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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.

IntroductionIncreased uncertainty is a major feature of the current society that poses significant challenges to university students' mental health and academics. However, current research has not paid sufficient attention to this issue, and no study has explored the underlying mechanisms between intolerance of uncertainty and academic burnout among university students.MethodsThis study examined the association between uncertainty intolerance and academic burnout among university students and the role of self-regulatory fatigue and self-compassion in light of the theory of limited resources. Convenience sampling was used to survey 1,022 Chinese university students.ResultsThe findings demonstrated that intolerance of uncertainty significantly influenced university students' academic burnout with self-regulatory fatigue serving as a key mediator. Additionally, self-compassion can effectively moderate the effects of intolerance of uncertainty on self-regulatory fatigue and academic burnout.DiscussionThese results indicated that the depletion of cognitive resources brought about by uncertainty in the current highly uncertain social environment may be one of the key pathways to academic burnout among university students. Furthermore, current research provides insights into how to mitigate the negative effects of uncertainty on university students.

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.

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.

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.

Objective： Optimized the drying process of jujube slices and improved the product quality. Methods： Taking jujube slices as the research object, the correlation between conversion moisture content, infrared temperature and slice thickness and drying time and drying rate was studied, and the change rule of effective moisture diffusion coefficient of jujube slices in FD-IRD with conversion moisture content, infrared temperature and slice thickness was calculated, and the drying activation energy of jujube slices in FD-IRD was calculated according to the test data. Results： The lower the conversion moisture content is, the shorter the infrared drying time was. But the lower the conversion moisture content would greatly increase the freeze drying time. Proper increase of infrared drying temperature was beneficial to increase the effective diffusion coefficient of water. The thinner the slice is, the higher the drying rate was. Reducing the slice thickness can improve the effective water diffusion coefficient and shorten the drying time. The front and rear two stages were both speeds reducing drying processes. The effective moisture diffusion coefficients of freeze-drying and infrared drying under different drying conditions by solving Fick's second law were 3.39×10-9~9.47×10-9 and 3.34×10-9~2.01×10-8 m2/s, respectively; The drying activation energy of the infrared drying stage was 59.03 kJ/mol calculated by Anius formula. Conclusion： The conversion moisture content is 30%, and the infrared temperature is 60 ℃. Under the condition of slice thickness of 6 mm, the freeze infrared combined drying technology has short drying time and high efficiency.

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.

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.

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.

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

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.

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.

Objective: This study aimed to the optimize infrared drying process of Hami-melon slices and improve quality and efficiency. Methods: Using ultrasonic treatment as a pretreatment method, the effects of drying temperature, slice thickness and ultrasonic treatment time on drying time, color difference value and vitamin C content were studied, and the drying time, quality and microstructure of the products were compared with those without ultrasonic treatment. Results: The optimal process parameters of ultrasonic pretreatment for infrared drying of Hami-melon slices were drying temperature 61 ℃, slice thickness 6 mm and ultrasonic treatment time 15 min. Under the control of these conditions, the drying time was 115 min, the color difference value was 13.79, and the vitamin C content was 112.1 mg/100 g. Compared with the untreated products, the drying time was shortened by 45.24%, the color difference was reduced by 13.38%, and the vitamin C content was increased by 16.71%. The microstructure showed that ultrasonic waves caused the expansion and contraction of the internal tissue of Hami-melon slices, and the structure was multi-channel. Conclusion: Ultrasonic treatment can be used as a pretreatment method to improve the infrared drying of Hami-melon slices, thereby improve the quality and efficiency of the drying process.

Skeletal undifferentiated pleomorphic sarcoma (SUPS) is an invasive pleomorphic soft tissue sarcoma with a high degree of malignancy and poor prognosis. It is prone to recur and metastasize. The tumor microenvironment (TME) and the pathophysiology of SUPS are barely described. Single-cell RNA sequencing (scRNA-seq) provides an opportunity to dissect the landscape of human diseases at an unprecedented resolution, particularly in diseases lacking animal models, such as SUPS. We performed scRNA-seq to analyze tumor tissues and paracancer tissues from a SUPS patient. We identified the cell types and the corresponding marker genes in this SUPS case. We further showed that CD8+ exhausted T cells and Tregs highly expressed PDCD1, CTLA4 and TIGIT. Thus, PDCD1, CTLA4 and TIGIT were identified as potential targets in this case. We applied copy number karyotyping of aneuploid tumors (CopyKAT) to distinguish malignant cells from normal cells in fibroblasts. Our study identified eight malignant fibroblast subsets in SUPS with distinct gene expression profiles. C1-malignant Fibroblast and C6-malignant Fibroblast in the TME play crucial roles in tumor growth, angiogenesis, metastasis and immune response. Hence, targeting malignant fibroblasts could represent a potential strategy for this SUPS therapy. Intervention via tirelizumab enabled disease control, and immune checkpoint inhibitors (ICIs) of PD-1 may be considered as the first-line option in patients with SUPS. Taken together, scRNA-seq analyses provided a powerful basis for this SUPS treatment, improved our understanding of complex human diseases, and may afforded an alternative approach for personalized medicine in the future.

The compact high-intensity proton cyclotron based on the stripping-extraction method has made great progress and obtained huge applications since the first cyclotron was applicated in 1932 in the world, especially in the field of nuclear medicine. China Institute of Atomic Energy (CIAE) built a 30 MeV compact high-intensity proton cyclotron in the 1990s in China and a series of compact high-intensity proton cyclotrons with energy of 10 MeV, 14 MeV, 100 MeV, 14 MeV/1 mA used in boron neutron capture therapy (BNCT) based on the stripping extraction technology have been developed. The 100 MeV compact high-intensity proton cyclotron (CYCIAE-100) built in 2014 is the largest compact high-intensity proton cyclotron with the higher energy in the world with a maximum current intensity of 520 μA and a beam power of 52 kW. The BNCT cyclotron is also the first high-intensity proton cyclotron with extracted beam reaching the mA level in China. A great progress on the stripping extraction technology used in cyclotrons has been achieved at CIAE during the 60 years development. The codes for stripping extraction studies, such as CYCTR, GOBLIN, STRIP-UBC and COMA, are developed by CIAE too. The study method with the code of GOBLIN for the beam dispersion effect in the stripping extraction cyclotrons was given in detail. The influence of the angle between the stripping foil and the beam to the quality of the extracted beam was analyzed in the paper. The single-turn stripping extraction technology for some special application was used in the stripping extraction cyclotrons. The stripping efficiency and the life of stripping foils were studied in the paper. The beam loss control in the stripping extraction field and stripping probe system were introduced in the end.

Gas turbines produce a large amount of NOx and CO due to high temperatures and insufficient combustion. Through the selective catalytic reduction of NO with CO (CO-SCR) in a gas turbine, the activities of the Mn-Fe-Ce/FA catalyst using fly ash (FA) as a carrier under different atmospheres were studied. The catalysts prepared by calcining different active materials under different atmospheres were used to analyze their denitrification abilities and resistance to water vapor. The denitrification performance of the catalyst prepared under reducing atmosphere is about 30 percent higher than that of the catalyst prepared under air atmosphere, and the decarburization performance is about 40 percent higher. In the presence of oxygen, the denitrification rate and decarburization rate of the 1:1 ratio of the Mn-Ce catalyst reach 67.16% and 59.57%, respectively. In an oxygen-containing atmosphere, the catalyst prepared by replacing Ce with Fe shows better denitrification and decarburization performances, which are 78.56% and 78.39%, respectively. When the flue gas space velocity is 4000 h−1 and the carbon-nitrogen ratio is 1.6, the catalyst shows better performance. After the water vapor is introduced, the denitrification and decarbonization rates of the catalyst decrease by about 10% and 9%, respectively. After ceasing water vapor, it rebounds by about 8%, and the activity could not be fully restored. However, the catalyst still shows strong water resistance in general.

C30H52O3, orthorhombic, P212121 (no. 19), a = 6.71147(14) Å, b = 16.6565(4) Å, c = 25.0815(6) Å, V = 2803.85(11) Å3, Z = 4, Rgt (F) = 0.0405, wRref (F2) = 0.1092, T = 293(2) K.

Surface-enhanced Raman spectroscopy (SERS) has attracted lots of interest in academic and industrial fields in recent years. The improvement in long-time sensitivity and repeatability is highly demanded by the on-site applications. Herein, we present an expedient SERS strip tactic with these desired advantages. Specifically, the tactic utilized the outstanding stability of colloidal particles to maintain the SERS materials during the storage. Upon usage, the strip is rapidly prepared on-site, and then the targets were sampled with a dip-coating and heating method, which is designed to standardize the whole detection process with the sensitivity kept. Thanks to the tactic, only one-third of SERS sensitivity decay was observed for rhodamine 6G after half a year. Besides rhodamine 6G, the SERS spectra of different animal blood samples were also investigated with the SERS strip tactic, and a species-based discrimination capability was preliminarily demonstrated.

Canopy gap is the driving force of forest succession. Due to the uncontrollability, however, the influences of natural disturbances on gap formation and gap distribution pattern have been rarely understood in temperate secondary forest ecosystems. We monitored the gap formation and gap distribution pattern using high-resolution remote sensing images before and after two disturbances (wind/snowstorm in 2003 and flood in 2013). The results showed that after wind/snowstorm, the gap nearest neighbor index (GNNI) decreased, the vacant land area did not obviously change while the gap fraction and gaps density (especially medium size) increased. After the flood, GNNI decreased, the number of small gaps increased but larger gaps were in many cases extended to vacant land areas leading to a smaller total number of medium and large gaps but considerable increase in vacant land area. We also found that the gap densities increased with slope and altitude for wind/snowstorm-formed gaps, but they increased with increasing slope and decreasing altitude for flood-formed gaps. These results indicated that gaps were aggregated in steep slope and high altitude areas after wind/snowstorm, but in steep slope and low altitude areas after the flood. Medium gaps were mainly created by the wind/snowstorm due to the individual-level death of dominant tree with the continuous fall of surrounding trees. While, vacant lands were obviously created during the flood because of integral sweeping. Besides, smaller trees were easily damaged by runoff of flood, which induced small gaps. In summary, forest managers may pay more attention to use gaps to accelerate forest succession after wind/snowstorms and to restore vegetation in vacant lands after floods.

BackgroundThe commercial potential of social media is utilized by tobacco manufacturers and vendors for tobacco promotion online. However, the prevalence and promotional strategies of pro-tobacco content in social media are still not widely understood. ObjectiveThe goal of this study was to reveal what is presented by the tobacco industry, and how it promotes itself, on social media sites. MethodsThe top 70 popular cigarette brands are divided into two groups according to their retail prices: group H (brands with high retail prices) and group L (brands with low retail prices). Three comprehensive searches were conducted on Facebook, Wikipedia, and YouTube respectively using the top 70 popular cigarette brands as keywords. We identified tobacco-related content including history and culture, product features, health warnings, home page of cigarette brands, and Web-based tobacco shops. Furthermore, we examined the promotional strategies utilized in social media. ResultsAccording to the data collected from March 3, 2014 to March 10, 2014, 43 of the 70 representative cigarette brands had created 238 Facebook fan pages, 46 cigarette brands were identified in Wikipedia, and there were over 120,000 pro-tobacco videos on YouTube, associated with 61 cigarette brands. The main content presented on the three social media websites differs significantly. Wikipedia focuses on history and culture (67%, 32/48; P

BackgroundAn easily accessible real-time Web-based utility to assess patient risks of future emergency department (ED) visits can help the health care provider guide the allocation of resources to better manage higher-risk patient populations and thereby reduce unnecessary use of EDs. ObjectiveOur main objective was to develop a Health Information Exchange-based, next 6-month ED risk surveillance system in the state of Maine. MethodsData on electronic medical record (EMR) encounters integrated by HealthInfoNet (HIN), Maine’s Health Information Exchange, were used to develop the Web-based surveillance system for a population ED future 6-month risk prediction. To model, a retrospective cohort of 829,641 patients with comprehensive clinical histories from January 1 to December 31, 2012 was used for training and then tested with a prospective cohort of 875,979 patients from July 1, 2012, to June 30, 2013. ResultsThe multivariate statistical analysis identified 101 variables predictive of future defined 6-month risk of ED visit: 4 age groups, history of 8 different encounter types, history of 17 primary and 8 secondary diagnoses, 8 specific chronic diseases, 28 laboratory test results, history of 3 radiographic tests, and history of 25 outpatient prescription medications. The c-statistics for the retrospective and prospective cohorts were 0.739 and 0.732 respectively. Integration of our method into the HIN secure statewide data system in real time prospectively validated its performance. Cluster analysis in both the retrospective and prospective analyses revealed discrete subpopulations of high-risk patients, grouped around multiple “anchoring” demographics and chronic conditions. With the Web-based population risk-monitoring enterprise dashboards, the effectiveness of the active case finding algorithm has been validated by clinicians and caregivers in Maine. ConclusionsThe active case finding model and associated real-time Web-based app were designed to track the evolving nature of total population risk, in a longitudinal manner, for ED visits across all payers, all diseases, and all age groups. Therefore, providers can implement targeted care management strategies to the patient subgroups with similar patterns of clinical histories, driving the delivery of more efficient and effective health care interventions. To the best of our knowledge, this prospectively validated EMR-based, Web-based tool is the first one to allow real-time total population risk assessment for statewide ED visits.

BackgroundIn this digital era, there is a growing tendency to use the popular Internet site YouTube as a new electronic-learning (e-learning) means for continuing medical education. Heart transplantation (HTx) remains the most viable option for patients with end-stage heart failure or severe coronary artery disease. There are plenty of freely accessible YouTube videos providing medical information about HTx. ObjectiveThe aim of the present study is to determine the effectiveness of YouTube as an e-learning source on HTx. MethodsIn order to carry out this study, YouTube was searched for videos uploaded containing surgical-related information using the four keywords: (1) “heart transplantation”, (2) “cardiac transplantation”, (3) “heart transplantation operation”, and (4) “cardiac transplantation operation”. Only videos in English (with comments or subtitles in English language) were included. Two experienced cardiac surgeons watched each video (N=1800) and classified them as useful, misleading, or recipients videos based on the HTx-relevant information. The kappa statistic was used to measure interobserver variability. Data was analyzed according to six types of YouTube characteristics including “total viewership”, “duration”, “source”, “days since upload”, “scores” given by the viewers, and specialized information contents of the videos. ResultsA total of 342/1800 (19.00%) videos had relevant information about HTx. Of these 342 videos, 215 (62.8%) videos had useful information about specialized knowledge, 7/342 (2.0%) were found to be misleading, and 120/342 (35.1%) only concerned recipients’ individual issues. Useful videos had 56.09% of total viewership share (2,175,845/3,878,890), whereas misleading had 35.47% (1,375,673/3,878,890). Independent user channel videos accounted for a smaller proportion (19% in total numbers) but might have a wider impact on Web viewers, with the highest mean views/day (mean 39, SD 107) among four kinds of channels to distribute HTx-related information. ConclusionsYouTube videos on HTx benefit medical professionals by providing a substantial amount of information. However, it is a time-consuming course to find high-quality videos. More authoritative videos by trusted sources should be posted for dissemination of reliable information. With an improvement of ranking system and content providers in future, YouTube, as a freely accessible outlet, will help to meet the huge informational needs of medical staffs and promote medical education on HTx.

The G-quadruplex formed in KRAS oncogene promoter (KRAS-G4) is a transcriptional modulator and amenable to small molecule targeting. Herein, the authors report the NMR solution structures of a bulge-containing KRAS-G4 that bound to two small molecules. The study provides molecular details of ligand interactions with KRAS-G4 and contributes insight into the design of specific KRAS-G4-interactive drugs.

The molecular differences between postpartum (PPBC) and nulliparous (NPBC) young women breast cancer (YWBC) patients remain unknown. Here the authors perform RNA sequencing and multiplex immunohistochemistry on an FFPE breast cancer cohort and suggest that PPBC is a unique entity within YWBC with poor prognosis.

Abstract Background A large-scale global outbreak of coronavirus disease-19 (COVID-19) out of Wuhan, from China, occurred in January 2020. To examine the clinical characteristics of COVID-19 in infected patients out of Wuhan, from China. Methods Thirteen patients were confirmed to be infected with novel coronavirus-2019 (2019-nCoV) between January 27 and February 8, 2020, in Baoji city, Shannxi, northwestern China. Epidemiological and clinical information, and computed to morphology imaging data from all COVID-19 patients were collected; cases were divided into two groups according to the severity of infection (mild or severe). Results Nine (9/13) COVID-19 patients exhibited mild disease severity, and defined as second-generation human-to-human transmission cases. Most patients (11/13) had a history of travel to or from Wuhan. There were no differences in sex and age between the mild and severe cases (all P > 0.05). A moderate degree of fever (11/13), cough (13/13), and fatigue (8/13) were common symptoms; however, there was no statistical difference between mild and severe cases in this regard (all P > 0.05). Oxyhemoglobin saturation and oxygenation index decreased, and C-reactive protein (CRP) and serum amyloid A (SAA) levels were elevated in all patients with COVID-19 infection, with statistically significant differences between those with severe disease and mild infection (all P

Neuroendocrine prostate cancer (NEPC) is the most virulent form of prostate cancer. Importantly, our recent work examining metastatic biopsy samples demonstrates NEPC is increasing in frequency. In contrast to prostate adenocarcinomas that express a luminal gene expression program, NEPC tumors express a neuronal gene expression program. Despite this distinction, the diagnosis of NEPC is often challenging, demonstrating an urgent need to identify new biomarkers and therapeutic targets. Our prior work demonstrated that the histone demethylase LSD1 (KDM1A) is important for survival of prostate adenocarcinomas, but little was known about LSD1’s role in NEPC. Recently, a neural-specific transcript variant of LSD1—LSD1+8a—was discovered and demonstrated to activate neuronal gene expression in neural cells. The splicing factor SRRM4 was previously shown to promote LSD1+8a splicing in neuronal cells, and SRRM4 promotes NEPC differentiation and cell survival. Therefore, we sought to determine if LSD1+8a might play a role in NEPC and whether LSD1+8a splicing was linked to SRRM4. To investigate a potential role for LSD1+8a in NEPC, we examined a panel of prostate adenocarcinoma and NEPC patient-derived xenografts and metastatic biopsies. LSD1+8a was expressed exclusively in NEPC samples and correlated significantly with elevated expression of SRRM4. Using SRRM4-overexpressing cell lines, we determined that SRRM4 mediates alternative splicing of LSD1+8a. Finally, using gain of function studies, we confirmed that LSD1+8a and SRRM4 co-regulate target genes distinct from canonical LSD1. Our findings suggest further study of the interplay between SRRM4 and LSD1+8a and mechanisms by which LSD1+8a regulates gene expression in NEPC is warranted.

Objective To investigate the clinical efficacy and advantages of the SuperPATH minimally invasive approach to total hip arthroplasty in the treatment of femoral neck fractures in the elderly. Methods From January 2016 to September 2018, 110 cases of elderly patients with femoral neck fractures were included in the present study. According to the method of operation, the patients were divided into two groups for comparison. There were 55 cases of the SuperPATH minimally invasive approach to total hip arthroplasty and 55 cases with the conventional posterolateral approach to total hip arthroplasty. The operation time, the length of incision, the amount of operative blood loss, the hospitalization time, and the hospitalization cost were compared between the two groups. The position of total hip prosthesis was observed during the follow‐up period. All patients were evaluated for the degree of hip joint pain and the function of the hip joint using the visual analog score (VAS) and the Harris score at 1 week, 1 month, 3 months, 6 months, and 12 months after the operation. Results All patients were followed up for at least 12 months. The operation time was 108.58 ± 15.87 min in the SuperPATH group and 102.51 ± 19.61 min in the conventional group. The length of incision was 6.65 ± 1.53 cm in the SuperPATH group and 17.08 ± 1.40 cm in the conventional group. The amount of operative blood loss was 147.51 ± 28.84 mL in the SuperPATH group and 170.22 ± 25.34 mL in the conventional group. The hospitalization time was 10.05 ± 2.52 days in the SuperPATH group and 13.36 ± 3.39 days in the conventional group. The hospitalization cost was 6871.78 ± 141.63 dollars in the SuperPATH group and 7791.09 ± 184.88 dollars in the conventional group. Compared with the conventional group, the SuperPATH group had shorter incision length, less blood loss, shorter hospitalization time, and lower hospitalization cost. There was significant difference between the two groups (P 0.05). Conclusion The SuperPATH minimally invasive approach to total hip arthroplasty is an ideal method for the treatment of femoral neck fractures in the elderly. This method has the advantages of the relatively simple operation, short incision, less blood loss, and less trauma. The patients had short hospitalization times, low hospitalization costs, and good recovery of hip joint function.

Abstract Mammalian target of rapamycin complex 1 (mTORC1) is evolutionally conserved and frequently activated in various tumors, including colorectal cancer (CRC). It has been reported that the ribosome assembly factor Urb1 acts downstream of mTORC1/raptor signaling and contributes to digestive organ development in zebrafish. Previously, we highlighted that URB1 was overexpressed in CRC. Here, we assessed the mTORC1/regulatory associated protein with mTOR (RAPTOR)‐URB1 axis in CRC tumorigenesis. We found that RAPTOR was overexpressed in CRC tissues and cell lines, was a favorable predictor in patients with CRC, and positively correlated with URB1. Silencing of RAPTOR suppressed CRC cell proliferation and migration and induced cell cycle arrest and apoptosis in vitro and inhibited xenograft growth in vivo. Moreover, ectopic overexpression of RAPTOR exerted an inverse biological phenotype. Knockdown of RAPTOR quenched mTORC1 activity and reduced the expression of URB1 and cyclinA2 (CCNA2). In contrast, overexpression of RAPTOR activated mTORC1 and upregulated URB1 and CCNA2. Furthermore, URB1 and CCNA2 expression were also impeded by rapamycin, which is a specific inhibitor of mTORC1. Thus, RAPTOR promoted CRC proliferation, migration, and cell cycle progression by inducing mTORC1 signaling and transcriptional activation of both URB1 and CCNA2. Taken together, we concluded that RAPTOR has the potential to serve as a novel biomarker and therapeutic target for CRC.

Abstract Background Formalin-fixed, paraffin-embedded (FFPE) tissues for RNA-seq have advantages over fresh frozen tissue including abundance and availability, connection to rich clinical data, and association with patient outcomes. However, FFPE-derived RNA is highly degraded and chemically modified, which impacts its utility as a faithful source for biological inquiry. Methods True archival FFPE breast cancer cases (n = 58), stored at room temperature for 2–23 years, were utilized to identify key steps in tissue selection, RNA isolation, and library choice. Gene expression fidelity was evaluated by comparing FFPE data to public data obtained from fresh tissues, and by employing single-gene, gene set and transcription network-based regulon analyses. Results We report a single 10 μm section of breast tissue yields sufficient RNA for RNA-seq, and a relationship between RNA quality and block age that was not linear. We find single-gene analysis is limiting with FFPE tissues, while targeted gene set approaches effectively distinguish ER+ from ER- breast cancers. Novel utilization of regulon analysis identified the transcription factor KDM4B to associate with ER+ disease, with KDM4B regulon activity and gene expression having prognostic significance in an independent cohort of ER+ cases. Conclusion Our results, which outline a robust FFPE-RNA-seq pipeline for broad use, support utilizing FFPE tissues to address key questions in the breast cancer field, including the delineation between indolent and life-threatening disease, biological stratification and molecular mechanisms of treatment resistance.

Abstract. Background:. Malignant pleural effusion (MPE) is a complicated condition of patients with advanced tumors. Further dissecting the microenvironment of infiltrated immune cells and malignant cells are warranted to understand the immune-evasion mechanisms of tumor development and progression. Methods:. The possible involvement of microRNAs (miRNAs) in malignant pleural fluid was investigated using small RNA sequencing. Regulatory T cell (Treg) markers (CD4, CD25, forkhead box P3), and Helios (also known as IKAROS Family Zinc Finger 2 [IKZF2]) were detected using flow cytometry. The expression levels of IKZF2 and miR-4772-3p were measured using quantitative real-time reverse transcription polymerase chain reaction. The interaction between miR-4772-3p and Helios was determined using dual-luciferase reporter assays. The effects of miR-4772-3p on Helios expression were evaluated using an in vitro system. Correlation assays between miR-4772-3p and functional molecules of Tregs were performed. Results:. Compared with non-malignant controls, patients with non-small cell lung cancer had an increased Tregs frequency with Helios expression in the MPE and peripheral blood mononuclear cells. The verified downregulation of miR-4772-3p was inversely related to the Helios+ Tregs frequency and Helios expression in the MPE. Overexpression of miR-4772-3p could inhibit Helios expression in in vitro experiments. However, ectopic expression of Helios in induced Tregs reversed the effects induced by miR-4772-3p overexpression. Additionally, miR-4772-3p could regulate Helios expression by directly targeting IKZF2 mRNA. Conclusion:. Downregulation of miR-4772-3p, by targeting Helios, contributes to enhanced Tregs activities in the MPE microenvironment.

Myotonic dystrophy type 1 (DM1) is caused by a CTG repeat expansion in the DMPK gene. Expression of pathogenic expanded CUG repeat (CUGexp) RNA causes multisystemic disease by perturbing the functions of RNA-binding proteins, resulting in expression of fetal protein isoforms in adult tissues. Cardiac involvement affects 50% of individuals with DM1 and causes 25% of disease-related deaths. We developed a transgenic mouse model for tetracycline-inducible and heart-specific expression of human DMPK mRNA containing 960 CUG repeats. CUGexp RNA is expressed in atria and ventricles and induced mice exhibit electrophysiological and molecular features of DM1 disease, including cardiac conduction delays, supraventricular arrhythmias, nuclear RNA foci with Muscleblind protein colocalization, and alternative splicing defects. Importantly, these phenotypes were rescued upon loss of CUGexp RNA expression. Transcriptome analysis revealed gene expression and alternative splicing changes in ion transport genes that are associated with inherited cardiac conduction diseases, including a subset of genes involved in calcium handling. Consistent with RNA-Seq results, calcium-handling defects were identified in atrial cardiomyocytes isolated from mice expressing CUGexp RNA. These results identify potential tissue-specific mechanisms contributing to cardiac pathogenesis in DM1 and demonstrate the utility of reversible phenotypes in our model to facilitate development of targeted therapeutic approaches.

Studies of cell fate focus on specification, but little is known about maintenance of the differentiated state. In this study, we find that the mouse tendon cell fate requires continuous maintenance in vivo and identify an essential role for TGFβ signaling in maintenance of the tendon cell fate. To examine the role of TGFβ signaling in tenocyte function the TGFβ type II receptor (Tgfbr2) was targeted in the Scleraxis-expressing cell lineage using the ScxCre deletor. Tendon development was not disrupted in mutant embryos, but shortly after birth tenocytes lost differentiation markers and reverted to a more stem/progenitor state. Viral reintroduction of Tgfbr2 to mutants prevented and even rescued tenocyte dedifferentiation suggesting a continuous and cell autonomous role for TGFβ signaling in cell fate maintenance. These results uncover the critical importance of molecular pathways that maintain the differentiated cell fate and a key role for TGFβ signaling in these processes.

The benefits of anti-cancer agents extend beyond direct tumor killing. One aspect of cell death is the potential to release antigens that initiate adaptive immune responses. Here, a diffusion enhanced formulation, INT230-6, containing potent anti-cancer cytotoxic agents, was administered intratumorally into large (approx. 300mm3) subcutaneous murine Colon26 tumors. Treatment resulted in regression from baseline in 100% of the tumors and complete response in up to 90%. CD8+ or CD8+/CD4+ T cell double-depletion at treatment onset prevented complete responses, indicating a critical role of T cells in promoting complete tumor regression. Mice with complete response were protected from subcutaneous and intravenous re-challenge of Colon26 cells in a CD4+/CD8+ dependent manner. Thus, immunological T cell memory was induced by INT230-6. Colon26 tumors express the endogenous retroviral protein gp70 containing the CD8+ T-cell AH-1 epitope. AH-1-specific CD8+ T cells were detected in peripheral blood of tumor-bearing mice and their frequency increased 14 days after treatment onset. AH-1-specific CD8+ T cells were also significantly enriched in tumors of untreated mice. These cells had an activated phenotype and highly expressed Programmed cell-death protein-1 (PD-1) but did not lead to tumor regression. CD8+ T cell tumor infiltrate also increased 11 days after treatment. INT230-6 synergized with checkpoint blockade, inducing a complete remission of the primary tumors and shrinking of untreated contralateral tumors, which demonstrates not only a local but also systemic immunological effect of the combined therapy. Similar T-cell dependent inhibition of tumor growth was also found in an orthotopic 4T1 breast cancer model.

Abstract Neuronal cells express considerable plasticity responding to environmental cues, in part, through subcellular mRNA regulation. Here we report on the extensive changes in distribution of mRNAs in the cell body and axon compartments of peripheral sensory neurons and the 3′ untranslated region (3′UTR) landscapes after unilateral sciatic nerve entrapment (SNE) injury in rats. Neuronal cells dissociated from SNE-injured and contralateral L4 and L5 dorsal root ganglia were cultured in a compartmentalized system. Axonal and cell body RNA samples were separately subjected to high throughput RNA sequencing (RNA-Seq). The injured axons exhibited enrichment of mRNAs related to protein synthesis and nerve regeneration. Lengthening of 3′UTRs was more prevalent in the injured axons, including the newly discovered alternative cleavage and polyadenylation of NaV1.8 mRNA. Alternative polyadenylation was largely independent from the relative abundance of axonal mRNAs; but they were highly clustered in functional pathways related to RNA granule formation in the injured axons. These RNA-Seq data analyses indicate that peripheral nerve injury may result in highly selective mRNA enrichment in the affected axons with 3′UTR alterations potentially contributing to the mechanism of neuropathic pain.

Multifunctional carbamate-type acetylcholinesterase (AChE) inhibitors with anti-amyloidogenic properties like phenserine are potential therapeutic agents for Alzheimer’s disease (AD). We reported here the design of new carbamates using pharmacophore model strategy to modulate both cholinesterase and amyloidogenesis. A five-feature pharmacophore model was generated based on 25 carbamate-type training set compounds. (−)-Meptazinol carbamates that superimposed well upon the model were designed and synthesized, which exhibited nanomolar AChE inhibitory potency and good anti-amyloidogenic properties in in vitro test. The phenylcarbamate 43 was highly potent (IC50 31.6 nM) and slightly selective for AChE, and showed low acute toxicity. In enzyme kinetics assay, 43 exhibited uncompetitive inhibition and reacted by pseudo-irreversible mechanism. 43 also showed amyloid-β (Aβ) lowering effects (51.9% decrease of Aβ42) superior to phenserine (31% decrease of total Aβ) in SH-SY5Y-APP695 cells at 50 µM. The dual actions of 43 on cholinergic and amyloidogenic pathways indicated potential uses as symptomatic and disease-modifying agents.

Estrogen receptor α (ERα) is the major driving transcription factor in the mammary gland development as well as breast cancer initiation and progression. However, the genomic landscape of ERα binding sites in the normal mouse mammary gland has not been completely elucidated. Here, we mapped genome-wide ERα binding events by chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) in the mouse mammary gland in response to estradiol. We identified 6237 high confidence ERα binding sites in two biological replicates and showed that many of these were located at distal enhancer regions. Furthermore, we discovered 3686 unique genes in the mouse genome that recruit ER in response to estradiol. Interrogation of ER-DNA binding sites in ER-positive luminal epithelial cells showed that the ERE, PAX2, SF1, and AP1 motifs were highly enriched at distal enhancer regions. In addition, comprehensive transcriptome analysis by RNA-seq revealed that 493 genes are differentially regulated by acute treatment with estradiol in the mouse mammary gland in vivo. Through integration of RNA-seq and ERα ChIP-seq data, we uncovered a novel ERα targetome in mouse mammary epithelial cells. Taken together, our study has identified the genomic landscape of ERα binding events in mouse mammary epithelial cells. Furthermore, our study also highlights the cis-regulatory elements and cofactors that are involved in estrogen signaling and may contribute to ductal elongation in the normal mouse mammary gland.

Drought, cadmium (Cd) stress, and root lesion nematode (RLN) infection are three of the most important stresses affecting ramie growth and development; therefore, ramie breeding programs focus on their management more than on any other abiotic or biotic stresses. The fact that only a small number of stress-responsive transcription factors (TFs) have been identified so far is a major obstacle in the elucidation of mechanisms regulating the response to these three stresses in ramie. In this study, in order to uncover more stress-responsive TFs, a total of 179 nonredundant genes with full-length open reading frames from the MYB, AP2/ERF, bZIP, HD-ZIP, and COL families were obtained by searching for against the ramie transcriptome. Expression pattern analysis demonstrated that most of these genes showed relatively higher expression in the stem xylem and bast than in other tissues. Among these genes, 96 genes were found to be involved in responses to drought, Cd exposure, or RLN-infection. The expression of 54 of these genes was regulated by at least two stresses. These stress-responsive TFs probably have roles in the regulation of stress tolerance. The discovery of these stress-responsive TFs will be helpful for furthering our understanding of the mechanisms that regulate stress responses in ramie.

To investigate the expression as well as biological roles of activating transcription factor 3 (ATF3) in human hepatocellular carcinoma (HCC) cells.

A major advantage of immunotherapy of cancer is that effector cells induced at one site should be able to kill metastatic cancer cells in other sites or tissues. However, different tissues have unique immune components, and very little is known about whether effector T cells induced against tumors in one tissue can work against the same tumors in other tissues. Here, we used CT26 murine tumor models to investigate anti-tumor immune responses in the skin and lungs and characterized cross-protection between the two tissues. Blockade of the function of Treg cells with anti-CD25 allowed for T cell-dependent rejection of s.c. tumors. When these mice were simultaneously inoculated i.v. with CT26, they also rejected tumors in the lung. Interestingly, in the absence of s.c. tumors, anti-CD25 treatment alone had no effect on lung tumor growth. These observations suggested that T cell-mediated anti-tumor protective immunity induced against s.c. tumors can also protect against lung metastases of the same tumors. In contrast, NKT cell-deficiency in CD1d−/− mice conferred significant protection against lung tumors but had no effect on the growth of tumors in the skin, and tumor rejection induced against the CT26 in the lung did not confer protection for the same tumor cells in the skin. Thus, effector cells against the same tumor do not work in all tissues, and the induction site of the effector T cells is critical to control metastasis. Further, the regulation of tumor immunity may be different for the same tumor in different anatomical locations.

A new trigonal phase with composition Al13Fe3 (tridecaaluminium triiron) was obtained in the binary Fe–Al diagram by high-pressure sintering (HPS) of a stoichiometric Al3Fe mixture. The refined crystal structure agrees with the descriptions of an unresolved rhombohedral phase reported 30 years ago [Chandrasekaran et al. (1988). Scr. Metall. 22, 797–802]. The structure was refined as an inversion twin with a ratio of 0.506 (18):0.494 (18) for the two twin components.

[This corrects the article DOI: 10.1371/journal.pgen.1006809.].

Postnatal development of skeletal muscle is a highly dynamic period of tissue remodeling. Here, we used RNA-seq to identify transcriptome changes from late embryonic to adult mouse muscle and demonstrate that alternative splicing developmental transitions impact muscle physiology. The first 2 weeks after birth are particularly dynamic for differential gene expression and alternative splicing transitions, and calcium-handling functions are significantly enriched among genes that undergo alternative splicing. We focused on the postnatal splicing transitions of the three calcineurin A genes, calcium-dependent phosphatases that regulate multiple aspects of muscle biology. Redirected splicing of calcineurin A to the fetal isoforms in adult muscle and in differentiated C2C12 slows the timing of muscle relaxation, promotes nuclear localization of calcineurin target Nfatc3, and/or affects expression of Nfatc transcription targets. The results demonstrate a previously unknown specificity of calcineurin isoforms as well as the broader impact of alternative splicing during muscle postnatal development.

Integrator is an RNA polymerase II (RNAPII)-associated complex that was recently identified to have a broad role in both RNA processing and transcription regulation. Importantly, its role in human development and disease is so far largely unexplored. Here, we provide evidence that biallelic Integrator Complex Subunit 1 (INTS1) and Subunit 8 (INTS8) gene mutations are associated with rare recessive human neurodevelopmental syndromes. Three unrelated individuals of Dutch ancestry showed the same homozygous truncating INTS1 mutation. Three siblings harboured compound heterozygous INTS8 mutations. Shared features by these six individuals are severe neurodevelopmental delay and a distinctive appearance. The INTS8 family in addition presented with neuronal migration defects (periventricular nodular heterotopia). We show that the first INTS8 mutation, a nine base-pair deletion, leads to a protein that disrupts INT complex stability, while the second missense mutation introduces an alternative splice site leading to an unstable messenger. Cells from patients with INTS8 mutations show increased levels of unprocessed UsnRNA, compatible with the INT function in the 3'-end maturation of UsnRNA, and display significant disruptions in gene expression and RNA processing. Finally, the introduction of the INTS8 deletion mutation in P19 cells using genome editing alters gene expression throughout the course of retinoic acid-induced neural differentiation. Altogether, our results confirm the essential role of Integrator to transcriptome integrity and point to the requirement of the Integrator complex in human brain development.

Oils with high content of free fatty acid (FFA) can be treated by acid esterification where an alcohol reacts with the given oil in the presence of acid catalyst. The investigated parameters include methanol to oil ratio, temperature and amount of catalyst. The optimum conditions for acid esterification which could reduce FFA content in the feedstock to less than 1.88% (acid value 3.76 mg KOH/g waste cooking oil) were 50 °C, 20% methanol to oil ratio (by volume) and 0.4 vol.% H2SO4 after 5 h. However, oil with an acid value of more than 1 mg KOH/g oil cannot meet the alkaline catalyzed transesterification conditions. Under the conditions of NaOH concentration 0.5 N, excess alkali 15%, 60 °C, 40 min, the FFA removal rate for deacidification reached 77.11% (acid value 0.86 mg KOH/g esterified oil). The acid value of deacidification product was reduced below 0.86 mg KOH/g esterified oil, thus meeting the base-catalyzed trans-esterification conditions.

Interleukin (IL)-15 has multiple roles in innate and adaptive immunity, especially regarding CD8+ T cells and natural killer cells. However, the role of IL-15 in regulating differentiation of T helper cell subsets and mononuclear phagocytes (MPs) in different tissues in vivo is unknown. Here we report that IL-15 indirectly regulates Th17 but not other Th subsets in the intestinal lamina propria (LP), apparently through effects on MPs. Th17 cells in the LP were more prevalent in IL-15 KO mice than their wild-type counterparts, and less prevalent in IL-15 transgenic mice than their wild-type littermates, even co-caged. MPs from the LP of these mice were sufficient to mimic the in vivo finding in vitro by skewing of cocultured wild type OVA-specific CD4+ T cells. However, production of IL-15 or lack thereof by these MPs was not sufficient to explain the skewing, as addition or blockade of IL-15 in the cultures had no effect. Rather, a skewing of the relative proportion of CD11b+, CD103+ and double positive LP MP subsets in transgenic and KO could explain the differences in Th17 cells. Thus, IL-15 may influence MP subsets in the gut in a novel way that alters the frequency of LP Th17 cells.

Leptocybe invasa Fisher & La Salle (Hymenoptera, Eulophidae) is an invasive pest in Eucalyptus plantations throughout the world. Potential biological control agents for L. invasa were investigated in the Fujian, Guangdong, Hainan, Guangxi, Jiangxi, and Sichuan provinces of China, where Eucalyptus spp. have been severely damaged by the eucalyptus gall wasp. Three hymenopteran parasitoids of L. invasa were identified: Quadrastichus mendeli Kim & La Salle (Eulophidae), Aprostocetus causalis La Salle & Wu (Eulophidae), and Megastigmus viggianii Narendran & Sureshan (Torymidae); M. viggianii is newly recorded in China. The percentages of parasitization by Q. mendeli, A. causalis, and M. viggianii were 2.96%–19.53%, 2.30%–26.38%, and 24.93%, respectively. The longevity and body length of females were significantly greater than for males in A. causalis and M. viggianii. No males of Q. mendeli were found in China. These parasitoids could be used as biological agents for L. invasa in China.