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The ion source is one of the key devices for the high-intensity cyclotron, which exerts influence on the beam intensity and applications of the machine. As part of the cyclotron research and development effort, China Institute of Atomic Energy (CIAE) has been developing arc discharge H- ion sources based on volume production and multi-cusp magnetic configuration since 1997. In 2000, 5.2 mA H- beam was reached and 15 mA H- beam was achieved in 2010. After a long break, H- ion source development started again in 2022 in order to improve performance of the main H- ion source of the CIAE 18 MeV cyclotron and to fulfill the requirement of future other high intensity proton beam cyclotrons for the high intensity H- ion. A new H- ion source and test stand was built at CIAE in 2023. The design of this new ion source was based on the experience on our previous 15-20 mA H- ion source and the source at TRIUMF. Major efforts included the study of the virtual filter magnetic field for filtering out fast electrons, multi-cusp confining magnetic field, four-half-circle ring filaments length and location, improvement of extraction structure and upgrading of vacuum system and power supplies. Up to now, more than 21 mA of H- beam were obtained at a high voltage of 35 kV from a plasma electrode hole of 13 mm in diameter when the hydrogen flux was 25 sccm. At this output the maximum arc power available is only 4.5 kW and the e/H- ratio is about 5. When the hydrogen flux is higher or extraction high voltage is higher, H- beam currents can reach 22 mA. However, the H- beam is very unstable with terrible sparks at extraction and acceleration gaps in this case, about five times a minute. This appears to be due to the lack of a differential pumping structure, which also results in an unexpectedly high hydrogen flux. In the experiment, the relationship between arc power and H- beam intensity was determined, also the optimal location of the four-filament structure was determined, which is obviously related to the virtual filter magnetic field distribution. At present, the emittance scanner is being processed and the measurement program is also updated and improved, the beam emittance has not been measured and analyzed at this stage. Subsequently, the vacuum chamber structure will be improved, the extraction structure also will be optimized to obtain brighter H- beam, and a long-lasting filament will be developed to reduce maintenance time.

IntroductionCurrent vaccines against COVID-19 administered via parenteral route have limited ability to induce mucosal immunity. There is a need for an effective mucosal vaccine to combat SARS-CoV-2 virus replication in the respiratory mucosa. Moreover, sex differences are known to affect systemic antibody responses against vaccines. However, their role in mucosal cellular responses against a vaccine remains unclear and is underappreciated.MethodsWe evaluated the mucosal immunogenicity of a booster vaccine regimen that is recombinant protein-based and administered intranasally in mice to explore sex differences in mucosal humoral and cellular responses.ResultsOur results showed that vaccinated mice elicited strong systemic antibody (Ab), nasal, and bronchiole alveolar lavage (BAL) IgA responses, and local T cell immune responses in the lung in a sex-biased manner irrespective of mouse genetic background. Monocytes, alveolar macrophages, and CD103+ resident dendritic cells (DCs) in the lungs are correlated with robust mucosal Ab and T cell responses induced by the mucosal vaccine.DiscussionOur findings provide novel insights into optimizing next-generation booster vaccines against SARS-CoV-2 by inducing spike-specific lung T cell responses, as well as optimizing mucosal immunity for other respiratory infections, and a rationale for considering sex differences in future vaccine research and vaccination practice.

In recent years, cryotherapy has gained increasing acceptance as a treatment for prostate cancer, offering complementary therapeutic benefits when combined with radical surgery and radiotherapy. Despite the potential for surgical complications, it stands as a safe and viable therapeutic modality. Cryotherapy provides an efficient approach for elderly patients, especially those with compromised physical conditions and individuals experiencing recurrence after initial treatment. It has shown promise in extending survival periods and improving the overall quality of life for these patients. This article aims to comprehensively examine the developmental trajectory, surgical techniques, indications, therapeutic outcomes, and potential complications associated within prostate cancer treatment.

Abstract Background In the field of biology and medicine, the interpretability and accuracy are both important when designing predictive models. The interpretability of many machine learning models such as neural networks is still a challenge. Recently, many researchers utilized prior information such as biological pathways to develop neural networks-based methods, so as to provide some insights and interpretability for the models. However, the prior biological knowledge may be incomplete and there still exists some unknown information to be explored. Results We proposed a novel method, named PathExpSurv, to gain an insight into the black-box model of neural network for cancer survival analysis. We demonstrated that PathExpSurv could not only incorporate the known prior information into the model, but also explore the unknown possible expansion to the existing pathways. We performed downstream analyses based on the expanded pathways and successfully identified some key genes associated with the diseases and original pathways. Conclusions Our proposed PathExpSurv is a novel, effective and interpretable method for survival analysis. It has great utility and value in medical diagnosis and offers a promising framework for biological research.

The Kangjiawan Pb-Zn deposit, situated within the Shuikoushan polymetallic ore field in Changning, Hunan Province, China, is a large-scale Pb-Zn deposit unearthed in 1976. Based on detailed geological field investigations, this study presents the results of the Rb-Sr isotopic dating, electron probe microanalyses (EPMAs), and LA-ICP-MS analyses of the Kangjiawan Pb-Zn deposit in order to determine the ore-forming age and the occurrence of trace elements in sphalerite and thereby constrain the genesis of the deposit. The Rb-Sr dating of quartz-hosted fluid inclusions yielded an Rb-Sr isochron age of 150 ± 4 Ma, with an initial 87Sr/86Sr ratio of 0.71101 ± 0.00008 (MSWD = 1.1), suggesting that the Pb-Zn mineralization of the Kangjiawan deposit took place during the Late Jurassic, coeval with the magmatic activities within the ore field. EPMA and LA-ICP-MS analyses showed that Fe, Mn, and Cd were primarily incorporated into the sphalerite lattice through isomorphous substitution. Specifically, Fe and Mn substituted for Zn, whereas Cd replaced both Fe and Zn. Other elements such as Cu, Sb, and Sn occurred within the sphalerite lattice through mineral micro-inclusions or isomorphic substitution. EPMAs and LA-ICP-MS results showed that the FeS contents in sphalerite were less than 14.33%, with corresponding ore-forming temperatures below 259 °C. The LA-ICP-MS results showed that sphalerites from the Kangjiawan Pb-Zn deposit had relatively high Ga/In ratios ranging from 0.01 to 144, providing further support for medium-to-low-temperature mineralization. The trace element compositions of sphalerites from the Kangjiawan Pb-Zn deposit exhibit skarn-type characteristics, suggesting a potential association with contemporary magmatic activities within the Shuikoushan ore field. During the Late Jurassic, extensive granitic magmatic activities occurred in the study area. At the late stage of magma crystallization, hydrothermal fluid containing Pb and Zn precipitated at medium-to-low temperatures and generated the Kangjiawan Pb-Zn deposit.

LnPO4·nH2O rhabdophane is considered as one of potential material for precipitation-enrichment actinides in high-level radioactive waste liquid owing to its outstanding properties relating to the high chemical stability and the high selectivity and strong incorporating capacity of actinides. In this work, the phase composition, microstructure and thermal behaviors of LnPO4·0.667H2O(Ln=La, Eu, Gd) were systematically investigated by combining with XRD, SEM, TG-DSC, BET and ICP-MS. Based on the PCT leaching test methods, the differences of chemical stability between LnPO4·0.667H2O and its thermal products were first discussed in detail. The results reveal that the single phase of LnPO4·0.667H2O(Ln=La, Eu, Gd) with the microstructure of hexagonal shaped nanorodcrystals can be synthesized by chemical precipitation reaction in 90 ℃ aqueous solution. LnPO4·0.667H2O has the excellent structural stability and the reversibility behaviors associated with dehydration and adsorption of water molecules. The process of phase transition can be described as: LnPO4·0.667H2O25-80 ℃LnPO4·0.5H2O80.240 ℃LnPO4(rhabdophane)661-935 ℃LnPO4(monazite). Moreover, the excellent chemical stability has been observed in LnPO4·0.667H2O rhabdophane and its thermal products in PCT leaching test. For instance, the values of LRLn are ranged from 10-7 g/(m2·d) to 10-4 g/(m2·d) after leaching 28 d in different leaching solutions(pH=3/7, T=90/150 ℃), where the acidic solution is more likely to corrode sample surface, further resulting in a relative high LRLn value. Importantly, the phase transition can improve the chemical stability of initial rhabdophane. As a typical example of Gd-rhabdophane, after leaching 28 d in 90 ℃/pH=3 solutions, the evolution of chemical stability is found as: GdPO4·0.667H2O(1.8×10-4 g/(m2·d))

Abstract Diffuse large B-cell lymphoma (DLBCL) exhibits significant genetic heterogeneity which contributes to drug resistance, necessitating development of novel therapeutic approaches. Pharmacological inhibitors of cyclin-dependent kinases (CDK) demonstrated pre-clinical activity in DLBCL, however many stalled in clinical development. Here we show that AZD4573, a selective inhibitor of CDK9, restricted growth of DLBCL cells. CDK9 inhibition (CDK9i) resulted in rapid changes in the transcriptome and proteome, with downmodulation of multiple oncoproteins (eg, MYC, Mcl-1, JunB, PIM3) and deregulation of phosphoinotiside-3 kinase (PI3K) and senescence pathways. Following initial transcriptional repression due to RNAPII pausing, we observed transcriptional recovery of several oncogenes, including MYC and PIM3. ATAC-Seq and ChIP-Seq experiments revealed that CDK9i induced epigenetic remodeling with bi-directional changes in chromatin accessibility, suppressed promoter activation and led to sustained reprograming of the super-enhancer landscape. A CRISPR library screen suggested that SE-associated genes in the Mediator complex, as well as AKT1, confer resistance to CDK9i. Consistent with this, sgRNA-mediated knockout of MED12 sensitized cells to CDK9i. Informed by our mechanistic findings, we combined AZD4573 with either PIM kinase or PI3K inhibitors. Both combinations decreased proliferation and induced apoptosis in DLBCL and primary lymphoma cells in vitro as well as resulted in delayed tumor progression and extended survival of mice xenografted with DLBCL in vivo. Thus, CDK9i induces reprogramming of the epigenetic landscape, and super-enhancer driven recovery of select oncogenes may contribute to resistance to CDK9i. PIM and PI3K represent potential targets to circumvent resistance to CDK9i in the heterogeneous landscape of DLBCL.

Lysine-specific demethylase 1 (LSD1) is a histone demethylase that promotes stemness and cell survival in cancers such as prostate cancer. Most prostate malignancies are adenocarcinomas with luminal differentiation. However, some tumors undergo cellular reprogramming to a more lethal subset termed neuroendocrine prostate cancer (NEPC) with neuronal differentiation. The frequency of NEPC is increasing since the widespread use of potent androgen receptor signaling inhibitors. Currently, there are no effective treatments for NEPC. We previously determined that LSD1 promotes survival of prostate adenocarcinoma tumors. However, the role of LSD1 in NEPC is unknown. Here, we determined that LSD1 is highly upregulated in NEPC versus adenocarcinoma patient tumors. LSD1 suppression with RNAi or allosteric LSD1 inhibitors — but not catalytic inhibitors — reduced NEPC cell survival. RNA-Seq analysis revealed that LSD1 represses pathways linked to luminal differentiation, and TP53 was the top reactivated pathway. We confirmed that LSD1 suppressed the TP53 pathway by reducing TP53 occupancy at target genes while LSD1’s catalytic function was dispensable for this effect. Mechanistically, LSD1 inhibition disrupted LSD1-HDAC interactions, increasing histone acetylation at TP53 targets. Finally, LSD1 inhibition suppressed NEPC tumor growth in vivo. These findings suggest that blocking LSD1’s noncatalytic function may be a promising treatment strategy for NEPC.

Abstract Pevonedistat (TAK924) is a Nedd8-activating enzyme inhibitor with preclinical activity in non-Hodgkin lymphoma (NHL). This open-label, Phase I, multicenter, investigator-sponsored study enrolled patients with relapsed/refractory (R/R) NHL and chronic lymphocytic leukemia (CLL). The primary objective was safety. Pevonedistat was given intravenously on days 1, 3, 5 of a 21-day cycle for 8 cycles at five dose levels (15 to 50 mg/m2); ibrutinib was administered at 420 or 560 mg orally daily continuously. Eighteen patients with NHL were enrolled, including 8 patients with mantle cell lymphoma (MCL) and 4 patients with CLL. One dose-limiting toxicity (mediastinal hemorrhage) occurred at 50 mg/m2 of pevonedistat which is the estimated maximum tolerated dose. Bruising and diarrhea were the most common adverse events (56% and 44%). Atrial fibrillation occurred in 3 patients (17%). Grade ≥3 toxicities included arthralgia, atrial fibrillation, bone pain, diarrhea, hypertension, and mediastinal hemorrhage (one patient each). The overall response rate (ORR) was 65% (100% ORR in MCL). Pevonedistat disposition was not modified by ibrutinib. scRNA-Seq analysis showed that pevonedistat downregulated NFκB signaling in malignant B-cells in vivo. Thus, pevonedistat combined with ibrutinib demonstrated safety and promising early efficacy in NHL and CLL. NAE inhibition downregulated NFκB signaling in vivo.

PurposeTo compare the effects of remimazolam and dexmedetomidine on early postoperative cognitive dysfunction (POCD) in aged gastric cancer patients.MethodsFrom June to December 2022, 104 elderly patients (aged 65–80 years) received laparoscopic radical resection of gastric cancer at the First Affiliated Hospital of Nanchang University. Using the random number table approach, the patients were separated into three groups: remimazolam (Group R), dexmedetomidine (Group D), and saline (Group C). The primary outcome was the incidence of POCD, and secondary outcomes included TNF-α and S-100β protein concentrations, hemodynamics, VAS scores, anesthesia recovery indicators, and the occurrence of adverse events within 48 h postoperatively.ResultsAt 3 and 7 days after surgery, there were no statistically significant differences in the incidence of POCD, the MMSE and MoCA scores between groups R and D (p > 0.05). However, compared to the saline group, both groups had higher MMSE and MoCA scores and decreased incidences of POCD. These differences were statistically significant (p 0.05) in the levels of TNF-α and S-100β protein at the three time points (at the end of the surgery, 1 day later, and 3 days later). Even though neither group’s concentration of the two factors was as high as that of the saline group, the differences were statistically significant (p group R > group D. Extubation and PACU residence times did not differ statistically significantly (p > 0.05) between the three groups. There was no significant difference in VAS scores between groups R and D after 24 h postoperatively (p > 0.05), although both had lower scores than group C, and the difference was statistically significant (p 0.05). Adverse reactions such as respiratory depression, hypotension, bradycardia, agitation, drowsiness, and nausea and vomiting had the lowest incidence in group R and the highest incidence in group C (p

Summary: Poxvirus infections of the skin are a recent emerging public health concern, yet the mechanisms that mediate protective immunity against these viral infections remain largely unknown. Here, we show that T helper 1 (Th1) memory CD4+ T cells are necessary and sufficient to provide complete and broad protection against poxvirus skin infections, whereas memory CD8+ T cells are dispensable. Core 2 O-glycan-synthesizing Th1 effector memory CD4+ T cells rapidly infiltrate the poxvirus-infected skin microenvironment and produce interferon γ (IFNγ) in an antigen-dependent manner, causing global changes in gene expression to promote anti-viral immunity. Keratinocytes express IFN-stimulated genes, upregulate both major histocompatibility complex (MHC) class I and MHC class II antigen presentation in an IFNγ-dependent manner, and require IFNγ receptor (IFNγR) signaling and MHC class II expression for memory CD4+ T cells to protect the skin from poxvirus infection. Thus, Th1 effector memory CD4+ T cells exhibit potent anti-viral activity within the skin, and keratinocytes are the key targets of IFNγ necessary for preventing poxvirus infection of the epidermis.

Lineage plasticity is increasingly recognized as an emergent resistance mechanism after treatment with androgen receptor signalling inhibitors. To understand determinants of resistance, the authors analyzed the transcriptomes of patient tumor biopsies before enzalutamide treatment and at progression and identified a gene expression program associated with lineage plasticity risk and poor outcomes.