Loss of the HVEM Tumor Suppressor in Lymphoma and Restoration by Modified CAR-T Cells.

The HVEM (TNFRSF14) receptor gene is among the most frequently mutated genes in germinal center lymphomas. We report that loss of HVEM leads to cell-autonomous activation of B cell proliferation and drives the development of GC lymphomas in vivo. HVEM-deficient lymphoma B cells also induce a tumor-supportive microenvironment marked by exacerbated lymphoid stroma activation and increased recruitment of T follicular helper (TFH) cells. These changes result from the disruption of inhibitory cell-cell interactions between the HVEM and BTLA (B and T lymphocyte attenuator) receptors. Accordingly, administration of the HVEM ectodomain protein (solHVEM(P37-V202)) binds BTLA and restores tumor suppression. To deliver solHVEM to lymphomas in vivo, we engineered CD19-targeted chimeric antigen receptor (CAR) T cells that produce solHVEM locally and continuously. These modified CAR-T cells show enhanced therapeutic activity against xenografted lymphomas. Hence, the HVEM-BTLA axis opposes lymphoma development, and our study illustrates the use of CAR-T cells as "micro-pharmacies" able to deliver an anti-cancer protein.

The Eph-receptor A7 is a soluble tumor suppressor for follicular lymphoma.

Insights into cancer genetics can lead to therapeutic opportunities. By cross-referencing chromosomal changes with an unbiased genetic screen we identify the ephrin receptor A7 (EPHA7) as a tumor suppressor in follicular lymphoma (FL). EPHA7 is a target of 6q deletions and inactivated in 72% of FLs. Knockdown of EPHA7 drives lymphoma development in a murine FL model. In analogy to its physiological function in brain development, a soluble splice variant of EPHA7 (EPHA7(TR)) interferes with another Eph-receptor and blocks oncogenic signals in lymphoma cells. Consistent with this drug-like activity, administration of the purified EPHA7(TR) protein produces antitumor effects against xenografted human lymphomas. Further, by fusing EPHA7(TR) to the anti-CD20 antibody (rituximab) we can directly target this tumor suppressor to lymphomas in vivo. Our study attests to the power of combining descriptive tumor genomics with functional screens and reveals EPHA7(TR) as tumor suppressor with immediate therapeutic potential.

Erythropoeitin Signaling in Macrophages Promotes Dying Cell Clearance and Immune Tolerance.

The failure of apoptotic cell clearance is linked to autoimmune diseases, nonresolving inflammation, and developmental abnormalities; however, pathways that regulate phagocytes for efficient apoptotic cell clearance remain poorly known. Apoptotic cells release find-me signals to recruit phagocytes to initiate their clearance. Here we found that find-me signal sphingosine 1-phosphate (S1P) activated macrophage erythropoietin (EPO) signaling promoted apoptotic cell clearance and immune tolerance. Dying cell-released S1P activated macrophage EPO signaling. Erythropoietin receptor (EPOR)-deficient macrophages exhibited impaired apoptotic cell phagocytosis. EPO enhanced apoptotic cell clearance through peroxisome proliferator activated receptor-γ (PPARγ). Moreover, macrophage-specific Epor(-/-) mice developed lupus-like symptoms, and interference in EPO signaling ameliorated the disease progression in lupus-like mice. Thus, we have identified a pathway that regulates macrophages to clear dying cells, uncovered the priming function of find-me signal S1P, and found a role of the erythropoiesis regulator EPO in apoptotic cell disposal, with implications for harnessing dying cell clearance.

Neurexins cluster Ca2+ channels within the presynaptic active zone.

To achieve ultrafast neurotransmission, neurons assemble synapses with highly organized presynaptic and postsynaptic nanomachines that are aligned by synaptic adhesion molecules. How functional assembly of presynaptic active zones is controlled via trans-synaptic interactions remains unknown. Here, we conditionally deleted all three neurexin adhesion molecules from presynaptic neurons of the calyx of Held in the mouse auditory system, a model synapse that allows precise biophysical analyses of synaptic properties. The pan-neurexin deletion had no effect on synapse development or the basic release machinery, but dramatically impaired fast neurotransmitter release. The overall properties of presynaptic calcium ion channels appeared normal, as reflected by the similar characteristics of calcium currents recorded at the nerve terminals. However, the pan-neurexin deletion significantly impaired the tight coupling of calcium influx to exocytosis, thereby suppressing neurotransmitter release. Furthermore, the pan-neurexin deletion reduced the function of calcium-activated BK potassium channels, whose activation depends on their tight association with presynaptic calcium channels. Together, these results suggest that neurexins perform a major function at the calyx synapse in coupling presynaptic calcium channels to release sites.

A Rapid Translational Immune Response Program in CD8 Memory T Lymphocytes.

The activation of memory T cells is a very rapid and concerted cellular response that requires coordination between cellular processes in different compartments and on different time scales. In this study, we use ribosome profiling and deep RNA sequencing to define the acute mRNA translation changes in CD8 memory T cells following initial activation events. We find that initial translation enables subsequent events of human and mouse T cell activation and expansion. Briefly, early events in the activation of Ag-experienced CD8 T cells are insensitive to transcriptional blockade with actinomycin D, and instead depend on the translation of pre-existing mRNAs and are blocked by cycloheximide. Ribosome profiling identifies ∼92 mRNAs that are recruited into ribosomes following CD8 T cell stimulation. These mRNAs typically have structured GC and pyrimidine-rich 5' untranslated regions and they encode key regulators of T cell activation and proliferation such as Notch1, Ifngr1, Il2rb, and serine metabolism enzymes Psat1 and Shmt2 (serine hydroxymethyltransferase 2), as well as translation factors eEF1a1 (eukaryotic elongation factor α1) and eEF2 (eukaryotic elongation factor 2). The increased production of receptors of IL-2 and IFN-γ precedes the activation of gene expression and augments cellular signals and T cell activation. Taken together, we identify an early RNA translation program that acts in a feed-forward manner to enable the rapid and dramatic process of CD8 memory T cell expansion and activation.

LncRNA Gm15834 Aggravates Cardiac Hypertrophy by Interacting with Sam68 and Activating NF-κB Mediated Inflammation.

BACKGROUND: Cardiac hypertrophy is the common pathological process of multiple cardiovascular diseases. However, the molecular mechanisms of cardiac hypertrophy are unclear. Long non-coding RNA (lncRNA), a newly discovered type of transcript that has been demonstrated to function as crucial regulators in the development of cardiovascular diseases. This study revealed a novel regulatory pathway of lncRNA in cardiac hypertrophy. METHODS: The cardiac hypertrophy models were established by transverse aortic constriction (TAC) in mice and angiotensin II (Ang II) in HL-1 cardiomyocytes. Adeno-associated virus 9 (AAV9) in vivo and lncRNA Gm15834 and shRNA plasmids in vitro were used to overexpress and knock down lncRNA Gm15834. The myocardial tissue structure, cardiomyocyte area, cardiac function, protein expressions, and binding of lncRNA Gm15834 and Src-associated substrate during mitosis of 68 KDa (Sam68) were detected by hematoxylin and eosin (HE) staining, immunofluorescence staining, echocardiography, western blot and RNA immunoprecipitation (RIP), respectively. RESULTS: In cardiac hypertrophy models, inhibiting lncRNA Gm15834 could decrease Sam68 expression and nuclear factor kappa-B (NF-κB) mediated inflammatory activities in vivo and in vitro, but overexpressing lncRNA Gm15834 showed the opposite results. RIP experiments validated the binding activities between lncRNA Gm15834 and Sam68. Overexpression of Sam68 could counteract the anti-hypertrophy effects of lncRNA Gm15834 knockdown. Meanwhile, in vivo inhibition of lncRNA Gm15834 could inhibit Sam68 expression, reduce NF-κB mediated inflammatory activity and attenuate cardiac hypertrophy. CONCLUSION: Our study revealed a novel regulatory axis of cardiac hypertrophy, which comprised lncRNA Gm15834/Sam68/NF-κB/inflammation, shedding a new light for identifying therapy target of cardiac hypertrophy in clinic.

Treatment plan complexity quantification for predicting gamma passing rates in patient-specific quality assurance for stereotactic volumetric modulated arc therapy.

PURPOSE: To investigate the beam complexity of stereotactic Volumetric Modulated Arc Therapy (VMAT) plans quantitively and predict gamma passing rates (GPRs) using machine learning. METHODS: The entire dataset is exclusively made of stereotactic VMAT plans (301 plans with 594 beams) from Varian Edge LINAC. The GPRs were analyzed using Varian's portal dosimetry with 2%/2 mm criteria. A total of 27 metrics were calculated to investigate the correlation between metrics and GPRs. Random forest and gradient boosting models were developed and trained to predict the GPRs based on the extracted complexity features. The threshold values of complexity metric were obtained to predict a given beam to pass or fail from ROC curve analysis. RESULTS: The three moderately significant values of Spearman's rank correlation to GPRs were 0.508 (p < 0.001), 0.445 (p < 0.001), and -0.416 (p < 0.001) for proposed metric LAAM, the ratio of the average aperture area over jaw area (AAJA) and index of modulation, respectively. The random forest method achieved 98.74% prediction accuracy with mean absolute error of 1.23% using five-fold cross-validation, and 98.71% with 1.25% for gradient boosting regressor method, respectively. LAAM, leaf travelling distance (LT), AAJA, LT modulation complexity score (LTMCS) and index of modulation, were the top five most important complexity features. The LAAM metric showed the best performance with AUC value of 0.801, and threshold value of 0.365. CONCLUSIONS: The calculated metrics were effective in quantifying the complexity of stereotactic VMAT plans. We have demonstrated that the GPRs could be accurately predicted using machine learning methods based on extracted complexity metrics. The quantification of complexity and machine learning methods have the potential to improve stereotactic treatment planning and identify the failure of QA results promptly.

Polarization-Sensitive Photodetector Based on High Crystallinity Quasi-1D BiSeI Nanowires Synthesized via Chemical Vapor Deposition.

Bismuth chalcohalides (BiSeI and BiSI), a class of superior light absorbers, have recently garnered great attention owing to their promise in constructing next-generation optoelectronic devices. However, to date, the photodetection application of bismuth chalcohalides is still limited due to the challenge in controllable preparation. Herein, the synthesis of large-scale quasi-1D BiSeI nanowires via chemical vapor deposition growth is reported. By precisely tuning the growth temperature and the Se supply, it can effectively control the growth thermodynamics and kinetics of BiSeI crystal, and thus achieve high purity quasi-1D BiSeI nanowires with high crystal quality, uniform diameter, and tunable domain length. Theory and optical characterizations of the quasi-1D BiSeI nanowires reveal an indirect bandgap of 1.57 eV with prominent optical linear dichroism. As a result, the quasi-1D BiSeI nanowire-based photodetector demonstrates a broadband photoresponse (400-800 nm) with high responsivity of 5880 mA W-1 , fast response speed of 0.11 ms and superior air stability. More importantly, the photodetector displays strong polarization sensitivity (anisotropic ratio = 1.77) under the 532 nm light irradiation. This work will provide important guides to the synthesis of other quais-1D metal chalcohalides and shed light on their potential in constructing novel multifunctional optoelectronic devices.

Air-Stable Violet Phosphorus/MoS2 van der Waals Heterostructure for High-Responsivity and Gate-Tunable Photodetection.

Violet phosphorus (VP), a newly emerging elemental 2D semiconductor, with attractive properties such as tunable bandgap, high carrier mobility, and unusual structural anisotropy, offers significant opportunities for designing high-performance electronic and optoelectronic devices. However, the study on fundamental property and device application of 2D VP is seriously hindered by its inherent instability in ambient air. Here, a VP/MoS2 van der Waals heterostructure is constructed by vertically staking few-layer VP and MoS2 , aiming to utilize the synergistic effect of the two materials to achieve a high-performance 2D photodetector. The strong optical absorption of VP combining with the type-II band alignment of VP/MoS2 heterostructure make VP play a prominent photogating effect. As a result, the VP/MoS2 heterostructure photodetector achieves an excellent photoresponse performances with ultrahigh responsivity of 3.82 × 105  A W-1 , high specific detectivity of 9.17 × 1013 Jones, large external quantum efficiency of 8.91 × 107 %, and gate tunability, which are much superior to that of individual MoS2 device or VP device. Moreover, the VP/MoS2 heterostructure photodetector indicates superior air stability due to the effective protection of VP by MoS2 encapsulation. This work sheds light on the future study of the fundamental property and optoelectronic device application of VP.

Time-resolved serial femtosecond crystallography at the European XFEL.

The European XFEL (EuXFEL) is a 3.4-km long X-ray source, which produces femtosecond, ultrabrilliant and spatially coherent X-ray pulses at megahertz (MHz) repetition rates. This X-ray source has been designed to enable the observation of ultrafast processes with near-atomic spatial resolution. Time-resolved crystallographic investigations on biological macromolecules belong to an important class of experiments that explore fundamental and functional structural displacements in these molecules. Due to the unusual MHz X-ray pulse structure at the EuXFEL, these experiments are challenging. Here, we demonstrate how a biological reaction can be followed on ultrafast timescales at the EuXFEL. We investigate the picosecond time range in the photocycle of photoactive yellow protein (PYP) with MHz X-ray pulse rates. We show that difference electron density maps of excellent quality can be obtained. The results connect the previously explored femtosecond PYP dynamics to timescales accessible at synchrotrons. This opens the door to a wide range of time-resolved studies at the EuXFEL.

Over 250 W low noise core-pumped single-frequency all-fiber amplifier.

A high-power linearly-polarized all-fiber single-frequency amplifier at 1 µm based on tandem core-pumping is demonstrated by using a large-mode-area Ytterbium-doped fiber with a core diameter of 20 µm, which nicely balances the stimulated Brillouin scattering effect, thermal load, and output beam quality. A maximum output power of more than 250 W with a corresponding slope efficiency of >85% is achieved at the operating wavelength of 1064 nm without being constrained by the saturation and nonlinear effects. Meanwhile, a comparable amplification performance is realized with a lower injection signal power of the wavelength near the peak gain of the Yb-doped fiber. The polarization extinction ratio and the M2 factor of the amplifier are respectively measured to be >17 dB and 1.15 under the maximal output power. In addition, by virtue of the single-mode 1018 nm pump laser, the intensity noise of the amplifier under maximal output power is measured to be comparable to that of the single-frequency seed laser at frequencies higher than 2 kHz, except for the emergence of parasitic peaks that can be eliminated by optimizing the driving electronics of the pump lasers, while the deterioration of the amplification process to the frequency noise and linewidth of the laser is negligible. To the best of our knowledge, this is the highest output power of a single-frequency all-fiber amplifier based on the core-pumping scheme.

Neoadjuvant toripalimab plus platinum-paclitaxel chemotherapy in stage II-III non-small cell lung cancer: a single-center, single-arm, phase I study in China.

BACKGROUND: Neoadjuvant and adjuvant immune checkpoint inhibitor treatments for non-small cell lung cancer (NSCLC) patients with resectable disease have presented promising results. This is a phase I study to evaluate the safety and efficacy of neoadjuvant toripalimab in combination with chemotherapy for NSCLC. METHODS: Treatment-naive patients with resectable NSCLC (stage II-IIIB) received two to four cycles of toripalimab (240 mg, intravenously, q3w) combined with platinum-paclitaxel chemotherapy. Surgical operation was performed approximately 4 weeks after the last cycle. The primary end point was safety. The efficacy endpoints included radiographic and pathological response rates, expression of programmed death ligand 1 (PD-L1) and molecular targets. RESULTS: A total of 11 patients were enrolled, consisting of 2 patients (18%) with adenocarcinoma and 9 patients (82%) with squamous cell carcinoma. All patients received two to four cycles of toripalimab plus chemotherapy and underwent radical resection. Regarding safety, 5 of 11 patients (45%) had neoadjuvant treatment-related adverse events, and 1 patient (9%) experienced grade 3 or worse treatment-related adverse events. Radiographic partial response was achieved in 10 patients, with an objective response rate of 91%. Among 11 patients, 6 (55%) achieved pathological complete response, including 1 PD-L1-negative patient. CONCLUSION: Neoadjuvant toripalimab plus platinum-paclitaxel chemotherapy was tolerable and induced a pathological complete response in 55% of resectable NSCLC patients.

Reflective epoxy resin/chitosan/PAA composite-functionalized fiber-optic interferometric probe sensor for sensitive heavy metal ion detection.

A highly sensitive label-free chemical sensing platform for the detection of various metal ions is demonstrated. The chemical sensor was derived from a single-mode fiber that is inserted into the ceramic tube with epoxy resin (ER) on the end face for reflecting light and forms the Fabry-Perot (F-P) interferometric cavity. Multilayer chitosan (CS)/polyacrylic acid (PAA) were coated on the surface of the epoxy resin and act as the sensitive film. Based on the analysis of the sensing principle and the F-P cavity structure, the parameters were numerically simulated and experimentally evaluated, which enables ease of fabrication and real-time modulation of the cavity length. The sensitivity of sensing Ni2+, Zn2+, and Na+ reached 9.95 × 10-4 nm ppb-1, 2.31 × 10-4 nm ppb-1, and 4 × 10-4 nm ppb-1, respectively, and the sensing results were theoretically analyzed by the Langmuir adsorption model, which corresponds to the surface atom percentage results obtained by SEM and EDS measurements for sensing three types of metal ions. The proposed ER/CS/PAA multilayer film-coated F-P sensor can be employed as a probe, which features label-free, highly sensitivity, real-time monitoring, ease of measurement, stability, and therefore provides a remarkable analytical platform for chemical applications.

Successful virologic outcomes over time among HAART-treated HIV-infected patients.

Few large studies evaluated the effects of time trends on virologic suppression in people living with HIV/AIDS (PLWHA) in China. To address this, An retrospective observational longitudinal study was conducted. We examined annual trends in the rate of virologic suppression, the viral load at the time of virologic suppression, and other determinants of virologic suppression in Zhejiang Province, China in PLWHA between January 2013 and July 2018. Patients who received a treatment regimen for at least 24 weeks were included. Virologic suppression was defined as VL ≤50 copies/mL. Generalized estimating equation logistic regression models were used to adjust for covariates. We included 16,265 patients with 45023 tests. The proportion of patients who experienced an unsuccessful virologic outcome decreased continuously throughout the observation period (18.14% to 6.64%). Time was significantly negatively associated with detectable VL (all ORs <1). Other factors were positively associated with detectable VL, including patients <30 years of age, single, non-adherent to treatment, and with a follow-up CD4 count <200 cells/µL. Patients infected through homosexual transmission and those with a longer ART duration were more likely to reach virologic suppression. We demonstrated outstanding time trend improvements in the virological outcomes of PLWHA in China.

Risk factors associated with recurrent febrile urinary tract infection in children with neurogenic bladder who perform clean intermittent catheterization.

OBJECTIVE: To identify the clinical and urodynamic risk factors associated with the development of recurrent febrile urinary tract infections (FUTIs) in children with neurogenic bladder (NB) who perform clean intermittent catheterization (CIC). METHODS: Children with NB receiving CIC were prospectively enrolled from January to December 2019 and followed up prospectively for 2 years. All data were compared between occasional (0-1 FUTI) and recurrent FUTIs (≥2 FUTI) groups. In addition, the risk factors for recurrent FUTIs in children were evaluated. RESULTS: Complete data from 321 children were analyzed. Occasional FUTIs occurred in 223 patients, and 98 patients experienced recurrent FUTIs. Univariate and multivariate analyses, showed late-initiation and low-frequency CIC, vesicoureteral reflux (VUR), small bladder capacity and low compliance, and detrusor overactivity were associated with an increased risk of recurrent FUTIs. Children with high-grade VUR (grades IV-V) had a higher risk of recurrent FUTIs than those with low-grade VUR (grades I-III) (odds ratio [OR]: 26.95 vs. OR: 4.78, p < 0.001). CONCLUSIONS: Our study suggests that late-initiation and low-frequency CIC, VUR, small bladder capacity and low compliance, and detrusor overactivity were associated with recurrent FUTIs in patients with NB. In addition, high-grade VUR is a crucial risk factor for recurrent FUTIs.

G3BP1 Inhibition Alleviates Intracellular Nucleic Acid-Induced Autoimmune Responses.

The detection of intracellular nucleic acids is a fundamental mechanism of host defense against infections. The dysregulated nucleic acid sensing, however, is a major cause for a number of autoimmune diseases. In this study, we report that GTPase-activating protein SH3 domain-binding protein 1 (G3BP1) is critical for both intracellular DNA- and RNA-induced immune responses. We found that in both human and mouse cells, the deletion of G3BP1 led to the dampened cGAS activation by DNA and the insufficient binding of RNA by RIG-I. We further found that resveratrol (RSVL), a natural compound found in grape skin, suppressed both intracellular DNA- and RNA-induced type I IFN production through inhibiting G3BP1. Importantly, using experimental mouse models for Aicardi-Goutières syndrome, an autoimmune disorder found in humans, we demonstrated that RSVL effectively alleviated intracellular nucleic acid-stimulated autoimmune responses. Thus, our study demonstrated a broader role of G3BP1 in sensing different kinds of intracellular nucleic acids and presented RSVL as a potential treatment for autoimmune conditions caused by dysregulated nucleic acid sensing.

Aberrant circulating tumor DNA methylation and exosomal microRNA biomarkers for early detection of colorectal cancer.

INTRODUCTION: Colorectal cancer (CRC) became the third most commonly diagnosed malignancy and the second leading cause of cancer death in 2020. However, the rates of early screening and early diagnosis for CRC remain unsatisfactory. Thus, it is essential to explore the initiating factors of CRC and strategies for its early diagnosis. Research progress in liquid biopsy has led to the finding that circulating tumor-derived DNA (ctDNA) and exosomes play vital roles in early detection of CRC. THE APPLICATIONS OF LIQUID BIOPSY FOR EARLY DETECTION OF COLORECTAL CANCER: Moreover, the increased understanding of epigenetics has highlighted the role of ctDNA methylation in CRC carcinogenesis, and the detection of aberrant ctDNA methylation markers is a feasible strategy for diagnosis of early-stage CRC. Among exosomal markers, microRNAs (miRNAs) are abundant and are the most researched. Upregulated or downregulated expression of exosome-derived miRNAs can indicate the occurrence of early-stage CRC. FUTURE PERSPECTIVE: The current research progress on aberrant ctDNA methylation and tumor exosomal miRNA biomarkers in early detection of CRC is summarized in this review, and the advantages and shortcomings of the methods are discussed.

Efficient genome editing in cotton using the virus-mediated CRISPR/Cas9 and grafting system.

KEY MESSAGE: The extensive application of CRISPR in cotton was limited due to the labor-intensive transformation process. Thus, we here established a convenient method of CRISPR in cotton by CLCrV-mediated sgRNA delivery.

Over 30 W single-frequency all-fiber amplifier at 1120 nm with high ASE suppression.

A 1120 nm linearly polarized all-fiber single-frequency amplifier based on Yb-doped fiber (YDF) is reported. A maximum output power of 30 W is achieved by 976 nm clad-pumping and 1018 nm core-pumping, with corresponding slope efficiencies of 51.9% and 70.0%, respectively. With the 976 nm clad-pumping configuration, a signal to amplified spontaneous emission (ASE) ratio of more than 45 dB is realized at maximum output power. The polarization extinction ratio of the amplifier is measured to be more than 21 dB in the whole power scaling process. In addition, the intensity noise of the amplifier at maximum output power is also characterized to be around -130d B c/H z at frequencies above 2 kHz and is comparable to that of the seed laser. Moreover, the deterioration of frequency noise and linewidth of the amplified laser is negligible. To the best of our knowledge, this is the highest output power of a single-frequency all-fiber amplifier that exploits the fundamental transition of YDF at 1120 nm, even without any external intervention for suppressing ASE in the short wavelength range.

Intensity noise transfer properties of a Yb-doped single-frequency fiber amplifier.

In this work, the intensity noise transfer properties of a two-stage single-frequency fiber amplifier at 1 µm are systematically investigated in the frequency domain. By applying an artificial modulation signal to the driving current of the first- and second-stage pump sources, the pump and signal transfer functions of the second-stage amplifier are experimentally measured from 10 Hz to 100 kHz. By associating the theoretical model, the effects of pump power, the operating wavelength, and the absorption coefficient of the gain fiber on the pump and signal transfer properties are analyzed based on the experimental measurements. It turns out that the gain dynamics of the last-stage amplifier play an important role in determining the noise performances of the final amplified laser. Because the pump and signal transfer functions essentially behave as a low pass and damped high pass filter, the pump intensity noise of the last-stage amplifier dominates the amplifier system's overall noise performance. In addition, the effects of amplified spontaneous emission (ASE) on the intensity noise transfer properties are nontrivial, although it is not included in the theoretical model. It is believed that the current work provides a useful guideline for optimizing the design of high-power single-frequency fiber amplifiers with low-intensity noise.