Acute military psychiatric casualties from the war in Iraq

Background: The view that most military personnel evacuated from war zones are suffering from combat stress reactions, or are otherwise traumatised by the horrors of war, has an impact on all aspects of military psychiatry. Aims: To delineate the reasons for psychiatric aeromedical evacuation from Iraq from the start of build-up of UK forces in January 2003 until the end of October that year, 6 months after the end of formal hostilities. Method: A retrospective study was conducted of field and in-patient psychiatric assessments of 116 military personnel evacuated to the UK military psychiatric in-patient facility in Catterick Garrison. Results: Evacuees were mainly non-combatants (69%). A significant proportion were in reserve service (21%) and had a history of contact with mental health services (37%). Only 3% had a combat stress reaction. In over 85% of cases evacuation was for low mood attributed to separation from friends or family, or difficulties adjusting to the environment. Conclusions: These findings have implications especially for screening for suitability for deployment, and for understanding any longer-term mental health problems arising in veterans from Iraq

Regulation of A disintegrin and metalloproteinase (ADAM) family sheddases ADAM10 and ADAM17: The emerging role of tetraspanins and rhomboids

A disintegrin and metalloprotease (ADAM) 10 and ADAM17 are ubiquitous transmembrane “molecular scissors” which proteolytically cleave, or shed, the extracellular regions of other transmembrane proteins. ADAM10 is essential for development because it cleaves Notch proteins to induce Notch signaling and regulate cell fate decisions. ADAM17 is regarded as a first line of defense against injury and infection, by releasing tumor necrosis factor α (TNFα) to promote inflammation and epidermal growth factor (EGF) receptor ligands to maintain epidermal barrier function. However, the regulation of ADAM10 and ADAM17 trafficking and activation are not fully understood. This review will describe how the TspanC8 subgroup of tetraspanins (Tspan5, 10, 14, 15, 17, and 33) and the iRhom subgroup of protease-inactive rhomboids (iRhom1 and 2) have emerged as important regulators of ADAM10 and ADAM17, respectively. In particular, they are required for the enzymatic maturation and trafficking to the cell surface of the ADAMs, and there is evidence that different TspanC8s and iRhoms target the ADAMs to distinct substrates. The TspanC8s and iRhoms have not been studied functionally on platelets. On these cells, ADAM10 is the principal sheddase for the platelet collagen receptor GPVI, and the regulatory TspanC8s are Tspan14, 15, and 33, as determined from proteomic data. Platelet ADAM17 is the sheddase for the von Willebrand factor (vWF) receptor GPIb, and iRhom2 is the only iRhom that is expressed. Induced shedding of either GPVI or GPIb has therapeutic potential, since inhibition of either receptor is regarded as a promising anti-thrombotic therapy. Targeting of Tspan14, 15, or 33 to activate platelet ADAM10, or iRhom2 to activate ADAM17, may enable such an approach to be realized, without the toxic side effects of activating the ADAMs on every cell in the body

TRPM7 Kinase Controls Calcium Responses in Arterial Thrombosis and Stroke in Mice

Objective: TRPM7 (transient receptor potential cation channel, subfamily M, member 7) is a ubiquitously expressed bifunctional protein comprising a transient receptor potential channel segment linked to a cytosolic alpha-type serine/threonine protein kinase domain. TRPM7 forms a constitutively active Mg2+ and Ca2+ permeable channel, which regulates diverse cellular processes in both healthy and diseased conditions, but the physiological role of TRPM7 kinase remains largely unknown. Approach and Results: Here we show that point mutation in TRPM7 kinase domain deleting the kinase activity in mice (Trpm7(R/R)) causes a marked signaling defect in platelets. Trpm7(R/R) platelets showed an impaired PIP2 (phosphatidylinositol-4,5-bisphosphate) metabolism and consequently reduced Ca2+ mobilization in response to stimulation of the major platelet receptors GPVI (glycoprotein VI), CLEC-2 (C-type lectin-like receptor), and PAR (protease-activated receptor). Altered phosphorylation of Syk (spleen tyrosine kinase) and phospholipase C gamma 2 and beta 3 accounted for these global platelet activation defects. In addition, direct activation of STIM1 (stromal interaction molecule 1) with thapsigargin revealed a defective store-operated Ca2+ entry mechanism in the mutant platelets. These defects translated into an impaired platelet aggregate formation under flow and protection of the mice from arterial thrombosis and ischemic stroke in vivo. Conclusions: Our results identify TRPM7 kinase as a key modulator of phospholipase C signaling and store-operated Ca2+ entry in platelets. The protection of Trpm7(R/R) mice from acute ischemic disease without developing intracranial hemorrhage indicates that TRPM7 kinase might be a promising antithrombotic target

Emotional ratings and skin conductance response to visual, auditory and haptic stimuli

The human emotional reactions to stimuli delivered by different sensory modalities is a topic of interest for many disciplines, from Human-Computer-Interaction to cognitive sciences. Different databases of stimuli eliciting emotional reaction are available, tested on a high number of participants. Interestingly, stimuli within one database are always of the same type. In other words, to date, no data was obtained and compared from distinct types of emotion-eliciting stimuli from the same participant. This makes it difficult to use different databases within the same experiment, limiting the complexity of experiments investigating emotional reactions. Moreover, whereas the stimuli and the participants’ rating to the stimuli are available, physiological reactions of participants to the emotional stimuli are often recorded but not shared. Here, we test stimuli delivered either through a visual, auditory, or haptic modality in a within participant experimental design. We provide the results of our study in the form of a MATLAB structure including basic demographics on the participants, the participant’s self-assessment of his/her emotional state, and his/her physiological reactions (i.e., skin conductance)

The tetraspanin Tspan15 is an essential subunit of an ADAM10 scissor complex

A disintegrin and metalloprotease 10 (ADAM10) is a transmembrane protein essential for embryonic development, and its dysregulation underlies disorders such as cancer, Alzheimer's disease, and inflammation. ADAM10 is a molecular scissor that proteolytically cleaves the extracellular region from >100 substrates, including Notch, amyloid precursor protein, cadherins, growth factors, and chemokines. ADAM10 has been recently proposed to function as six distinct scissors with different substrates, depending on its association with one of six regulatory tetraspanins, termed TspanC8s. However, it remains unclear to what degree ADAM10 function critically depends on a TspanC8 partner, and a lack of monoclonal antibodies specific for most TspanC8s has hindered investigation of this question. To address this knowledge gap, here we designed an immunogen to generate the first monoclonal antibodies targeting Tspan15, a model TspanC8. The immunogen was created in an ADAM10-knockout mouse cell line stably overexpressing human Tspan15, because we hypothesized that expression in this cell line would expose epitopes that are normally blocked by ADAM10. Following immunization of mice, this immunogen strategy generated four Tspan15 antibodies. Using these antibodies, we show that endogenous Tspan15 and ADAM10 co-localize on the cell surface, that ADAM10 is the principal Tspan15-interacting protein, that endogenous Tspan15 expression requires ADAM10 in cell lines and primary cells, and that a synthetic ADAM10/Tspan15 fusion protein is a functional scissor. Furthermore, two of the four antibodies impaired ADAM10/Tspan15 activity. These findings suggest that Tspan15 directly interacts with ADAM10 in a functional scissor complex

Above- and below-ground vertebrate herbivory may each favour a different subordinate species in an aquatic plant community

At least two distinct trade-offs are thought to facilitate higher diversity in productive plant communities under herbivory. Higher investment in defence and enhanced colonization potential may both correlate with decreased competitive ability in plants. Herbivory may thus promote coexistence of plant species exhibiting divergent life history strategies. How different seasonally tied herbivore assemblages simultaneously affect plant community composition and diversity is, however, largely unknown. Two contrasting types of herbivory can be distinguished in the aquatic vegetation of the shallow lake Lauwersmeer. In summer, predominantly above-ground tissues are eaten, whereas in winter, waterfowl forage on below-ground plant propagules. In a 4-year exclosure study we experimentally separated above-ground herbivory by waterfowl and large fish in summer from below-ground herbivory by Bewick’s swans in winter. We measured the individual and combined effects of both herbivory periods on the composition of the three-species aquatic plant community. Herbivory effect sizes varied considerably from year to year. In 2 years herbivore exclusion in summer reinforced dominance of Potamogeton pectinatus with a concomitant decrease in Potamogeton pusillus, whereas no strong, unequivocal effect was observed in the other 2 years. Winter exclusion, on the other hand, had a negative effect on Zannichellia palustris, but the effect size differed considerably between years. We suggest that the colonization ability of Z. palustris may have enabled this species to be more abundant after reduction of P. pectinatus tuber densities by swans. Evenness decreased due to herbivore exclusion in summer. We conclude that seasonally tied above- and below-ground herbivory may each stimulate different components of a macrophyte community as they each favoured a different subordinate plant species

T Cell Cancer Therapy Requires CD40-CD40L Activation of Tumor Necrosis Factor and Inducible Nitric-Oxide-Synthase-Producing Dendritic Cells

Effective cancer immunotherapy requires overcoming immunosuppressive tumor microenvironments. We\ua0found that local nitric oxide (NO) production by tumor-infiltrating myeloid cells is important for adoptively transferred CD8(+) cytotoxic T\ua0cells to destroy tumors. These myeloid cells are phenotypically similar to inducible nitric oxide synthase (NOS2)- and tumor necrosis factor (TNF)-producing dendritic cells (DC), or Tip-DCs. Depletion of immunosuppressive, colony stimulating factor 1 receptor (CSF-1R)-dependent arginase 1(+) myeloid cells enhanced NO-dependent tumor killing. Tumor elimination via NOS2 required the CD40-CD40L pathway. We also uncovered a strong correlation between survival of colorectal cancer patients and NOS2, CD40, and TNF expression in their tumors. Our results identify a network of pro-tumor factors that can be targeted to boost cancer immunotherapies

Density Contrast Sedimentation Velocity for the Determination of Protein Partial-Specific Volumes

The partial-specific volume of proteins is an important thermodynamic parameter required for the interpretation of data in several biophysical disciplines. Building on recent advances in the use of density variation sedimentation velocity analytical ultracentrifugation for the determination of macromolecular partial-specific volumes, we have explored a direct global modeling approach describing the sedimentation boundaries in different solvents with a joint differential sedimentation coefficient distribution. This takes full advantage of the influence of different macromolecular buoyancy on both the spread and the velocity of the sedimentation boundary. It should lend itself well to the study of interacting macromolecules and/or heterogeneous samples in microgram quantities. Model applications to three protein samples studied in either H2O, or isotopically enriched H218O mixtures, indicate that partial-specific volumes can be determined with a statistical precision of better than 0.5%, provided signal/noise ratios of 50–100 can be achieved in the measurement of the macromolecular sedimentation velocity profiles. The approach is implemented in the global modeling software SEDPHAT

Consensus guidelines for the use and interpretation of angiogenesis assays

The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference

Twelve-month observational study of children with cancer in 41 countries during the COVID-19 pandemic

Introduction Childhood cancer is a leading cause of death. It is unclear whether the COVID-19 pandemic has impacted childhood cancer mortality. In this study, we aimed to establish all-cause mortality rates for childhood cancers during the COVID-19 pandemic and determine the factors associated with mortality. Methods Prospective cohort study in 109 institutions in 41 countries. Inclusion criteria: children <18 years who were newly diagnosed with or undergoing active treatment for acute lymphoblastic leukaemia, non-Hodgkin's lymphoma, Hodgkin lymphoma, retinoblastoma, Wilms tumour, glioma, osteosarcoma, Ewing sarcoma, rhabdomyosarcoma, medulloblastoma and neuroblastoma. Of 2327 cases, 2118 patients were included in the study. The primary outcome measure was all-cause mortality at 30 days, 90 days and 12 months. Results All-cause mortality was 3.4% (n=71/2084) at 30-day follow-up, 5.7% (n=113/1969) at 90-day follow-up and 13.0% (n=206/1581) at 12-month follow-up. The median time from diagnosis to multidisciplinary team (MDT) plan was longest in low-income countries (7 days, IQR 3-11). Multivariable analysis revealed several factors associated with 12-month mortality, including low-income (OR 6.99 (95% CI 2.49 to 19.68); p<0.001), lower middle income (OR 3.32 (95% CI 1.96 to 5.61); p<0.001) and upper middle income (OR 3.49 (95% CI 2.02 to 6.03); p<0.001) country status and chemotherapy (OR 0.55 (95% CI 0.36 to 0.86); p=0.008) and immunotherapy (OR 0.27 (95% CI 0.08 to 0.91); p=0.035) within 30 days from MDT plan. Multivariable analysis revealed laboratory-confirmed SARS-CoV-2 infection (OR 5.33 (95% CI 1.19 to 23.84); p=0.029) was associated with 30-day mortality. Conclusions Children with cancer are more likely to die within 30 days if infected with SARS-CoV-2. However, timely treatment reduced odds of death. This report provides crucial information to balance the benefits of providing anticancer therapy against the risks of SARS-CoV-2 infection in children with cancer