The dispersive sweep of fast radio bursts (FRBs) has been used to probe the ionized baryon content of the intergalactic medium
, which is assumed to dominate the total extragalactic dispersion. ...Although the host-galaxy contributions to the dispersion measure appear to be small for most FRBs
, in at least one case there is evidence for an extreme magneto-ionic local environment
and a compact persistent radio source
. Here we report the detection and localization of the repeating FRB 20190520B, which is co-located with a compact, persistent radio source and associated with a dwarf host galaxy of high specific-star-formation rate at a redshift of 0.241 ± 0.001. The estimated host-galaxy dispersion measure of approximately Formula: see text parsecs per cubic centimetre, which is nearly an order of magnitude higher than the average of FRB host galaxies
, far exceeds the dispersion-measure contribution of the intergalactic medium. Caution is thus warranted in inferring redshifts for FRBs without accurate host-galaxy identifications.
Fast radio bursts (FRBs) are millisecond-duration radio transients of unknown physical origin observed at extragalactic distances
. It has long been speculated that magnetars are the engine powering ...repeating bursts from FRB sources
, but no convincing evidence has been collected so far
. Recently, the Galactic magnetar SRG 1935+2154 entered an active phase by emitting intense soft γ-ray bursts
. One FRB-like event with two peaks (FRB 200428) and a luminosity slightly lower than the faintest extragalactic FRBs was detected from the source, in association with a soft γ-ray/hard-X-ray flare
. Here we report an eight-hour targeted radio observational campaign comprising four sessions and assisted by multi-wavelength (optical and hard-X-ray) data. During the third session, 29 soft-γ-ray repeater (SGR) bursts were detected in γ-ray energies. Throughout the observing period, we detected no single dispersed pulsed emission coincident with the arrivals of SGR bursts, but unfortunately we were not observing when the FRB was detected. The non-detection places a fluence upper limit that is eight orders of magnitude lower than the fluence of FRB 200428. Our results suggest that FRB-SGR burst associations are rare. FRBs may be highly relativistic and geometrically beamed, or FRB-like events associated with SGR bursts may have narrow spectra and characteristic frequencies outside the observed band. It is also possible that the physical conditions required to achieve coherent radiation in SGR bursts are difficult to satisfy, and that only under extreme conditions could an FRB be associated with an SGR burst.
The event rate, energy distribution and time-domain behaviour of repeating fast radio bursts (FRBs) contain essential information regarding their physical nature and central engine, which are as yet ...unknown
. As the first precisely localized source, FRB 121102 (refs.
) has been extensively observed and shows non-Poisson clustering of bursts over time and a power-law energy distribution
. However, the extent of the energy distribution towards the fainter end was not known. Here we report the detection of 1,652 independent bursts with a peak burst rate of 122 h
, in 59.5 hours spanning 47 days. A peak in the isotropic equivalent energy distribution is found to be approximately 4.8 × 10
erg at 1.25 GHz, below which the detection of bursts is suppressed. The burst energy distribution is bimodal, and well characterized by a combination of a log-normal function and a generalized Cauchy function. The large number of bursts in hour-long spans allows sensitive periodicity searches between 1 ms and 1,000 s. The non-detection of any periodicity or quasi-periodicity poses challenges for models involving a single rotating compact object. The high burst rate also implies that FRBs must be generated with a high radiative efficiency, disfavouring emission mechanisms with large energy requirements or contrived triggering conditions.
Aims/hypothesis
Increased inflammation and oxidative stress are associated with insulin resistance (IR) and metabolic disorders. Serum histidine levels are lower and are negatively associated with ...inflammation and oxidative stress in obese women. The objective of this study was to evaluate the efficacy of histidine supplementation on IR, inflammation, oxidative stress and metabolic disorders in obese women with the metabolic syndrome (MetS).
Methods
A total of 100 obese women aged 33–51 years with BMI ≥ 28 kg/m
2
and diagnosed with MetS were included following a health examination in the community hospital in this randomised, double-blinded, placebo-controlled trial. Participants were allocated to interventions by an investigator using sequentially numbered sealed envelopes and received 4 g/day histidine (
n
= 50) or identical placebo (
n
= 50) for 12 weeks. Participants then attended the same clinic every 2 weeks for scheduled interviews and to count tablets returned. Serum histidine, HOMA-IR, BMI, waist circumference, fat mass, serum NEFA, and variables connected to inflammation and oxidative stress were measured at baseline and 12 weeks. Participants, examining physicians and investigators assessing the outcomes were blinded to group assignment. In addition, the inflammatory mechanisms of histidine were also explored in adipocytes.
Results
At 12 weeks, a total of 92 participants completed this trail. Compared with the placebo group (
n
= 47), histidine supplementation significantly decreased HOMA-IR (−1.09 95% CI −1.49, −0.68), BMI (−0.86 kg/m
2
95% CI −1.55, −0.17), waist circumference (−2.86 cm 95% CI −3.86, −1.86), fat mass (−2.71 kg 95% CI −3.69, −1.73), serum NEFA (−173.26 μmol/l 95% CI −208.57, −137.94), serum inflammatory cytokines (TNF-α, −3.96 pg/ml 95% CI −5.29, −2.62; IL-6, −2.15 pg/ml 95% CI −2.52, −1.78), oxidative stress (superoxide dismutase, 17.84 U/ml 95% CI 15.03, 20.65; glutathione peroxidase, 13.71 nmol/ml 95% CI 9.65, 17.78) and increased serum histidine and adiponectin by 18.23 μmol/l 95% CI 11.74, 24.71 and 2.02 ng/ml 95% CI 0.60, 3.44 in histidine supplementation group (
n
= 45), respectively. There were significant correlations between changes in serum histidine and changes of IR and its risk factors. No side effects were observed during the intervention. In vitro study indicated that histidine suppresses
IL6
and
TNF
mRNA expression and nuclear factor kappa-B (NF-κB) protein production in palmitic acid-induced adipocytes in a dose-dependent manner, and these changes were diminished by an inhibitor of NF-κB.
Conclusions/interpretation
Histidine supplementation could improve IR, reduce BMI, fat mass and NEFA and suppress inflammation and oxidative stress in obese women with MetS; histidine could improve IR through suppressed pro-inflammatory cytokine expression, possibly by the NF-κB pathway, in adipocytes.
Trial registration
www.chictr.org/cn/ChiCTR-TRC-11001551
Funding
The study was supported by the National Natural Science Fund of China (No. 81202184, 81130049, 81102112), Heilongjiang Post/doctoral Fund (No. LBN-Z12193) and Key Laboratory of Nutrition and Food Hygiene (Harbin Medical University, Heilongjiang Higher Education Institutions, No. YYKFKT1202).
The diversities in crystal structures and ways of doping result in extremely diversified phase diagrams for iron-based superconductors. With angle-resolved photoemission spectroscopy, we have ...systematically studied the effects of chemical substitution on the electronic structure of various series of iron-based superconductors. Beyond the Fermi-surface alteration that has been reported most often in the past, we found two more extraordinary effects of doping: (1) the site and band dependencies of quasiparticle scattering and, more importantly, (2) the ubiquitous and significant change of electronic correlation by both isovalent and heterovalent dopants in the iron-anion layer. Moreover, we found that the electronic correlation could be suppressed by applying either the chemical pressure or doping electrons but not by doping holes. Together with other findings provided here, these results complete the microscopic picture of the electronic effects of dopants, which facilitates a unified understanding of the diversified phase diagrams and resolutions to many open issues of various iron-based superconductors.
ABSTRACT
We report the phase-connected timing ephemeris, polarization pulse profiles, Faraday rotation measurements, and Rotating-Vector-Model (RVM) fitting results of 12 millisecond pulsars (MSPs) ...discovered with the Five-hundred-meter Aperture Spherical radio Telescope (FAST) in the Commensal Radio Astronomy FAST survey (CRAFTS). The timing campaigns were carried out with FAST and Arecibo over 3 yr. 11 of the 12 pulsars are in neutron star–white dwarf binary systems, with orbital periods between 2.4 and 100 d. 10 of them have spin periods, companion masses, and orbital eccentricities that are consistent with the theoretical expectations for MSP–Helium white dwarf (He WD) systems. The last binary pulsar (PSR J1912−0952) has a significantly smaller spin frequency and a smaller companion mass, the latter could be caused by a low orbital inclination for the system. Its orbital period of 29 d is well within the range of orbital periods where some MSP–He WD systems have shown anomalous eccentricities, however, the eccentricity of PSR J1912−0952 is typical of what one finds for the remaining MSP–He WD systems.
In this first-in-human phase 1 study (NCT02964013; MK-7684-001), we investigated the safety and efficacy of the anti-TIGIT (T cell immunoglobulin and ITIM domain) antibody vibostolimab as monotherapy ...or in combination with pembrolizumab.
Part A enrolled patients with advanced solid tumors, and part B enrolled patients with non-small-cell lung cancer (NSCLC). Patients received vibostolimab 2.1-700 mg alone or with pembrolizumab 200 mg in part A and vibostolimab 200 mg alone or with pembrolizumab 200 mg in part B. Primary endpoints were safety and tolerability. Secondary endpoints included pharmacokinetics and objective response rate (ORR) per RECIST v1.1.
Part A enrolled 76 patients (monotherapy, 34; combination therapy, 42). No dose-limiting toxicities were reported. Across doses, 56% of patients receiving monotherapy and 62% receiving combination therapy had treatment-related adverse events (TRAEs); grade 3-4 TRAEs occurred in 9% and 17% of patients, respectively. The most common TRAEs were fatigue (15%) and pruritus (15%) with monotherapy and pruritus (17%) and rash (14%) with combination therapy. Confirmed ORR was 0% with monotherapy and 7% with combination therapy. In part B, 39 patients had anti-PD-1 (programmed cell death protein 1)/PD-L1 (programmed death-ligand 1)-naive NSCLC (all received combination therapy), and 67 had anti-PD-1/PD-L1-refractory NSCLC (monotherapy, 34; combination therapy, 33). In patients with anti-PD-1/PD-L1-naive NSCLC: 85% had TRAEs–the most common were pruritus (38%) and hypoalbuminemia (31%); confirmed ORR was 26%, with responses occurring in both PD-L1-positive and PD-L1-negative tumors. In patients with anti-PD-1/PD-L1-refractory NSCLC: 56% receiving monotherapy and 70% receiving combination therapy had TRAEs–the most common were rash and fatigue (21% each) with monotherapy and pruritus (36%) and fatigue (24%) with combination therapy; confirmed ORR was 3% with monotherapy and 3% with combination therapy.
Vibostolimab plus pembrolizumab was well tolerated and demonstrated antitumor activity in patients with advanced solid tumors, including patients with advanced NSCLC.
•First-in-human phase 1 study in patients with advanced solid tumors who received vibostolimab alone or with pembrolizumab.•Vibostolimab plus pembrolizumab was well tolerated in advanced solid tumors.•Vibostolimab plus pembrolizumab demonstrated antitumor activity in patients with advanced solid tumors.
Abstract
PSR J2150+3427 is a 0.654 s pulsar discovered by the Commensal Radio Astronomy FAST Survey. From the follow-up observations, we find that the pulsar is in a highly eccentric orbit (
e
= ...0.601) with an orbital period of 10.592 days and a projected semimajor axis of 25.488 lt-s. Using 2.7 yr of timing data, we also measured the rate of periastron advance
ω
̇
= 0.0115(4) deg yr
−1
. An estimate for the total mass of the system using the
ω
̇
gives
M
tot
= 2.59(13)
M
⊙
, which is consistent with most of the known double neutron star (DNS) systems and one neutron star (NS)–white dwarf (WD) system named B2303+46. Combining
ω
̇
with the mass function of the system gives the masses of
M
p
< 1.67 and
M
c
> 0.98
M
⊙
for the pulsar and the companion star, respectively. This constraint, along with the spin period and orbital parameters, suggests that it is possibly a DNS system, and we cannot entirely rule out the possibility of an NS–WD system. Future timing observations will vastly improve the uncertainty in
ω
̇
, and are likely to allow the detection of additional relativistic effects, which can be used to modify the values of
M
p
and
M
c
. With a spin-down luminosity of
E
̇
= 5.07(6) × 10
29
erg s
−1
, PSR J2150+3427 is a very low-luminosity pulsar, with only the binary pulsar J2208+4610 having a smaller
E
̇
.
Acquired therapeutic resistance is the major drawback to effective systemic therapies for cancers. Aggressive triple-negative breast cancers (TNBC) develop resistance to chemotherapies rapidly, ...whereas the underlying mechanisms are not completely understood. Here we show that genotoxic treatments significantly increased the expression of miR-181a in TNBC cells, which enhanced TNBC cell survival and metastasis upon Doxorubicin treatment. Consistently, high miR-181a level associated with poor disease free survival and overall survival after treatments in breast cancer patients. The upregulation of miR-181a was orchestrated by transcription factor STAT3 whose activation depended on NF-κB-mediated IL-6 induction in TNBC cells upon genotoxic treatment. Intriguingly, activated STAT3 not only directly bound to MIR181A1 promoter to drive transcription but also facilitated the recruitment of MSK1 to the same region where MSK1 promoted a local active chromatin state by phosphorylating histone H3. We further identified BAX as a direct functional target of miR-181a, whose suppression decreased apoptosis and increased invasion of TNBC cells upon Dox treatment. These results were further confirmed by evidence that suppression of miR-181a significantly enhanced therapeutic response and reduced lung metastasis in a TNBC orthotopic model. Collectively, our data suggested that miR-181a induction had a critical role in promoting therapeutic resistance and aggressive behavior of TNBC cells upon genotoxic treatment. Antagonizing miR-181a may serve as a promising strategy to sensitize TNBC cells to chemotherapy and mitigate metastasis.
The mechanism of high superconducting transition temperatures (Tc) in bismuthates remains under debate despite more than 30 years of extensive research. Our angle-resolved photoemission spectroscopy ...studies on Ba0.51K0.49BiO3 reveal an unexpectedly 34% larger bandwidth than in conventional density functional theory calculations. This can be reproduced by calculations that fully account for long-range Coulomb interactions-the first direct demonstration of bandwidth expansion due to the Fock exchange term, a long-accepted and yet uncorroborated fundamental effect in many body physics.Furthermore, we observe an isotropic superconducting gap with 2Δ0/kBTc=3.51±0.05, and strong electron-phonon interactions with a coupling constant λ∼1.3±0.2. These findings solve a long-standing mystery-Ba0.51K0.49BiO3 is an extraordinary Bardeen-Cooper-Schrieffer superconductor, where long-range Coulomb interactions expand the bandwidth, enhance electron-phonon coupling, and generate the high Tc. Such effects will also be critical for finding new superconductors.
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