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Drought indices based on precipitation are commonly used to identify and characterize droughts. Due to the general complexity of droughts, the comparison of index-identified events with droughts at different levels of the complete system, including soil humidity or river discharges, relies typically on model simulations of the latter, entailing potentially significant uncertainties. The present study explores the potential of using precipitation-based indices to reproduce observed droughts in the lower part of the Jinsha River basin (JRB), proposing an innovative approach for a catchment-wide drought detection and characterization. Two indicators, namely the Overall Drought Extension (ODE) and the Overall Drought Indicator (ODI), have been defined. These indicators aim at identifying and characterizing drought events on the basin scale, using results from four meteorological drought indices (standardized precipitation index, SPI; rainfall anomaly index, RAI; percent of normal precipitation, PN; deciles, DEC) calculated at different locations of the basin and for different timescales. Collected historical information on drought events is used to contrast results obtained with the indicators. This method has been successfully applied to the lower Jinsha River basin in China, a region prone to frequent and severe droughts. Historical drought events that occurred from 1960 to 2014 have been compiled and cataloged from different sources, in a challenging process. The analysis of the indicators shows a good agreement with the recorded historical drought events on the basin scale. It has been found that the timescale that best reproduces observed events across all the indices is the 6-month timescale.

With NATO and the NATO Nations being heavily dependent on their communication and information systems, ensuring their proper operation is a critical task. Establishing appropriate cyber defence capabilities is a major endeavour and one which a lot of nations are currently putting increased focus on. The multinational approach to cyber defence capability development presented in this paper is an approach to leverage the common interest nations have in this area to efficiently develop high-quality capabilities through cooperation and coordination. The paper goes on to present initial topics where the approach could be immediately leveraged, including information sharing, situational awareness, and distributed sensor collection and coordination capabilities. The paper concludes that this way forward could significantly improve our cyber defence capabilities and contribute to the overall security of the Alliance. [PUBLICATION ABSTRACT]

In the ever-increasing pace of technological development and the emergence of new stateless adversaries and threat vectors, the traditional NATO approach to the technical capability development struggles to address the emerging security challenges in cyberspace. In order to mitigate this situation, we describe an incubator framework, which provides a physical and virtual environment enabling industry, in particular small and medium sized enterprises, science and technology organizations, academia, and national defence labs, to collaborate on innovation projects on the basis of either voluntary, nationally funded, or NATO commonly funded contributions. The proposed incubator framework has been practically validated and technical results have confirmed the feasibility as well as the benefits of setting up a cyber incubator within NATO. This disruptive approach to capability development requires the updating of several internal processes and procedures and the adoption of a new innovation-friendly and risk-tolerant organizational culture within the Organization. We describe the main lessons learned from our experiment and the recommendations regarding required changes to the internal and external NATO processes and procedures.

The inflammatory bowel diseases (IBD), comprising Crohn’s disease (CD) and ulcerative colitis (UC), are chronic, progressive, inflammatory conditions of the gastrointestinal tract. Imbalance in the gut microbial community, or dysbiosis, and the subsequent immune response, represent the critical relationship between genetic susceptibility, microbes, and environment factors, that result in IBD. Gastrointestinal pathogens – a common cause of dysbiosis – have been implicated as an environmental trigger in new onset IBD, as well as flare of existing IBD. In this article, we systematically review clinical data regarding the association between specific gastrointestinal pathogens and IBD. Numerous bacteria, viruses, fungi, and parasites have been implicated in the pathogenesis of IBD, and exacerbations of existing disease. In this article, we will also specifically discuss the less recognized microbes that have an inverse association with IBD, including certain bacterial pathogens, such as Helicobacter pylori, and parasites, such as Trichuris species. Future prospective and experimental studies are required to establish causality and clarify potential mechanisms of enteric pathogens in modifying the risk and course of IBD.

Damage to specific brain circuits can cause specific neuropsychiatric symptoms. Therapeutic stimulation to these same circuits may modulate these symptoms. To determine whether these circuits converge, we studied depression severity after brain lesions ( n  = 461, five datasets), transcranial magnetic stimulation ( n  = 151, four datasets) and deep brain stimulation ( n  = 101, five datasets). Lesions and stimulation sites most associated with depression severity were connected to a similar brain circuit across all 14 datasets ( P  < 0.001). Circuits derived from lesions, deep brain stimulation and transcranial magnetic stimulation were similar ( P  < 0.0005), as were circuits derived from patients with major depression versus other diagnoses ( P  < 0.001). Connectivity to this circuit predicted out-of-sample antidepressant efficacy of transcranial magnetic stimulation and deep brain stimulation sites ( P  < 0.0001). In an independent analysis, 29 lesions and 95 stimulation sites converged on a distinct circuit for motor symptoms of Parkinson’s disease ( P  < 0.05). We conclude that lesions, transcranial magnetic stimulation and DBS converge on common brain circuitry that may represent improved neurostimulation targets for depression and other disorders. Which brain circuits are causally involved in depression? Using the human connectome as a wiring diagram, Siddiqi et al. combine data from lesions, deep brain stimulation and transcranial magnetic stimulation studies to show that these three methods converge in identifying a single depression circuit.

Psychiatric disorders share neurobiology and frequently co-occur. This neurobiological and clinical overlap highlights opportunities for transdiagnostic treatments. In this study, we used coordinate and lesion network mapping to test for a shared brain network across psychiatric disorders. In our meta-analysis of 193 studies, atrophy coordinates across six psychiatric disorders mapped to a common brain network defined by positive connectivity to anterior cingulate and insula, and by negative connectivity to posterior parietal and lateral occipital cortex. This network was robust to leave-one-diagnosis-out cross-validation and specific to atrophy coordinates from psychiatric versus neurodegenerative disorders (72 studies). In 194 patients with penetrating head trauma, lesion damage to this network correlated with the number of post-lesion psychiatric diagnoses. Neurosurgical ablation targets for psychiatric illness (four targets) also aligned with the network. This convergent brain network for psychiatric illness may partially explain high rates of psychiatric comorbidity and could highlight neuromodulation targets for patients with more than one psychiatric disorder. The authors use morphometric and brain lesion data to identify a convergent brain network shared by psychiatric disorders.

Alterations in commensal bacteria are associated with an increased risk of allergic disease. David Artis and his colleagues now report that commensal-derived signals influence basophil development and T H 2 cytokine–dependent allergic airway inflammation by suppressing serum IgE levels. Individuals with hyper IgE syndrome also have elevated circulating basophil numbers, suggesting a mechanistic link between commensal bacteria, B cell–mediated production of IgE and basophil hematopoiesis. Commensal bacteria that colonize mammalian barrier surfaces are reported to influence T helper type 2 (T H 2) cytokine-dependent inflammation and susceptibility to allergic disease, although the mechanisms that underlie these observations are poorly understood. In this report, we find that deliberate alteration of commensal bacterial populations via oral antibiotic treatment resulted in elevated serum IgE concentrations, increased steady-state circulating basophil populations and exaggerated basophil-mediated T H 2 cell responses and allergic inflammation. Elevated serum IgE levels correlated with increased circulating basophil populations in mice and subjects with hyperimmunoglobulinemia E syndrome. Furthermore, B cell–intrinsic expression of myeloid differentiation factor 88 (MyD88) was required to limit serum IgE concentrations and circulating basophil populations in mice. Commensal-derived signals were found to influence basophil development by limiting proliferation of bone marrow–resident precursor populations. Collectively, these results identify a previously unrecognized pathway through which commensal-derived signals influence basophil hematopoiesis and susceptibility to T H 2 cytokine–dependent inflammation and allergic disease.

The introduction of neonicotinoids for managing insecticide resistance in mosquitoes is of high interest as they interact with a biochemical target not previously used in public health. In this concern, Bayer developed a combination of the neonicotinoid clothianidin and the pyrethroid deltamethrin (brand name Fludora Fusion) as a new vector control tool. Although this combination proved to be efficient against pyrethroid-resistant mosquitoes, its ability to prevent the selection of pyrethroid and neonicotinoid resistance alleles was not investigated. In this context, the objective of this work was to study the dynamics and the molecular mechanisms of resistance of An. gambiae to the separated or combined components of this combination. A field-derived An. gambiae line carrying resistance alleles to multiple insecticides at low frequencies was used as a starting for 33 successive generations of controlled selection. Resistance levels to each insecticide and target site mutation frequencies were monitored throughout the selection process. Cross resistance to other public health insecticides were also investigated. RNA-seq was used to compare gene transcription variations and polymorphisms across all lines. This study confirmed the potential of this insecticide combination to impair the selection of resistance as compared to its two separated components. Deltamethrin selection led to the rapid enrichment of the kdr L1014F target-site mutation. Clothianidin selection led to the over-transcription of multiple cytochrome P450s including some showing high homology with those conferring neonicotinoid resistance in other insects. A strong selection signature associated with clothianidin selection was also observed on a P450 gene cluster previously associated with resistance. Within this cluster, the gene CYP6M1 showed the highest selection signature together with a transcription profile supporting a role in clothianidin resistance. Modelling the impact of point mutations selected by clothianidin on CYP6M1 protein structure showed that selection retained a protein variant with a modified active site potentially enhancing clothianidin metabolism. In the context of the recent deployment of neonicotinoids for mosquito control and their frequent usage in agriculture, the present study highlights the benefit of combining them with other insecticides for preventing the selection of resistance and sustaining vector control activities.

Cancer immunotherapy based on genetically redirecting T cells has been used successfully to treat B cell malignancies 1 – 3 . In this strategy, the T cell genome is modified by integration of viral vectors or transposons encoding chimaeric antigen receptors (CARs) that direct tumour cell killing. However, this approach is often limited by the extent of expansion and persistence of CAR T cells 4 , 5 . Here we report mechanistic insights from studies of a patient with chronic lymphocytic leukaemia treated with CAR T cells targeting the CD19 protein. Following infusion of CAR T cells, anti-tumour activity was evident in the peripheral blood, lymph nodes and bone marrow; this activity was accompanied by complete remission. Unexpectedly, at the peak of the response, 94% of CAR T cells originated from a single clone in which lentiviral vector-mediated insertion of the CAR transgene disrupted the methylcytosine dioxygenase TET2 gene. Further analysis revealed a hypomorphic mutation in this patient’s second TET2 allele. TET2 -disrupted CAR T cells exhibited an epigenetic profile consistent with altered T cell differentiation and, at the peak of expansion, displayed a central memory phenotype. Experimental knockdown of TET2 recapitulated the potency-enhancing effect of TET2 dysfunction in this patient’s CAR T cells. These findings suggest that the progeny of a single CAR T cell induced leukaemia remission and that TET2 modification may be useful for improving immunotherapies. Genetically engineered T cells that induced remission in a patient with chronic lymphocytic leukaemia were found to have disruption of the TET2 gene, which caused T cell changes that potentiated their anti-tumour effects.

Bacteriophages infect gram-negative bacteria by attaching to molecules present on the bacterial surface, often lipopolysaccharides (LPS). Modification of LPS can lead to resistance to phage infection. In addition, LPS modifications can impact antibiotic susceptibility, allowing for phage–antibiotic synergism. The evolutionary mechanism(s) behind such synergistic interactions remain largely unclear. Here, we show that the presence of antibiotics can affect the evolution of resistance to phage infection, using phage ΦX174 and Escherichia coli C. We use a collection of 34 E . coli C LPS strains, each of which is resistant to ΦX174, and has either a “rough” or “deep rough” LPS phenotype. Growth of the bacterial strains with the deep rough phenotype is inhibited at low concentrations of chloramphenicol and, to a much lesser degree, gentamicin. Treating E . coli C wild type with ΦX174 and chloramphenicol eliminates the emergence of mutants with the deep rough phenotype, and thereby slows the evolution of resistance to phage infection. At slightly lower chloramphenicol concentrations, phage resistance rates are similar to those observed at high concentrations; yet, we show that the diversity of possible mutants is much larger than at higher chloramphenicol concentrations. These data suggest that specific antibiotic concentrations can lead to synergistic phage–antibiotic interactions that disappear at higher antibiotic concentrations. Overall, we show that the change in survival of various ΦX174-resistant E . coli C mutants in the presence of antibiotics can explain the observed phage–antibiotic synergism.