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Key Points A dust devil frequency of occurrence of between 1.3 and 3.4 dust devils km−2 sol−1 was derived from MEDA-RDS observations for the first 365 sols, displaying the maximum activity at around noon and increasing as we move from spring into summer We find an average dust devil diameter of 29 m (or a median diameter of 25 m) and maximum and minimum diameters of 132 ± 63.4 m and 5.6 ± 5.5 m Dust devil migration directions are in agreement with the MEDA background wind direction measurements The Mars Environmental Dynamics Analyzer, onboard the Perseverance rover, is a meteorological station that is operating on Mars and includes, among other sensors, the radiometer Radiation and Dust Sensor (RDS). From RDS irradiance observations, a total of 374 dust devils (DDs) were detected for the first 365 sols of the mission (Ls = 6°–182°), which along with wind and pressure measurements, we estimated a DD frequency of formation at Jezero between 1.3 and 3.4 DD km−2 sol−1 (increasing as we move from spring into summer). This frequency is found to be smaller than that estimated at the Spirit or Pathfinder landing sites but much greater than that derived at InSight landing site. The maximum in DD frequency occurs between 12:00 and 13:00 local true solar time, which is when the convective heat flux and lower planetary boundary layer IR heating are both predicted to peak in Jezero crater. DD diameter, minimum height, and trajectory were studied showing (a) an average diameter of 29 m (or a median of 25 m) and a maximum and minimum diameter of 132 ± 63.4 and 5.6 ± 5.5 m; (b) an average minimum DD height of 231 m and a maximum minimum-height of 872 m; and (c) the DD migration direction is in agreement with wind measurements. For all the cases, DDs decreased the UV irradiance, while at visible or near-IR wavelengths both increases and decreases were observed. Contrary to the frequency of formation, these results indicate similar DD characteristics in average for the studied period. This work has been funded by the Spanish Ministry of Economy and Competitiveness, through the projects no. ESP2014-54256-C4-1-R (also -2-R, -3-R and -4-R); Ministry of Science, Innovation and Universities, projects no. ESP2016-79612-C3-1-R (also -2-R and -3-R); Ministry of Science and Innovation/State Agency of Research (10.13039/501100011033), projects no. ESP2016-80320-C2-1-R, RTI2018-098728-B-C31 (also -C32 and -C33), RTI2018-099825-B-C31. RH and ASL were supported by the Spanish project PID2019-109467GB-I00 funded by MCIN/AEI/10.13039/50110001103 and by Grupos Gobierno Vasco IT1742-22. The US co-authors performed their work under sponsorship from NASA’s Mars 2020 project, from the Game Changing Development programme within the Space Technology Mission Directorate and from the Human Exploration and Operations Directorate. Part of this research was carried out at the Jet Propulsion Laboratory, California Institute of Technology, under a contract with the National Aeronautics and Space Administration (80NM0018D0004). G.M. acknowledges JPL funding from USRA Contract Number 1638782. ML is supported by contract 15-712 from Arizona State University and 1607215 from Caltech-JPL. Peerreview

International audience; Two >130-meter-diameter impact craters formed on Mars during the later half of 2021. These are the two largest fresh impact craters discovered by the Mars Reconnaissance Orbiter since operations started 16 years ago. The impacts created two of the largest seismic events (magnitudes greater than 4) recorded by InSight during its 3-year mission. The combination of orbital imagery and seismic ground motion enables the investigation of subsurface and atmospheric energy partitioning of the impact process on a planet with a thin atmosphere and the first direct test of martian deep-interior seismic models with known event distances. The impact at 35°N excavated blocks of water ice, which is the lowest latitude at which ice has been directly observed on Mars.

Background Extracellular vesicles (EVs) are nano-sized particles secreted by most cells. EVs carry nucleic acids that hold promise as potential biomarkers in various diseases. Human immunodeficiency virus type 1 (HIV) infects CD4+ T cells and induces immune dysfunction, inflammation, and EV secretion, but little is known about EV small RNA cargo in relation to immune dysregulation in HIV-infected individuals. Here, we characterize small RNA carried by circulating EVs in HIV-positive subjects on antiretroviral therapy (ART) relative to uninfected controls by next-generation RNA sequencing. Results Plasma EVs isolated from HIV-positive and HIV-negative subjects in test (n = 24) and validation (n = 16) cohorts were characterized by electron microscopy, nanoparticle tracking analysis, and immunoblotting for exosome markers. EVs were more abundant in plasma from HIV-positive compared to HIV-negative subjects. Small RNA sequencing of plasma EVs in the test cohort identified diverse small RNA species including miRNA, piRNA, snRNA, snoRNA, tRNA, and rRNA, with miRNA being the most abundant. A total of 351 different miRNAs were detected in plasma EVs, with the top 50 miRNAs accounting for 90% of all miRNA reads. miR-26a-5p was the most abundant miRNA, followed by miR-21-5p and miR-148-3p. qRT-PCR analysis showed that six miRNAs (miR-10a-5p, − 21-5p, −27b-3p, − 122-5p, −146a-5p, − 423-5p) were significantly increased in plasma EVs from HIV-positive compared to HIV-negative subjects in the validation cohort. Furthermore, miR-21-5p, −27b-3p, −146a-5p, and − 423-5p correlated positively with metabolite markers of oxidative stress and negatively with anti-inflammatory polyunsaturated fatty acids. Over-representation and pathway enrichment analyses of miRNAs and their target genes predicted functional association with oxidative stress responses, interferon gamma signaling, Toll-like receptor signaling, TGF beta signaling, and Notch signaling. Conclusions HIV-positive individuals on ART have increased abundance of circulating EVs carrying diverse small RNAs, with miRNAs being the most abundant. Several miRNAs associated with inflammation and oxidative stress are increased in circulating EVs of HIV-positive individuals, representing potential biomarkers of targetable pathways that contribute to disease pathogenesis.

Summary Background Lung disease is a common comorbidity in people with HIV/AIDS, independent of smoking status. The effects of marijuana smoking on risk of lung disease in HIV-infected individuals are unclear. Methods In this prospective cohort study, we quantified lung disease risk among men enrolled in the Multicenter AIDS Cohort Study (MACS), a long-term observational cohort of HIV-infected and uninfected men who have sex with men. Eligible participants were aged ≥30 years with self-reported marijuana and tobacco smoking data from biannual study visits between 1996 and 2014. Pulmonary diagnoses were obtained from self-report and medical records. Analyses were performed using Cox models and Generalized Estimating Equations adjusted for tobacco smoking, CD4 T cell count, and other risk factors. Findings 1630 incident pulmonary diagnoses were reported among 1352 HIV-seropositive and 1352 HIV-seronegative eligible participants matched for race and baseline age (53,794 total person-visits, median follow-up 10.5 years). 27% of HIV-infected participants reported daily or weekly marijuana smoking for one or more years in follow-up, compared to 18% of uninfected participants (median 4·0 and 4·5 years daily/weekly use, respectively). HIV-infected participants had an increased likelihood of infectious or non-infectious pulmonary diagnoses compared to uninfected participants (33·2% vs. 21·5%, and 20·6% vs. 17·2%, respectively). Among HIV-infected participants, recent marijuana smoking was associated with increased risk of infectious pulmonary diagnoses and chronic bronchitis independent of tobacco smoking and other risk factors for lung disease (hazard ratio [95% confidence interval] 1·43 [1·09–1·86], and 1·54 [1·11–2·13], respectively); these risks were additive in participants smoking both substances. There was no association between marijuana smoking and pulmonary diagnoses in HIV-uninfected participants. Interpretation In this longitudinal study, long-term marijuana smoking was associated with lung disease independent of tobacco smoking and other risk factors in HIV-infected individuals. These findings could be used to reduce modifiable risks of lung disease in high-risk populations. Funding U.S. National Institutes of Health.

Objective: The relationship of cerebrospinal fluid (CSF) extracellular vesicles to neurocognitive impairment (NCI) in HIV-infected individuals is unclear. Here, we characterize CSF extracellular vesicles and their association with central nervous system (CNS) injury related biomarkers [neurofilament light (NFL), S100B, neopterin] and NCI in HIV-positive individuals on combination antiretroviral therapy (cART). Design: A cross-sectional and longitudinal study of CSF samples from HIV-positive individuals on cART. Methods: NFL, S100B and neopterin were measured by ELISA in 190 CSF samples from 112 individuals (67 HIV-positive and 45 HIV-negative). CSF extracellular vesicles were isolated and characterized by electron microscopy, nanoparticle tracking analysis, immunoblotting for exosome markers (CD9, CD63, CD81, FLOT-1) and ELISA for HLA-DR. Results: HIV-positive individuals had median age 52 years, 67% with suppressed plasma viral load (< 50 copies/ml), median CD4+ nadir 66 cells/μl and CD4+ cell count 313 cells/μl. CSF NFL, S100B and neopterin levels were higher in HIV-positive vs. HIV-negative individuals, and nonsuppressed vs. suppressed HIV-positive individuals. Although CSF NFL and S100B levels were higher in NCI vs. unimpaired HIV-positive individuals (P

For many years the Shouldice technique was the gold standard for inguinal hernia repair. Nowadays mesh repair has been proven to entail better results in randomized trials. Since the first publication 1953 the Repair has been described in detail in many textbooks, articles and You Tube videos. It appears that the original technique is used almost exclusively in the Shouldice Hospital in Thornhill/ Canada and despite the success of the Shouldice Hospital many surgeons inexplicably modify this original technique in their daily practice. In the last couple of years there appears to be an increasing interest in pure tissue repairs for various reasons, often fear of mesh-related pain. The aim of the study was to review the current evidence and to define an updated standard with key principles of the Shouldice repair. Because of unpublished evidence regarding many operative details the organizing group decided to create a technical update via a consensus meeting with 13 international designated hernia surgeons from six countries. In preparation of the meeting a review of the current literature regarding Shouldice repair was done by the organizing group. A questionnaire was prepared and sent to all participants before the meeting to get an independent answer on all critical aspects. All questions regarding a detailed standard of the operation technique could be outlined. As result of the consensus meeting the participants have formulated all key-points of preparation/dissection and repair of the Shouldice technique. For 5 of 6 critical technical surgical steps a strong consensus could be defined in the group. There was no consensus among the group regarding the cremaster resection and the ideal indication for Shouldice repair. After a 75-year history of the Shouldice repair the technique should continue to merit consideration by all hernia surgeons. After this consensus meeting a clear binding standard of the Shouldice technique for all interested surgeons is proposed.

Background: Marijuana smoke contains some of the same toxicants present in tobacco smoke. Marijuana smoking is prevalent among HIV+ individuals, but few studies have characterized smoke-related toxicants or associated health outcomes in exclusive marijuana users. Methods: This longitudinal study included 245 participants over age 40 (76% HIV+). 33 plasma and 28 urine metabolites of nicotine, ∆-9-trans-tetrahydrocannabinol, polycyclic aromatic hydrocarbons, and volatile organic compounds were assayed by liquid or gas chromatography/mass spectrometry. Exposures and health outcomes were assessed from surveys and medical records. Findings: At baseline, 18% of participants were marijuana-only smokers, 20% tobacco-only smokers, and 24% dual marijuana-tobacco smokers (median (IQR) age 53 (47–60) years, 78% male, 54% white race). Marijuana smoking was independently associated with elevated plasma naphthalenes, 2-hydroxyfluorene sulfate, 4-vinylphenol sulfate, and o-cresol sulfate (p

Prediabetes is a high-risk condition for type 2 diabetes (T2D). Pancreatic &beta, cells adapt to impaired glucose regulation in prediabetes by increasing insulin secretion and &beta, cell mass expansion. In people with prediabetes, metformin has been shown to prevent prediabetes conversion to diabetes. However, emerging evidence indicates that metformin has negative effects on &beta, cell function and survival. Our previous study established the Nile rat (NR) as a model for prediabetes, recapitulating characteristics of human &beta, cell compensation in function and mass expansion. In this study, we investigated the action of metformin on &beta, cells in vivo and in vitro. A 7-week metformin treatment improved glucose tolerance by reducing hepatic glucose output and enhancing insulin secretion. Although high-dose metformin inhibited &beta, cell glucose-stimulated insulin secretion in vitro, stimulation of &beta, cell insulin secretion was preserved in metformin-treated NRs via an indirect mechanism. Moreover, &beta, cells in NRs receiving metformin exhibited increased endoplasmic reticulum (ER) chaperones and alleviated apoptotic unfold protein response (UPR) without changes in the expression of cell identity genes. Additionally, metformin did not suppress &beta, cell mass compensation or proliferation. Taken together, despite the conflicting role indicated by in vitro studies, administration of metformin does not exert a negative effect on &beta, cell function or cell mass and, instead, early metformin treatment may help protect &beta, cells from exhaustion and decompensation.

Background Umbilical and epigastric hernia repairs are frequently performed surgical procedures with an expected low complication rate. Nevertheless, the optimal method of repair with best short- and long-term outcomes remains debatable. The aim was to develop guidelines for the treatment of umbilical and epigastric hernias. Methods The guideline group consisted of surgeons from Europe and North America including members from the European Hernia Society and the Americas Hernia Society. The Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach, the Scottish Intercollegiate Guidelines Network (SIGN) critical appraisal checklists, and the Appraisal of Guidelines for Research and Evaluation (AGREE) instrument were used. A systematic literature search was done on 1 May 2018, and updated on 1 February 2019. Results Literature reporting specifically on umbilical and epigastric hernias was limited in quantity and quality, resulting in a majority of the recommendations being graded as weak, based on low-quality evidence. The main recommendation was to use mesh for repair of umbilical and epigastric hernias to reduce the recurrence rate. Most umbilical and epigastric hernias may be repaired by an open approach with a preperitoneal flat mesh. A laparoscopic approach may be considered if the hernia defect is large, or if the patient has an increased risk of wound morbidity. Conclusion This is the first European and American guideline on the treatment of umbilical and epigastric hernias. It is recommended that symptomatic umbilical and epigastric hernias are repaired by an open approach with a preperitoneal flat mesh.

BackgroundExtracellular vesicles (EVs) are nano-sized particles present in most body fluids including cerebrospinal fluid (CSF). Little is known about CSF EV proteins in HIV+ individuals. Here, we characterize the CSF EV proteome in HIV+ subjects and its relationship to neuroinflammation, stress responses, and HIV-associated neurocognitive disorders (HAND).MethodsCSF EVs isolated from 20 HIV+ subjects with (n = 10) or without (n = 10) cognitive impairment were characterized by electron microscopy, nanoparticle tracking analysis, immunoblotting, and untargeted LC/MS/MS mass spectrometry. Functional annotation was performed by gene ontology (GO) mapping and expression annotation using Biobase Transfac and PANTHER software. Cultured astrocytic U87 cells were treated with hydrogen peroxide for 4 h to induce oxidative stress and EVs isolated by ultracentrifugation. Selected markers of astrocytes (GFAP, GLUL), inflammation (CRP), and stress responses (PRDX2, PARK7, HSP70) were evaluated in EVs released by U87 cells following induction of oxidative stress and in CSF EVs from HIV+ patients by immunoblotting.ResultsMass spectrometry identified 2727 and 1626 proteins in EV fractions and EV-depleted CSF samples, respectively. CSF EV fractions were enriched with exosomal markers including Alix, syntenin, tetraspanins, and heat-shock proteins and a subset of neuronal, astrocyte, oligodendrocyte, and choroid plexus markers, in comparison to EV-depleted CSF. Proteins related to synapses, immune/inflammatory responses, stress responses, metabolic processes, mitochondrial functions, and blood-brain barrier were also identified in CSF EV fractions by GO mapping. HAND subjects had higher abundance of CSF EVs and proteins mapping to GO terms for synapses, glial cells, inflammation, and stress responses compared to those without HAND. GFAP, GLUL, CRP, PRDX2, PARK7, and HSP70 were confirmed by immunoblotting of CSF EVs from subjects with HAND and were also detected in EVs released by U87 cells under oxidative stress.ConclusionsThese findings suggest that CSF EVs derived from neurons, glial cells, and choroid plexus carry synaptic, immune/inflammation-related, and stress response proteins in HIV+ individuals with cognitive impairment, representing a valuable source for biomarker discovery.

Exosomes are nanovesicles released from most cell types including immune cells. Prior studies suggest exosomes play a role in HIV pathogenesis, but little is known about exosome cargo in relation to immune responses and oxidative stress. Here, we characterize plasma exosomes in HIV patients and their relationship to immunological and oxidative stress markers. Plasma exosome fractions were isolated from HIV-positive subjects on ART with suppressed viral load and HIV-negative controls. Exosomes were characterized by electron microscopy, nanoparticle tracking, immunoblotting, and LC-MS/MS proteomics. Plasma exosomes were increased in HIV-positive subjects compared to controls, and correlated with increased oxidative stress markers (cystine, oxidized cys-gly) and decreased PUFA (DHA, EPA, DPA). Untargeted proteomics detected markers of exosomes (CD9, CD63, CD81), immune activation (CD14, CRP, HLA-A, HLA-B), oxidative stress (CAT, PRDX1, PRDX2, TXN), and Notch4 in plasma exosomes. Exosomal Notch4 was increased in HIV-positive subjects versus controls and correlated with immune activation markers. Treatment of THP-1 monocytic cells with patient-derived exosomes induced expression of genes related to interferon responses and immune activation. These results suggest that exosomes in ART-treated HIV patients carry proteins related to immune activation and oxidative stress, have immunomodulatory effects on myeloid cells, and may have pro-inflammatory and redox effects during pathogenesis.

Supplemental Digital Content is Available in the Text., Background: Cerebrospinal fluid (CSF) viral escape is an increasingly recognized clinical event among HIV-1-infected adults. We analyzed longitudinal data and drug-resistance mutations to characterize profiles of HIV-1-infected patients on antiretroviral therapy with discordant CSF and plasma HIV-1 RNA levels. Methods: Forty-one cases of CSF escape defined as detectable CSF HIV-1 RNA when plasma levels were undetectable, or HIV-1 RNA >0.5-log higher in CSF than plasma were identified from Boston Hospitals and National NeuroAIDS Tissue Consortium (NNTC) from 2005 to 2016. Results: Estimated prevalence of CSF escape in Boston and NNTC cohorts was 6.0% and 6.8%, respectively; median age was 50, duration of HIV-1 infection 17 years, CD4 count 329 cells/mm3 and CD4 nadir 21 cells/mm3. Neurological symptoms were present in 30 cases; 4 had repeat episodes of CSF escape. Cases were classified into subtypes based plasma HIV-1 RNA levels in the preceding 24 months: high-level viremia (1000 copies/mL), low-level viremia (LLV: 51–999 copies/mL), and plasma suppression with CSF blip or escape (CSF RNA 15 years, previous LLV, and M184V/I mutations in CSF. Classification based on preceding plasma HIV RNA levels provides a useful conceptual framework to identify causal factors and test therapeutics.

Objectives Nitrite inhalants (poppers) are commonly used recreational drugs among MSM and were previously associated with elevated rates of high-risk sexual behavior, HIV and human herpesvirus type 8 (HHV-8) seroconversion, and transient immunosuppressive effects in experimental models. Whether long-term popper use is associated with cancer risk among MSM in the HAART era is unclear. Design Prospective cohort study of cancer risk in 3223 HIV-infected and uninfected MSM in the Multicenter AIDS Cohort Study from 1996-2010. Methods Poisson regression models were used to examine the association between heavy popper use (defined as daily or weekly use for at least 1 year) and risk of individual cancers or composite category of virus-associated cancers. Results Among all participants, heavy popper use was not associated with increased risk of any individual cancers. Among HIV-uninfected men aged 50-70, heavy popper use was associated with increased risk of virus-associated cancer with causes linked to human papillomavirus, HHV-8, and Epstein-Barr virus in models adjusted for demographics, number of sexual partners, immunological parameters (CD4 cell counts or CD4/CD8 ratios), and hepatitis B and C viruses [incidence rate ratio (IRR), 95% confidence interval (CI) 3.24, 1.05-9.96], or sexually transmitted infections (IRR 3.03, 95% CI, 1.01-9.09), as was cumulative use over a 5-year period (IRR 1.012, 95% CI 1.003-1.021; P = 0.007). There was no significant association between heavy popper use and virus-associated cancer in HIV-infected men. Conclusions Long-term heavy popper use is associated with elevated risk of some virus-associated cancers with causes related to human papillomavirus, HHV-8, and Epstein-Barr virus infections in older HIV-uninfected MSM independent of sexual behavior and immunological parameters.

Introduction The recommendation in the European Hernia Society Guidelines for the treatment of recurrent inguinal hernias is to modify the technique in relation to the previous technique, and use a new plane of dissection for mesh implantation. However, the registry data show that even following previous open suture and mesh repair to treat a primary inguinal hernia, open suture and mesh repair can be used once again for a recurrent hernia. It is therefore important to know what the outcome of open repair of recurrent inguinal hernias is compared with open repair of primary inguinal hernias, while taking the previous operation into account. Patients and methods In the Herniamed Registry, a total of 17,594 patients with an open primary or recurrent unilateral inguinal hernia repair in men with a 1-year follow-up were prospectively documented between September 1, 2009 and August 31, 2013. Of these patients, 15,274 (86.8 %) had an open primary and 2320 (13.2 %) open recurrent repair. In the unadjusted and multivariable analyses, the dependent variables were intra- and postoperative complications, reoperations, recurrences, pain at rest, pain on exertion, and pain requiring treatment. Results Open recurrent repair compared with the open primary operation is a significant influence factor for higher intraoperative (p = 0.01) and postoperative (p = 0.05) complication rates, recurrence rate (p

Immunological parameters that influence susceptibility to virus-associated cancers in HIV-seronegative individuals are unclear. We conducted a case-control cohort study of immunological parameters associated with development of incident virus-associated cancers among 532 HIV-seronegative men who have sex with men (MSM) enrolled in the Multicenter AIDS Cohort Study (MACS) with median (IQR) 21 (8–26) years of follow-up. Thirty-two incident virus-associated cancers (anal cancer, non-Hodgkin lymphoma, liver cancer, other cancers with etiologies linked to human papillomavirus [HPV], Epstein-Barr virus [EBV], hepatitis B virus [HBV], or human herpesvirus-8 [HHV-8]) were identified among 3,408 HIV-seronegative men in the MACS during 1984–2010. Cases were matched for demographics, smoking, and follow-up to 500 controls without cancer. Mixed-effects and Cox regression models were used to examine associations between nadir or recent CD4, CD8, and white blood cell (WBC) counts or CD4:CD8 ratios and subsequent diagnosis of virus-associated cancers. Men with incident virus-associated cancers had lower CD4 and WBC counts over a six year-window prior to diagnosis compared to men without cancer (p=0.001 and 0.03, respectively). Low CD4 cell count and nadir, CD4 count-nadir differential, and CD4:CD8 ratio nadir were associated with increased two-year risk of incident virus-associated cancers in models adjusted for demographics and smoking (hazard ratios 1.2–1.3 per 100 or 0.1 unit decrease, respectively; p

Background Hyperglycemia leading to increased oxidative stress is implicated in the increased risk for the development of macrovascular and microvascular complications in patients with type 1 diabetes mellitus. Methods and Results A random subcohort of 349 participants was selected from the DCCT / EDIC (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications) cohort. This included 320 controls and 29 cardiovascular disease cases that were augmented with 98 additional known cases to yield a case cohort of 447 participants (320 controls, 127 cases). Biosamples from DCCT baseline, year 1, and closeout of DCCT , and 1 to 2 years post‐ DCCT ( EDIC years 1 and 2) were measured for markers of oxidative stress, including plasma myeloperoxidase, paraoxonase activity, urinary F 2α isoprostanes, and its metabolite, 2,3 dinor‐8 iso prostaglandin F 2α . Following adjustment for glycated hemoblobin and weighting the observations inversely proportional to the sampling selection probabilities, higher paraoxonase activity, reflective of antioxidant activity, and 2,3 dinor‐8 iso prostaglandin F 2α , an oxidative marker, were significantly associated with lower risk of cardiovascular disease (−4.5% risk for 10% higher paraoxonase, P iso prostaglandin F 2α , P =0.0092). In contrast, the oxidative markers myeloperoxidase and F 2α isoprostanes were not significantly associated with cardiovascular disease after adjustment for glycated hemoblobin. There were no significant differences between DCCT intensive and conventional treatment groups in the change in all biomarkers across time segments. Conclusions Heightened antioxidant activity (rather than diminished oxidative stress markers) is associated with lower cardiovascular disease risk in type 1 diabetes mellitus, but these biomarkers did not change over time with intensification of glycemic control. Clinical Trial Registration URL : https://www.clinicaltrials.gov . Unique identifiers: NCT 00360815 and NCT 00360893.

Histone modifiers play essential roles in controlling transcription and organizing eukaryotic genomes into functional domains. Here, we show that Set1, the catalytic subunit of the highly conserved Set1C/COMPASS complex responsible for histone H3K4 methylation (H3K4me), behaves as a repressor of the transcriptome largely independent of Set1C and H3K4me in the fission yeast Schizosaccharomyces pombe. Intriguingly, while Set1 is enriched at highly expressed and repressed loci, Set1 binding levels do not generally correlate with the levels of transcription. We show that Set1 is recruited by the ATF/CREB homolog Atf1 to heterochromatic loci and promoters of stress-response genes. Moreover, we demonstrate that Set1 coordinates with the class II histone deacetylase Clr3 in heterochromatin assembly at prominent chromosomal landmarks and repression of the transcriptome that includes Tf2 retrotransposons, noncoding RNAs, and regulators of development and stress-responses. Our study delineates a molecular framework for elucidating the functional links between transcriptome control and chromatin organization. DOI: http://dx.doi.org/10.7554/eLife.04506.001, eLife digest Genes can be turned on or off at different times in an organism's life. In humans, yeast and other eukaryotes, this is mainly controlled by the way DNA is packaged with proteins—known as histones—in a structure called chromatin. Genes that are switched on, or only temporarily switched off, are associated with areas of the genome where the chromatin is loosely packed. In contrast, genes that remain switched off for long periods of time are found in regions—known as heterochromatin—where the chromatin is tightly packed. There are many enzymes that can modify histones to change the structure of chromatin. One enzyme—called Set1—adds a methyl tag to chromatin, which is known to be associated with genes being switched on. However, Lorenz et al. found that Set1 also has other roles in modifying chromatin in the yeast Schizosaccharomyces pombe. The experiments found that Set1 helps to keep genes switched off and that this role is largely independent of its ability to add the methyl tag to chromatin. Set1 is recruited to many sites across the genome by another protein called Atf1, which is involved in the cell's response to environmental stresses. Lorenz et al. believe that this helps to put these genes in a ‘poised’ off state so that they are ready to be switched on rapidly if needed. Set1 also works with another protein that removes acetyl tags—which encourage chromatin to be less tightly packed—from histones. Together, both proteins contribute to the assembly of heterochromatin and keep genes involved in development and stress responses switched off when they are not required. Collectively, these experiments reveal unexpected and important insights into how Set1—which plays critical roles in many aspects of human health including aging and cancer—works in cells. DOI: http://dx.doi.org/10.7554/eLife.04506.002

The surface of Titan is highly diverse with a remarkable landscape including dunes, streambeds, and presently liquid-filled lakes, as well as mountain ridges, depressions, and rare, eroded impact structures. The geology is characterized by both smooth and rough surfaces with height variations (slopes) on short scales. Radar altimetry suggests the overall height variation is low, typically no more than 150 meters. However, occasional elevation changes of 500 meters have been discovered and Titan has mountains that sometimes reach several hundred meters to more than 1 kilometer in height. The process of identifying potential landing sites on Titan is based on the analyses of science cases, the definition of candidate sites, and engineering considerations. Regions for in-situ observations are the atmosphere, the surface, including both solid and liquid surfaces, and the subsurface. Concerning the surface solid areas as well as liquid zones must be considered. The most critical engineering constraints are atmospheric density and composition, temperature, surface hardness, roughness, inclination, sub-surface hardness, mechanical uniformity, composition, layering depths, and wind and seismic levels. The most promising sites are wet polar regions or dry equatorial regions because of their high compositional diversity and the mobility of material.

Background The GeparQuinto study showed that adding bevacizumab to 24 weeks of anthracycline–taxane–based neoadjuvant chemotherapy increases pathological complete response (pCR) rates overall and specifically in patients with triple-negative breast cancer (TNBC). No difference in pCR rate was observed for adding everolimus to paclitaxel in nonearly responding patients. Here, we present disease-free (DFS) and overall survival (OS) analyses. Patients and methods Patients (n = 1948) with HER2-negative tumors of a median tumor size of 4 cm were randomly assigned to neoadjuvant treatment with epirubicin/cyclophosphamide followed by docetaxel (EC-T) with or without eight infusions of bevacizumab every 3 weeks before surgery. Patients without clinical response to EC ± Bevacizumab were randomized to 12 weekly cycles paclitaxel with or without everolimus 5 mg/day. To detect a hazard ratio (HR) of 0.75 (α = 0.05, β = 0.8) 379 events had to be observed in the bevacizumab arms. Results With a median follow-up of 3.8 years, 3-year DFS was 80.8% and 3-year OS was 89.7%. Outcome was not different for patients receiving bevacizumab (HR 1.03; P = 0.784 for DFS and HR 0.974; P = 0.842 for OS) compared with patients receiving chemotherapy alone. Patients with TNBC similarly showed no improvement in DFS (HR = 0.99; P = 0.941) and OS (HR = 1.02; P = 0.891) when treated with bevacizumab. No other predefined subgroup (HR+/HER2-; locally advanced (cT4 or cN3) or not; cT1–3 or cT4; pCR or not) showed a significant benefit. No difference in DFS (HR 0.997; P = 0.987) and OS (HR 1.11; P = 0.658) was observed for nonearly responding patients receiving paclitaxel with or without everolimus overall as well as in subgroups. Conclusions Long-term results, in opposite to the results of pCR, do not support the neoadjuvant use of bevacizumab in addition to an anthracycline–taxane-based chemotherapy or everolimus in addition to paclitaxel for nonearly responding patients. Clinical trial number NCT 00567554, www.clinicaltrials.gov .

Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs ∼US$2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for finding germline mutations. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Of 598 patients, 30.6% had SDHx germline mutations: 34.4% in SDHB, 14.2% SDHC, and 51.4% SDHD. Predictors for an SDHx mutation are family history [odds ratio (OR), 37.9], previous pheochromocytoma (OR, 10.9), multiple HNP (OR, 10.6), age ≤40 years (OR, 4.0), and male gender (OR, 3.5). By screening only preselected cases and a stepwise approach, 60% cost reduction can be achieved, with 91.8% sensitivity and 94.5% negative predictive value. Our data give evidence that clinical parameters can predict for mutation and help prioritize gene testing to reduce costs in HNP. Such strategy is cost-saving in the practice of genetics-based personalized health care. [Cancer Res 2009;69(8):3650–6]

The Plethodon glutinosus complex is a geographically widespread salamander group inhabiting forests throughout the eastern United States and is locally abundant throughout the coastal plain. As such it is exposed to a variety of climatic conditions and makes the perfect candidate group for examining large-scale variation in thermal tolerance limits and heat shock protein expression. Thirteen populations of the P. glutinosus complex representing three physiographic regions were examined for variation in thermotolerant capabilities along environmental gradients. Measures of thermotolerance included the preferred temperature (PT), critical thermal maximum (CTM), and levels of heat shock protein 70 (hsp70) as detected by ELISA. Within the P. glutinosus complex there was an unexpected inverse relationship between the stress response and climate. While salamanders exhibited a significant amount of geographic variation in PT and CTM, there was a significant negative relationship between CTM and both geographic location and climate – salamanders from warm, southern climates had lower CTMs then salamanders from northern, cool climates. Hsp70 levels varied significantly among populations and physiographic regions but not among heat shocked or control treatment groups. In addition, piedmont populations contained significantly higher levels of hsp70 than either coastal plain or montane populations. Patterns observed in the stress response of the P. glutinosus complex reflect a "constitutive" based heat shock strategy. This strategy acknowledges that hsp70 induction incurs a fitness cost and that organisms from both relatively stable and highly disturbed habitats should trade-off inducible thermotolerance for high levels of constitutive protein. This strategy predicts that organisms from habitats with intermediate levels of disturbance would have the highest levels of inducible protein. However, because this confers a potentially high energetic cost, selection should ultimately push the population towards one side of the model or the other. Salamanders occupy relatively stable habitats on a global scale of disturbance, but even within these types of habitats trade-offs are evident. Piedmont salamanders which occupy the intermediately disturbed habitats had hsp70 levels that exceeded levels observed in both montane and coastal plain populations. Coastal plain populations behaviorally avoid stressful conditions and hence have stress responses similar to the lower stress montane populations.

Background and aims: After an initial period of excellent results with newly introduced imaging procedures, the accuracy of most imaging methods declines in later publications. This effect may be due to various methodological factors involved in the research. Using the example of endoscopic ultrasound (EUS), this study aimed to elucidate one of the factors possibly concerned—namely, the extent to which the examiners are adequately blinded. Methods: Well documented videotapes of EUS examinations of 101 patients with resected tumours of the oesophagus (n=32), stomach (n=33), or pancreas (n=36) were evaluated in three different ways: firstly, retrospective analysis under routine clinical conditions; secondly, evaluation of EUS videotapes in a strictly blinded fashion; and thirdly, evaluation of the same videotapes but with additional information from the video endoscopic appearance (oesophageal/gastric cancer) or from computed tomography results (pancreatic cancer). Histopathological T staging was used as the reference method. Results: The accuracy of EUS in T staging was 73% under routine conditions. This value fell significantly to 53% for the blinded evaluation but increased again to 62% for the unblinded evaluation. The sensitivity of staging T1/T2 tumours was 72% (routine EUS), 59% (blinded EUS), and 70% (unblinded EUS). The respective values for advanced tumours were 85%, 74%, and 72%. Conclusions: The accuracy of EUS for T staging in clinical practice appears to be lower than has previously been reported. In addition, blinded analysis produced significantly poorer results, which improved when another test was added. It may be speculated that better results with routine EUS obtained in a clinical setting are due to additional sources of information.