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During the pandemic, many older adults felt out of place in their home, work, and community spaces with potentially long-term consequences for health and wellbeing. Using national data from the COVID-19 Coping Study, thematic analysis of online long-answer responses (n = 1171; mean age 68 years; 71% female; 93% non-Hispanic White; 86% with at least a 4-year college degree; data collected April-June 2022) identified four themes regarding why particular places are challenging since the pandemic onset: (1) viral exposure fears, (2) frustrating regulations, (3) uncomfortable and hostile social dynamics, and (4) out of place negative emotions. Participants also shared how they continuously address or adapt to place-based challenges through lifestyle adjustments and coping strategies. Novel findings may inform multi-scalar policymaking and interventions to support wellbeing in later life in times of stress and instability.

Choroid plexus carcinomas (CPC) are early childhood cancers characterized by loss of TP53 function and poor survival. We are analyzing data on TP53 status, survival, and second cancers from the largest cohort of CPC receiving chemotherapy followed by consolidation with marrow-ablative chemotherapy (HDCx). Additionally, we discuss the rationale for targeted therapies for CPC patients. Currently, 8 of the 13 with Li-Fraumeni Syndrome-associated CPC were treated and continued CPC-free, indicating that HDCx improves CPC-free survival in young children with TP53-mutated CPC. These data justify the inclusion of HDCx in the planned prospective international trial for children with TP53-mutated CPC.

Soil fungi belonging to different functional guilds, such as saprotrophs, pathogens, and mycorrhizal symbionts, play key roles in forest ecosystems. To date, no study has compared the actual gene expression of these guilds in different forest soils. We used metatranscriptomics to study the competition for organic resources by these fungal groups in boreal, temperate, and Mediterranean forest soils. Using a dedicated mRNA annotation pipeline combined with the JGI MycoCosm database, we compared the transcripts of these three fungal guilds, targeting enzymes involved in C- and N mobilization from plant and microbial cell walls. Genes encoding enzymes involved in the degradation of plant cell walls were expressed at a higher level in saprotrophic fungi than in ectomycorrhizal and pathogenic fungi. However, ectomycorrhizal and saprotrophic fungi showed similarly high expression levels of genes encoding enzymes involved in fungal cell wall degradation. Transcripts for N-related transporters were more highly expressed in ectomycorrhizal fungi than in other groups. We showed that ectomycorrhizal and saprotrophic fungi compete for N in soil organic matter, suggesting that their interactions could decelerate C cycling. Metatranscriptomics provides a unique tool to test controversial ecological hypotheses and to better understand the underlying ecological processes involved in soil functioning and carbon stabilization.

There is concern that the time taken to publish academic papers in microbiological science has significantly increased in recent years. While the data do not specifically support this, evidence suggests that editors are having to invite more and more reviewers to identify those willing to perform peer review.

Combining genomic and geospatial data can be useful for understanding Mycobacterium tuberculosis transmission in high-burden tuberculosis (TB) settings. We performed whole-genome sequencing on M. tuberculosis DNA extracted from sputum cultures from a population-based TB study conducted in Gaborone, Botswana, during 2012-2016. We determined spatial distribution of cases on the basis of shared genotypes among isolates. We considered clusters of isolates with ≤5 single-nucleotide polymorphisms identified by whole-genome sequencing to indicate recent transmission and clusters of ≥10 persons to be outbreaks. We obtained both molecular and geospatial data for 946/1,449 (65%) participants with culture-confirmed TB; 62 persons belonged to 5 outbreaks of 10-19 persons each. We detected geospatial clustering in just 2 of those 5 outbreaks, suggesting heterogeneous spatial patterns. Our findings indicate that targeted interventions applied in smaller geographic areas of high-burden TB identified using integrated genomic and geospatial data might help interrupt TB transmission during outbreaks.

SARS-CoV-2 causes profound changes in the sense of smell, including total smell loss. Although these alterations are often transient, many patients with COVID-19 exhibit olfactory dysfunction that lasts months to years. Although animal and human autopsy studies have suggested mechanisms driving acute anosmia, it remains unclear how SARS-CoV-2 causes persistent smell loss in a subset of patients. To address this question, we analyzed olfactory epithelial samples collected from 24 biopsies, including from nine patients with objectively quantified long-term smell loss after COVID-19. This biopsy-based approach revealed a diffuse infiltrate of T cells expressing interferon-γ and a shift in myeloid cell population composition, including enrichment of CD207+ dendritic cells and depletion of anti-inflammatory M2 macrophages. Despite the absence of detectable SARS-CoV-2 RNA or protein, gene expression in the barrier supporting cells of the olfactory epithelium, termed sustentacular cells, appeared to reflect a response to ongoing inflammatory signaling, which was accompanied by a reduction in the number of olfactory sensory neurons relative to olfactory epithelial sustentacular cells. These findings indicate that T cell-mediated inflammation persists in the olfactory epithelium long after SARS-CoV-2 has been eliminated from the tissue, suggesting a mechanism for long-term post-COVID-19 smell loss.

Predicting the survival outcomes of patients with colorectal cancer (CRC) remains challenging. We investigated the prognostic significance of the transcriptome and tumour-infiltrating lymphocyte T-cell receptor (TIL/Tc-TCR) repertoire and analysed TIL/Tc-TCR sequences of The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumor Analysis Consortium (CPTAC) CRC cohorts. Using a multivariate Cox regression, we tested whether TIL/Tc-TCR repertoire, patient and tumour characteristics (stage, sidedness, total non-synonymous mutations, microsatellite instability (MSI) and transcriptional signatures) correlated with patient overall survival (OS) and designed a prognostic nomogram. A multivariate analysis (C-index = 0.75) showed that only patient age, disease stage, TIL/Tc degree of infiltration and clonality were independent prognostic factors for OS. The cut-offs for patients’ allocation to TIL/Tc abundance subgroups were determined using a strategy of maximally selected rank statistics with the OptimalCutpoints R package. These were “high”, “low” and “very high” (90 th percentile) TIL/Tc infiltration-stratified OS (median not reached, 67 and 44.3 months; p < 0.001); the results were validated in the CPTAC cohort. TIL/Tc clonality was prognostic (median OS in “high” vs. “low” clonality not reached and 67.3 months; p = 0.041) and independent of TIL/Tc infiltration. Whilst tumour sidedness was not prognostic, the “very highly” infiltrated tumours were prevalent among right-sided CRCs (p = 0.039) and showed distinct immunological features, with lower Th1 signature (p = 0.004), higher PD-L1 expression (p < 0.001) and likely enrichment in highly suppressory IL1R1+ Tregs (FoxP3 and IL1R1 overexpression, p < 0.001). TIL/Tc abundance and clonality are independent prognosticators in CRC and, combined with clinical variables, refine risk stratification. We identified a subset of CRCs with “very high” TIL/Tc infiltration, poor prognosis and distinct genetic and immunologic features, which may benefit from alternative therapeutic approaches. These results need validation in prospective patient cohorts.

Fish in coastal ecosystems can be exposed to acute variations in CO2 of between 0.2 and 1 kPa CO2 (2000-10,000 µatm). Coping with this environmental challenge will depend on the ability to rapidly compensate for the internal acid-base disturbance caused by sudden exposure to high environmental CO2 (blood and tissue acidosis); however, studies about the speed of acid-base regulatory responses in marine fish are scarce. We observed that upon sudden exposure to ∼1 kPa CO2, European sea bass (Dicentrarchus labrax) completely regulate erythrocyte intracellular pH within ∼40 min, thus restoring haemoglobin-O2 affinity to pre-exposure levels. Moreover, blood pH returned to normal levels within ∼2 h, which is one of the fastest acid-base recoveries documented in any fish. This was achieved via a large upregulation of net acid excretion and accumulation of HCO3- in blood, which increased from ∼4 to ∼22 mmol l-1. While the abundance and intracellular localisation of gill Na+/K+-ATPase (NKA) and Na+/H+ exchanger 3 (NHE3) remained unchanged, the apical surface area of acid-excreting gill ionocytes doubled. This constitutes a novel mechanism for rapidly increasing acid excretion during sudden blood acidosis. Rapid acid-base regulation was completely prevented when the same high CO2 exposure occurred in seawater with experimentally reduced HCO3- and pH, probably because reduced environmental pH inhibited gill H+ excretion via NHE3. The rapid and robust acid-base regulatory responses identified will enable European sea bass to maintain physiological performance during large and sudden CO2 fluctuations that naturally occur in coastal environments.

IntroductionCancer is the second leading cause of death among women in the United States. Previous studies demonstrate a higher prevalence of cancer among female orthopaedic surgeons. This study aimed to provide an updated prevalence of breast and all-cause cancer among female orthopaedic surgeons using a larger and more current study population.MethodsWe distributed surveys to female orthopaedic surgeons in national orthopaedic specialty societies. Six hundred seventy-two survey responses were collected. We calculated standardized prevalence ratios (SPRs) and 95% confidence intervals (CIs) based on gender-specific, race-specific, and age-specific cancer prevalence statistics in the US population. We compared the distribution of breast cancer risk factors with that of women in the 2018 and 2009 California Health Interview Survey.ResultsFifty-one of the 672 surveyed surgeons reported a diagnosis of invasive cancer. Twenty reported breast cancer with a prevalence higher among female orthopaedic surgeons compared with the US female population (SPR: 2.89, 95% CI: 2.16 to 3.81, P < 0.001). The breast cancer prevalence was also higher among orthopaedic surgeons compared with the US female population (SPR: 3.97, 95% CI: 2.43 to 6.14, P = 0.003).DiscussionThe increased prevalence of breast and all-cause cancer among a larger and more diverse cohort of female orthopaedic surgeons confirms previous studies and provides an update regarding a concerning public health issue within this specialty.

Despite decades of policy that strives to reduce nutrient and sediment export from agricultural fields, surface water quality in intensively managed agricultural landscapes remains highly degraded. Recent analyses show that current conservation efforts are not sufficient to reverse widespread water degradation in Midwestern agricultural systems. Intensifying row crop agriculture and increasing climate pressure require a more integrated approach to water quality management that addresses diverse sources of nutrients and sediment and off-field mitigation actions. We used multiobjective optimization analysis and integrated three biophysical models to evaluate the cost-effectiveness of alternative portfolios of watershed management practices at achieving nitrate and suspended sediment reduction goals in an agricultural basin of the Upper Midwestern United States. Integrating watershed-scale models enabled the inclusion of near-channel management alongside more typical field management and thus directly the comparison of cost-effectiveness across portfolios. The optimization analysis revealed that fluvial wetlands (i.e., wide, slow-flowing, vegetated water bodies within the riverine corridor) are the single-most cost-effective management action to reduce both nitrate and sediment loads and will be essential for meeting moderate to aggressive water quality targets. Although highly cost-effective, wetland construction was costly compared to other practices, and it was not selected in portfolios at low investment levels. Wetland performance was sensitive to placement, emphasizing the importance of watershed scale planning to realize potential benefits of wetland restorations. We conclude that extensive interagency cooperation and coordination at a watershed scale is required to achieve substantial, economically viable improvements in water quality under intensive row crop agricultural production.

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Repetitive elements (REs) compose ∼50% of the human genome and are normally transcriptionally silenced, although the mechanism has remained elusive. Through an RNAi screen, we identified FBXO44 as an essential repressor of REs in cancer cells. FBXO44 bound H3K9me3-modified nucleosomes at the replication fork and recruited SUV39H1, CRL4, and Mi-2/NuRD to transcriptionally silence REs post-DNA replication. FBXO44/SUV39H1 inhibition reactivated REs, leading to DNA replication stress and stimulation of MAVS/STING antiviral pathways and interferon (IFN) signaling in cancer cells to promote decreased tumorigenicity, increased immunogenicity, and enhanced immunotherapy response. FBXO44 expression inversely correlated with replication stress, antiviral pathways, IFN signaling, and cytotoxic T cell infiltration in human cancers, while a FBXO44-immune gene signature correlated with improved immunotherapy response in cancer patients. FBXO44/SUV39H1 were dispensable in normal cells. Collectively, FBXO44/SUV39H1 are crucial repressors of RE transcription, and their inhibition selectively induces DNA replication stress and viral mimicry in cancer cells.

Introduction: Pediatric hospital care is becoming increasingly regionalized, with fewer facilities providing inpatient care for common conditions such as asthma. That trend has major implications for emergency medical services (EMS) medical care and operations because EMS historically transports patients to the closest facility. This study describes EMS transport patterns of pediatric asthma patients in greater depth, including an analysis of facility bypass rates and the association of bypass with demographics and clinical outcomes. Methods: This was a retrospective study of pediatric asthma patients ages 2-18 years transported by  Lee County, FL EMS between March 1, 2018 – December 31, 2019. A priori, we defined bypass as greater than five minutes extra transport time. We performed geospatial analysis and mapping of EMS pediatric asthma encounters. We used the Pediatric Destination Tree (PDTree) project’s tiered approach to characterize receiving hospital facility pediatric capability. We analyzed incidence and characteristics of bypass, and bypass and non-bypass patient characteristics including demographics, emergency department (ED) clinical outcomes, and socioeconomic disadvantage (SED).  Results: From the study period, there were a total of 262 encounters meeting inclusion criteria, 254 (96.9%) of which could be geocoded to EMS incident and destination locations. Most encounters (72.8%) bypassed at least one facility, and the average number of facilities bypassed per encounter was 1.52. For all 185 bypass encounters, there was a median additional travel time of 13.5 minutes (interquartile range 7.5 – 17.5). Using the PDTree’s classification of pediatric capability of destination facilities, 172 of the 185 bypasses (93%) went to a Level I facility. Bypass incidence varied significantly by age, but not by minority status, asthma severity, or by the area deprivation index of the patient’s home address. Overall, the highest concentrations of EMS incidents tended to occur in areas of greater SED. With regard to ED outcomes, ED length of stay did not vary between bypass and non-bypass patients (P = 0.54), and neither did hospitalization (P = 0.80). Conclusion: We found high rates of bypass for pediatric EMS encounters for asthma exacerbations, and that bypass frequency was significantly higher in younger age groups. With national trends pointing toward increasing pediatric healthcare regionalization, bypass has significant implications for EMS operations.

Medulloblastoma is among the most common malignant brain tumors in children. Recent studies have identified at least four subgroups of the disease that differ in terms of molecular characteristics and patient outcomes. Despite this heterogeneity, most patients with medulloblastoma receive similar therapies, including surgery, radiation, and intensive chemotherapy. Although these treatments prolong survival, many patients still die from the disease and survivors suffer severe long-term side effects from therapy. We hypothesize that each patient with medulloblastoma is sensitive to different therapies and that tailoring therapy based on the molecular and cellular characteristics of patients' tumors will improve outcomes. To test this, we assembled a panel of orthotopic patient-derived xenografts (PDX) and subjected them to DNA sequencing, gene expression profiling, and high-throughput drug screening. Analysis of DNA sequencing revealed that most medulloblastomas do not have actionable mutations that point to effective therapies. In contrast, gene expression and drug response data provided valuable information about potential therapies for every tumor. For example, drug screening demonstrated that actinomycin D, which is used for treatment of sarcoma but rarely for medulloblastoma, was active against PDXs representing Group 3 medulloblastoma, the most aggressive form of the disease. Functional analysis of tumor cells was successfully used in a clinical setting to identify more treatment options than sequencing alone. These studies suggest that it should be possible to move away from a one-size-fits-all approach and begin to treat each patient with therapies that are effective against their specific tumor. SIGNIFICANCE: These findings show that high-throughput drug screening identifies therapies for medulloblastoma that cannot be predicted by genomic or transcriptomic analysis.

Background  Recent advances in the understanding of ulnar-sided wrist pathologies such as ulnar abutment syndrome (UAS) have brought increased attention to the anatomy of the distal radioulnar joint (DRUJ). Previous work established three anatomical variants of the sigmoid notch (parallel, oblique, and reverse oblique). The reverse oblique DRUJ poses theoretical risk of increased contact forces following ulnar shortening osteotomy, a common method of treating UAS. Purpose  As prevalence of reverse oblique morphology has been under-reported, this study aims to better define the prevalence of reverse oblique morphology in the adult population. Methods  Institutional Review Board-approved review of 1,000 radiographs over a 2-year period was performed. Demographic data and radiographic measurements were recorded (ulnar variance, notch inclination, and presence of arthritis). Correlation tests, a test of proportions, a t -test, and linear and logic regression tests were used to examine associations between ulnar variance, sigmoid inclination, sex, age, and presence of arthritis. Results  One thousand radiographs were analyzed revealing prevalence rates of: parallel-68%, oblique-26%, and reverse oblique-6%. Females were significantly more likely to have reverse inclination. No significant correlation was noted for morphology by age. Ulna positive variance was negatively correlated with reverse inclination. DRUJ arthritis was noted in 14% of patients. Higher sigmoid inclination was associated with higher odds of presence of arthritis, adjusting for sex and age. Higher incidence of arthritis was noted among patients with the oblique (20.8%) or reverse oblique (24.6%) compared with parallel (10.5%) morphology. Conclusion  This series of 1,000 radiographs demonstrates a 6% overall prevalence of reverse obliquity. This large dataset allows for better quantification of the prevalence of DRUJ morphologies and determination of correlations that have clinical implications for patients with ulnar-sided wrist pathology. Level of Evidence  This is a Level IV study.

BackgroundInitiating screening at an earlier age based on cancer family history is one of the primary recommended strategies for the prevention and detection of early-onset colorectal cancer (EOCRC), but data supporting the effectiveness of this approach are limited. The authors assessed the performance of family history-based guidelines for identifying individuals with EOCRC.MethodsThe authors conducted a population-based, case-control study of individuals aged 40 to 49 years with (2473 individuals) and without (772 individuals) incident CRC in the Colon Cancer Family Registry from 1998 through 2007. They estimated the sensitivity and specificity of family history-based criteria jointly recommended by the American Cancer Society, the US Multi-Society Task Force on CRC, and the American College of Radiology in 2008 for early screening, and the age at which each participant could have been recommended screening initiation if these criteria had been applied.ResultsFamily history-based early screening criteria were met by approximately 25% of cases (614 of 2473 cases) and 10% of controls (74 of 772 controls), with a sensitivity of 25% and a specificity of 90% for identifying EOCRC cases aged 40 to 49 years. Among 614 individuals meeting early screening criteria, 98.4% could have been recommended screening initiation at an age younger than the observed age of diagnosis.ConclusionsOf CRC cases aged 40 to 49 years, 1 in 4 met family history-based early screening criteria, and nearly all cases who met these criteria could have had CRC diagnosed earlier (or possibly even prevented) if earlier screening had been implemented as per family history-based guidelines. Additional strategies are needed to improve the detection and prevention of EOCRC for individuals not meeting family history criteria for early screening.

Tuberculosis caused by concurrent infection with multiple Mycobacterium tuberculosis strains (i.e., mixed infection) challenges clinical and epidemiologic paradigms. We explored possible transmission mechanisms of mixed infection in a population-based, molecular epidemiology study in Botswana during 2012-2016. We defined mixed infection as multiple repeats of alleles at >2 loci within a discrete mycobacterial interspersed repetitive unit-variable-number tandem-repeat (MIRU-VNTR) result. We compared mixed infection MIRU-VNTR results with all study MIRU-VNTR results by considering all permutations at each multiple allele locus; matched MIRU-VNTR results were considered evidence of recently acquired strains and nonmatched to any other results were considered evidence of remotely acquired strains. Among 2,051 patients, 34 (1.7%) had mixed infection, of which 23 (68%) had recently and remotely acquired strains. This finding might support the mixed infection mechanism of recent transmission and simultaneous remote reactivation. Further exploration is needed to determine proportions of transmission mechanisms in settings where mixed infections are prevalent.

Tuberculosis caused by concurrent infection with multiple Mycobacterium tuberculosis strains (i.e., mixed infection) challenges clinical and epidemiologic paradigms. We explored possible transmission mechanisms of mixed infection in a population-based, molecular epidemiology study in Botswana during 2012-2016. We defined mixed infection as multiple repeats of alleles at >2 loci within a discrete mycobacterial interspersed repetitive unit-variable-number tandem-repeat (MIRU-VNTR) result. We compared mixed infection MIRU-VNTR results with all study MIRU-VNTR results by considering all permutations at each multiple allele locus; matched MIRU-VNTR results were considered evidence of recently acquired strains and nonmatched to any other results were considered evidence of remotely acquired strains. Among 2,051 patients, 34 (1.7%) had mixed infection, of which 23 (68%) had recently and remotely acquired strains. This finding might support the mixed infection mechanism of recent transmission and simultaneous remote reactivation. Further exploration is needed to determine proportions of transmission mechanisms in settings where mixed infections are prevalent.

Tuberculosis caused by concurrent infection with multiple Mycobacterium tuberculosis strains (i.e., mixed infection) challenges clinical and epidemiologic paradigms. We explored possible transmission mechanisms of mixed infection in a population-based, molecular epidemiology study in Botswana during 2012-2016. We defined mixed infection as multiple repeats of alleles at >2 loci within a discrete mycobacterial interspersed repetitive unit-variable-number tandem-repeat (MIRU-VNTR) result. We compared mixed infection MIRU-VNTR results with all study MIRU-VNTR results by considering all permutations at each multiple allele locus; matched MIRU-VNTR results were considered evidence of recently acquired strains and nonmatched to any other results were considered evidence of remotely acquired strains. Among 2,051 patients, 34 (1.7%) had mixed infection, of which 23 (68%) had recently and remotely acquired strains. This finding might support the mixed infection mechanism of recent transmission and simultaneous remote reactivation. Further exploration is needed to determine proportions of transmission mechanisms in settings where mixed infections are prevalent.

Many migratory species, from monarch butterflies to wildebeest, express partial migration, where only a subset of a population migrates. This intraspecific variation is likely to have large ecological consequences. We studied the ecological consequences of partial migration in a salmonid fish, Oncorhynchus mykiss , in coastal streams in California, USA. One ecotype, steelhead trout, migrates to the ocean, whereas the other, rainbow trout, completes its lifecycle in freshwater. Migration has a strong genetic basis in O. mykiss . In one stream, we found differences in the frequency of migration‐linked genotypes below and above a waterfall barrier (migratory allele frequency of 60% below vs. 31% above). Below the waterfall, in the migratory‐dominated region, the density of young fish (1 yr old) in pools downstream of the waterfall (0.05 vs. 0.13 individuals/m2). In a second stream, between‐year variation in the dominance of migratory vs. resident fish allowed us to explore differences in fish density and size structure through time, and we found a consistent pattern. In brief, when migratory genotypes dominated, we found higher densities of young fish and lower densities of older fish, resulting in a simpler size structure, compared to when resident genotypes dominated. Moreover, large resident trout had a slightly higher trophic position than young fish (3.92 vs. 3.42 in one creek and 3.77 vs. 3.17 in the other), quantified with stable isotope data. The difference in fish size structure did not generate trophic cascades. Partial migration is widespread among migratory populations, as is phenotypic divergence between resident and migratory forms, suggesting the potential for widespread ecological effects arising from this common form of intraspecific variation.

BackgroundIn the criminal justice system, special populations, such as older adults or patients with infectious diseases, have been identified as particularly vulnerable to poor health outcomes. Military veterans involved in the criminal justice system are also a vulnerable population warranting attention because of their unique healthcare needs. This review aims to provide an overview of existing literature on justice-involved veterans' health and healthcare to identify research gaps and inform policy and practice.MethodsA systematic search was conducted to identify research articles related to justice-involved veterans' health and healthcare that were published prior to December 2017. Study characteristics including healthcare category, study design, sample size, and funding source were extracted and summarized with the aim of providing an overview of extant literature.ResultsThe search strategy initially identified 1830 unique abstracts with 1387 abstracts then excluded. Full-text review of 443 articles was conducted with 252 excluded. There were 191 articles included, most related to veterans' mental health (130/191, 68%) or homelessness (24/191, 13%). Most studies used an observational design (173/191, 91%).ConclusionsKnowledge gaps identified from the review provide guidance on future areas of research. Studies on different sociodemographic groups, medical conditions, and the management of multiple conditions and psychosocial challenges are needed. Developing and testing interventions, especially randomized trials, to address justice-involved veterans care needs will help to improve their health and healthcare. Finally, an integrated conceptual framework that draws from diverse disciplines, such as criminology, health services, psychology, and implementation science is needed to inform research, policy and practice focused on justice-involved veterans.

In unassuming neighborhood locales, such as coffee shops, hair salons, and malls, people meet to socialize, express themselves, and support one another. These 'third places' enrich social interaction, sense of community, and belonging outside of the home and workplace. Yet third places are closing across the United States. Americans may be losing access to key services, goods, and amenities, in addition to community sites that help buffer against loneliness, stress, and alienation. The relevance of third places to health and quality life is under-researched. These sites may support wellbeing through mechanisms of stimulation, support, protection, and care. We call on researchers to investigate how third places contribute to wellbeing and consider the consequences that the disappearance of such places has for public health. Future research on third places may be mobilized to innovatively reduce health disparities and improve quality of life.

Cross-boundary transfers of nutrients can profoundly shape the ecology of recipient systems. The common hippopotamus, Hippopotamus amphibius, is a significant vector of such subsidies from terrestrial to river ecosystems. We compared river pools with high and low densities of H. amphibius to determine how H. amphibius subsidies shape the chemistry and ecology of aquatic communities. Our study watershed, like many in sub-Saharan Africa, has been severely impacted by anthropogenic water abstraction reducing dry-season flow to zero. We conducted observations for multiple years over wet and dry seasons to identify how hydrological variability influences the impacts of H. amphibius During the wet season, when the river was flowing, we detected no differences in water chemistry and nutrient parameters between pools with high and low densities of H. amphibius Likewise, the diversity and abundance of fish and aquatic insect communities were indistinguishable. During the dry season, however, high-density H. amphibius pools differed drastically in almost all measured attributes of water chemistry and exhibited depressed fish and insect diversity and fish abundance compared with low-density H. amphibius pools. Scaled up to the entire watershed, we estimate that H. amphibius in this hydrologically altered watershed reduces dry-season fish abundance and indices of gamma-level diversity by 41% and 16%, respectively, but appears to promote aquatic invertebrate diversity. Widespread human-driven shifts in hydrology appear to redefine the role of H. amphibius, altering their influence on ecosystem diversity and functioning in a fashion that may be more severe than presently appreciated.

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Eukaryotic microbes have three primary mechanisms for obtaining nutrients and energy: phagotrophy, photosynthesis and osmotrophy. Traits associated with the latter two functions arose independently multiple times in the eukaryotes. The Fungi successfully coupled osmotrophy with filamentous growth, and similar traits are also manifested in the Pseudofungi (oomycetes and hyphochytriomycetes). Both the Fungi and the Pseudofungi encompass a diversity of plant and animal parasites. Genome-sequencing efforts have focused on host-associated microbes (mutualistic symbionts or parasites), providing limited comparisons with free-living relatives. Here we report the first draft genome sequence of a hyphochytriomycete 'pseudofungus'; Hyphochytrium catenoides Using phylogenomic approaches, we identify genes of recent viral ancestry, with related viral derived genes also present on the genomes of oomycetes, suggesting a complex history of viral coevolution and integration across the Pseudofungi. H. catenoides has a complex life cycle involving diverse filamentous structures and a flagellated zoospore with a single anterior tinselate flagellum. We use genome comparisons, drug sensitivity analysis and high-throughput culture arrays to investigate the ancestry of oomycete/pseudofungal characteristics, demonstrating that many of the genetic features associated with parasitic traits evolved specifically within the oomycete radiation. Comparative genomics also identified differences in the repertoire of genes associated with filamentous growth between the Fungi and the Pseudofungi, including differences in vesicle trafficking systems, cell-wall synthesis pathways and motor protein repertoire, demonstrating that unique cellular systems underpinned the convergent evolution of filamentous osmotrophic growth in these two eukaryotic groups.

Eukaryotic microbes have three primary mechanisms for obtaining nutrients and energy: phagotrophy, photosynthesis and osmotrophy. Traits associated with the latter two functions arose independently multiple times in the eukaryotes. The Fungi successfully coupled osmotrophy with filamentous growth, and similar traits are also manifested in the Pseudofungi (oomycetes and hyphochytriomycetes). Both the Fungi and the Pseudofungi encompass a diversity of plant and animal parasites. Genome-sequencing efforts have focused on host-associated microbes (mutualistic symbionts or parasites), providing limited comparisons with free-living relatives. Here we report the first draft genome sequence of a hyphochytriomycete 'pseudofungus'; Hyphochytrium catenoides Using phylogenomic approaches, we identify genes of recent viral ancestry, with related viral derived genes also present on the genomes of oomycetes, suggesting a complex history of viral coevolution and integration across the Pseudofungi. H. catenoides has a complex life cycle involving diverse filamentous structures and a flagellated zoospore with a single anterior tinselate flagellum. We use genome comparisons, drug sensitivity analysis and high-throughput culture arrays to investigate the ancestry of oomycete/pseudofungal characteristics, demonstrating that many of the genetic features associated with parasitic traits evolved specifically within the oomycete radiation. Comparative genomics also identified differences in the repertoire of genes associated with filamentous growth between the Fungi and the Pseudofungi, including differences in vesicle trafficking systems, cell-wall synthesis pathways and motor protein repertoire, demonstrating that unique cellular systems underpinned the convergent evolution of filamentous osmotrophic growth in these two eukaryotic groups.

Epithelial ovarian cancer (EOC) is the most deadly gynecologic malignancy on account of its late stage at diagnosis and frequency of drug resistant recurrences. Novel therapies to overcome these barriers are urgently needed. TWIST is a developmental transcription factor reactivated in cancers and linked to angiogenesis, metastasis, cancer stem cell phenotype, and drug resistance, making it a promising therapeutic target. In this work, we demonstrate the efficacy of TWIST siRNA (siTWIST) and two nanoparticle delivery platforms to reverse chemoresistance in EOC models. Polyamidoamine dendrimers and mesoporous silica nanoparticles (MSNs) carried siTWIST into target cells and led to sustained TWIST knockdown in vitro. Mice treated with cisplatin plus MSN-siTWIST exhibited lower tumor burden than mice treated with cisplatin alone, with most of the effect coming from reduction in disseminated tumors. This platform has potential application for overcoming the clinical challenges of metastasis and chemoresistance in EOC and other TWIST overexpressing cancers.

The realization that an intricate link exists between the metabolic state of immune cells and the nature of the elicited immune responses has brought a dramatic evolution to the field of immunology. We will focus on how metabolic reprogramming through the use of glycolysis and fatty-acid oxidation (sugar or fat) regulates the capacity of immune cells to mount robust and effective immune responses. We will also discuss how fine-tuning sugar and fat metabolism may be exploited as a novel immunotherapeutic strategy to fight viral infections or improve vaccine efficacy.

The realization that an intricate link exists between the metabolic state of immune cells and the nature of the elicited immune responses has brought a dramatic evolution to the field of immunology. We will focus on how metabolic reprogramming through the use of glycolysis and fatty-acid oxidation (sugar or fat) regulates the capacity of immune cells to mount robust and effective immune responses. We will also discuss how fine-tuning sugar and fat metabolism may be exploited as a novel immunotherapeutic strategy to fight viral infections or improve vaccine efficacy.

Management of patients with central nervous system tumors relies largely on magnetic resonance imaging scans to document disease progression or recurrence. The finding of new lesions always presents the challenge of differentiating between post-surgical changes, radiation necrosis, gliosis, and tumor, submitting these patients to more aggressive therapy and more toxicity. We reviewed the medical records of three patients with primary central nervous system tumors treated at the Children’s Hospital Los Angeles who had new false-positive magnetic resonance imaging findings suggestive of tumor recurrence. All of them had complete total resection of primary tumor, had received involved-field radiation therapy, had biopsies confirming absence of viable tumor, and all three patients are long-term survivors. These cases exemplify that not everything that enhances on brain or spine magnetic resonance imaging is viable tumor, and a biopsy should always be considered in the decision-making process in evaluation of potentially recurrent central nervous system tumors in pediatric patients. A step-wise approach for such challenging cases is presented in this article.

BackgroundChildhood brain tumor survivors (CBTS) often experience treatment-related neurocognitive deficits affecting quality of life (QOL), but systemic chemotherapy contributions to outcomes are unclear. Our objective was to relate brain tissue changes to neurocognitive and QOL effects after systemic myeloablative chemotherapy with autologous hematopoietic progenitor cell rescue in CBTS.ProcedureRegional brain volumes and diffusion tensor indices were correlated with neurocognitive, behavioral, and QOL measures, and compared between 8 CBTS (mean age 8.5 years, mean age at diagnosis 32 months), and 9 healthy controls (mean 9.3 years).ResultsOverall QOL, school, and psychosocial functioning were significantly lower in patients (P < .05). Most patients scored within normative ranges on neurocognitive and behavioral assessment. Elevated mean diffusivity and decreased fractional anisotropy, indicating gray and white matter injury, respectively, appeared in memory and executive functioning areas. Low scores on Inhibition on the Neuropsychological Assessment-II were correlated with elevated mean diffusivity in prefrontal cortex.ConclusionsBrain injury, decreased QOL, and to a lesser extent, executive functioning deficits appear in CBTS treated with myeloablative chemotherapy and autologous hematopoietic progenitor cell rescue. Early cognitive and psychological assessment and intervention are warranted in this population.

BackgroundMaternal mortality remains the leading cause of death and disability for reproductive-age women in resource-poor countries. The impact of a mother's death on child outcomes is likely severe but has not been well quantified. This analysis examines survival outcomes for children whose mothers die during or shortly after childbirth in Butajira, Ethiopia.MethodsThis study uses data from the Butajira Health and Demographic Surveillance System (HDSS) site. Child outcomes were assessed using statistical tests to compare survival trajectories and age-specific mortality rates for children who did and did not experience a maternal death. The analyses leveraged the advantages of a large, long-term longitudinal dataset with a high frequency of data collection; but used a strict date-based method to code maternal deaths (as occurring within 42 or 365 days of childbirth), which may be subject to misclassification or recall bias.ResultsBetween 1987 and 2011, there were 18189 live births to 5119 mothers; and 73 mothers of 78 children died within the first year of their child's life, with 45% of these (n=30) classified as maternal deaths due to women dying within 42 days of childbirth. Among the maternal deaths, 81% of these infants also died. Children who experienced a maternal death within 42 days of their birth faced 46 times greater risk of dying within one month when compared to babies whose mothers survived (95% confidence interval 25.84-81.92; or adjusted ratio, 57.24 with confidence interval 25.31-129.49).ConclusionsWhen a woman in this study population experienced a maternal death, her infant was much more likely to die than to survive--and the survival trajectory of these children is far worse than those of mothers who do not die postpartum. This highlights the importance of investigating how clinical care and socio-economic support programs can better address the needs of orphans, both throughout the intra- and post-partum periods as well as over the life course.

Growth and progression of solid tumors depend on the integration of multiple pro-growth and survival signals, including the induction of angiogenesis. TWIST1 is a transcription factor whose reactivation in tumors leads to epithelial to mesenchymal transition (EMT), including increased cancer cell stemness, survival, and invasiveness. Additionally, TWIST1 drives angiogenesis via activation of IL-8 and CCL2, independent of VEGF signaling. In this work, results suggest that chemically modified siRNA against TWIST1 reverses EMT both in vitro and in vivo. siRNA delivery with a polyethyleneimine-coated mesoporous silica nanoparticle (MSN) led to reduction of TWIST1 target genes and migratory potential in vitro. In mice bearing xenograft tumors, weekly intravenous injections of the siRNA-nanoparticle complexes resulted in decreased tumor burden together with a loss of CCL2 suggesting a possible anti-angiogenic response. Therapeutic use of TWIST1 siRNA delivered via MSNs has the potential to inhibit tumor growth and progression in many solid tumor types.From the clinical editorTumor progression and metastasis eventually lead to patient mortality in the clinical setting. In other studies, it has been found that TWIST1, a transcription factor, if reactivated in tumors, would lead to downstream events including angiogenesis and result in poor prognosis in cancer patients. In this article, the authors were able to show that when siRNA against TWIST1 was delivered via mesoporous silica nanoparticle, there was tumor reduction in an in-vivo model. The results have opened up a new avenue for further research in this field.

Long-term culture and monitoring of individual multicellular spheroids and embryoid bodies (EBs) remains a challenge for in vitro cell propagation. Here, we used a continuous 3D projection printing approach - with an important modification of nonlinear exposure - to generate concave hydrogel microstructures that permit spheroid growth and long-term maintenance, without the need for spheroid transfer. Breast cancer spheroids grown to 10 d in the concave structures showed hypoxic cores and signs of necrosis using immunofluorescent and histochemical staining, key features of the tumor microenvironment in vivo. EBs consisting of induced pluripotent stem cells (iPSCs) grown on the hydrogels demonstrated narrow size distribution and undifferentiated markers at 3 d, followed by signs of differentiation by the presence of cavities and staining of the three germ layers at 10 d. These findings demonstrate a new method for long-term (e.g. beyond spheroid formation at day 2, and with media exchange) 3D cell culture that should be able to assist in cancer spheroid studies as well as embryogenesis and patient-derived disease modeling with iPSC EBs.

Long-term culture and monitoring of individual multicellular spheroids and embryoid bodies (EBs) remains a challenge for in vitro cell propagation. Here, we used a continuous 3D projection printing approach - with an important modification of nonlinear exposure - to generate concave hydrogel microstructures that permit spheroid growth and long-term maintenance, without the need for spheroid transfer. Breast cancer spheroids grown to 10 d in the concave structures showed hypoxic cores and signs of necrosis using immunofluorescent and histochemical staining, key features of the tumor microenvironment in vivo. EBs consisting of induced pluripotent stem cells (iPSCs) grown on the hydrogels demonstrated narrow size distribution and undifferentiated markers at 3 d, followed by signs of differentiation by the presence of cavities and staining of the three germ layers at 10 d. These findings demonstrate a new method for long-term (e.g. beyond spheroid formation at day 2, and with media exchange) 3D cell culture that should be able to assist in cancer spheroid studies as well as embryogenesis and patient-derived disease modeling with iPSC EBs.

BackgroundMaternal mortality remains the leading cause of death and disability for reproductive-age women in resource-poor countries. The impact of a mother's death on child outcomes is likely severe but has not been well quantified. This analysis examines survival outcomes for children whose mothers die during or shortly after childbirth in Butajira, Ethiopia.MethodsThis study uses data from the Butajira Health and Demographic Surveillance System (HDSS) site. Child outcomes were assessed using statistical tests to compare survival trajectories and age-specific mortality rates for children who did and did not experience a maternal death. The analyses leveraged the advantages of a large, long-term longitudinal dataset with a high frequency of data collection; but used a strict date-based method to code maternal deaths (as occurring within 42 or 365 days of childbirth), which may be subject to misclassification or recall bias.ResultsBetween 1987 and 2011, there were 18189 live births to 5119 mothers; and 73 mothers of 78 children died within the first year of their child's life, with 45% of these (n=30) classified as maternal deaths due to women dying within 42 days of childbirth. Among the maternal deaths, 81% of these infants also died. Children who experienced a maternal death within 42 days of their birth faced 46 times greater risk of dying within one month when compared to babies whose mothers survived (95% confidence interval 25.84-81.92; or adjusted ratio, 57.24 with confidence interval 25.31-129.49).ConclusionsWhen a woman in this study population experienced a maternal death, her infant was much more likely to die than to survive--and the survival trajectory of these children is far worse than those of mothers who do not die postpartum. This highlights the importance of investigating how clinical care and socio-economic support programs can better address the needs of orphans, both throughout the intra- and post-partum periods as well as over the life course.

A key aim of systems biology is the reconstruction of molecular networks. We do not yet, however, have networks that integrate information from all datasets available for a particular clinical condition. This is in part due to the limited scalability, in terms of required computational time and power, of existing algorithms. Network reconstruction methods should also be scalable in the sense of allowing scientists from different backgrounds to efficiently integrate additional data. We present a network model of acute myeloid leukemia (AML). In the current version (AML 2.1), we have used gene expression data (both microarray and RNA-seq) from 5 different studies comprising a total of 771 AML samples and a protein-protein interactions dataset. Our scalable network reconstruction method is in part based on the well-known property of gene expression correlation among interacting molecules. The difficulty of distinguishing between direct and indirect interactions is addressed by optimizing the coefficient of variation of gene expression, using a validated gold-standard dataset of direct interactions. Computational time is much reduced compared to other network reconstruction methods. A key feature is the study of the reproducibility of interactions found in independent clinical datasets. An analysis of the most significant clusters, and of the network properties (intraset efficiency, degree, betweenness centrality, and PageRank) of common AML mutations demonstrated the biological significance of the network. A statistical analysis of the response of blast cells from 11 AML patients to a library of kinase inhibitors provided an experimental validation of the network. A combination of network and experimental data identified CDK1, CDK2, CDK4, and CDK6 and other kinases as potential therapeutic targets in AML.

A key aim of systems biology is the reconstruction of molecular networks. We do not yet, however, have networks that integrate information from all datasets available for a particular clinical condition. This is in part due to the limited scalability, in terms of required computational time and power, of existing algorithms. Network reconstruction methods should also be scalable in the sense of allowing scientists from different backgrounds to efficiently integrate additional data. We present a network model of acute myeloid leukemia (AML). In the current version (AML 2.1), we have used gene expression data (both microarray and RNA-seq) from 5 different studies comprising a total of 771 AML samples and a protein-protein interactions dataset. Our scalable network reconstruction method is in part based on the well-known property of gene expression correlation among interacting molecules. The difficulty of distinguishing between direct and indirect interactions is addressed by optimizing the coefficient of variation of gene expression, using a validated gold-standard dataset of direct interactions. Computational time is much reduced compared to other network reconstruction methods. A key feature is the study of the reproducibility of interactions found in independent clinical datasets. An analysis of the most significant clusters, and of the network properties (intraset efficiency, degree, betweenness centrality, and PageRank) of common AML mutations demonstrated the biological significance of the network. A statistical analysis of the response of blast cells from 11 AML patients to a library of kinase inhibitors provided an experimental validation of the network. A combination of network and experimental data identified CDK1, CDK2, CDK4, and CDK6 and other kinases as potential therapeutic targets in AML.

© 2015 McCauley et al. The common hippopotamus, Hippopotamus amphibius, transports millions of tons of organic matter annually from its terrestrial feeding grounds into aquatic habitats. We evaluated whether carbon stable isotopes (δ13C) can be used as tracers for determining whether H. amphibius-vectored allochthonous material is utilized by aquatic consumers. Two approaches were employed to make this determination: (1) lab-based feeding trials where omnivorous river fish were fed a H. amphibius dung diet and (2) field sampling of fish and aquatic insects in pools with and without H. amphibius. Lab trials revealed that fish fed exclusively H. amphibius dung exhibited significantly more positive δ13C values than fish not fed dung. Fish and aquatic insects sampled in a river pool used for decades by H. amphibius also exhibited more positive δ13C values at the end of the dry season than fish and insects sampled from an upstream H. amphibius-free reference pool. Fish sampled in these same pools at the end of the wet season (high flow) showed no significant differences in δ13C values, suggesting that higher flows reduced retention and use of H. amphibius subsidies. These data provide preliminary evidence that δ13C values may be useful, in certain contexts, for quantifying the importance H. amphibius organic matter.

Background: Bacterial virulence-associated type III secretion system (T3SS) assembly requires a dedicated enzyme to penetrate peptidoglycan (PG).Results: We structurally characterized a T3SS PG-lytic enzyme, identified catalytically important residues, and characterized its activity.Conclusion: The active site is similar to lysozymes and lytic transglycosylases and interaction with the T3SS enhances activity.Significance: Structural information is critical for development of drugs targeting T3SS PG-lytic enzymes.The Gram-negative bacterium enteropathogenic Escherichia coli uses a syringe-like type III secretion system (T3SS) to inject virulence or “effector” proteins into the cytoplasm of host intestinal epithelial cells. To assemble, the T3SS must traverse both bacterial membranes, as well as the peptidoglycan layer. Peptidoglycan is made of repeating N-acetylmuramic acid and N-acetylglucosamine disaccharides cross-linked by pentapeptides to form a tight mesh barrier. Assembly of many macromolecular machines requires a dedicated peptidoglycan lytic enzyme (PG-lytic enzyme) to locally clear peptidoglycan. Here we have solved the first structure of a T3SS-associated PG-lytic enzyme, EtgA from enteropathogenic E. coli. Unexpectedly, the active site of EtgA has features in common with both lytic transglycosylases and hen egg white lysozyme. Most notably, the β-hairpin region resembles that of lysozyme and contains an aspartate that aligns with lysozyme Asp-52 (a residue critical for catalysis), a conservation not observed in other previously characterized lytic transglycosylase families to which the conserved T3SS enzymes had been presumed to belong. Mutation of the EtgA catalytic glutamate, Glu-42, conserved across lytic transglycosylases and hen egg white lysozyme, and this differentiating aspartate diminishes type III secretion in vivo, supporting its essential role in clearing the peptidoglycan for T3SS assembly. Finally, we show that EtgA forms a 1:1 complex with the building block of the polymerized T3SS inner rod component, EscI, and that this interaction enhances PG-lytic activity of EtgA in vitro, collectively providing the necessary strict localization and regulation of the lytic activity to prevent overall cell lysis.

Children with high-grade glioma (HGG) have a poor prognosis compared to those with low-grade glioma (LGG). Adjuvant chemotherapy may be beneficial, but its optimal use remains undetermined. Histology and extent of resection are important prognostic factors. We tested the hypothesis that patients with midline HGG treated on Children's Cancer Group Study (CCG) CCG-945 have a worse prognosis compared to the entire group. Of 172 children eligible for analysis, 60 had midline tumors primarily localized to the thalamus, hypothalamus and basal ganglia. Time-to-progression and death were determined from the date of initial diagnosis, and survival curves were calculated. Univariate analyses were undertaken for extent of resection, chemotherapy regimen, anatomic location, histology, proliferation index, MGMT status and p53 over-expression. For the entire midline tumor group, 5-year PFS and OS were 18.3 ± 4.8 and 25 ± 5.4 %, respectively. Many patients only had a biopsy (43.3 %). The sub-groups with near/total resection and hypothalamic location appeared to have better PFS and OS. However, the effect of tumor histology on OS was significant for children with discordant diagnoses on central pathology review of LGG compared to HGG. Proliferative index (MIB-1 > 36 %), MGMT and p53 over-expression correlated with poor outcomes. Children treated on CCG-945 with midline HGG have a worse prognosis when compared to the entire group. The midline location may directly influence the extent of resection. Central pathology review and entry of patients on clinical trials continue to be priorities to improve outcomes for children with HGG.

Young children with brain tumors are often treated with high-dose chemotherapy after surgery to avoid brain tissue injury associated with irradiation. The effects of systemic chemotherapy on healthy brain tissue in this population, however, are unclear. Our objective was to compare gray and white matter integrity using MRI procedures in children with brain tumors (n = 7, mean age 8.3 years), treated with surgery and high-dose chemotherapy followed by autologous hematopoietic cell rescue (AuHCR) an average of 5.4 years earlier, to age- and gender-matched healthy controls (n = 9, mean age 9.3 years). Diffusion tensor imaging data were collected to evaluate tissue integrity throughout the brain, as measured by mean diffusivity (MD), a marker of glial, neuronal, and axonal status, and fractional anisotropy (FA), an index of axonal health. Individual MD and FA maps were calculated, normalized, smoothed, and compared between groups using analysis of covariance, with age and sex as covariates. Higher MD values, indicative of injury, emerged in patients compared with controls (p < .05, corrected for multiple comparisons), and were especially apparent in the central thalamus, external capsule, putamen, globus pallidus and pons. Reduced FA values in some regions did not reach significance after correction for multiple comparisons. Children treated with surgery and high-dose chemotherapy with AuHCR for brain tumors an average of 5.4 years earlier show alterations in white and gray matter in multiple brain areas distant from the tumor site, raising the possibility for long-term consequences of the tumor or treatment.

Efforts to understand nervous system structure and function have received new impetus from the federal Brain Research through Advancing Innovative Neurotechnologies (BRAIN) Initiative. Comparative analyses can contribute to this effort by leading to the discovery of general principles of neural circuit design, information processing, and gene-structure-function relationships that are not apparent from studies on single species. We here propose to extend the comparative approach to nervous system 'maps' comprising molecular, anatomical, and physiological data. This research will identify which neural features are likely to generalize across species, and which are unlikely to be broadly conserved. It will also suggest causal relationships between genes, development, adult anatomy, physiology, and, ultimately, behavior. These causal hypotheses can then be tested experimentally. Finally, insights from comparative research can inspire and guide technological development. To promote this research agenda, we recommend that teams of investigators coalesce around specific research questions and select a set of 'reference species' to anchor their comparative analyses. These reference species should be chosen not just for practical advantages, but also with regard for their phylogenetic position, behavioral repertoire, well-annotated genome, or other strategic reasons. We envision that the nervous systems of these reference species will be mapped in more detail than those of other species. The collected data may range from the molecular to the behavioral, depending on the research question. To integrate across levels of analysis and across species, standards for data collection, annotation, archiving, and distribution must be developed and respected. To that end, it will help to form networks or consortia of researchers and centers for science, technology, and education that focus on organized data collection, distribution, and training. These activities could be supported, at least in part, through existing mechanisms at NSF, NIH, and other agencies. It will also be important to develop new integrated software and database systems for cross-species data analyses. Multidisciplinary efforts to develop such analytical tools should be supported financially. Finally, training opportunities should be created to stimulate multidisciplinary, integrative research into brain structure, function, and evolution.

Abstract Background Metastasis is the primary cause of death for cancer patients. TWIST1, an evolutionarily conserved basic helix-loop-helix (bHLH) transcription factor, is a strong promoter of metastatic spread and its expression is elevated in many advanced human carcinomas. However, the molecular events triggered by TWIST1 to motivate dissemination of cancer cells are largely unknown. Results Here we show that TWIST1 induces the production of interleukin 8 (IL8), which activates matrix metalloproteinases and promotes invasion of breast epithelial and cancer cells. In this novel mechanism, TWIST1-mediated IL8 transcription is induced through the TWIST1 carboxy-terminal WR (Trp-Arg) domain instead of the classic DNA binding bHLH domain. Co-immunoprecipitation analyses revealed that the WR domain mediates the formation of a protein complex comprised of TWIST1 and the nuclear factor-kappaB (NF-κB) subunit RELA (p65/NF-κB3), which synergistically activates the transcriptional activity of NF-κB. This activation leads to increased DNA binding affinity of RELA to the IL8 promoter and thus induces the expression of the cytokine. Blockage of IL8 signaling by IL8 neutralizing antibodies or receptor inhibition reduced the invasiveness of both breast epithelial and cancer cells, indicating that TWIST1 induces autonomous cell invasion by establishing an IL8 antocrine loop. Conclusions Our data demonstrate that the TWIST1 WR domain plays a critical role in TWIST1-induced IL8 expression through interactions with and activation of NF-κB. The produced IL8 signals through an autocrine loop and promotes extracellular matrix degradation to enable cell invasion across the basement membrane.

MR spectroscopy has demonstrated extrahippocampal NAA/(Cr+Cho) reductions in medial temporal lobe epilepsy with (TLE-MTS) and without (TLE-no) mesial temporal sclerosis. Because of the limited brain coverage of those previous studies, it was, however, not possible to assess differences in the distribution and extent of these abnormalities between TLE-MTS and TLE-no. This study used a 3D whole brain echoplanar spectroscopic imaging (EPSI) sequence to address the following questions: (1) Do TLE-MTS and TLE-no differ regarding severity and distribution of extrahippocampal NAA/(Cr+Cho) reductions? (2) Do extrahippocampal NAA/(Cr+Cho) reductions provide additional information for focus lateralization? Forty-three subjects (12 TLE-MTS, 13 TLE-no, 18 controls) were studied with 3D EPSI. Statistical parametric mapping (SPM2) was used to identify regions of significantly decreased NAA/(Cr+Cho) in TLE groups and in individual patients. TLE-MTS and TLE-no had widespread extrahippocampal NAA/(Cr+Cho) reductions. NAA/(Cr+Cho) reductions had a bilateral fronto-temporal distribution in TLE-MTS and a more diffuse, less well defined distribution in TLE-no. Extrahippocampal NAA/(Cr+Cho) decreases in the single subject analysis showed a large inter-individual variability and did not provide additional focus lateralizing information. Extrahippocampal NAA/(Cr+Cho) reductions in TLE-MTS and TLE-no are neither focal nor homogeneous. This reduces their value for focus lateralization and suggests a heterogeneous etiology of extrahippocampal spectroscopic metabolic abnormalities in TLE.

MR spectroscopy has demonstrated extrahippocampal NAA/(Cr+Cho) reductions in medial temporal lobe epilepsy with (TLE-MTS) and without (TLE-no) mesial temporal sclerosis. Because of the limited brain coverage of those previous studies, it was, however, not possible to assess differences in the distribution and extent of these abnormalities between TLE-MTS and TLE-no. This study used a 3D whole brain echoplanar spectroscopic imaging (EPSI) sequence to address the following questions: (1) Do TLE-MTS and TLE-no differ regarding severity and distribution of extrahippocampal NAA/(Cr+Cho) reductions? (2) Do extrahippocampal NAA/(Cr+Cho) reductions provide additional information for focus lateralization? Forty-three subjects (12 TLE-MTS, 13 TLE-no, 18 controls) were studied with 3D EPSI. Statistical parametric mapping (SPM2) was used to identify regions of significantly decreased NAA/(Cr+Cho) in TLE groups and in individual patients. TLE-MTS and TLE-no had widespread extrahippocampal NAA/(Cr+Cho) reductions. NAA/(Cr+Cho) reductions had a bilateral fronto-temporal distribution in TLE-MTS and a more diffuse, less well defined distribution in TLE-no. Extrahippocampal NAA/(Cr+Cho) decreases in the single subject analysis showed a large inter-individual variability and did not provide additional focus lateralizing information. Extrahippocampal NAA/(Cr+Cho) reductions in TLE-MTS and TLE-no are neither focal nor homogeneous. This reduces their value for focus lateralization and suggests a heterogeneous etiology of extrahippocampal spectroscopic metabolic abnormalities in TLE.

How well anthropometric indices such as body mass index (BMI), waist circumference, waist-stature ratio, and waist index correlate with direct measures of body composition (lean body mass, body fat) in men and women with chronic heart failure (CHF) has not been reported. Body composition was assessed by dual-energy x-ray absorptiometry in 140 patients with CHF. Age-adjusted Pearson correlations between each index and measures of body composition for men and women were calculated. Diagnostic accuracy of detecting obesity or high central fat was also examined. In men, all of the anthropometric indices except waist index were just as strongly correlated with lean body mass (correlation coefficients varied between 0.56 for waist-stature ratio to 0.74 for BMI) as with percentage of body fat (correlation coefficients varied between 0.72 for BMI to 0.79 for waist circumference). In women, all 4 anthropometric measures were unable to significantly differentiate between body fat and lean body mass. The positive likelihood ratios for the detection of obesity varied between 2.26 for waist circumference and 3.42 for BMI, waist-stature ratio, and waist index. Anthropometric indices do not accurately reflect body composition in patients with CHF, especially in women. When accurate assessment of body composition is required, direct measurements should be obtained.

How well anthropometric indices such as body mass index (BMI), waist circumference, waist-stature ratio, and waist index correlate with direct measures of body composition (lean body mass, body fat) in men and women with chronic heart failure (CHF) has not been reported. Body composition was assessed by dual-energy x-ray absorptiometry in 140 patients with CHF. Age-adjusted Pearson correlations between each index and measures of body composition for men and women were calculated. Diagnostic accuracy of detecting obesity or high central fat was also examined. In men, all of the anthropometric indices except waist index were just as strongly correlated with lean body mass (correlation coefficients varied between 0.56 for waist-stature ratio to 0.74 for BMI) as with percentage of body fat (correlation coefficients varied between 0.72 for BMI to 0.79 for waist circumference). In women, all 4 anthropometric measures were unable to significantly differentiate between body fat and lean body mass. The positive likelihood ratios for the detection of obesity varied between 2.26 for waist circumference and 3.42 for BMI, waist-stature ratio, and waist index. Anthropometric indices do not accurately reflect body composition in patients with CHF, especially in women. When accurate assessment of body composition is required, direct measurements should be obtained.

BackgroundWe examined the validity of leg-to-leg bioelectrical impedance analysis (BIA) and near-infrared interactance (NIR) to assess body composition in chronic heart failure (CHF) patients.Methods and resultsA total of 140 patients with CHF were enrolled in this cross-sectional study between June 2008 and July 2009. Dual energy x-ray absorptiometry (DEXA) served as the reference standard. A priori, desired precision levels were set at ± 3.5% body fat and ± 3.5 kg lean body mass. Mean age was 63, 74% were male, and 90% were Caucasian. BIA- and NIR-ascertained percent body fat and lean body mass were highly correlated to DEXA. Mean differences and limits of agreement for NIR were -0.3% ± 5.1% for percent body fat and 2.9 kg ± 4.3 kg for lean body mass. Mean difference and limits of agreement for BIA percent body fat was 0.8% ± 5.8%. BIA lean body mass showed poor agreement with DEXA because of variable limits of agreement across the range of measurement (Pitman's test P < .0001).ConclusionsIn patients with CHF, both NIR and BIA accurately measure body fat. However, both methods were imprecise. NIR overestimated lean body mass and BIA was not useful to assess this parameter. Further study is required, including examination of the utility of these field methods in serially assessing body composition.