Abstract
We conducted observations of multiple HC
3
N (
J
= 10−9, 12−11, and 16−15) lines and the N
2
H
+
(
J
= 1−0) line toward a large sample of 61 ultracompact (UC) H
ii
regions, through the ...Institut de Radioastronomie Millmétrique 30 m and the Arizona Radio Observatory 12 m telescopes. The N
2
H
+
J
= 1−0 line is detected in 60 sources and HC
3
N is detected in 59 sources, including 40 sources with three lines, 9 sources with two lines, and 10 sources with one line. Using the rotational diagram, the rotational temperature and column density of HC
3
N were estimated toward sources with at least two HC
3
N lines. For 10 sources with only one HC
3
N line, their parameters were estimated, taking one average value of
T
rot
. For N
2
H
+
, we estimated the optical depth of the N
2
H
+
J
= 1−0 line, based on the line intensity ratio of its hyperfine structure lines. Then the excitation temperature and column density were calculated. When combining our results in UC H
ii
regions and previous observation results on high-mass starless cores, the
N
(HC
3
N)/
N
(N
2
H
+
) ratio clearly increases from the region stage. This means that the abundance ratio changes with the evolution of high-mass star-forming regions (HMSFRs). Moreover, positive correlations between the ratio and other evolutionary indicators (dust temperature, bolometric luminosity, and luminosity-to-mass ratio) are found. Thus we propose the ratio of
N
(HC
3
N)/
N
(N
2
H
+
) as a reliable chemical clock of HMSFRs.
The broadband parasitic amplification in a diode-seeded nanosecond ytterbium-doped fiber laser amplifier system is numerically and experimentally investigated. The amplification is originated from a ...weak and pulsed parasitic signal associated with the 1064-nm seed diode laser. Although the average power of the parasitic pulse is less than 5% of the total seed laser power, a significant transient spike is observed during the amplification. In agreement with the simulation, nonlinear effects caused by the transient spike limits the scaling of signal peak power in fiber preamplifiers. With the utilization of a narrow bandwidth filter to eliminate the parasitic pulse, the power and energy scalability of a multistage diode-seeded fiber amplifier laser system has been significantly improved. At 1064 nm, pulses with the peak power of 120 kW and energy of 1.2 mJ have been successfully generated in the multistage \hbox{Yb}^{3+} -doped fiber amplifier with an energy gain of 63 dB and 56% conversion efficiency. In viewing of the parasitic pulse's 8.8-nm bandwidth, it has the potential to become a novel seed source for high-peak-power fiber amplifiers.
Fibrils of the hamster prion peptide (sHaPrP, sequence 108–144) were prepared in an acidic solution, and their structure was solved by cryogenic electron microscopy with a resolution of 2.23 Å based ...on the gold-standard Fourier shell correlation (FSC) curve. The fibril has a novel architecture that has never been found in other amyloid fibrils. Each fibril is assembled by four protofilaments (PFs) and has an ordered water channel in the center. Each protofilament contains three β-strands (125–130, 133–135, and 138–141) arranged in an “R”-shaped construct. The structural data indicate that these three β-strand segments are the most amyloidogenic region of the prion peptide/protein and might be the site of nucleation during fibrillization under conditions without denaturants.
Treatment options for vancomycin-resistant enterococci (VRE) bloodstream infection are limited. Studies comparing daptomycin or linezolid in treating VRE bloodstream infection have conflicting ...results and suggest daptomycin underdosing. The responses to different daptomycin doses have not been studied. We conducted a multicentre prospective cohort study to compare linezolid and daptomycin (≥6 mg/kg) for the treatment of VRE bloodstream infection. The primary outcome was 14-day mortality. We used multivariate logistic regression analysis for outcome analysis and a generalized additive model for dose-dependent response estimation. Two hundred twelve patients were included (daptomycin, n = 141; linezolid, n = 71). All-cause 14-day mortality was higher in the daptomycin group (36.9% vs. 21.1%; p 0.03). After adjusting for confounders in logistic regression, mortality was lower in the linezolid group (adjusted odds ratio (aOR), 0.45; 95% confidence interval (CI), 0.21–0.96; p 0.04). The generalized additive model showed that higher-dose daptomycin (≥9 mg/kg) was associated with better survival than lower-dose daptomycin (6–9 mg/kg). Logistic regression showed that linezolid (aOR, 0.36; 95% CI, 0.17–0.79; p 0.01) and higher-dose daptomycin (aOR, 0.26; 95% CI, 0.09–0.74; p 0.01) independently predicted lower mortality compared to lower-dose daptomycin. Linezolid was not superior to higher-dose daptomycin in terms of mortality (aOR, 1.40; 95% CI, 0.45–4.37; p 0.57). Higher-dose daptomycin had lower mortality than lower-dose daptomycin. Despite higher mortality for lower-dose daptomycin than linezolid, linezolid conferred no survival benefit compared to higher-dose daptomycin. Our findings suggest that the recommended daptomycin dose is suboptimal for treating VRE bacteraemia.
Icotinib has been previously shown to be non-inferior to gefitinib in non-selected advanced non-small-cell lung cancer patients when given as second- or further-line treatment. In this open-label, ...randomized, phase 3 CONVINCE trial, we assessed the efficacy and safety of first-line icotinib versus cisplatin/pemetrexed plus pemetrexed maintenance in lung adenocarcinoma patients with epidermal growth factor receptor (EGFR) mutation.
Eligible participants were adults with stage IIIB/IV lung adenocarcinoma and exon 19/21 EGFR mutations. Participants were randomly allocated (1 : 1) to receive oral icotinib or 3-week cycle of cisplatin plus pemetrexed for up to four cycles; non-progressive patients after four cycles were maintained with pemetrexed until disease progression or intolerable toxicity. The primary end point was progression-free survival (PFS) assessed by independent response evaluation committee. Other end points included overall survival (OS) and safety.
Between January 2013 and August 2014, 296 patients were randomized, and 285 patients were treated (148 to icotinib, 137 to chemotherapy). Independent response evaluation committee-assessed PFS was significantly longer in the icotinib group (11.2 versus 7.9 months; hazard ratio, 0.61, 95% confidence interval 0.43-0.87; P = 0.006). No significant difference for OS was observed between treatments in the overall population or in EGFR-mutated subgroups (exon 19 Del/21 L858R). The most common grade 3 or 4 adverse events (AEs) in the icotinib group were rash (14.8%) and diarrhea (7.4%), compared with nausea (45.9%), vomiting (29.2%), and neutropenia (10.9%) in the chemotherapy group. AEs (79.1% versus 94.2%; P < 0.001) and treatment-related AEs (54.1% versus 90.5%; P < 0.001) were significantly fewer in the icotinib group than in the chemotherapy group.
First-line icotinib significantly improves PFS of advanced lung adenocarcinoma patients with EGFR mutation with a tolerable and manageable safety profile. Icotinib should be considered as a first-line treatment for this patient population.
Proteolytic processing of amyloid precursor protein (APP) C-terminal fragments (CTFs) by γ-secretase underlies the pathogenesis of Alzheimer’s disease (AD). An RNA interference screen using APP-CTF ...99-residue CTF (C99)- and Notch-specific γ-secretase interaction assays identified a unique ErbB2-centered signaling network that was predicted to preferentially govern the proteostasis of APP-C99. Consistently, significantly elevated levels of ErbB2 were confirmed in the hippocampus of human AD brains. We then found that ErbB2 effectively suppressed autophagic flux by physically dissociating Beclin-1 from the Vps34–Vps15 complex independent of its kinase activity. Down-regulation of ErbB2 by CL-387,785 decreased the levels of C99 and secreted amyloid-β in cellular, zebrafish, and mouse models of AD, through the activation of autophagy. Oral administration of an ErbB2-targeted CL-387,785 for 3 wk significantly improves the cognitive functions of APP/presenilin-1 (PS1) transgenic mice. This work unveils a noncanonical function of ErbB2 in modulating autophagy and establishes ErbB2 as a therapeutic target for AD.
High tumor mutational burden (TMB-H) is correlated with enhanced objective response rate (ORR) and progression-free survival (PFS) for certain cancers receiving immunotherapy. This study aimed to ...investigate the safety and efficacy of toripalimab, a humanized programmed death-1 (PD-1) antibody, in advanced gastric cancer (AGC), and the predictive survival benefit of TMB and PD-L1.
We reported on the AGC cohort of phase Ib/II trial evaluating the safety and activity of toripalimab in patients with AGC, oesophageal squamous cell carcinoma, nasopharyngeal carcinoma and head and neck squamous cell carcinoma. In cohort 1, 58 chemo-refractory AGC patients received toripalimab (3 mg/kg d1, Q2W) as a monotherapy. In cohort 2, 18 chemotherapy-naive AGC patients received toripalimab (360 mg d1, Q3W) with oxaliplatin 130 mg/m2 qd, d1, capecitabine 1000 mg/m2 b.i.d., d1–d14, Q3W as first-line treatment. Primary end point was ORR. Biomarkers such as PD-L1 and TMB were evaluated for correlation with clinical efficacy.
In cohort 1, the ORR was 12.1% and the disease control rate (DCR) was 39.7%. Median PFS was 1.9 months and median OS was 4.8 months. The TMB-H group showed significant superior OS than the TMB-L group 14.6 versus 4.0 months, HR = 0.48 (96% CI 0.24–0.96), P = 0.038, while PD-L1 overexpression did not correlate with significant survival benefit. A 77.6% of patients experienced at least one treatment-related adverse event (TRAE), and 22.4% of patients experienced a grade 3 or higher TRAE. In cohort 2, the ORR was 66.7% and the DCR was 88.9%. A 94.4% of patients experienced at least one TRAE and 38.9% of patients experienced grade 3 or higher TRAEs.
Toripalimab has demonstrated a manageable safety profile and promising antitumor activity in AGC patients, especially in combination with XELOX. High TMB may be a predictive marker for OS of AGC patients receiving toripalimab as a single agent.
ClinicalTrials.gov NCT02915432.
Antler and limb bone have a similar microstructure and chemical composition. Both are primarily composed of type I collagen and a mineral phase (carbonated apatite), arranged in osteons in compact ...(cortical bone) sections and a lamellar structure in the cancellous (spongy or trabecular bone) sections. The mineral content is lower in antler bone and it has a core of cancellous bone surrounded by compact bone running through the main beam and tines. The mineral content is higher in the compact compared with the cancellous bone, although there is no difference in ratios of the mineral elements with calcium. Mechanical tests (bend and compression) on longitudinal and transverse orientations of dry and rehydrated compact bone of North American elk (Cervus elaphus canadensis) antlers are compared with known data on other antlers as well as bovine femora. Both dry and rehydrated bones are highly anisotropic, with the bending and compressive strength and elastic modulus higher in the longitudinal than in the transverse direction. There is no significant difference between the bend strength and elastic modulus between dry and rehydrated samples tested in the transverse direction. The elastic modulus measured from the bending tests is compared with composite models. The elastic modulus and bend strengths are lower in the rehydrated condition, but the strain to failure and fracture toughness is much higher compared with dry samples. All antler bone mechanical properties are lower than that of bovine femora. The antler has a much higher fracture toughness compared with bovine femora, which correlates with their main function in intraspecific combat as a high impact resistant, energy absorbent material. A model of compression deformation is proposed, which is based on osteon sliding during shear.
There are few data on the molecular epidemiology of cryptococcosis in China. Here we investigated the species distribution, molecular types and antifungal susceptibilities of 312 Cryptococcus ...neoformans species complex isolates from ten hospitals over 5 years. Isolates were identified by internal transcribed spacer (ITS) sequencing and by two matrix-assisted laser desorption–ionization time-of-flight mass spectrometry (MALDI-TOF MS) systems. Multilocus sequence typing (MLST) was used to verify species/variety and to designate molecular types. Susceptibility to six antifungal drugs was determined by the Sensititre YeastOne™ method. Cryptococcus neoformans was the predominant species (305/312 isolates (97.8%), all were ITS type 1, serotype A), of which 89.2% (272/305) were C. neoformans var. grubii MLST sequence type (ST) 5 and 6.2% (19/305) were ST31. Other C. neoformans var. grubii STs were rare but included six novel STs. Only two strains were C. neoformans var. neoformans (both serotype AD). Cryptococcus gattii was uncommon (n = 7, four ITS types) and comprised five MLST STs including one novel ST. For C. neoformans var. grubii, the proportion of isolates with non-wild-type MICs to fluconazole significantly rose in the fourth study year (from 0% (0/56 isolates) in the first year to 23.9% (17/71) in the fourth year), including five isolates with fluconazole MICs of ≥32 mg/L. The study has provided useful data on the species epidemiology and their genetic diversity and antifungal susceptibility. The proportional increase in isolates with non-wild-type MICs to fluconazole is noted.
ABSTRACT
We studied the 2018 outburst of the black hole transient H 1743 − 322 with a series of Insight-HXMT, NICER, and NuSTAR observations, covering the 1–120 keV band. With our broad-band X-ray ...spectral modelling, we confirm that the source remained in the low/hard state throughout the month-long outburst, although it became marginally softer at peak flux. We detected Type-C quasi-periodic oscillations (QPOs) and followed the evolution of their properties. The QPO frequency increased from ∼0.1 to ∼0.4 Hz during the rising phase of the outburst and decreased again in the decline. Continuum X-ray flux, power-law photon index, QPO frequency, and QPO root-mean-square amplitude were positively correlated. The QPO amplitude was slightly higher in the soft X-ray band (typical values of 12–16 per cent, compared with 8–10 per cent in the hard band). Our spectral-timing results shed light on the initial rising phase in the low/hard state, which has rarely been monitored with such high cadence, time resolution, and broad-band coverage. Combining spectral and timing properties, we find that ‘failed’ (hard state only) and ‘successful’ outbursts follow the same initial evolutionary track, although the former class of outburst never reaches the threshold for a transition to softer (thermally dominated) accretion regimes.
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