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Systemic lupus erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with SLE, we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK . Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, NRTKs regulate activation, migration, and proliferation of immune cells. We found that the patients' ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced pluripotent stem cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages., Competing Interests: SG, TL, NJ, BB, MT, BC, TZ, CN, RB, HY, FR, RF, SD, DI, DD, NL, OE, AV, NS, LA, SN, MH, WM, JC, FG No competing interests declared, (© 2024, Guillet, Lazarov et al.)

An open prospective, multicenter study enrolled 48 selected patients with chronic immune thrombocytopenia who achieved complete response for 1 year on thrombopoietin receptor agonists, half of the patients maintained a sustained response off treatment 4 years after treatment discontinuation. NCT03119974., (Copyright © 2024 American Society of Hematology.)

Debris-flow activity in the Alps is anticipated to undergo pronounced changes in response to a warming climate. Yet, a fundamental challenge in comprehensively assessing changes in process activity is the systematic lack of long-term observational debris-flow records. Here, we reconstruct the longest, continuous time series (1626-2020) of debris flows at Multetta, a supply-limited torrential system in the Eastern Swiss Alps. Relying on growth-ring records of trees that were damaged by debris flows, we do not detect significant changes in the frequency or magnitude over time. This seeming absence of a direct climatic influence on debris-flow initiation aligns with the regular distribution of repose time patterns, indicating a dependence of local process activity on sediment discharge and recharge. This stark difference in process behavior between our supply-limited site and transport-limited catchments has implications for assessing torrential hazard and risk mitigation in a context of global warming., (© 2024. The Author(s).)

Systemic Lupus Erythematosus (SLE) is an autoimmune disease, the pathophysiology and genetic basis of which are incompletely understood. Using a forward genetic screen in multiplex families with systemic lupus erythematosus (SLE) we identified an association between SLE and compound heterozygous deleterious variants in the non-receptor tyrosine kinases (NRTKs) ACK1 and BRK. Experimental blockade of ACK1 or BRK increased circulating autoantibodies in vivo in mice and exacerbated glomerular IgG deposits in an SLE mouse model. Mechanistically, non-receptor tyrosine kinases (NRTKs) regulate activation, migration, and proliferation of immune cells. We found that the patients' ACK1 and BRK variants impair efferocytosis, the MERTK-mediated anti-inflammatory response to apoptotic cells, in human induced Pluripotent Stem Cell (hiPSC)-derived macrophages, which may contribute to SLE pathogenesis. Overall, our data suggest that ACK1 and BRK deficiencies are associated with human SLE and impair efferocytosis in macrophages.

We present a glacial-related lake inventory for a region spanning 41.5° - 47° S in Patagonian Andes, where information on past glacier lake outburst floods (GLOF's) has hitherto remained significantly underreported. Analyzing remotely sensed images, we obtained data on 702 glacial-related lakes. Through detailed geomorphic assessments and manual supervision, we revised current inventories and added 35 GLOFs triggered from moraine/bedrock dammed lakes failures. The regional GLOF inventory presented contains information on 71 historical failures of moraine/bedrock dammed glacial lakes. From this database we analyzed outburst timing and managed to constrain 37 events occurrences within a period of 1 year. Around 40 % of them have occurred since the early 2000's, most of them originating from lakes probably formed as a delayed response to the glacial retreat imposed by the end of the Little Ice Age. On the other hand, we analyzed meteorological conditions for a sub-set of 10 events constrained within a 10-days period, finding a strong link between atmospheric rivers, cut-off lows impacting the southern Andes, and GLOFs. Only one case is likely to have been triggered by a Mw 4.9 earthquake. Based on topographic potential for avalanching, we estimated GLOF hazard potential, recognizing at least 3 subregions with high hazard, which moreover can be highly susceptible to climate conditions that regionally affect GLOF occurrence., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

In this Letter, we use a model fluid mechanics experiment to elucidate the impact of curvature heterogeneities on two-dimensional fields deriving from harmonic potential functions. This result is directly relevant to explain the smooth stationary structures in physical systems as diverse as curved liquid crystal and magnetic films, heat and Ohmic transport in wrinkled two-dimensional materials, and flows in confined channels. Combining microfluidic experiments and theory, we explain how curvature heterogeneities shape confined viscous flows. We show that isotropic bumps induce local distortions to Darcy's flows, whereas anisotropic curvature heterogeneities disturb them algebraically over system-spanning scales. Thanks to an electrostatic analogy, we gain insight into this singular geometric perturbation, and quantitatively explain it using both conformal mapping and numerical simulations. Altogether, our findings establish the robustness of our experimental observations and their broad relevance to all Laplacian problems beyond the specifics of our fluid mechanics experiment.

The structures, strain fields, and defect distributions in solid materials underlie the mechanical and physical properties across numerous applications. Many modern microstructural microscopy tools characterize crystal grains, domains and defects required to map lattice distortions or deformation, but are limited to studies of the (near) surface. Generally speaking, such tools cannot probe the structural dynamics in a way that is representative of bulk behavior. Synchrotron X-ray diffraction based imaging has long mapped the deeply embedded structural elements, and with enhanced resolution, dark field X-ray microscopy (DFXM) can now map those features with the requisite nm-resolution. However, these techniques still suffer from the required integration times due to limitations from the source and optics. This work extends DFXM to X-ray free electron lasers, showing how the [Formula: see text] photons per pulse available at these sources offer structural characterization down to 100 fs resolution (orders of magnitude faster than current synchrotron images). We introduce the XFEL DFXM setup with simultaneous bright field microscopy to probe density changes within the same volume. This work presents a comprehensive guide to the multi-modal ultrafast high-resolution X-ray microscope that we constructed and tested at two XFELs, and shows initial data demonstrating two timing strategies to study associated reversible or irreversible lattice dynamics., (© 2023. Springer Nature Limited.)

The primary goal of paleoflood hydrology is to estimate the frequency and magnitude of past floods. Botanical evidence, and particularly scars on trees, has been used repeatedly as paleostage indicators to reconstruct peak discharges and flood height. Yet, these reconstructions depend on the presence of visible scars on tree stems which tend to be masked as trees grow older. Here, we estimated flood magnitude using an alternative approach based on growth disturbances in tree-ring series, tree positions and the minimal discharge necessary to submerge the root collar of a tree as estimated by hydraulic modeling. We tested the reliability of this newly developed approach by using the traditional scar-based reconstruction as a benchmark. To this end, we sampled 60 trees showing evidence of flood damage on their stems along a 787-m long segment of the Asco river (Corsica, France). Based on 440 growth disturbances dated in tree-ring series, we reconstructed 28 floods between 1759 and 2020 and 18 during the 20th century. Using the two-dimensional Iber hydraulic model and detailed topographic data of the study site obtained from UAV imagery, we estimated that peak discharges of the 28 reconstructed events ranged between 10 and 210 m 3 s -1 , with 200 m 3 s -1 being considered as the threshold for extreme floods. Not only do the scar-based and root collar submersion approaches yield similar results, findings are also clearly in line with the sparse information available from historical archives and short gauge station records on past floods. The unprecedented length and depth of the record presented here opens new avenues for climate change and flood impact research., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Markus Stoffel reports financial support was provided by Chinese Scholarship Council., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Sustained response off treatment (SROT) after thrombopoietin receptor agonist (TPO-RA) discontinuation has been reported in immune thrombocytopenia (ITP). This prospective multicenter interventional study enrolled adults with persistent or chronic primary ITP and complete response (CR) on TPO-RAs. The primary end point was the proportion of patients achieving SROT (platelet count >30 × 109/L and no bleeding) at week 24 (W24) with no other ITP-specific medications. Secondary end points included the proportion of sustained CR off-treatment (SCROT, platelet count >100 × 109/L and no bleeding) and SROT at W52, bleeding events, and pattern of response to a new course of TPO-RAs. We included 48 patients with a median age of 58.5 years; 30 of 48 had chronic ITP at TPO-RA initiation. In the intention-to-treat analysis, 27 of 48 achieved SROT, 15 of 48 achieved SCROT at W24; 25 of 48 achieved SROT, and 14 of 48 achieved SCROT at W52. No severe bleeding episode occurred in patients who relapsed. Among patients rechallenged with TPO-RA, 11 of 12 achieved CR. We found no significant clinical predictors of SROT at W24. Single-cell RNA sequencing revealed enrichment of a tumor necrosis factor α signaling via NF-κB signature in CD8+ T cells of patients with no sustained response after TPO-RA discontinuation, which was further confirmed by a significant overexpression of CD69 on CD8+ T cells at baseline in these patients as compared with those achieving SCROT/SROT. Our results strongly support a strategy based on progressive tapering and discontinuation of TPO-RAs for patients with chronic ITP who achieved a stable CR on treatment. This trial was registered at www.clinicaltrials.gov as #NCT03119974., (© 2023 by The American Society of Hematology.)

Explosive volcanism is a key contributor to climate variability on interannual to centennial timescales 1 . Understanding the far-field societal impacts of eruption-forced climatic changes requires firm event chronologies and reliable estimates of both the burden and altitude (that is, tropospheric versus stratospheric) of volcanic sulfate aerosol 2,3 . However, despite progress in ice-core dating, uncertainties remain in these key factors 4 . This particularly hinders investigation of the role of large, temporally clustered eruptions during the High Medieval Period (HMP, 1100-1300 CE), which have been implicated in the transition from the warm Medieval Climate Anomaly to the Little Ice Age 5 . Here we shed new light on explosive volcanism during the HMP, drawing on analysis of contemporary reports of total lunar eclipses, from which we derive a time series of stratospheric turbidity. By combining this new record with aerosol model simulations and tree-ring-based climate proxies, we refine the estimated dates of five notable eruptions and associate each with stratospheric aerosol veils. Five further eruptions, including one responsible for high sulfur deposition over Greenland circa 1182 CE, affected only the troposphere and had muted climatic consequences. Our findings offer support for further investigation of the decadal-scale to centennial-scale climate response to volcanic eruptions., (© 2023. The Author(s).)

The risk of immune thrombocytopenia (ITP) worsening during pregnancy and neonatal ITP (NITP) have never been prospectively studied. We included 180 pregnant and 168 nonpregnant women with ITP in a prospective, multicenter, observational cohort study. A total of 131 pregnant women with ITP were matched to 131 nonpregnant women with ITP by history of splenectomy, ITP status (no response, response, complete response), and duration. Groups were followed for 15 months. The primary outcome was the first occurrence of ITP worsening defined by a composite end point including bleeding events and/or severe thrombocytopenia (<30 × 109/L) and/or ITP treatment modification. We also studied the recurrence of ITP worsening and the incidence of NITP and risk factors. The first occurrence of ITP worsening did not differ between pregnant and nonpregnant women with ITP (53.4 per 100 person-years [95% confidence interval {CI}, 40.8-69.9] vs 37.1 [95% CI, 27.5-50.0]; hazard ratio {HR}, 1.35 [95% CI, 0.89-2.03], P = .16). Pregnant women with ITP were more likely to have recurrence of severe thrombocytopenia and treatment modification (HR, 2.71 [95% CI, 1.41-5.23], P = .003; HR, 2.01 [95% CI, 1.14-3.57], P = .017, respectively). However, recurrence of severe bleeding events was not different between groups (P = .4). Nineteen (14%) neonates showed NITP <50 × 109/L. By multivariable analysis, NITP was associated with a previous offspring with NITP and maternal platelet count <50 × 109/L within 3 months before delivery (adjusted odds ratio, 5.55 [95% CI, 1.72-17.89], P = .004 and 4.07 [95% CI, 1.41-11.73], P = .009). To conclude, women with ITP do not increase their risk of severe bleeding during pregnancy. NITP is associated with NITP history and the severity of maternal ITP during pregnancy. These results will be useful for counseling women with ITP., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Autoimmune conditions in B-cell lymphomas are frequent. Steroids are standard of care, but many patients require other immunosuppressive agents. Ibrutinib is a Bruton Tyrosine Kinase inhibitor that is approved for B-cell indolent lymphoma treatment. We evaluated the use of ibrutinib in previously treated hematologic immune manifestations associated with B-cell lymphomas., Results: We conducted a retrospective multicentric observational study. Patients presenting with active, relapsed/refractory B-cell lymphoma associated hematological immune manifestation (autoimmune cytopenia, acquired immune-mediated bleeding disorders) were included. Twenty-five patients were identified. Median age at ibrutinib introduction was 69 years (range 44-84) and median number of previous treatment lines before ibrutinib was 2 (1-7). Twenty-two patients (88%) were on concomitant stable treatment at inclusion. Within a median exposure of 8 months (2-35), overall response rate to ibrutinib on immune manifestations was 76% (95% CI, 54.9-90.6); complete response rate 44%. Fourteen patients (63%) were able to be weaned from concomitant treatments. Fourteen patients (56%) presented treatment-related adverse events, mostly Grade 1 or 2., Conclusions: Ibrutinib in this setting provides good efficacy and safety profile. Clinical trials are needed to define subgroups of patients who will benefit from this strategy and establish its place in the therapeutic arsenal., (© 2022 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

The Arctic is warming faster than any other region on Earth. Putting this rapid warming into perspective is challenging because instrumental records are often short or incomplete in polar regions and precisely-dated temperature proxies with high temporal resolution are largely lacking. Here, we provide this long-term perspective by reconstructing past summer temperature variability at Yamal Peninsula - a hotspot of recent warming - over the past 7638 years using annually resolved tree-ring records. We demonstrate that the recent anthropogenic warming interrupted a multi-millennial cooling trend. We find the industrial-era warming to be unprecedented in rate and to have elevated the summer temperature to levels above those reconstructed for the past seven millennia (in both 30-year mean and the frequency of extreme summers). This is undoubtedly of concern for the natural and human systems that are being impacted by climatic changes that lie outside the envelope of natural climatic variations for this region., (© 2022. The Author(s).)

Use of edible insects as an alternative source of proteins in food and feed is increasing. These last years, numerous companies in Europe have started producing insects for food and feed purposes. In the European Union, the use of edible insects for human consumption falls within Regulation (EU) No. 2015/2283 on novel foods. For feed, Commission Regulation (EU) 2017/893 authorizes seven insect species as processed animal proteins for aquaculture. Methods of authentication are required to check the conformity of the products. In this study, we propose a real-time polymerase chain reaction (PCR) method for the specific detection of the lesser mealworm ( Alphitobius diaperinus ), one of the species included in the shortlist of authorized insects. The selected target is the cadherin gene with a single-copy (per haploid genome) illustrated by our experimental evidence. The PCR test amplified a 134-bp fragment of the cadherin gene. The qualitative method was assessed toward several performance criteria. Specificity was checked against 54 insect species next to other animal and plant species. The sensitivity, efficiency, robustness, and transferability of the PCR assay were also successfully tested. Finally, the applicability of the test was assessed on real-life processed samples (industrial meals) of A. diaperinus . The study also showed that there seems to be a huge confusion on the correct labeling of the marketed mealworms. We did not succeed to get Alphitobius laevigatus samples. They all appeared to belong to the A. diaperinus taxon., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Marien, Sedefoglu, Dubois, Maljean, Francis, Berben, Guillet, Morin, Fumière and Debode.)

Idiopathic multicentric Castleman disease (iMCD) is a non-clonal inflammatory lymphoproliferative disorder of unknown origin. Recently, TAFRO syndrome (thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly) emerged as a singular variant of iMCD in Asia and was associated with a severe course and a poor outcome. The present study describes the first large Western cohort of TAFRO syndrome patients (n = 25) meeting the All Japan TAFRO Syndrome Research Group diagnostic criteria. Characteristics of TAFRO patients were compared to iMCD-not otherwise specified (iMCD-NOS) patients used as a control group (n = 43). Our results show that despite baseline characteristics in accordance with previously reported series, Western TAFRO syndrome patients do not appear to present with a worse outcome than iMCD-NOS patients. There were no significant differences between the two groups regarding treatment choice, response to rituximab (71% vs. 67%) or tocilizumab (69% vs. 91%) in TAFRO and iMCD-NOS, respectively. The two-year overall survival was above 95% in both groups. Limits of inclusion and exclusion criteria for TAFRO definition are also discussed. Our findings raise the question of the singularity of the TAFRO entity in Western countries. The data should promote further research using unsupervised models to identify markers of disease severity in Western cohorts of iMCD patients., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

Tree-ring chronologies underpin the majority of annually-resolved reconstructions of Common Era climate. However, they are derived using different datasets and techniques, the ramifications of which have hitherto been little explored. Here, we report the results of a double-blind experiment that yielded 15 Northern Hemisphere summer temperature reconstructions from a common network of regional tree-ring width datasets. Taken together as an ensemble, the Common Era reconstruction mean correlates with instrumental temperatures from 1794-2016 CE at 0.79 (p < 0.001), reveals summer cooling in the years following large volcanic eruptions, and exhibits strong warming since the 1980s. Differing in their mean, variance, amplitude, sensitivity, and persistence, the ensemble members demonstrate the influence of subjectivity in the reconstruction process. We therefore recommend the routine use of ensemble reconstruction approaches to provide a more consensual picture of past climate variability.

Newly developed millennial δ 13 C larch tree-ring chronology from Siberia allows reconstruction of summer (July) vapor pressure deficit (VPD) changes in a temperature-limited environment. VPD increased recently, but does not yet exceed the maximum values reconstructed during the Medieval Warm Anomaly. The most humid conditions in the Siberian North were recorded in the Early Medieval Period and during the Little Ice Age. Increasing VPD under elevated air temperature affects the hydrology of these sensitive ecosystems by greater evapotranspiration rates. Further VPD increases will significantly affect Siberian forests most likely leading to drought and forest mortality even under additional access of thawed permafrost water. Adaptation strategies are needed for Siberian forest ecosystems to protect them in a warming world.

In September 2014, the Kashmir valley (north-west India) experienced a massive flood causing significant economic losses and fatalities. This disaster underlined the high vulnerability of the local population and raised questions regarding the resilience of Kashmiris to future floods. Although the magnitude of the 2014 flood has been considered unprecedented within the context of existing measurements, we argue that the short flow series may lead to spurious misinterpretation of the probability of such extreme events. Here we use a millennium-long record of past floods in Kashmir based on historical and tree-ring records to assess the probability of 2014-like flood events in the region. Our flood chronology (635 CE-nowadays) provides key insights into the recurrence of flood disasters and propels understanding of flood variability in this region over the last millennium, showing enhanced activity during the Little Ice Age. We find that high-impact floods have frequently disrupted the Kashmir valley in the past. Thus, the inclusion of historical records reveals large flood hazard levels in the region. The newly gained information also underlines the critical need to take immediate action in the region, so as to reduce the exposure of local populations and to increase their resilience, despite existing constraints in watershed management related to the Indus Water Treaty., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

We provide first evidence that under certain conditions, 1/2-spin fermions may naturally behave like a Grover search, looking for topological defects in a material. The theoretical framework is that of discrete-time quantum walks (QWs), i.e., local unitary matrices that drive the evolution of a single particle on the lattice. Some QWs are well known to recover the (2+1)-dimensional Dirac equation in continuum limit, i.e., the free propagation of the 1/2-spin fermion. We study two such Dirac QWs, one on the square grid and the other on a triangular grid reminiscent of graphenelike materials. The numerical simulations show that the walker localizes around the defects in O(sqrt[N]) steps with probability O(1/logN), in line with previous QW search on the grid. The main advantage brought by those of this Letter is that they could be implemented as "naturally occurring" freely propagating particles over a surface featuring topological defects-without the need for a specific oracle step. From a quantum computing perspective, however, this hints at novel applications of QW search: instead of using them to look for "good" solutions within the configuration space of a problem, we could use them to look for topological properties of the entire configuration space.

Recently revised ice core chronologies for Greenland have newly identified one of the largest sulfate deposition signals of the last millennium as occurring between 1108 and 1113 CE. Long considered the product of the 1104 CE Hekla (Iceland) eruption, this event can now be associated with substantial deposition seen in Antarctica under a similarly revised chronology. This newly recognized bipolar deposition episode has consequently been deemed to reveal a previously unknown major tropical eruption in 1108 CE. Here we show that a unique medieval observation of a "dark" total lunar eclipse attests to a dust veil over Europe in May 1110 CE, corroborating the revised ice-core chronologies. Furthermore, careful evaluation of ice core records points to the occurrence of several closely spaced volcanic eruptions between 1108 and 1110 CE. The sources of these eruptions remain unknown, but we propose that Mt. Asama, whose largest Holocene eruption occurred in August 1108 CE and is credibly documented by a contemporary Japanese observer, is a plausible contributor to the elevated sulfate in Greenland. Dendroclimatology and historical documentation both attest, moreover, to severe climatic anomalies following the proposed eruptions, likely providing the environmental preconditions for subsistence crises experienced in Western Europe between 1109 and 1111 CE.

The conversion of light into usable chemical and mechanical energy is pivotal to several biological and chemical processes, many of which occur in solution. To understand the structure-function relationships mediating these processes, a technique with high spatial and temporal resolutions is required. Here, we report on the design and commissioning of a liquid-phase mega-electron-volt (MeV) ultrafast electron diffraction instrument for the study of structural dynamics in solution. Limitations posed by the shallow penetration depth of electrons and the resulting information loss due to multiple scattering and the technical challenge of delivering liquids to vacuum were overcome through the use of MeV electrons and a gas-accelerated thin liquid sheet jet. To demonstrate the capabilities of this instrument, the structure of water and its network were resolved up to the 3 rd hydration shell with a spatial resolution of 0.6 Å; preliminary time-resolved experiments demonstrated a temporal resolution of 200 fs., (© 2020 Author(s).)

The current aim of the fight against the HIV epidemic is to reduce the proportion of missed opportunities for HIV diagnosis. Erotic industry Shows (ES) were deemed to be appropriate events to organize awareness campaigns and to propose HIV Rapid Diagnostic Test (HIV-RDT) to people who are sexually active and likely to engage in unsafe sex practices. In 2015, a cross-sectional study in 4 ES was conducted to document the sexual risk factors associated with HIV-screening test approach and the proportion of positive HIV-RDT. Prevention booths were set up to offer HIV-screening to individuals ≥18 years volunteers for HIV-RDT and to respond to a validated anonymous self-reported questionnaire. In 4 ES, 943 participants were questioned and tested, mainly men (64%), young (mean age 30 years old), living as a couple (63.7%). A large majority (95.1%) reported sexual intercourse over the last year. The mean number of partners was 4.8. About 2/3 had unprotected sex. 37.5% had never been tested and had their first test during this campaign. The 430 participants who reported no previous HIV-testing during the last 5 years more frequently declared heterosexual intercourse (OR: 2.31), identifying as a male (OR: 1.82), having transactional sex (OR: 1.92), living as a couple (OR: 1.67), having fewer sexual partners (OR: 1.06) and being younger (OR = 1.02). Three people (0.32%) were tested positive for the HIV-RDT; linkage with care was ensured for confirmatory test. This innovative and original intervention showed for the first time the usefulness of HIV-screening and awareness campaigns, in fun and commercial backdrop event. Individuals who had never been HIV-tested and who had no intention of doing so before this campaign were reached and engaged. ES are potential new locations to get HIV information and screening, to tackle sexual health-related issues and reflect on sexual risk behaviors.

The Macromolecular Femtosecond Crystallography (MFX) instrument at the Linac Coherent Light Source (LCLS) is the seventh and newest instrument at the world's first hard X-ray free-electron laser. It was designed with a primary focus on structural biology, employing the ultrafast pulses of X-rays from LCLS at atmospheric conditions to overcome radiation damage limitations in biological measurements. It is also capable of performing various time-resolved measurements. The MFX design consists of a versatile base system capable of supporting multiple methods, techniques and experimental endstations. The primary techniques supported are forward scattering and crystallography, with capabilities for various spectroscopic methods and time-resolved measurements. The location of the MFX instrument allows for utilization of multiplexing methods, increasing user access to LCLS by running multiple experiments simultaneously., (open access.)

In this work, we monitor the onset of nonthermal melting in single-crystal silicon by implementing an x-ray pump-x-ray probe scheme. Using the ultrashort pulses provided by the Linac Coherent Light Source (SLAC) and a custom-built split-and-delay line for hard x rays, we achieve the temporal resolution needed to detect the onset of the transition. Our data show no loss of long-range order up to 150±40  fs from photoabsorption, which we interpret as the time needed for the electronic system to equilibrate at or above the critical nonthermal melting temperature. Once such equilibration is reached, the loss of long-range atomic order proceeds inertially and is completed within 315±40  fs from photoabsorption.

The Eldgjá lava flood is considered Iceland's largest volcanic eruption of the Common Era. While it is well established that it occurred after the Settlement of Iceland (circa 874 CE), the date of this great event has remained uncertain. This has hampered investigation of the eruption's impacts, if any, on climate and society. Here, we use high-temporal resolution glaciochemical records from Greenland to show that the eruption began in spring 939 CE and continued, at least episodically, until at least autumn 940 CE. Contemporary chronicles identify the spread of a remarkable haze in 939 CE, and tree ring-based reconstructions reveal pronounced northern hemisphere summer cooling in 940 CE, consistent with the eruption's high yield of sulphur to the atmosphere. Consecutive severe winters and privations may also be associated with climatic effects of the volcanic aerosol veil. Iceland's formal conversion to Christianity dates to 999/1000 CE, within two generations or so of the Eldgjá eruption. The end of the pagan pantheon is foretold in Iceland's renowned medieval poem, Vǫluspá ('the prophecy of the seeress'). Several lines of the poem describe dramatic eruptive activity and attendant meteorological effects in an allusion to the fiery terminus of the pagan gods. We suggest that they draw on first-hand experiences of the Eldgjá eruption and that this retrospection of harrowing volcanic events in the poem was intentional, with the purpose of stimulating Iceland's Christianisation over the latter half of the tenth century.

We investigate the sensitivity of the relict, endemic Cretan tree species Zelkova abelicea (Lam.) Boiss. (Ulmaceae) to several climate variables (temperature, precipitation and drought). For this purpose, we establish the first centennial tree-ring chronology for the species, and the first ever tree-ring chronology for a broadleaved species on Crete. We demonstrate the strong sensitivity of Z. abelicea towards precipitation and drought in late spring to early summer and the absence of a significant response to abundant precipitation occurring during winter or early spring. Whereas the late spring sensitivity is strong and consistent through time, the species seems to be experiencing a loss of signal towards early summer conditions since the 1970s, interpreted as an earlier cessation of cambial activity due to the increase in summer drought conditions on Crete. However, despite a reduced vegetative period, no significant decrease in radial growth of Z. abelicea was observed in the tree-ring series for the last decades, thus highlighting the capacity of Z. abelicea to withstand changing environmental conditions., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Plasmacytoid dendritic cells (pDCs) are a subset of dendritic cells specialized in the production of type I interferon (IFN-α/β) and involved in various cutaneous inflammatory and autoimmune disorders, such as cutaneous lupus erythematosus (CLE) and vitiligo. Heat shock proteins (HSPs) are molecular chaperones essential for maintaining cellular functions, but they can act as a danger signal during inflammation., Objectives: To decipher the role of HSP70 in the production of IFN-α by pDCs in CLE and vitiligo., Methods: Expression of HSP70 and CD123 + pDCs was analysed by immunohistochemistry or immunofluorescence in CLE and vitiligo skin samples. Flow cytometry was performed to analyse expression of HSP70 receptors, activation markers on pDCs and DNA uptake by pDCs in the presence of HSP70. The impact of HSP70 on DNA-induced IFN-α secretion by pDCs was evaluated by enzyme-linked immunosorbent assay (ELISA). The effect of IFN-α on chemokine (C-X-C motif) ligand 9 (CXCL9)/10 gene and protein expression by keratinocytes was determined by real-time polymerase chain reaction and ELISA., Results: Infiltration of pDCs in CLE and progressive vitiligo was primarily located in the epidermis, close to keratinocytes expressing HSP70. In vitro experiments revealed that the pDCs expressing HSP70 receptor Lox-1 (lectin-like oxidized low-density lipoprotein-receptor-1) were able to aggregate HSP70. Exogenous HSP70 induced activation of pDCs and increased the uptake of exogenous DNA. Furthermore, HSP70 potentiated DNA-induced IFN-α production by pDCs. Finally, IFN-α induced expression of CXCL9 and CXCL10 by keratinocytes., Conclusions: These data demonstrate that interaction between HSP70 and pDCs in CLE and vitiligo is a prerequisite for the enhancement of IFN-α production, and could be an interesting target., (© 2017 British Association of Dermatologists.)

We provide a detailed description of selenobiotinyl-streptavidin (Se-B SA) co-crystal datasets recorded using the Coherent X-ray Imaging (CXI) instrument at the Linac Coherent Light Source (LCLS) for selenium single-wavelength anomalous diffraction (Se-SAD) structure determination. Se-B SA was chosen as the model system for its high affinity between biotin and streptavidin where the sulfur atom in the biotin molecule (C 10 H 16 N 2 O 3 S) is substituted with selenium. The dataset was collected at three different transmissions (100, 50, and 10%) using a serial sample chamber setup which allows for two sample chambers, a front chamber and a back chamber, to operate simultaneously. Diffraction patterns from Se-B SA were recorded to a resolution of 1.9 Å. The dataset is publicly available through the Coherent X-ray Imaging Data Bank (CXIDB) and also on LCLS compute nodes as a resource for research and algorithm development.

Ring width (TRW) chronologies from Siberian (Pinus sibirica) and Scots (Pinus sylvestris) pine trees were sampled at Mukhrino - a large mire complex in central-western Siberia - to evaluate the impacts of hydroclimatic variability on tree growth over the last three centuries. For this purpose, we compared climate-growth correlation profiles from trees growing on peat soils with those growing on adjacent mineral soils. Tree growth at both peat and mineral soils was positively correlated to air temperature during the vegetation period. This finding can be explained by (i) the positive influence of temperature on plant physiological processes (i.e. growth control) during the growing season and (ii) the indirect impact of air temperatures on water table fluctuations. We observe also a strong link between TRW and the winter Palmer Drought Severity Index (PDSI), especially in Siberian pine, reflecting the isolating effect of snow and limited freezing damage in roots. Significant negative relations were, by contrast, observed between bog TRW chronologies and hydroclimatic indices during spring and summer; they are considered an expression of the negative impacts of high water levels and moist peat soils on root development. Some unusually old bog pines - exhibiting >500 growth rings - apparently colonized the site at the beginning of the Little Ice Age, and therefore seem to confirm that (i) peat conditions may have been drier in Siberia than in most other regions of western Europe during this period. At the same time, the bog trees also point to (ii) their strong dependence on surface conditions., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Structural information about biological macromolecules near the atomic scale provides important insight into the functions of these molecules. To date, X-ray crystallography has been the predominant method used for macromolecular structure determination. However, challenges exist when solving structures with X-rays, including the phase problem and radiation damage. X-ray-free electron lasers (X-ray FELs) have enabled collection of diffraction information before the onset of radiation damage, yet the majority of structures solved at X-ray FELs have been phased using external information via molecular replacement. De novo phasing at X-ray FELs has proven challenging due in part to per-pulse variations in intensity and wavelength. Here we report the solution of a selenobiotinyl-streptavidin structure using phases obtained by the anomalous diffraction of selenium measured at a single wavelength (Se-SAD) at the Linac Coherent Light Source. Our results demonstrate Se-SAD, routinely employed at synchrotrons for novel structure determination, is now possible at X-ray FELs.

Human immunodeficiency virus (HIV)-associated primary effusion lymphoma (PEL) is a rare B-cell non-Hodgkin lymphoma with poor prognosis. Lymphoma cells are always infected with human herpesvirus-8 (HHV-8) and in most cases coinfected with Epstein-Barr virus. In classic presentation, PEL is characterized by body cavity effusions with or without mass lesions. A variant with only extracavitary localization has also been described. We report on a large single-center series of patients with PEL in the era of combined antiretroviral therapy (cART). The main objective was to compare the characteristics and the outcome of patients with classic (n = 34) and extracavitary (n = 17) variant PEL. At PEL diagnosis, no major difference was observed between the two groups in terms of demographic and HIV characteristics. Extracavitary localizations were exclusively nodal in six patients and involved various organs in 11 patients. Another HHV-8-associated disease was observed in 31 patients, Kaposi sarcoma in 25, and multicentric Castleman disease in 18 patients, without difference between the two groups. Thirty-two patients were treated with CHOP associated with high-dose methotrexate, 13 were treated with CHOP-derived regimen alone, and six patients received low-dose/no chemotherapy. Complete remission was achieved in 21 (62%) and seven (41%) patients of the classic and extracavitary groups, respectively. The median overall survival (OS) was 10.2 months. Despite a higher disease-free survival in the extracavitary group, there was no difference in OS between the two variants. Based on this series, characteristics of classic and extracavitary variants were very close. Although prognosis of PEL remains very severe in cART era, the median survival compares favorably with earlier series., (© 2015 Wiley Periodicals, Inc.)

The frequency and risk factors for central venous catheter-related thrombosis (CRT) during prolonged intravenous (i.v.) antibiotic therapy have rarely been reported. The primary objective of this study was to evaluate the frequency, incidence, and risk factors for CRT among patients being treated with prolonged i.v. antibiotic therapy. The secondary objective was to describe the clinical manifestations, diagnostic evaluation, and clinical management. This cohort study was conducted between August 2004 and May 2010 in a French referral center for osteoarticular infections. All patients treated for bone and joint infections with i.v. antimicrobial therapy through a central venous catheter (CVC) for ≥2 weeks were included. Risk factors were identified using nonparametric tests and logistic regression. A case-control study investigated the role of vancomycin and catheter malposition. A total of 892 patients matched the inclusion criteria. CRT developed in 16 infections occurring in 16 patients (incidence, 0.39/1,000 catheter days). The median time to a CRT was 29 days (range, 12 to 48 days). Local clinical signs, fever, and secondary complications of CRT were present in 15, 8, and 4 patients, respectively. The median C-reactive protein level was 95 mg/liter. The treatment combined catheter removal and a median of 3 months (1.5 to 6 months) of anticoagulation therapy. The outcome was good in all patients, with no recurrence of CRT. Three risk factors were identified by multivariate analysis: male sex (odds ratio [OR], 5.4; 95% confidence interval [CI], 1.1 to 26.6), catheter malposition (OR, 5.3; 95% CI, 1.6 to 17.9), and use of vancomycin (OR, 22.9; 95% CI, 2.8 to 188). Catheter-related thrombosis is a rare but severe complication in patients treated with prolonged antimicrobial therapy. Vancomycin use was the most important risk factor identified., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Aims: Paramedical personnel are exposed to tobacco smoking. Electronic cigarettes (e-cigarettes) may be considered as a lower-risk substitute for cigarettes. The aim of the study was to estimate the prevalence of e-cigarette use, the motives for use and the perceptions among French military nurses., Methods: A cross-sectional survey, using self-administered questionnaires, was conducted in 2013 among 300 students and instructors of the French school of military paramedical personnel. Prevalences of e-cigarette use among smokers and nonsmokers were compared using logistic regressions adjusted on age and gender., Results: The prevalence of smoking was 40% among the 200 responders. E-cigarette current use prevalence was 25% (6% daily users), without significant difference according to gender and age. Tobacco smokers reported significantly more e-cigarette current use (51% vs7%). Motives for e-cigarette use reported by smokers were curiosity (48%), intention to reduce tobacco consumption (43%) or to quit smoking (8%). Among users of both tobacco and e-cigarettes, 48% reported a significant decrease in tobacco consumption following e-cigarette initiation (average decrease of 5-10 cigarettes smoked per day; p <0.001). Both tobacco smokers and nonsmokers (88%) estimated that e-cigarette use was potentially harmful for health, but it was perceived as less harmful than tobacco by 46%., Conclusions: E-cigarette use among military nurses follows the trends observed in the general population in terms of prevalence and motives. E-cigarettes, which are seen as an attractive alternative to cigarettes, may contribute to a reduction in tobacco use among healthcare workers.

The Coherent X-ray Imaging (CXI) instrument specializes in hard X-ray, in-vacuum, high power density experiments in all areas of science. Two main sample chambers, one containing a 100 nm focus and one a 1 µm focus, are available, each with multiple diagnostics, sample injection, pump-probe and detector capabilities. The flexibility of CXI has enabled it to host a diverse range of experiments, from biological to extreme matter.

Introduction: In resource limited settings, patients entering an antiretroviral therapy (ART) program comprise ART naive and ART pre-treated patients who may show differential virological outcomes., Methods: This retrospective study, conducted in 2010-2012 in the HIV clinic of Calmette Hospital located in Phnom Penh (Cambodia) assessed virological failure (VF) rates and patterns of drug resistance of naive and pre-treated patients. Naive and ART pre-treated patients were included when a Viral Load (VL) was performed during the first year of ART for naive subjects or at the first consultation for pre-treated individuals. Patients showing Virological failure (VF) (>1,000 copies/ml) underwent HIV DR genotyping testing. Interpretation of drug resistance mutations was done according to 2013 version 23 ANRS algorithms., Results: On a total of 209 patients, 164 (78.4%) were naive and 45 (21.5%) were ART pre-treated. Their median initial CD4 counts were 74 cells/mm3 (IQR: 30-194) and 279 cells/mm3 (IQR: 103-455) (p<0.001), respectively. Twenty seven patients (12.9%) exhibited VF (95% CI: 8.6-18.2%), including 10 naive (10/164, 6.0%) and 17 pre-treated (17/45, 37.8%) patients (p<0.001). Among these viremic patients, twenty-two (81.4%) were sequenced in reverse transcriptase and protease coding regions. Overall, 19 (86.3%) harbored ≥1 drug resistance mutations (DRMs) whereas 3 (all belonging to pre-treated patients) harbored wild-types viruses. The most frequent DRMs were M184V (86.3%), K103N (45.5%) and thymidine analog mutations (TAMs) (40.9%). Two (13.3%) pre-treated patients harbored viruses that showed a multi-nucleos(t)ide resistance including Q151M, K65R, E33A/D, E44A/D mutations., Conclusion: In Cambodia, VF rates were low for naive patients but the emergence of DRMs to NNRTI and 3TC occurred relatively quickly in this subgroup. In pre-treated patients, VF rates were much higher and TAMs were relatively common. HIV genotypic assays before ART initiation and for ART pre-treated patients infection should be considered as well.

Polar ice core records attest to a colossal volcanic eruption that took place ca. A.D. 1257 or 1258, most probably in the tropics. Estimates based on sulfate deposition in these records suggest that it yielded the largest volcanic sulfur release to the stratosphere of the past 7,000 y. Tree rings, medieval chronicles, and computational models corroborate the expected worldwide atmospheric and climatic effects of this eruption. However, until now there has been no convincing candidate for the mid-13th century "mystery eruption." Drawing upon compelling evidence from stratigraphic and geomorphic data, physical volcanology, radiocarbon dating, tephra geochemistry, and chronicles, we argue the source of this long-sought eruption is the Samalas volcano, adjacent to Mount Rinjani on Lombok Island, Indonesia. At least 40 km(3) (dense-rock equivalent) of tephra were deposited and the eruption column reached an altitude of up to 43 km. Three principal pumice fallout deposits mantle the region and thick pyroclastic flow deposits are found at the coast, 25 km from source. With an estimated magnitude of 7, this event ranks among the largest Holocene explosive eruptions. Radiocarbon dates on charcoal are consistent with a mid-13th century eruption. In addition, glass geochemistry of the associated pumice deposits matches that of shards found in both Arctic and Antarctic ice cores, providing compelling evidence to link the prominent A.D. 1258/1259 ice core sulfate spike to Samalas. We further constrain the timing of the mystery eruption based on tephra dispersal and historical records, suggesting it occurred between May and October A.D. 1257.

Background: Large-cell transformation in mycosis fungoides [MF] is associated with an aggressive clinical course and poor survival. In addition to tumour progression, infectious complications may be the cause of death. We report a case of aseptic pustular dermatosis in transformed MF that very quickly became aggressive and was followed by rapid death of the patient., Patients and Methods: A 47-year-old man presented with disseminated CD30+ transformed MF skin tumours refractory to chemotherapy for nine consecutive months. Ten days after a first course of dexamethasone, cytarabine and carboplatin, he was hospitalized for febrile neutropenia. Following this episode of neutropenia, he developed a febrile pustular rash disseminated on the tumours and on plaques, associated with marked neutrophilic leucocytosis. Bacteriological and mycological skin and blood samples were negative. Tumour biopsies showed a dermal infiltrate of CD30+ T-cells corresponding to the transformed MF, mixed with neutrophils. The pustule biopsies revealed intra-epidermal pustules and dermal-epidermal infiltration of neutrophils. The pustular eruption regressed with corticosteroids. Despite a last line of treatment with romidepsin, the patient died 6 weeks after the "neutrophilic" event., Discussion: Episodes of neutrophilic dermatosis [ND] are frequently seen in haematological disease and some substances can induce a variant form of eccrine hidradenitis. However, our patient's presentation was different, without the appearance of "classic" ND but rather diffuse pustular lesions carrying a poor prognosis, which was followed by rapid death. Once the hypothesis of infectious complications has been ruled out, treatment is based on systemic corticosteroids associated with specific treatment of the lymphoma., (Copyright © 2013 Elsevier Masson SAS. All rights reserved.)