes (DEG) modulated by WPS. In silico analysis was performed to analyze the impact of these genes in HN cancer patient&rsquo, s biology and outcome. We found that WPS can induce the epithelial&ndash, mesenchymal transition (EMT: hallmark of cancer progression) of HNOE cells. More significantly, our analysis of NanoString revealed 23 genes deregulated under the effect of WPS, responsible for the modulation of cell cycle, proliferation, migration/invasion, apoptosis, signal transduction, and inflammatory response. Further analysis was performed using qRT-PCR of HNOE WPS-exposed and unexposed cells supported the reliability of our NanoString data. Moreover, we demonstrate those DEG to be upregulated in cancer compared with normal tissue. Using the Kaplan&ndash, Meier analysis, we observed a significant association between WPS-deregulated genes and relapse-free survival/overall survival in HN cancer patients. Our findings imply that WPS can modulate EMT as well as a set of genes that are directly involved in human HN carcinogenesis, thereby affecting HN cancer patients&rsquo, survival.

The main goal of this collaborative effort is to provide genome wide data for the previously underrepresented population in Eastern Europe, and to provide cross-validation of the data from genome sequences and genotypes of the same individuals acquired by different technologies. We collected 97 genome-grade DNA samples from consented individuals representing major regions of Ukraine that were consented for the public data release. DNBSEQ-G50 sequences, and genotypes by an Illumina GWAS chip were cross-validated on multiple samples, and additionally referenced to one sample that has been resequenced by Illumina NovaSeq6000 S4 at high coverage. The genome data has been searched for genomic variation represented in this population, and a number of variants have been reported: large structural variants, indels, CNVs, SNPs and microsatellites. This study provides the largest to-date survey of genetic variation in Ukraine, creating a public reference resource aiming to provide data for historic and medical research in a large understudied population. While most of the common variation is shared with other European populations, this survey of population variation contributes a number of novel SNPs and structural variants that have not been reported in the gnomAD/1KG databases representing global distribution of genomic variation. These endemic variants will become a valuable resource for designing future population and clinical studies, help address questions about ancestry and admixture, and will fill a missing place in the puzzle characterizing human population diversity in Eastern Europe. Our results indicate that genetic diversity of the Ukrainian population is uniquely shaped by the evolutionary and demographic forces, and cannot be ignored in the future genetic and biomedical studies. This data will contribute a wealth of new information bringing forth different risk and/or protective alleles. The newly discovered low frequency and local variants can be added to the current genotyping arrays for genome wide association studies, clinical trials, and in genome assessment of proliferating cancer cells.

BackgroundThe main goal of this collaborative effort is to provide genome-wide data for the previously underrepresented population in Eastern Europe, and to provide cross-validation of the data from genome sequences and genotypes of the same individuals acquired by different technologies. We collected 97 genome-grade DNA samples from consented individuals representing major regions of Ukraine that were consented for public data release. BGISEQ-500 sequence data and genotypes by an Illumina GWAS chip were cross-validated on multiple samples and additionally referenced to 1 sample that has been resequenced by Illumina NovaSeq6000 S4 at high coverage.ResultsThe genome data have been searched for genomic variation represented in this population, and a number of variants have been reported: large structural variants, indels, copy number variations, single-nucletide polymorphisms, and microsatellites. To our knowledge, this study provides the largest to-date survey of genetic variation in Ukraine, creating a public reference resource aiming to provide data for medical research in a large understudied population.ConclusionsOur results indicate that the genetic diversity of the Ukrainian population is uniquely shaped by evolutionary and demographic forces and cannot be ignored in future genetic and biomedical studies. These data will contribute a wealth of new information bringing forth a wealth of novel, endemic and medically related alleles.

Swift recruitment of phagocytic leucocytes is critical in preventing infection when bacteria breach through the protective layers of the skin. According to canonical models, this occurs via an indirect process that is initiated by contact of bacteria with resident skin cells and which is independent of the pathogenic potential of the invader. Here we describe a more rapid mechanism of leucocyte recruitment to the site of intrusion of the important skin pathogen Staphylococcus aureus that is based on direct recognition of specific bacterial toxins, the phenol-soluble modulins (PSMs), by circulating leucocytes. We used a combination of intravital imaging, ear infection and skin abscess models, and in vitro gene expression studies to demonstrate that this early recruitment was dependent on the transcription factor EGR1 and contributed to the prevention of infection. Our findings refine the classical notion of the non-specific and resident cell-dependent character of the innate immune response to bacterial infection by demonstrating a pathogen-specific high-alert mechanism involving direct recruitment of immune effector cells by secreted bacterial products.

Loss of machining efficiency, part repair, and replacement of mechanical components due to friction and wear is a recurring problem for performance industrial system applications. Recent studies on surface modification and micro-scale texturing have shown successful results in reducing friction and wear of lubricated surfaces. By acting as lubricant reservoirs and wear particle receptacles, micro-scale artificial surface textures positively influence lubrication regimes. In the present experimental study, a Stribeck curve is generated to compare the tribological properties of untextured and textured surfaces created by modulation-assisted machining. Aluminum 6061-T6 disks are mated with high-speed steel pins on a pin-on-disk tribometer configuration for varying speed and texture depth and density. The results suggest that the textured surfaces produced by modulation-assisted machining accelerate the appearance of the elasto-hydrodynamic regime, while also reducing friction by 56% and wear by almost 90%. The enhanced friction and wear reduction were obtained under the lower speeds studied. In general, the disk with shallower dimples presented lower values of friction under the conditions studied. No major differences were found for textures with different dimple densities.

Nguyen, P., Shukla, S., Liu, R., Abbineni, G. and Smart, D. K. Sirt2 Regulates Radiation-Induced Injury. Radiat. Res. 191, 398–412 (2019).Sirtuin 2 (SIRT2) plays a major role in aging, carcinogenesis and neurodegeneration. While it has been shown that SIRT2 is a mediator of stress-induced cell death, the mechanism remains unclear. In this study, we report the role of SIRT2 in mediating radiation-induced cell death and DNA damage using mouse embryonic fibroblasts (MEFs), progenitor cells and tissues from Sirt2 wild-type and genomic knockout mice, and human tumor and primary cell lines as models. The presence of Sirt2 in cells and tissues significantly enhanced the cell's sensitivity to radiation-induced cytotoxicity by delaying the dispersion of radiation-induced γ-H2AX and 53BP1 foci. This enhanced cellular radiosensitivity correlated with reduced expression of pro-survival and DNA repair proteins, and decreased DNA repair capacities involving both homologous repair and non-homologous end joining DNA repair mechanisms compared to those in Sirt2 knockout (KO) and knockdown (KD) phenotypes. Together, these data suggest SIRT2 plays a critical role in mediating the radiation-induced DNA damage response, thus regulating radiation-induced cell death and survival.

Bacterial sepsis is a major global cause of death. However, the pathophysiology of sepsis has remained poorly understood. In industrialized nations, Staphylococcus aureus represents the pathogen most commonly associated with mortality due to sepsis. Because of the alarming spread of antibiotic resistance, anti-virulence strategies are often proposed to treat staphylococcal sepsis. However, we do not yet completely understand if and how bacterial virulence contributes to sepsis, which is vital for a thorough assessment of such strategies. We here examined the role of virulence and quorum-sensing regulation in mouse and rabbit models of sepsis caused by methicillin-resistant S. aureus (MRSA). We determined that leukopenia was a predictor of disease outcome during an early critical stage of sepsis. Furthermore, in device-associated infection as the most frequent type of staphylococcal blood infection, quorum-sensing deficiency resulted in significantly higher mortality. Our findings give important guidance regarding anti-virulence drug development strategies for the treatment of staphylococcal sepsis. Moreover, they considerably add to our understanding of how bacterial sepsis develops by revealing a critical early stage of infection during which the battle between bacteria and leukocytes determines sepsis outcome. While sepsis has traditionally been attributed mainly to host factors, our study highlights a key role of the invading pathogen and its virulence mechanisms., Author summary Bacterial infections often develop sepsis as a complication. Sepsis is a severe blood infection and one of the main reasons for death, especially in hospitals of the developed world. Sepsis is believed to be due to an overshooting immune reaction to structures that most bacteria share. However, this model fails to explain why some bacteria cause more frequent and severe sepsis than others. In our study, which we performed with the main sepsis-causing bacteria, Staphylococcus aureus, we show that the outcome of sepsis depends on the battle between bacteria and white blood cells that happens early during infection. Many of the weapons that bacteria use for that battle are controlled by a quorum-sensing regulator, which implies that so-called anti-virulence strategies directed at that regulator may work to treat sepsis. However, we also show that targeting quorum-sensing is counterproductive when sepsis originates from biofilms on implanted catheters, which it often does. Our study shows that bacterial weaponry plays a key role in sepsis and gives important advice on how to use this finding for alternative drug development.

The present work combines quantitative orientation imaging microscopy and in situ digital image correlation to identify heterogeneities in the coupled mechanics and microstructure evolution occurring in the deformed subsurface during transient shear-based surface generation. Subsurface microstructure exhibited heterogeneities in terms of thickness of the ultrafine-grained layer and recrystallization fraction as a function of position along the surface wavelength. It was observed that subsurface microstructure evolution followed accelerated recrystallization kinetics due to strain path changes occurring in the subsurface during transient surface generation. The magnitudes of these strain path changes and pre-straining of the deformed subsurface were observed to correlate well with changes in the information entropy of the corresponding subsurface crystallographic textures. A phenomenological model for predicting the information entropy of the orientation distribution function based on strain path changes and strain history was formulated and validated for monotonic loading paths. The implications of this generalized framework for modeling and controlling subsurface microstructure in transient surface generation are briefly discussed.

© 2019 American Society of Human Genetics The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.

The initiation and evolution of the localized corrosion in carbon steel were investigated in a simulated marine environment of Xisha Island in the South China Sea. In the initial stage, localized corrosion occurred in the form of corrosion spot. The localized corrosion morphology and electrochemical information during corrosion process were tracked by field emission scanning electron microscopy energy dispersive spectrometry (FE-SEM-EDS), scanning vibrating electrode technique (SVET) and scanning Kelvin probe force microscopy (SKPFM). Localized corrosion was induced by the microcrevices around Al2O3 inclusions. The occluded cells and oxygen concentration cell formed in the pits could accelerate the localized corrosion. Pearlite accelerated the dissolution of the inside and surrounding ferrite via the galvanic effect between Fe3C and ferrite. Overall, the localized corrosion was initiated and evaluated under a synergistic effect of crevice corrosion, occluded cells, oxygen concentration cell and the galvanic couple between FeC3 and ferrite.

Bicycling has been increasing in North America, and intersections have been modified to accommodate the increase in cyclists. However, the increase in cycling is outpacing the supply of high-quality cycling markings, signing, signals, and general infrastructure at intersections. For example, recent research indicates that more than 50% of bicyclists do not understand that the 9C-7 bicycle stencil symbol from the Manual on Uniform Traffic Control Devices (MUTCD) indicates the optimal waiting position for a cyclist to call a green light. Subsequently, people on bicycles may run red lights because they do not understand how the MUTCD 9C-7 pavement marking works. This infrastructure shortcoming illustrates the need to study how new roadway information may affect user behavior and traffic signal compliance. This research documents the effects of an active feedback device on cyclist behavior in an effort to improve the cycling experience. A blue light feedback device was installed at a signalized intersection approach, and its impact on bicyclist behavior was studied. A statistically significant increase in the number of bicyclists who used the MUTCD 9C-7 marking (instead of the existing bicycle push button) occurred after installation of the blue light feedback device and especially after a sandwich board sign was installed that described the purpose of the blue light. These results indicate that a blue light feedback device (accompanied with bicycle detection and the standard marking) could be used effectively in lieu of bicycle push buttons. Also, the effect of the blue light feedback device on bicyclist compliance with traffic signals (red light runners) was negligible.