Abstract: The Crab Nebula is a bright source of gamma rays powered by the Crab Pulsar’s rotational energy through the formation and termination of a relativistic electron-positron wind. We report the detection of gamma rays from this source with energies from 5 × 10 −4 to 1.1 peta–electron volts with a spectrum showing gradual steepening over three energy decades. The ultrahigh-energy photons imply the presence of a peta–electron volt electron accelerator (a pevatron) in the nebula, with an acceleration rate exceeding 15% of the theoretical limit. We constrain the pevatron’s size between 0.025 and 0.1 parsecs and the magnetic field to ≈110 microgauss. The production rate of peta–electron volt electrons, 2.5 × 10 36 ergs per second, constitutes 0.5% of the pulsar spin-down luminosity, although we cannot exclude a contribution of peta–electron volt protons to the production of the highest-energy gamma rays.

Abstract: Observations of the bright gamma-ray burst GRB 221009A at tera–electron volt energies show that it contained a very narrow jet.

Abstract: De novo mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole-genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) Program, we called 93,325 single-nucleotide DNMs across 1,465 trios from an array of diverse human populations, and used them to directly estimate and analyze DNM counts, rates, and spectra. We find a significant positive correlation between local recombination rate and local DNM rate, and that DNM rate explains a substantial portion (8.98 to 34.92%, depending on the model) of the genome-wide variation in population-level genetic variation from 41K unrelated TOPMed samples. Genome-wide heterozygosity does correlate with DNM rate, but only explains 〈 1% of variation. While we are underpowered to see small differences, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, we did find significantly fewer DNMs in Amish individuals, even when compared with other Europeans, and even after accounting for parental age and sequencing center. Specifically, we found significant reductions in the number of C→A and T→C mutations in the Amish, which seem to underpin their overall reduction in DNMs. Finally, we calculated near-zero estimates of narrow sense heritability ( h 2 ), which suggest that variation in DNM rate is significantly shaped by nonadditive genetic effects and the environment.

Abstract: Neutralizing antibodies could potentially be used as antivirals against the coronavirus disease 2019 (COVID-19) pandemic. Here, we report isolation of four human-origin monoclonal antibodies from a convalescent patient, all of which display neutralization abilities. The antibodies B38 and H4 block binding between the spike glycoprotein receptor binding domain (RBD) of the virus and the cellular receptor angiotensin-converting enzyme 2 (ACE2). A competition assay indicated different epitopes on the RBD for these two antibodies, making them a potentially promising virus-targeting monoclonal antibody pair for avoiding immune escape in future clinical applications. Moreover, a therapeutic study in a mouse model validated that these antibodies can reduce virus titers in infected lungs. The RBD-B38 complex structure revealed that most residues on the epitope overlap with the RBD-ACE2 binding interface, explaining the blocking effect and neutralizing capacity. Our results highlight the promise of antibody-based therapeutics and provide a structural basis for rational vaccine design.

Abstract: Tibet’s ancient topography and its role in climatic and biotic evolution remain speculative due to a paucity of quantitative surface-height measurements through time and space, and sparse fossil records. However, newly discovered fossils from a present elevation of ∼4,850 m in central Tibet improve substantially our knowledge of the ancient Tibetan environment. The 70 plant fossil taxa so far recovered include the first occurrences of several modern Asian lineages and represent a Middle Eocene (∼47 Mya) humid subtropical ecosystem. The fossils not only record the diverse composition of the ancient Tibetan biota, but also allow us to constrain the Middle Eocene land surface height in central Tibet to ∼1,500 ± 900 m, and quantify the prevailing thermal and hydrological regime. This “Shangri-La”–like ecosystem experienced monsoon seasonality with a mean annual temperature of ∼19 °C, and frosts were rare. It contained few Gondwanan taxa, yet was compositionally similar to contemporaneous floras in both North America and Europe. Our discovery quantifies a key part of Tibetan Paleogene topography and climate, and highlights the importance of Tibet in regard to the origin of modern Asian plant species and the evolution of global biodiversity.

Abstract: Relapsed and refractory (R/R) multiple myeloma (MM) patients have very poor prognosis. Chimeric antigen receptor modified T (CAR T) cells is an emerging approach in treating hematopoietic malignancies. Here we conducted the clinical trial of a biepitope-targeting CAR T against B cell maturation antigen (BCMA) (LCAR-B38M) in 17 R/R MM cases. CAR T cells were i.v. infused after lymphodepleting chemotherapy. Two delivery methods, three infusions versus one infusion of the total CAR T dose, were tested in, respectively, 8 and 9 cases. No response differences were noted among the two delivery subgroups. Together, after CAR T cell infusion, 10 cases experienced a mild cytokine release syndrome (CRS), 6 had severe but manageable CRS, and 1 died of a very severe toxic reaction. The abundance of BCMA and cytogenetic marker del(17p) and the elevation of IL-6 were the key indicators for severe CRS. Among 17 cases, the overall response rate was 88.2%, with 13 achieving stringent complete response (sCR) and 2 reaching very good partial response (VGPR), while 1 was a nonresponder. With a median follow-up of 417 days, 8 patients remained in sCR or VGPR, whereas 6 relapsed after sCR and 1 had progressive disease (PD) after VGPR. CAR T cells were high in most cases with stable response but low in 6 out of 7 relapse/PD cases. Notably, positive anti-CAR antibody constituted a high-risk factor for relapse/PD, and patients who received prior autologous hematopoietic stem cell transplantation had more durable response. Thus, biepitopic CAR T against BCMA represents a promising therapy for R/R MM, while most adverse effects are clinically manageable.

Abstract: Genomic instability (GI) drives tumor heterogeneity and promotes tumor progression and therapy resistance. However, causative factors underlying GI and means for clinical detection of GI in glioma are inadequately identified. We describe here that elevated expression of a gene module coexpressed with CDC20 (CDC20-M), the activator of the anaphase-promoting complex in the cell cycle, marks GI in glioma. The CDC20-M, containing 139 members involved in cell proliferation, DNA damage response, and chromosome segregation, was found to be consistently coexpressed in glioma transcriptomes. The coexpression of these genes was conserved across multiple species and organ systems, particularly in human neural stem and progenitor cells. CDC20-M expression was not correlated with the morphological subtypes, nor with the recently defined molecular subtypes of glioma. CDC20-M signature was an independent and robust predictor for poorer prognosis in over 1,000 patients from four large databases. Elevated CDC20-M signature enabled the identification of individual glioma samples with severe chromosome instability and mutation burden and of primary glioma cell lines with extensive mitotic errors leading to chromosome mis-segregation. AURKA, a core member of CDC20-M, was amplified in one-third of CDC20-M–high gliomas with gene-dosage–dependent expression. MLN8237, a Food and Drug Administration-approved AURKA inhibitor, selectively killed temozolomide-resistant primary glioma cells in vitro and prolonged the survival of a patient-derived xenograft mouse model with a high–CDC20-M signature. Our findings suggest that application of the CDC20-M signature may permit more selective use of adjuvant therapies for glioma patients and that dysregulated CDC20-M members may provide a therapeutic vulnerability in glioma.

Abstract: On-animal suction cups with embedded hydrophones allow examination of how signals on the forehead of echolocating odontocetes relate to the internal anatomical structure and the transmission beampattern. Risso’s dolphin (Grampus griseus) is an interesting species for this investigation due to the presence of a unique vertical groove in the middle of their forehead. In this study, a linear array of six broadband suction cup hydrophones were attached along the forehead groove of an adult female Risso’s dolphin trained to catch freshly thawed dead squid in front of an eight-element far-field hydrophone array. The animal’s movement was simultaneously observed using an underwater video camera. A total of nine successful prey captures were recorded. During each catch, the animal first emitted regular echolocation clicks, which quickly transitioned into buzzes (clicks with distinctively high repetition rate) until prey capture. The amplitude and relative time of arrival of these signals across all channels were analyzed. For a subset of trials, the relative amplitude distribution across channels vary significantly between regular clicks and buzzes in a manner that may be explained by beampattern changes. These observations were investigated jointly with data from the hydrophone array and interpreted in light of anatomical structure of the melon.

Abstract: The contradiction between “high yielding” and “early maturing” hampers further improvement of annual rice yield. Here we report the positional cloning of a major maturity duration regulatory gene, Early flowering-completely dominant ( Ef-cd ), and demonstrate that natural variation in Ef-cd could be used to overcome the above contradictory. The Ef-cd locus gives rise to a long noncoding RNA (lncRNA) antisense transcript overlapping the OsSOC1 gene. Ef-cd lncRNA expression positively correlates with the expression of OsSOC1 and H3K36me3 deposition. Field test comparisons of early maturing Ef-cd near-isogenic lines with their wild types as well as of the derivative early maturing hybrids with their wild-type hybrids conducted under different latitudes determined that the early maturing Ef-cd allele shortens maturity duration (ranging from 7 to 20 d) without a concomitant yield penalty. Ef-cd facilitates nitrogen utilization and also improves the photosynthesis rate. Analysis of 1,439 elite hybrid rice varieties revealed that the 16 homozygotes and 299 heterozygotes possessing Ef-cd matured significantly earlier. Therefore, Ef-cd could be a vital contributor of elite early maturing hybrid varieties in balancing grain yield with maturity duration.

Abstract: In summary, our results show the existence of mechanisms that prevent the rapid depletion of synaptic vesicles at release sites when the supply of such vesicles is drastically reduced by the absence of both dynamin 1 and dynamin 3. They suggest that, when synaptic vesicle components are stranded within clathrin-coated pits (which happens in the absence of dynamin 1 and 3) with a resulting dramatic accumulation of membrane at the cell surface, a feedback mechanism exists that affects the probability of release. This finding reveals an interesting example of the coupling between endocytosis and exocytosis, a process that is increasingly recognized as playing an important role in short-term synaptic plasticity and thus in the proper functioning of neuronal networks. Overnight silencing of the DKO cultures with tetrodotoxin, which blocks the sodium ion channels responsible for the propagation of electrical impulses along axons, decreased both the synaptic facilitation and the activation of CaMKII. This finding indicates that the effects observed in DKO cultures are dependent on neuronal activity and most likely result (at least to a great extent) from the trapping of recycling vesicle membranes in endocytic intermediates. Inhibition of CaMKII also reversed the facilitation observed at DKO synapses, suggesting that this enzyme plays a role in relaying the status of endocytic traffic to the exocytic machinery. We also examined the physiological parameters of DKO synapses that could account for these observations. The size of the readily releasable pool of vesicles, which was assessed by two independent methods, was greatly decreased at DKO synapses, although not as strongly as was the amplitude decrease of the EPSCs. Likewise, EM showed that docked vesicles at active zones (i.e., the vesicles thought to reflect the readily releasable pool) were less abundant in DKO cultures. Why then did DKO synapses not quickly run out of vesicles, resulting in transmission failure? Additional analysis revealed a reduction in release probability ( p ). A lower p (reluctance to release the available vesicles) explains the greater effect of the loss of dynamin 1 and 3 on EPSCs than on the readily releasable pool. It also, therefore, explains the enhanced preservation of a secretory response from this pool during a stimulus train. We additionally found an increased activation state of a calcium/calmodulin-dependent protein kinase (CaMKII) in DKO cultures, consistent with the previously reported increase in the state of phosphorylation of synapsin 1 (a synaptic vesicle associate protein that is a substrate of this kinase) ( 1 ). Surprisingly, instead of a faster depression, we have now found robust synaptic facilitation on repeated stimulation at synapses of cultured neurons derived from DKO newborn mice. Although the average amplitude of the first excitatory postsynaptic current (EPSC) in a stimulus train was dramatically reduced in DKO cultures, subsequent EPSCs in the train were higher than the first response. They did, however, remain much smaller in absolute values than in control neurons ( Fig. P1 B , Upper ). After this initial facilitation phase, the response underwent depression, but the average normalized EPSC curves revealed overall lower depression in DKO cultures relative to controls throughout the train ( Fig. P1 B ). Here, we have investigated the impact of the combined absence of dynamin 1 and 3 [double KO (DKO)] on short-term synaptic plasticity (i.e., the changes in the strength of synaptic transmission that occur in response to repetitive stimulation). In cortical neuron cultures, most synapses exhibit a progressively smalle r postsynaptic response, known as depression, in response to a train of electrical pulses or action potentials ( Fig. P1 B ). This response is caused by a progressive depletion of vesicles available for release ( 4 ). As shown by studies in mice and other species, such depression is typically enhanced at the synapses of neurons, where the function of endocytic proteins has been impaired by either gene disruption or other manipulations, reflecting the less-efficient resupply of synaptic vesicles and thus, the smaller pools of available vesicles. For example, using precisely the same conditions used here for studies of dynamin DKO neurons, enhanced depression was observed at synapses of endophilin triple KO mouse neurons ( 5 ). Three dynamin genes are present in mammals and encode three very similar proteins, dynamins 1, 2, and 3. Although dynamin 2 performs functions in all cells, dynamin 1 and 3 are expressed primarily in the nervous system, where they are present at very high levels (particularly dynamin 1) and contribute to most of the dynamin levels in neurons. Recent studies of neurons from newborn mice in which the genes that encode dynamin 1 and 3 had been knocked out have shown a major exo-/endocytosis imbalance; synaptic vesicles are greatly reduced in number, and much of the synaptic vesicle membrane material is sequestered in endocytic clathrin-coated pits ( 1 – 3 ). However, synaptic transmission, albeit greatly reduced, is not abolished ( 1 – 3 ). Most likely, the low levels of dynamin 2 in such neurons are sufficient to support low level of vesicle endocytosis, although a dynamin-independent endocytosis cannot be excluded. At synapses—the sites where nerve cells pass signals to each other—the fusion of small membrane-bound packages known as synaptic vesicles with the plasma membrane (i.e., exocytosis) is rapidly followed by the reinternalization (i.e., endocytosis) of their membranes to regenerate new vesicles. Much of this endocytic recycling occurs by clathrin-mediated endocytosis, and the enzyme dynamin plays a critical role in this process by mediating the fission of clathrin-coated pits to generated free vesicles. Here, we have investigated the impact of the absence of the bulk of neuronal dynamin on synaptic changes in response to repetitive stimulation. In contrast to the expectation that such absence would result in enhanced postsynaptic depression on repetitive stimulation, we found synaptic facilitation and reduced depression, and we further investigated the mechanism behind this effect.