To be able to achieve their physics goals, future neutrino-oscillation experiments will need to reconstruct the neutrino energy with very high accuracy. In this work, we analyze how the energy ...reconstruction may be affected by realistic detection capabilities, such as energy resolutions, efficiencies, and thresholds. This allows us to estimate how well the detector performance needs to be determined a priori in order to avoid a sizable bias in the measurement of the relevant oscillation parameters. We compare the kinematic and calorimetric methods of energy reconstruction in the context of two νμ → νμ disappearance experiments operating in different energy regimes. For the calorimetric reconstruction method, we find that the detector performance has to be estimated with an O(10%) accuracy to avoid a significant bias in the extracted oscillation parameters. Thus, in the case of kinematic energy reconstruction, we observe that the results exhibit less sensitivity to an overestimation of the detector capabilities.
Background: As pathogens that circumvent the host immune response are favoured by selection, so are host alleles that reduce parasite load. Such evolutionary processes leave their signature on the ...genes involved. Deciphering modes of selection operating on immune genes might reveal the nature of host-pathogen interactions and factors that govern susceptibility in host populations. Such understanding would have important public health implications. Methodology/Findings: We analyzed polymorphisms in four mosquito immune genes (SP14D1, GNBP, defensin, and gambicin) to decipher selection effects, presumably mediated by pathogens. Using samples of Anopheles arabiensis, An. quadriannulatus and four An. gambiae populations, as well as published sequences from other Culicidae, we contrasted patterns of polymorphisms between different functional units of the same gene within and between populations. Our results revealed selection signatures operating on different time scales. At the most recent time scale, within-population diversity revealed purifying selection. Between populations and between species variation revealed reduced differentiation (GNBP and gambicin) at coding vs. noncoding- regions, consistent with balancing selection. McDonald-Kreitman tests between An. quadriannulatus and both sibling species revealed higher fixation rate of synonymous than nonsynonymous substitutions (GNBP) in accordance with frequency dependent balancing selection. At the longest time scale (>100 my), PAML analysis using distant Culicid taxa revealed positive selection at one codon in gambicin. Patterns of genetic variation were independent of exposure to human pathogens. Significance and Conclusions: Purifying selection is the most common form of selection operating on immune genes as it was detected on a contemporary time scale on all genes. Selection for “hypervariability” was not detected, but negative balancing selection, detected at a recent evolutionary time scale between sibling species may be rather common. Detection of positive selection at the deepest evolutionary time scale suggests that it occurs infrequently, possibly in association with speciation events. Our results provided no evidence to support the hypothesis that selection was mediated by pathogens that are transmitted to humans.
Background Autism spectrum disorders (ASD) are associated with severe impairments in social functioning. Because faces provide nonverbal cues that support social interactions, many studies of ASD ...have examined neural structures that process faces, including the amygdala, ventromedial prefrontal cortex and superior and middle temporal gyri. However, increases or decreases in activation are often contingent on the cognitive task. Specifically, the cognitive domain of attention influences group differences in brain activation. We investigated brain function abnormalities in participants with ASD using a task that monitored attention bias to emotional faces. Methods Twenty-four participants (12 with ASD, 12 controls) completed a functional magnetic resonance imaging study while performing an attention cuing task with emotional (happy, sad, angry) and neutral faces. Results In response to emotional faces, those in the ASD group showed greater right amygdala activation than those in the control group. A preliminary psychophysiological connectivity analysis showed that ASD participants had stronger positive right amygdala and ventromedial prefrontal cortex coupling and weaker positive right amygdala and temporal lobe coupling than controls. There were no group differences in the behavioural measure of attention bias to the emotional faces. Limitations The small sample size may have affected our ability to detect additional group differences. Conclusion When attention bias to emotional faces was equivalent between ASD and control groups, ASD was associated with greater amygdala activation. Preliminary analyses showed that ASD participants had stronger connectivity between the amygdala ventromedial prefrontal cortex (a network implicated in emotional modulation) and weaker connectivity between the amygdala and temporal lobe (a pathway involved in the identification of facial expressions, although areas of group differences were generally in a more anterior region of the temporal lobe than what is typically reported for emotional face processing). These alterations in connectivity are consistent with emotion and face processing disturbances in ASD.
Previous studies in Taiwan utilizing the Taiwan's National Health Insurance Database (NHIRD) have estimated the direct healthcare costs of RA patients, but they have not focused on patients on ...bDMARDs, or considered patients' response to therapy.
The objective of this study was to estimate the rate of inadequate response for patients newly treated with biologic disease-modifying antirheumatic drugs (bDMARDs) as well as their costs and resource use.
Data were from the catastrophic illness file within the NHIRD from 1/1/2009 to 12/31/2013. Patients with RA, which was categorized by the presence of a catastrophic illness card, that were previously bDMARD-naïve, were included in this study if they initiated their first bDMARD during the index period. The index period included all of 2010, a pre-index period consisting of the index date- 365 days, and a follow-up period including the index date to 365 days post-index, were also included. Previously biologically-naïve patients were indexed into the study on the date of their first claim for a bDMARD. A validated algorithm was used to examine the rate of inadequate response (IR) in the biologically-naïve cohort of patients. Inadequate responders met one or more of the following criteria during their year of follow-up: low adherence (proportion of days covered <0.80); switched to or added a second bDMARD; added a new conventional synthetic DMARD (csDMARD); received ≥1 glucocorticoid injection; or increased oral glucocorticoid dosing. All-cause mean annual direct costs and resource use were measured in the year of follow-up. Costs were converted from NT$ to USD using 1 NT$ = 0.033 USD.
A total of 818 patients with RA initiated their first bDMARD (54% etanercept and 46% adalimumab) in 2010. After one year of follow-up, 32% (n = 258) were classified as stable, 66% (n = 540) had an IR, and 2% (n = 20) were lost to follow-up. During the follow-up period mean annual total direct costs were $16,136 for stable patients compared to $14,154 for patients with IR. Mean annual non-medication direct costs were $937 for stable patients and $1,574 for patients with IR. Mean annual hospitalizations were higher for patients with IR (0.46) compared to stable patients (0.10) during the one year follow-up period.
The majority of patients that were previously naïve to bDMARDs had an IR to their first bDMARD during the year of follow-up. Patients with an IR had numerically increased all-cause resource utilization and non-medication costs during the follow-up period compared to patients with stable disease. This level of IR suggests an unmet need in the RA treatment paradigm.
Transcriptional control plays an important role in regulating submergence responses in plants. Although numerous genes are highly induced during hypoxia, their individual roles in hypoxic responses ...are still poorly understood. Here, we found that expression of genes that encode members of the WRKY transcription factor family was rapidly and strongly induced upon submergence in Arabidopsis thaliana, and this induction correlated with induction of a large portion of innate immunity marker genes. Furthermore, prior submergence treatment conferred higher resistance to the bacterial pathogen Pseudomonas syringae in Arabidopsis. Among the WRKY genes tested, WRKY22 had the highest level of induction during the early stages of submergence. Compared with the wild type, WRKY22 T-DNA insertion mutants wrky22-1 and wrky22-2 had lower disease resistance and lower induction of innate immunity markers, such as FLG22-INDUCED RECEPTOR-LIKE KINASE1 (FRK1) and WRKY53, after submergence. Furthermore, transcriptomic analyses of wrky22-2 and chromatin immunoprecipitation identified several potential targets of WRKY22, which included genes encoding a TIR domain—containing protein, a plant peptide hormone, and many OLIGO PEPTIDE TRANSPORTER genes, all of which may lead to induction of innate immunity. In conclusion, we propose that submergence triggers innate immunity in Arabidopsis via WRKY22, a response that may protect against a higher probability of pathogen infection either during or after flooding.
The continuous emergence of SARS-CoV-2 variants has led to a protracted global COVID-19 pandemic with significant impacts on public health and global economy. While there are currently available ...SARS-CoV-2 vaccines and therapeutics, most of the FDA-approved antiviral agents directly target viral proteins. However, inflammation is the initial immune pathogenesis induced by SARS-CoV-2 infection, there is still a need to find additional agents that can control the virus in the early stages of infection to alleviate disease progression for the next pandemic. Here, we find that both the spike protein and its receptor CD147 are crucial for inducing inflammation by SARS-CoV-2 in THP-1 monocytic cells. Moreover, we find that 3-
-betulin, isolated from
, reduces the level of proinflammatory cytokines induced by SARS-CoV-2, consequently resulting in a decreased viral RNA accumulation and plaque formation. In addition, 3-
-betulin displays a broad-spectrum inhibition of entry of SARS-CoV-2 pseudoviruses, including Alpha (B.1.1.7), Eplison (B.1.429), Gamma (P1), Delta (B.1.617.2) and Omicron (BA.1). Moreover, 3-
-betulin potently inhibits SARS-CoV-2 infection with an EC
of <20 μM in Calu-3 lung epithelial cells. Bioinformatic analysis reveals the chemical interaction between the 3-
-betulin and the spike protein, along with the critical amino acid residues in the spike protein that contribute to the inhibitory activity of 3-
-betulin against virus entry. Taken together, our results suggest that 3-
-betulin exhibits dual effect: it reduces SARS-CoV-2-induced inflammation and inhibits virus entry, positioning it as a potential antiviral agent against SARS-CoV-2.
Summary
The aim of this study was to compare high‐dose volumetric modulated arc therapy (VMAT) and fixed‐field intensity‐modulated radiotherapy (ff‐IMRT) plans for the treatment of patients with ...middle‐thoracic esophageal cancer. Eight patients with cT2‐3N0M0 middle‐thoracic esophageal cancer were enrolled. The treatment planning system was the version 9 of the Pinnacle3 with SmartArc (Philips Healthcare, Fitchburg, WI, USA). VMAT and ff‐IMRT treatment plans were generated for each case, and both techniques were used to deliver 50 Gy to the planning target volume (PTV50) and then provided a 16‐Gy boost (PTV66). The VMAT plans provided superior PTV66 coverage compared with the ff‐IMRT plans (P = 0.034), whereas the ff‐IMRT plans provided more appropriate dose homogeneity to the PTV50 (P = 0.017). In the lung, the V5 and V10 were lower for the ff‐IMRT plans than for the VMAT plans, whereas the V20 was lower for the VMAT plans. The delivery time was significantly shorter for the VMAT plans than for the ff‐IMRT plans (P = 0.012). In addition, the VMAT plans delivered fewer monitor units. The VMAT technique required a shorter planning time than the ff‐IMRT technique (3.8 ± 0.8 hours vs. 5.4 ± 0.6 hours, P = 0.011). The major advantages of VMAT plans are higher efficiency and an approximately 50% reduction in delivery time compared with the ff‐IMRT plans, with comparable plan quality. Further clinical investigations to evaluate the use of high‐dose VMAT for the treatment of esophageal cancer are warranted.
As influenza viruses have developed resistance towards current drugs, new inhibitors that prevent viral replication through different inhibitory mechanisms are useful. In this study, we developed a ...screening procedure to search for new antiinfluenza inhibitors from 1,200,000 compounds and identified previously reported as well as new antiinfluenza compounds. Several antiinfluenza compounds were inhibitory to the influenza RNA-dependent RNA polymerase (RdRP), including nucleozin and its analogs. The most potent nucleozin analog, 3061 (FA-2), inhibited the replication of the influenza A/WSN/33 (H1N1) virus in MDCK cells at submicromolar concentrations and protected the lethal H1N1 infection of mice. Influenza variants resistant to 3061 (FA-2) were isolated and shown to have the mutation on nucleoprotein (NP) that is distinct from the recently reported resistant mutation of Y289H Kao R, et al. (2010) Nat Biotechnol 28:600. Recombinant influenza carrying the Y52H NP is also resistant to 3061 (FA-2), and NP aggregation induced by 3061 (FA-2) was identified as the most likely cause for inhibition. In addition, we identified another antiinfluenza RdRP inhibitor 367 which targets PB1 protein but not NP. A mutant resistant to 367 has H456P mutation at the PB1 protein and both the recombinant influenza and the RdRP expressing the PB1 H456P mutation have elevated resistance to 367. Our high-throughput screening (HTS) campaign thus resulted in the identification of antiinfluenza compounds targeting RdRP activity.
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