A Patient-Derived Glioblastoma Organoid Model and Biobank Recapitulates Inter- and Intra-tumoral Heterogeneity.

Glioblastomas exhibit vast inter- and intra-tumoral heterogeneity, complicating the development of effective therapeutic strategies. Current in vitro models are limited in preserving the cellular and mutational diversity of parental tumors and require a prolonged generation time. Here, we report methods for generating and biobanking patient-derived glioblastoma organoids (GBOs) that recapitulate the histological features, cellular diversity, gene expression, and mutational profiles of their corresponding parental tumors. GBOs can be generated quickly with high reliability and exhibit rapid, aggressive infiltration when transplanted into adult rodent brains. We further demonstrate the utility of GBOs to test personalized therapies by correlating GBO mutational profiles with responses to specific drugs and by modeling chimeric antigen receptor T cell immunotherapy. Our studies show that GBOs maintain many key features of glioblastomas and can be rapidly deployed to investigate patient-specific treatment strategies. Additionally, our live biobank establishes a rich resource for basic and translational glioblastoma research.

A binary pulsar in a 53-minute orbit.

Spider pulsars are neutron stars that have a companion star in a close orbit. The companion star sheds material to the neutron star, spinning it up to millisecond rotation periods, while the orbit shortens to hours. The companion is eventually ablated and destroyed by the pulsar wind and radiation1,2. Spider pulsars are key for studying the evolutionary link between accreting X-ray pulsars and isolated millisecond pulsars, pulsar irradiation effects and the birth of massive neutron stars3-6. Black widow pulsars in extremely compact orbits (as short as 62 minutes7) have companions with masses much smaller than 0.1 M⊙. They may have evolved from redback pulsars with companion masses of about 0.1-0.4 M⊙ and orbital periods of less than 1 day8. If this is true, then there should be a population of millisecond pulsars with moderate-mass companions and very short orbital periods9, but, hitherto, no such system was known. Here we report radio observations of the binary millisecond pulsar PSR J1953+1844 (M71E) that show it to have an orbital period of 53.3 minutes and a companion with a mass of around 0.07 M⊙. It is a faint X-ray source and located 2.5 arcminutes from the centre of the globular cluster M71.

A highly distorted ultraelastic chemically complex Elinvar alloy.

The development of high-performance ultraelastic metals with superb strength, a large elastic strain limit and temperature-insensitive elastic modulus (Elinvar effect) are important for various industrial applications, from actuators and medical devices to high-precision instruments1,2. The elastic strain limit of bulk crystalline metals is usually less than 1 per cent, owing to dislocation easy gliding. Shape memory alloys3-including gum metals4,5 and strain glass alloys6,7-may attain an elastic strain limit up to several per cent, although this is the result of pseudo-elasticity and is accompanied by large energy dissipation3. Recently, chemically complex alloys, such as 'high-entropy' alloys8, have attracted tremendous research interest owing to their promising properties9-15. In this work we report on a chemically complex alloy with a large atomic size misfit usually unaffordable in conventional alloys. The alloy exhibits a high elastic strain limit (approximately 2 per cent) and a very low internal friction (less than 2 × 10-4) at room temperature. More interestingly, this alloy exhibits an extraordinary Elinvar effect, maintaining near-constant elastic modulus between room temperature and 627 degrees Celsius (900 kelvin), which is, to our knowledge, unmatched by the existing alloys hitherto reported.

Molecular landscapes of human hippocampal immature neurons across lifespan.

Immature dentate granule cells (imGCs) arising from adult hippocampal neurogenesis contribute to plasticity and unique brain functions in rodents1,2 and are dysregulated in multiple human neurological disorders3-5. Little is known about the molecular characteristics of adult human hippocampal imGCs, and even their existence is under debate1,6-8. Here we performed single-nucleus RNA sequencing aided by a validated machine learning-based analytic approach to identify imGCs and quantify their abundance in the human hippocampus at different stages across the lifespan. We identified common molecular hallmarks of human imGCs across the lifespan and observed age-dependent transcriptional dynamics in human imGCs that suggest changes in cellular functionality, niche interactions and disease relevance, that differ from those in mice9. We also found a decreased number of imGCs with altered gene expression in Alzheimer's disease. Finally, we demonstrated the capacity for neurogenesis in the adult human hippocampus with the presence of rare dentate granule cell fate-specific proliferating neural progenitors and with cultured surgical specimens. Together, our findings suggest the presence of a substantial number of imGCs in the adult human hippocampus via low-frequency de novo generation and protracted maturation, and our study reveals their molecular properties across the lifespan and in Alzheimer's disease.

Burning plasma achieved in inertial fusion.

Obtaining a burning plasma is a critical step towards self-sustaining fusion energy1. A burning plasma is one in which the fusion reactions themselves are the primary source of heating in the plasma, which is necessary to sustain and propagate the burn, enabling high energy gain. After decades of fusion research, here we achieve a burning-plasma state in the laboratory. These experiments were conducted at the US National Ignition Facility, a laser facility delivering up to 1.9 megajoules of energy in pulses with peak powers up to 500 terawatts. We use the lasers to generate X-rays in a radiation cavity to indirectly drive a fuel-containing capsule via the X-ray ablation pressure, which results in the implosion process compressing and heating the fuel via mechanical work. The burning-plasma state was created using a strategy to increase the spatial scale of the capsule2,3 through two different implosion concepts4-7. These experiments show fusion self-heating in excess of the mechanical work injected into the implosions, satisfying several burning-plasma metrics3,8. Additionally, we describe a subset of experiments that appear to have crossed the static self-heating boundary, where fusion heating surpasses the energy losses from radiation and conduction. These results provide an opportunity to study α-particle-dominated plasmas and burning-plasma physics in the laboratory.

The role of CBL-CIPK signaling in plant responses to biotic and abiotic stresses.

Plants have a variety of regulatory mechanisms to perceive, transduce, and respond to biotic and abiotic stress. One such mechanism is the calcium-sensing CBL-CIPK system responsible for the sensing of specific stressors, such as drought or pathogens. CBLs perceive and bind Calcium (Ca2+) in response to stress and then interact with CIPKs to form an activated complex. This leads to the phosphorylation of downstream targets, including transporters and ion channels, and modulates transcription factor levels and the consequent levels of stress-associated genes. This review describes the mechanisms underlying the response of the CBL-CIPK pathway to biotic and abiotic stresses, including regulating ion transport channels, coordinating plant hormone signal transduction, and pathways related to ROS signaling. Investigation of the function of the CBL-CIPK pathway is important for understanding plant stress tolerance and provides a promising avenue for molecular breeding.

Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study.

BACKGROUND: Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC. PATIENTS AND METHODS: Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib [50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle)]. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety. RESULTS: A total of 421 patients were randomized to receive toripalimab plus axitinib (n = 210) or sunitinib (n = 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P = 0.0028]. The median PFS was 18.0 months in the toripalimab-axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab-axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab-axitinib group and 58.6% of patients in the sunitinib group. CONCLUSION: In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile TRIAL REGISTRATION: ClinicalTrials.gov NCT04394975.

Sniffing out meaning: Chemosensory and semantic neural network changes in sommeliers.

Wine tasting is a very complex process that integrates a combination of sensation, language, and memory. Taste and smell provide perceptual information that, together with the semantic narrative that converts flavor into words, seem to be processed differently between sommeliers and naïve wine consumers. We investigate whether sommeliers' wine experience shapes only chemosensory processing, as has been previously demonstrated, or if it also modulates the way in which the taste and olfactory circuits interact with the semantic network. Combining diffusion-weighted images and fMRI (activation and connectivity) we investigated whether brain response to tasting wine differs between sommeliers and nonexperts (1) in the sensory neural circuits representing flavor and/or (2) in the neural circuits for language and memory. We demonstrate that training in wine tasting shapes the microstructure of the left and right superior longitudinal fasciculus. Using mediation analysis, we showed that the experience modulates the relationship between fractional anisotropy and behavior: the higher the fractional anisotropy the higher the capacity to recognize wine complexity. In addition, we found functional differences between sommeliers and naïve consumers affecting the flavor sensory circuit, but also regions involved in semantic operations. The former reflects a capacity for differential sensory processing, while the latter reflects sommeliers' ability to attend to relevant sensory inputs and translate them into complex verbal descriptions. The enhanced synchronization between these apparently independent circuits suggests that sommeliers integrated these descriptions with previous semantic knowledge to optimize their capacity to distinguish between subtle differences in the qualitative character of the wine.

Linearization of wavelength sweeping lasers for the construction of 4-D FMCW LiDAR images of slow-moving objects using baseband beat note signals.

A FMCW LiDAR system of both the distributed feedback laser and external cavity laser is established in baseband beat notes, rather than up-conversion to an intermediate frequency to exclude flicker noise. Meanwhile, utilizing fast-scanning MEMS mirrors, high-quality real-time (1 fps) 4-D images of the slow-moving object (10 mm/s) can be directly constructed at the baseband with a central frequency as low as 100 kHz and a small Doppler shift. The proposed LiDAR architecture based on such a low-frequency baseband significantly improves the optical power budget on the transmitter side and eliminates the costly high-speed sampling circuits on the receiver side.

First Measurement of Discrimination between Helium and Electron Recoils in Liquid Xenon for Low-Mass Dark Matter Searches.

We report the first measurement of discrimination between low-energy helium recoils and electron recoils in liquid xenon. This result is relevant to proposed low-mass dark matter searches which seek to dissolve light target nuclei in the active volume of liquid-xenon time projection chambers. Low-energy helium recoils were produced by degrading α particles from ^{210}Po with a gold foil situated on the cathode of a liquid xenon time-projection chamber. The resulting population of helium recoil events is well separated from electron recoils and is also offset from the expected position of xenon nuclear recoil events.

Search for a Sub-eV Sterile Neutrino Using Daya Bay's Full Dataset.

This Letter presents results of a search for the mixing of a sub-eV sterile neutrino with three active neutrinos based on the full data sample of the Daya Bay Reactor Neutrino Experiment, collected during 3158 days of detector operation, which contains 5.55×10^{6} reactor ν[over ¯]_{e} candidates identified as inverse beta-decay interactions followed by neutron capture on gadolinium. The analysis benefits from a doubling of the statistics of our previous result and from improvements of several important systematic uncertainties. No significant oscillation due to mixing of a sub-eV sterile neutrino with active neutrinos was found. Exclusion limits are set by both Feldman-Cousins and CLs methods. Light sterile neutrino mixing with sin^{2}2θ_{14}≳0.01 can be excluded at 95% confidence level in the region of 0.01 eV^{2}≲|Δm_{41}^{2}|≲0.1 eV^{2}. This result represents the world-leading constraints in the region of 2×10^{-4} eV^{2}≲|Δm_{41}^{2}|≲0.2 eV^{2}.

Measurements of Normalized Differential Cross Sections of Inclusive η Production in e

Using data samples collected with the BESIII detector operating at the BEPCII storage ring, the cross section of the inclusive process e^{+}e^{-}→η+X, normalized by the total cross section of e^{+}e^{-}→hadrons, is measured at eight center-of-mass energy points from 2.0000 to 3.6710 GeV. These are the first measurements with momentum dependence in this energy region. Our measurement shows a significant discrepancy compared to the existing fragmentation functions. To address this discrepancy, a new QCD analysis is performed at the next-to-next-to-leading order with hadron mass corrections and higher twist effects, which can explain both the established high-energy data and our measurements reasonably well.

First Study of Antihyperon-Nucleon Scattering Λ[over ¯]p→Λ[over ¯]p and Measurement of Λp→Λp Cross Section.

Using (10.087±0.044)×10^{9} J/ψ events collected with the BESIII detector at the BEPCII storage ring, the processes Λp→Λp and Λ[over ¯]p→Λ[over ¯]p are studied, where the Λ/Λ[over ¯] baryons are produced in the process J/ψ→ΛΛ[over ¯] and the protons are the hydrogen nuclei in the cooling oil of the beam pipe. Clear signals are observed for the two reactions. The cross sections in -0.9≤cosθ_{Λ/Λ[over ¯]}≤0.9 are measured to be σ(Λp→Λp)=(12.2±1.6_{stat}±1.1_{syst}) and σ(Λ[over ¯]p→Λ[over ¯]p)=(17.5±2.1_{stat}±1.6_{syst}) mb at the Λ/Λ[over ¯] momentum of 1.074 GeV/c within a range of ±0.017 GeV/c, where the θ_{Λ/Λ[over ¯]} are the scattering angles of the Λ/Λ[over ¯] in the Λp/Λ[over ¯]p rest frames. Furthermore, the differential cross sections of the two reactions are also measured, where there is a slight tendency of forward scattering for Λp→Λp, and a strong forward peak for Λ[over ¯]p→Λ[over ¯]p. We present an approach to extract the total elastic cross sections by extrapolation. The study of Λ[over ¯]p→Λ[over ¯]p represents the first study of antihyperon-nucleon scattering, and these new measurements will serve as important inputs for the theoretical understanding of the (anti)hyperon-nucleon interaction.

Properties of Cosmic Deuterons Measured by the Alpha Magnetic Spectrometer.

Precision measurements by the Alpha Magnetic Spectrometer (AMS) on the International Space Station of the deuteron (D) flux are presented. The measurements are based on 21×10^{6} D nuclei in the rigidity range from 1.9 to 21 GV collected from May 2011 to April 2021. We observe that over the entire rigidity range the D flux exhibits nearly identical time variations with the p, ^{3}He, and ^{4}He fluxes. Above 4.5 GV, the D/^{4}He flux ratio is time independent and its rigidity dependence is well described by a single power law ∝R^{Δ} with Δ_{D/^{4}He}=-0.108±0.005. This is in contrast with the ^{3}He/^{4}He flux ratio for which we find Δ_{^{3}He/^{4}He}=-0.289±0.003. Above ∼13 GV we find a nearly identical rigidity dependence of the D and p fluxes with a D/p flux ratio of 0.027±0.001. These unexpected observations indicate that cosmic deuterons have a sizable primarylike component. With a method independent of cosmic ray propagation, we obtain the primary component of the D flux equal to 9.4±0.5% of the ^{4}He flux and the secondary component of the D flux equal to 58±5% of the ^{3}He flux.

Investigation of the ΔI=1/2 Rule and Test of CP Symmetry through the Measurement of Decay Asymmetry Parameters in Ξ

Using (10087±44)×10^{6} J/ψ events collected with the BESIII detector, numerous Ξ^{-} and Λ decay asymmetry parameters are simultaneously determined from the process J/ψ→Ξ^{-}Ξ[over ¯]^{+}→Λ(pπ^{-})π^{-}Λ[over ¯](n[over ¯]π^{0})π^{+} and its charge-conjugate channel. The precisions of α_{Λ0} for Λ→nπ^{0} and α[over ¯]_{Λ0} for Λ[over ¯]→n[over ¯]π^{0} compared to world averages are improved by factors of 4 and 1.7, respectively. The ratio of decay asymmetry parameters of Λ→nπ^{0} to that of Λ→pπ^{-}, ⟨α_{Λ0}⟩/⟨α_{Λ-}⟩, is determined to be 0.873±0.012_{-0.010}^{+0.011}, where the first and the second uncertainties are statistical and systematic, respectively. The ratio is smaller than unity more than 5σ, which signifies the existence of the ΔI=3/2 transition in Λ for the first time. Besides, we test for CP symmetry in Ξ^{-}→Λπ^{-} and in Λ→nπ^{0} with the best precision to date.

First Measurement of the Decay Asymmetry in the Pure W-Boson-Exchange Decay Λ_{c}

Based on 4.4 fb^{-1} of e^{+}e^{-} annihilation data collected at the center-of-mass energies between 4.60 and 4.70 GeV with the BESIII detector at the BEPCII collider, the pure W-boson-exchange decay Λ_{c}^{+}→Ξ^{0}K^{+} is studied with a full angular analysis. The corresponding decay asymmetry is measured for the first time to be α_{Ξ^{0}K^{+}}=0.01±0.16(stat)±0.03(syst). This result reflects the noninterference effect between the S- and P-wave amplitudes. The phase shift between S- and P-wave amplitudes has two solutions, which are δ_{p}-δ_{s}=-1.55±0.25(stat)±0.05(syst) rad or 1.59±0.25(stat)±0.05(syst) rad.

Determination of the Σ

Based on data samples collected with the BESIII detector at the BEPCII collider, the process e^{+}e^{-}→Σ^{+}Σ[over ¯]^{-} is studied at center-of-mass energies sqrt[s]=2.3960, 2.6454, and 2.9000 GeV. Using a fully differential angular description of the final state particles, both the relative magnitude and phase information of the Σ^{+} electromagnetic form factors in the timelike region are extracted. The relative phase between the electric and magnetic form factors is determined to be sinΔΦ=-0.67±0.29(stat)±0.18(syst) at sqrt[s]=2.3960 GeV, ΔΦ=55°±19°(stat)±14°(syst) at sqrt[s]=2.6454 GeV, and 78°±22°(stat)±9°(syst) at sqrt[s]=2.9000 GeV. For the first time, the phase of the hyperon electromagnetic form factors is explored in a wide range of four-momentum transfer. The evolution of the phase along with four-momentum transfer is an important input for understanding its asymptotic behavior and the dynamics of baryons.

Observation of D_{s}

By analyzing 7.33 fb^{-1} of e^{+}e^{-} annihilation data collected at center-of-mass energies between 4.128 and 4.226 GeV with the BESIII detector, we report the observation of the semileptonic decay D_{s}^{+}→η^{'}µ^{+}ν_{µ}, with a statistical significance larger than 10σ, and the measurements of the D_{s}^{+}→ηµ^{+}ν_{µ} and D_{s}^{+}→η^{'}µ^{+}ν_{µ} decay dynamics for the first time. The branching fractions of D_{s}^{+}→ηµ^{+}ν_{µ} and D_{s}^{+}→η^{'}µ^{+}ν_{µ} are determined to be (2.235±0.051_{stat}±0.052_{syst})% and (0.801±0.055_{stat}±0.028_{syst})%, respectively, with precision improved by factors of 6.0 and 6.6 compared to the previous best measurements. Combined with the results for the decays D_{s}^{+}→ηe^{+}ν_{e} and D_{s}^{+}→η^{'}e^{+}ν_{e}, the ratios of the decay widths are examined both inclusively and in several ℓ^{+}ν_{ℓ} four-momentum transfer ranges. No evidence for lepton flavor universality violation is found within the current statistics. The products of the hadronic form factors f_{+,0}^{η^{(')}}(0) and the c→s Cabibbo-Kobayashi-Maskawa matrix element |V_{cs}| are determined. The results based on the two-parameter series expansion are f_{+,0}^{η}(0)|V_{cs}|=0.452±0.010_{stat}±0.007_{syst} and f_{+,0}^{η^{'}}(0)|V_{cs}|=0.504±0.037_{stat}±0.012_{syst}, which help to constrain present models on f_{+,0}^{η^{(')}}(0). The forward-backward asymmetries are determined to be ⟨A_{FB}^{η}⟩=-0.059±0.031_{stat}±0.005_{syst} and ⟨A_{FB}^{η^{'}}⟩=-0.064±0.079_{stat}±0.006_{syst} for the first time, which are consistent with the theoretical calculation.

First Observation of a Three-Resonance Structure in e

We report the measurement of the inclusive cross sections for e^{+}e^{-}→nOCH (where nOCH denotes non-open charm hadrons) with improved precision at center-of-mass (c.m.) energies from 3.645 to 3.871 GeV. We observe three resonances: R(3760), R(3780), and R(3810) with significances of 8.1σ, 13.7σ, and 8.8σ, respectively. The R(3810) state is observed for the first time, while the R(3760) and R(3780) states are observed for the first time in the nOCH cross sections. Two sets of resonance parameters describe the energy-dependent line shape of the cross sections well. In set I [set II], the R(3810) state has mass (3805.7±1.1±2.7) [(3805.7±1.1±2.7)] MeV/c^{2}, total width (11.6±2.9±1.9) [(11.5±2.8±1.9)] MeV, and an electronic width multiplied by the nOCH decay branching fraction of (10.9±3.8±2.5) [(11.0±3.4±2.5)] eV. In addition, we measure the branching fractions B[R(3760)→nOCH]=(25.2±16.1±30.4)%[(6.4±4.8±7.7)%] and B[R(3780)→nOCH]=(12.3±6.6±8.3)%[(10.4±4.8±7.0)%] for the first time. The R(3760) state can be interpreted as an open-charm (OC) molecular state, but containing a simple four-quark state component. The R(3810) state can be interpreted as a hadrocharmonium state.

Observation of Structures in the Processes e

We present measurements of the Born cross sections for the processes e^{+}e^{-}→ωχ_{c1} and ωχ_{c2} at center-of-mass energies sqrt[s] from 4.308 to 4.951 GeV. The measurements are performed with data samples corresponding to an integrated luminosity of 11.0 fb^{-1} collected with the BESIII detector operating at the Beijing Electron Positron Collider storage ring. Assuming the e^{+}e^{-}→ωχ_{c2} signals come from a single resonance, the mass and width are determined to be M=(4413.6±9.0±0.8) MeV/c^{2} and Γ=(110.5±15.0±2.9) MeV, respectively, which is consistent with the parameters of the well-established resonance ψ(4415). In addition, we also use one single resonance to describe the e^{+}e^{-}→ωχ_{c1} line shape and determine the mass and width to be M=(4544.2±18.7±1.7) MeV/c^{2} and Γ=(116.1±33.5±1.7) MeV, respectively. The structure of this line shape, observed for the first time, requires further understanding.