Germanium has long been regarded as a promising laser material for silicon based opto-electronics. It is CMOS-compatible and has a favourable band structure, which can be tuned by strain or alloying ...with Sn to become direct, as it was found to be required for interband semiconductor lasers. Here, we report lasing in the mid-infrared region (from λ = 3.20 μm up to λ = 3.66 μm) in tensile strained Ge microbridges uniaxially loaded above 5.4% up to 5.9% upon optical pumping, with a differential quantum efficiency close to 100% with a lower bound of 50% and a maximal operating temperature of 100 K. We also demonstrate the effect of a non-equilibrium electron distribution in k-space which reveals the importance of directness for lasing. With these achievements the strained Ge approach is shown to compare well to GeSn, in particular in terms of efficiency.
The randomized phase II OPUS (Oxaliplatin and Cetuximab in First-Line Treatment of Metastatic Colorectal Cancer) study showed that tumor KRAS mutation status was predictive for outcome in patients ...receiving cetuximab plus FOLFOX-4 (oxaliplatin/5-fluorouracil/folinic acid) as first-line therapy for metastatic colorectal cancer (mCRC).
The biomarker analysis was extended through the use of additional DNA samples extracted from stained tissue sections. KRAS and BRAF tumor mutation status was determined for new (and for BRAF, existing) samples using a PCR technique. Clinical outcome was reassessed according to mutation status. Overall survival data are presented.
Of 315 KRAS evaluable patient samples (93%), 179 tumors (57%) were KRAS wild type. Eleven of 309 (4%) KRAS/BRAF evaluable tumors (all KRAS wild type) carried BRAF mutations. The addition of cetuximab to FOLFOX-4 significantly improved progression-free survival (hazard ratio 0.567, P = 0.0064) and response (odds ratio 2.551, P = 0.0027) in patients with KRAS wild-type tumors. A favorable effect on survival was also observed.
These results confirm the efficacy of cetuximab plus FOLFOX-4 in the first-line treatment of patients with KRAS wild-type mCRC and confirm KRAS mutation status as an effective predictive biomarker. The small number of tumors with BRAF mutations precluded the drawing of definitive conclusions concerning the predictive or prognostic utility of this biomarker.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) has emerged as a crucial cytokine produced by auto-reactive T helper (Th) cells that initiate tissue inflammation. Multiple cell types can ...sense GM-CSF, but the identity of the pathogenic GM-CSF-responsive cells is unclear. By using conditional gene targeting, we systematically deleted the GM-CSF receptor (Csf2rb) in specific subpopulations throughout the myeloid lineages. Experimental autoimmune encephalomyelitis (EAE) progressed normally when either classical dendritic cells (cDCs) or neutrophils lacked GM-CSF responsiveness. The development of tissue-invading monocyte-derived dendritic cells (moDCs) was also unperturbed upon Csf2rb deletion. Instead, deletion of Csf2rb in CCR2+Ly6Chi monocytes phenocopied the EAE resistance seen in complete Csf2rb-deficient mice. High-dimensional analysis of tissue-infiltrating moDCs revealed that GM-CSF initiates a combination of inflammatory mechanisms. These results indicate that GM-CSF signaling controls a pathogenic expression signature in CCR2+Ly6Chi monocytes and their progeny, which was essential for tissue damage.
•GM-CSF controls diverse pathogenic capabilities of inflammatory myeloid cells•GM-CSF induces an inflammatory response in CCR2+ monocytes required for tissue damage•Neutrophils, cDCs, and microglia do not require GM-CSF signaling for EAE development•GM-CSF signaling triggers an inflammatory signature in human monocytes
GM-CSF is crucial for the development of tissue inflammation in EAE, but the identity of the pathogenic GM-CSF-responsive cells is unclear. By targeted deletion of the GM-CSF receptor, Becher and colleagues reveal that CCR2+ monocytes require GM-CSF to initiate tissue damage, with similar mechanisms operating in both mouse and human.
Immune-checkpoint blockade has revolutionized cancer therapy. In particular, inhibition of programmed cell death protein 1 (PD-1) has been found to be effective for the treatment of metastatic ...melanoma and other cancers. Despite a dramatic increase in progression-free survival, a large proportion of patients do not show durable responses. Therefore, predictive biomarkers of a clinical response are urgently needed. Here we used high-dimensional single-cell mass cytometry and a bioinformatics pipeline for the in-depth characterization of the immune cell subsets in the peripheral blood of patients with stage IV melanoma before and after 12 weeks of anti-PD-1 immunotherapy. During therapy, we observed a clear response to immunotherapy in the T cell compartment. However, before commencing therapy, a strong predictor of progression-free and overall survival in response to anti-PD-1 immunotherapy was the frequency of CD14
CD16
HLA-DR
monocytes. We confirmed this by conventional flow cytometry in an independent, blinded validation cohort, and we propose that the frequency of monocytes in PBMCs may serve in clinical decision support.
Facial vibrissae (whiskers) are thin, tapered, flexible, hair-like structures that are an important source of tactile sensory information for many species of mammals. In contrast to insect antennae, ...whiskers have no sensors along their lengths. Instead, when a whisker touches an object, the resulting deformation is transmitted to mechanoreceptors in a follicle at the whisker base. Previous work has shown that the mechanical signals transmitted along the whisker will depend strongly on the whisker's geometric parameters, specifically on its taper (how diameter varies with arc length) and on the way in which the whisker curves, often called "intrinsic curvature." Although previous studies have largely agreed on how to define taper, multiple methods have been used to quantify intrinsic curvature. The present work compares and contrasts different mathematical approaches towards quantifying this important parameter. We begin by reviewing and clarifying the definition of "intrinsic curvature," and then show results of fitting whisker shapes with several different functions, including polynomial, fractional exponent, elliptical, and Cesàro. Comparisons are performed across ten species of whiskered animals, ranging from rodents to pinnipeds. We conclude with a discussion of the advantages and disadvantages of using the various models for different modeling situations. The fractional exponent model offers an approach towards developing a species-specific parameter to characterize whisker shapes within a species. Constructing models of how the whisker curves is important for the creation of mechanical models of tactile sensory acquisition behaviors, for studies of comparative evolution, morphology, and anatomy, and for designing artificial systems that can begin to emulate the whisker-based tactile sensing of animals.
Individual reports suggest that the central nervous system (CNS) contains multiple immune cell types with diverse roles in tissue homeostasis, immune defense, and neurological diseases. It has been ...challenging to map leukocytes across the entire brain, and in particular in pathology, where phenotypic changes and influx of blood-derived cells prevent a clear distinction between reactive leukocyte populations. Here, we applied high-dimensional single-cell mass and fluorescence cytometry, in parallel with genetic fate mapping systems, to identify, locate, and characterize multiple distinct immune populations within the mammalian CNS. Using this approach, we revealed that microglia, several subsets of border-associated macrophages and dendritic cells coexist in the CNS at steady state and exhibit disease-specific transformations in the immune microenvironment during aging and in models of Alzheimer’s disease and multiple sclerosis. Together, these data and the described framework provide a resource for the study of disease mechanisms, potential biomarkers, and therapeutic targets in CNS disease.
Display omitted
•High-dimensional cytometry reveals diverse immune cells in the steady-state CNS•CD38 and MHCII distinguish CNS border-associated macrophage (BAM) subsets•A subset of microglia responds to aging and neurodegeneration•All microglia are homogenously affected in neuroinflammatory disease
It has been challenging to map leukocytes in the brain, particularly during pathology. Mrdjen et al. combine high-dimensional single-cell cytometry with fate mapping to capture the immune landscape of the brain. They identify different subsets of myeloid cells and the phenotypic changes in CNS immune cells during aging and in models of Alzheimer’s disease and multiple sclerosis.
Mental health professionals typically encounter patients at 1 point in patients' lives. This cross-sectional window understandably fosters focus on the current presenting diagnosis. Research ...programs, treatment protocols, specialist clinics, and specialist journals are oriented to presenting diagnoses, on the assumption that diagnosis informs about causes and prognosis. This study tests an alternative hypothesis: people with mental disorders experience many different kinds of disorders across diagnostic families, when followed for 4 decades.
To describe mental disorder life histories across the first half of the life course.
This cohort study involved participants born in New Zealand from 1972 to 1973 who were enrolled in the population-representative Dunedin Study. Participants were observed from birth to age 45 years (until April 2019). Data were analyzed from May 2019 to January 2020.
Diagnosed impairing disorders were assessed 9 times from ages 11 to 45 years. Brain function was assessed through neurocognitive examinations conducted at age 3 years, neuropsychological testing during childhood and adulthood, and midlife neuroimaging-based brain age.
Of 1037 original participants (535 male 51.6%), 1013 had mental health data available. The proportions of participants meeting the criteria for a mental disorder were as follows: 35% (346 of 975) at ages 11 to 15 years, 50% (473 of 941) at age 18 years, 51% (489 of 961) at age 21 years, 48% (472 of 977) at age 26 years, 46% (444 of 969) at age 32 years, 45% (429 of 955) at age 38 years, and 44% (407 of 927) at age 45 years. The onset of the disorder occurred by adolescence for 59% of participants (600 of 1013), eventually affecting 86% of the cohort (869 of 1013) by midlife. By age 45 years, 85% of participants (737 of 869) with a disorder had accumulated comorbid diagnoses. Participants with adolescent-onset disorders subsequently presented with disorders at more past-year assessments (r = 0.71; 95% CI, 0.68 to 0.74; P < .001) and met the criteria for more diverse disorders (r = 0.64; 95% CI, 0.60 to 0.67; P < .001). Confirmatory factor analysis summarizing mental disorder life histories across 4 decades identified a general factor of psychopathology, the p-factor. Longitudinal analyses showed that high p-factor scores (indicating extensive mental disorder life histories) were antedated by poor neurocognitive functioning at age 3 years (r = -0.18; 95% CI, -0.24 to -0.12; P < .001), were accompanied by childhood-to-adulthood cognitive decline (r = -0.11; 95% CI, -0.17 to -0.04; P < .001), and were associated with older brain age at midlife (r = 0.14; 95% CI, 0.07 to 0.20; P < .001).
These findings suggest that mental disorder life histories shift among different successive disorders. Data from the present study, alongside nationwide data from Danish health registers, inform a life-course perspective on mental disorders. This perspective cautions against overreliance on diagnosis-specific research and clinical protocols.
PDF
