ABSTRACT BACKGROUND Peer review is used to determine what research is funded and published, yet little is known about its effectiveness, and it is suspected that there may be biases. We investigated ...the variability of peer review and factors influencing ratings of grant applications. METHODS We evaluated all grant applications submitted to the Canadian Institutes of Health Research between 2012 and 2014. The contribution of application, principal applicant and reviewer characteristics to overall application score was assessed after adjusting for the applicant’s scientific productivity. RESULTS Among 11 624 applications, 66.2% of principal applicants were male and 64.1% were in a basic science domain. We found a significant nonlinear association between scientific productivity and final application score that differed by applicant gender and scientific domain, with higher scores associated with past funding success and h -index and lower scores associated with female applicants and those in the applied sciences. Significantly lower application scores were also associated with applicants who were older, evaluated by female reviewers only (v. male reviewers only, −0.05 points, 95% confidence interval CI −0.08 to −0.02) or reviewers in scientific domains different from the applicant’s (−0.07 points, 95% CI −0.11 to −0.03). Significantly higher application scores were also associated with reviewer agreement in application score (0.23 points, 95% CI 0.20 to 0.26), the existence of reviewer conflicts (0.09 points, 95% CI 0.07 to 0.11), larger budget requests (0.01 points per $100 000, 95% CI 0.007 to 0.02), and resubmissions (0.15 points, 95% CI 0.14 to 0.17). In addition, reviewers with high expertise were more likely than those with less expertise to provide higher scores to applicants with higher past success rates (0.18 points, 95% CI 0.08 to 0.28). INTERPRETATION There is evidence of bias in peer review of operating grants that is of sufficient magnitude to change application scores from fundable to nonfundable. This should be addressed by training and policy changes in research funding.
Garnet amphibolites can provide valuable insights into geological processes of orogenic belts, but their metamorphic evolution is still poorly constrained. Garnet amphibolites from the Wutai–Hengshan ...area of the North China Craton mainly consist of garnet, hornblende, plagioclase, quartz, rutile and ilmenite, with or without titanite and epidote. Four samples selected in a south–north profile were studied by the pseudosection approach in order to elucidate the characteristics of their metamorphic evolution, and to better reveal the northwards prograde change in P–T conditions as established previously. For the sample from the lower Wutai Subgroup, garnet exhibits obvious two‐substage growth zoning characteristic of pyrope (Xpy) increasing but grossular (Xgr) decreasing outwards in the core, and both Xpy and Xgr increasing outwards in the rim. Phase modelling using thermocalc suggests that the garnet cores were formed by chlorite breakdown over 7–9 kbar at 530–600 °C, and rims grew from hornblende and epidote breakdown over 9.5–11.5 kbar at 600–670 °C. The isopleths of the minimum An in plagioclase and maximum Xpy in garnet were used to constrain the peak P–T conditions of ~11.5 kbar/670 °C. The modelled peak assemblage garnet + hornblende + epidote+ plagioclase + rutile + quartz matches well the observed one. Plagioclase–hornblende coronae around garnet indicate post‐peak decompression and fluid ingress. For the samples from the south Hengshan Complex, the garnet zoning weaken gradually, reflecting modifications during decompression of the rocks. Using the same approach, the rocks are inferred to have suprasolidus peak conditions, increasing northwards from 11.5 kbar/745 °C, 12.5 kbar/780 °C to 13 kbar/800 °C. Their modelled peak assemblages involve diopside, garnet, hornblende, plagioclase, rutile and quartz, yet diopside is not observed petrographically. The post‐peak decompression is characterized by diopside + garnet + quartz + melt = hornblende + plagioclase, causing the diopside consumption and garnet compositions to be largely modified. Thus, the pesudosection approach is expected to provide better pressure results than conventional thermobarometry, because the later approach cannot be applied with confidence to rocks with multi‐generation assemblages. U–Pb dating of zircon in the Wutai sample records a protolith age of c. 2.50 Ga, and a metamorphic age of c. 1.95 Ga, while zircon in the Hengshan samples records metamorphic ages of c. 1.92 Ga. The c. 1.95 Ga is interpreted to represent the pre‐peak or peak metamorphic stages, and the ages of c. 1.92 Ga are assigned to represent the cooling stages. All rocks in the Wutai–Hengshan area share similar clockwise P–T morphologies. They may represent metamorphic products at different crustal depths in one orogenic event, which included a main thickening stage at c. 1.95 Ga followed by a prolonged uplift and cooling after 1.92 Ga.
Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To ...elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.
Interoception, the ability to timely and precisely sense changes inside the body, is critical for survival
. Vagal sensory neurons (VSNs) form an important body-to-brain connection, navigating ...visceral organs along the rostral-caudal axis of the body and crossing the surface-lumen axis of organs into appropriate tissue layers
. The brain can discriminate numerous body signals through VSNs, but the underlying coding strategy remains poorly understood. Here we show that VSNs code visceral organ, tissue layer and stimulus modality-three key features of an interoceptive signal-in different dimensions. Large-scale single-cell profiling of VSNs from seven major organs in mice using multiplexed projection barcodes reveals a 'visceral organ' dimension composed of differentially expressed gene modules that code organs along the body's rostral-caudal axis. We discover another 'tissue layer' dimension with gene modules that code the locations of VSN endings along the surface-lumen axis of organs. Using calcium-imaging-guided spatial transcriptomics, we show that VSNs are organized into functional units to sense similar stimuli across organs and tissue layers; this constitutes a third 'stimulus modality' dimension. The three independent feature-coding dimensions together specify many parallel VSN pathways in a combinatorial manner and facilitate the complex projection of VSNs in the brainstem. Our study highlights a multidimensional coding architecture of the mammalian vagal interoceptive system for effective signal communication.
The role of human occupancy as a source of indoor biological aerosols is poorly understood. Size‐resolved concentrations of total and biological particles in indoor air were quantified in a classroom ...under occupied and vacant conditions. Per‐occupant emission rates were estimated through a mass‐balance modeling approach, and the microbial diversity of indoor and outdoor air during occupancy was determined via rDNA gene sequence analysis. Significant increases of total particle mass and bacterial genome concentrations were observed during the occupied period compared to the vacant case. These increases varied in magnitude with the particle size and ranged from 3 to 68 times for total mass, 12–2700 times for bacterial genomes, and 1.5–5.2 times for fungal genomes. Emission rates per person‐hour because of occupancy were 31 mg, 37 × 106 genome copies, and 7.3 × 106 genome copies for total particle mass, bacteria, and fungi, respectively. Of the bacterial emissions, ∼18% are from taxa that are closely associated with the human skin microbiome. This analysis provides size‐resolved, per person‐hour emission rates for these biological particles and illustrates the extent to which being in an occupied room results in exposure to bacteria that are associated with previous or current human occupants.
Practical Implications
Presented here are the first size‐resolved, per person emission rate estimates of bacterial and fungal genomes for a common occupied indoor space. The marked differences observed between total particle and bacterial size distributions suggest that size‐dependent aerosol models that use total particles as a surrogate for microbial particles incorrectly assess the fate of and human exposure to airborne bacteria. The strong signal of human microbiota in airborne particulate matter in an occupied setting demonstrates that the aerosol route can be a source of exposure to microorganisms emitted from the skin, hair, nostrils, and mouths of other occupants.
Financing firms in India Allen, Franklin; Chakrabarti, Rajesh; De, Sankar ...
Journal of financial intermediation,
07/2012, Letnik:
21, Številka:
3
Journal Article
Recenzirano
Odprti dostop
With extensive cross-country datasets and India firm samples, as well as our own surveys of small and medium firms, we examine the legal and business environments, financing channels, and growth ...patterns of different types of firms in India. Despite the English common-law origin and a British-style judicial system, Indian firms face weak investor protection in practice and poor institutions characterized by corruption and inefficiency. Alternative finance, including financing from all nonbank, nonmarket sources, and generally backed by nonlegal mechanisms, constitutes the most important form of external finance. Bank loans provide the second most important external financing source. Firms with access to bank or market finance are not associated with higher growth rates. Our results indicate that bank and market finance is not superior to alternative finance in fast-growing economies such as India.
We study the nonlinear optomechanically induced transparency (OMIT) with gain and loss. We find that (i) for a single active cavity, significant enhancement can be achieved for the higher-order ...sidebands, including the transmission rate and the group delay; (ii) for active-passive-coupled cavities, hundreds of microsecond of optical delay or advance are attainable for the nonlinear sideband pulses in the parity-time-symmetric regime. The active higher-order OMIT effects, as firstly revealed here, open up the way to make a low-power optomechaical amplifier, which can amplify both the strength and group delay of not only the probe light but also its higher-order sidebands.
Gastric cancer (GC) is a leading cause of cancer deaths worldwide. Since the approval of trastuzumab, targeted therapies are emerging as promising treatment options for the disease. This study aimed ...to explore the molecular segmentation of several known therapeutics targets, human epidermal growth factor receptor 2 (HER2), MET and fibroblast growth factor receptor 2 (FGFR2), within GC using clinically approved or investigational kits and scoring criteria. Knowledge of how these markers are segmented in the same cohort of GC patients could improve future clinical trial designs.
Using immunohistochemistry (IHC) and FISH methods, overexpression and amplification of HER2, FGFR2 and MET were profiled in a cohort of Chinese GC samples. The correlations between anti-tumour sensitivity and the molecular segments of HER2, MET and FGFR2 alterations were further tested in a panel of GC cell lines and the patient-derived GC xenograft (PDGCX) model using the targeted inhibitors.
Of 172 GC patients, positivity for HER2, MET and FGFR2 alternations was found in 23 (13.4%), 21 (12.2%) and 9 (5.2%) patients, respectively. Positivity for MET was found in 3 of 23 HER2-positive GC patients. Co-positivity for FGFR2 and MET was found in 1 GC patient, and amplification of the two genes was found in different tumour cells. Our study in a panel of GC cell lines showed that in most cell lines, amplification or high expression of a particular molecular marker was mutually exclusive and in vitro sensitivity to the targeted agents lapatinib, PD173074 and crizotinib was only observed in cell lines with the corresponding high expression of the drugs' target protein. SGC031, an MET-positive PDGCX mouse model, responded to crizotinib but not to lapatinib or PD173074.
Human epidermal growth factor receptor 2, MET and FGFR2 oncogenic driver alterations (gene amplification and overexpression) occur in three largely distinct molecular segments in GC. A significant proportion of HER2-negative patients may potentially benefit from MET- or FGFR2-targeted therapies.
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