Hollow Core-Shelled Na4Fe2.4Ni0.6(PO4)2P2O7 with Tiny-Void Space Capable Fast-Charge and Low-Temperature Sodium Storage.

Iron-based mixed polyanion phosphate Na4Fe3(PO4)2P2O7 (NFPP) is recognized as a promising cathode for Sodium-ion Batteries (SIBs) due to its low cost and environmental friendliness. However, its inherent low conductivity and sluggish Na+ diffusion limit fast charge and low-temperature sodium storage. This study pioneers a scalable synthesis of hollow core-shelled Na4Fe2.4Ni0.6(PO4)2P2O7 with tiny-void space (THoCS-0.6Ni) via a one-step spray-drying combined with calcination process due to the different viscosity, coordination ability, molar ratios, and shrinkage rates between citric acid and polyvinylpyrrolidone. This unique structure with interconnected carbon networks ensures rapid electron transport and fast Na+ diffusion, as well as efficient space utilization for relieve volume expansion. Incorporating regulation of lattice structure by doping Ni heteroatom to effectively improve intrinsic electron and Na+ diffusion path and energy barrier, which achieves fast charge and low-temperature sodium storage. As a result, THoCS-0.6Ni exhibits superior rate capability (86.4 mAh g-1 at 25 C). Notably, THoCS-0.6Ni demonstrates exceptional cycling stability at -20 °C with a capacity of 43.6 mAh g-1 after 2500 cycles at 5 C. This work provides a universal strategy to design the hollow core-shelled structure with tiny-void space cathode materials for reversible batteries with fast-charge and low-temperature storage features.

Involvement of a rice mutation in storage protein biogenesis in endosperm and its genomic location.

MAIN CONCLUSION: A mutation was first found to cause the great generation of glutelin precursors (proglutelins) in rice (Oryza sativa L.) endosperm, and thus referred to as GPGG1. The GPGG1 was involved in synthesis and compartmentation of storage proteins. The PPR-like gene in GPGG1-mapped region was determined as its candidate gene. In the wild type rice, glutelins and prolamins are synthesized on respective subdomains of rough endoplasmic reticulum (ER) and intracellularly compartmentalized into different storage protein bodies. In this study, a storage protein mutant was obtained and characterized by the great generation of proglutelins combining with the lacking of 13 kD prolamins. A dominant genic-mutation, referred to as GPGG1, was clarified to result in the proteinous alteration. Novel saccular composite-ER was shown to act in the synthesis of proglutelins and 14 kD prolamins in the mutant. Additionally, a series of organelles including newly occurring several compartments were shown to function in the transfer, trans-plasmalemmal transport, delivery, deposition and degradation of storage proteins in the mutant. The GPGG1 gene was mapped to a 67.256 kb region of chromosome 12, the pentatricopeptide repeat (PPR)-like gene in this region was detected to contain mutational sites.

Potential salivary and serum biomarkers for burning mouth syndrome and their relationship with anxiety/depression.

Background/purpose: The pathophysiology of burning mouth syndrome (BMS), although considered a multifactorial etiology including psychological factors, is still not well understood. Hence, this study aimed to investigate the potential usage of salivary and serum biomarkers, including brain-derived neurotrophic factor (BDNF), interferon-gamma (IFN-γ), interleukin-1beta (IL-1ß), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-alpha (TNF-α), in diagnosing BMS and their correlations with anxiety/depression. Materials and methods: 45 BMS patients and 14 healthy volunteers were enrolled. The patients were divided into BMS with anxiety/depression group and BMS without anxiety/depression group according to the scores of the Zung Self-rating Anxiety Scale (SAS) and Zung Self-rating Depression Scale (SDS). Additionally, concentrations of BDNF, IFN-γ, IL-1ß, IL-6, IL-8, and TNF-α in saliva and those in serum among the patients and healthy volunteers were assessed by multiplex assay using Luminex 200TM system and Enzyme-linked immunosorbent assay (ELISA), respectively. Results: Among all the serum biomarkers, only BDNF showed a statistically significant decrease in the patients than the healthy volunteers (P < 0.05). Regarding saliva biomarkers, BDNF, IL-1ß, and IL-8 all exhibited a statistically significant increase in all the BMS patients versus the healthy volunteers (P < 0.05) but only BDNF was significantly different between patients with anxiety/depression and healthy individuals when considering anxiety/depression. Among BMS patients with anxiety/depression, saliva TNF-α had positive associations with other biomarkers including BDNF, IFN-γ, IL-1ß, IL-6, and IL-8 (P < 0.05). Conclusion: The increased concentration of saliva BDNF holds strong potential for diagnosing BMS and the elevated level of saliva TNF-α is crucial in identifying BMS patients with anxiety/depression.

MoS2 Hollow Multishelled Nanospheres Doped Fe Single Atoms Capable of Fast Phase Transformation for Fast-charging Na-ion Batteries.

Low Na+ and electron diffusion kinetics severely restrain the rate capability of MoS2 as anode for sodium-ion batteries (SIBs). Slow phase transitions between 2H and 1T, and from NaxMoS2 to Mo and Na2S as well as the volume change during cycling, induce a poor cycling stability. Herein, an original Fe single atom doped MoS2 hollow multishelled structure (HoMS) is designed for the first time to address the above challenges. The Fe single atom in MoS2 promotes the electron transfer, companying with shortened charge diffusion path from unique HoMS, thereby achieving excellent rate capability. The strong adsorption with Na+ and self-catalysis of Fe single atom facilitates the reversible conversion between 2H and 1T, and from NaxMoS2 to Mo and Na2S. Moreover, the buffering effect of HoMS on volume change during cycling improves the cyclic stability. Consequently, the Fe single atom doped MoS2 quadruple-shelled sphere exhibits a high specific capacity of 213.3 mAh g-1 at an ultrahigh current density of 30 A g-1, which is superior to previously-reported results. Even at 5 A g-1, 259.4 mAh g-1 (83.68 %) was reserved after 500 cycles. Such elaborate catalytic site decorated HoMS is also promising to realize other "fast-charging" high-energy-density rechargeable batteries.

Chondroitin sulfate/silk fibroin hydrogel incorporating graphene oxide quantum dots with photothermal-effect promotes type H vessel-related wound healing.

Chronic wounds with bacterial infection present formidable clinical challenges. In this study, a versatile hydrogel dressing with antibacterial and angiogenic activity composite of silk fibroin (SF), chondroitin sulfate (CS), and graphene oxide quantum dots (GOQDs) is fabricated. GOQDs@SF/CS (GSC) hydrogel is rapidly formed through the enzyme catalytic action of horseradish peroxidase. With the incorporation of GOQDs both gelation speed and mechanical properties have been enhanced, and the photothermal characteristics of GOQDs in GSC hydrogel enabled bacterial killing through photothermal treatment (PTT) at ∼51 °C. In vitro studies show that the GSC hydrogels demonstrate excellent antibacterial performance and induce type H vessel differentiation of endothelial cells via the activated ERK1/2 signaling pathway and upregulated SLIT3 expression. In vivo results show that the hydrogel significantly promotes type H vessels formation, which is related to the collagen deposition, epithelialization and, ultimately, accelerates the regeneration of infected skin defects. Collectively, this multifunctional GSC hydrogel, with dual action of antibacterial efficacy and angiogenesis promotion, emerges as an innovative skin dressing with the potential for advancing in infected wound healing.

Inorganic-Organic Nanoarchitectonics: MXene/Covalent Organic Framework Heterostructure for Superior Microextraction.

One of the difficulties limiting covalent organic frameworks (COFs) from becoming excellent adsorbents is their stacking/aggregation architectures owing to poor morphology/structure control during the synthesis process. Herein, an inorganic-organic nanoarchitectonics strategy to synthesize the MXene/COF heterostructure (Ti3 C2 Tx /TAPT-TFP) is developed by the assembly of ß-ketoenamine-linked COF on the Ti3 C2 Tx MXene nanosheets. The as-prepared Ti3 C2 Tx /TAPT-TFP retains the 2D architecture and high adsorption capacity of MXenes as well as large specific surface area and hierarchical porous structure of COFs. As a proof of concept, the potential of Ti3 C2 Tx /TAPT-TFP for solid-phase microextraction (SPME) of trace organochlorine pesticides (OCPs) is investigated. The Ti3 C2 Tx /TAPT-TFP based SPME method achieves low limits of detection (0.036-0.126 ng g-1 ), wide linearity ranges (0.12-20.0 ng g-1 ), and acceptable repeatabilities for preconcentrating trace OCPs from fruit and vegetable samples. This study offers insights into the potential of constructing COF or MXene-based heterostructures for the microextraction of environmental pollutants.

Surface Crystal Modification of Na3 V2 (PO4 )3 to Cast Intermediate Na2 V2 (PO4 )3 Phase toward High-Rate Sodium Storage.

The two-phase reaction of Na3 V2 (PO4 )3 - Na1 V2 (PO4 )3 in Na3 V2 (PO4 )3 (NVP) is hindered by low electronic and ionic conductivity. To address this problem, a surface-N-doped NVP encapsulating by N-doped carbon nanocage (N-NVP/N-CN) is rationally constructed, wherein the nitrogen is doped in both the surface crystal structure of NVP and carbon layer. The surface crystal modification decreases the energy barrier of Na+ diffusion from bulk to electrolyte, enhances intrinsic electronic conductivity, and releases lattice stress. Meanwhile, the porous architecture provides more active sites for redox reactions and shortens the diffusion path of ion. Furthermore, the new interphase of Na2 V2 (PO4 )3 is detected by in situ XRD and clarified by density functional theory (DFT) calculation with a lower energy barrier during the fast reversible electrochemical three-phase reaction of Na3 V2 (PO4 )3 - Na2 V2 (PO4 )3 - Na1 V2 (PO4 )3 . Therefore, as cathode of sodium-ion battery, the N-NVP/N-CN exhibited specific capacities of 119.7 and 75.3 mAh g-1 at 1 C and even 200 C. Amazingly, high capacities of 89.0, 86.2, and 84.6 mAh g-1 are achieved after overlong 10000 cycles at 20, 40, and 50 C, respectively. This approach provides a new idea for surface crystal modification to cast intermediate Na2 V2 (PO4 )3 phase for achieving excellent cycling stability and rate capability.

Pathologist-trained machine learning classifiers developed to quantitate celiac disease features differentiate endoscopic biopsies according to modified marsh score and dietary intervention response.

BACKGROUND: Histologic evaluation of the mucosal changes associated with celiac disease is important for establishing an accurate diagnosis and monitoring the impact of investigational therapies. While the Marsh-Oberhuber classification has been used to categorize the histologic findings into discrete stages (i.e., Type 0-3c), significant variability has been documented between observers using this ordinal scoring system. Therefore, we evaluated whether pathologist-trained machine learning classifiers can be developed to objectively quantitate the pathological changes of villus blunting, intraepithelial lymphocytosis, and crypt hyperplasia in small intestine endoscopic biopsies. METHODS: A convolutional neural network (CNN) was trained and combined with a secondary algorithm to quantitate intraepithelial lymphocytes (IEL) with 5 classes on CD3 immunohistochemistry whole slide images (WSI) and used to correlate feature outputs with ground truth modified Marsh scores in a total of 116 small intestine biopsies. RESULTS: Across all samples, median %CD3 counts (positive cells/enterocytes) from villous epithelium (VE) increased with higher Marsh scores (Type 0%CD3 VE = 13.4; Type 1-3%CD3 VE = 41.9, p < 0.0001). Indicators of villus blunting and crypt hyperplasia were also observed (Type 0-2 villous epithelium/lamina propria area ratio = 0.81; Type 3a-3c villous epithelium/lamina propria area ratio = 0.29, p < 0.0001), and Type 0-1 crypt/villous epithelial area ratio = 0.59; Type 2-3 crypt/villous epithelial area ratio = 1.64, p < 0.0001). Using these individual features, a combined feature machine learning score (MLS) was created to evaluate a set of 28 matched pre- and post-intervention biopsies captured before and after dietary gluten restriction. The disposition of the continuous MLS paired biopsy result aligned with the Marsh score in 96.4% (27/28) of the cohort. CONCLUSIONS: Machine learning classifiers can be developed to objectively quantify histologic features and capture additional data not achievable with manual scoring. Such approaches should be further investigated to improve biopsy evaluation, especially for clinical trials.

NCAPG2 could be an immunological and prognostic biomarker: From pan-cancer analysis to pancreatic cancer validation.

More recently, NCAPG2 has emerged as an intrinsically essential participant of the condensin II complex involved in the process of chromosome cohesion and stabilization in mitosis, and its position in particular tumours is now being highlighted. Simultaneously, the genetic properties of NCAPG2 hint that it might have enormous potential to interpret the malignant progression of tumors in a broader perspective, that is, in pan-cancer. Yet, at present, this recognition remains merely superficial and there is a lack of more detailed studies to explore the underlying pathogenesis. To meet this need, the current study was undertaken to comprehensively elucidate the potential functions of NCAPG2 in pan-cancer, based on a combination of existing databases like TCGA and GTEx. NCAPG2 was identified to be overexpressed in almost every tumor and to exhibit significant prognostic and diagnostic efficacy. Furthermore, the correlation between NCAPG2 and selected immune features, namely immune cell infiltration, immune checkpoint genes, TMB, MSI, etc. also indicates that NCAPG2 could potentially be applied in guidance of immunotherapy. Subsequently, in pancreatic cancer, this study further clarified the utility of NCAPG2 that downregulation of its expression could result in reduced proliferation, invasion and metastasis of pancreatic cancer cells, among such phenotypical changes, the epithelial-mesenchymal transition disruption could be at least one of the possible mechanisms raising or enhancing tumorigenesis. Taken above, NCAPG2, as a member of pan-oncogenes, would serve as a biomarker and potential therapeutic target for a range of malignancies, sharing new insights into precision medicine.

Heterointerface optimization in a covalent organic framework-on-MXene for high-performance capacitive deionization of oxygenated saline water.

Capacitive deionization (CDI) provides a promising option for affordable freshwater while simultaneously storing energy, but its large-scale application is usually limited owing to the poor performance of conventional materials in natural (oxygenated) saline water. Herein, we report heterointerface optimization in a covalent organic framework (COF)-on-MXene heterostructure achieving a high CDI performance for desalination of oxygenated saline water. The 2D heterostructure with the optimal core-shell architecture inherits the high conductivity and reversible ion intercalation/deintercalation ability of MXene, and the hierarchical porous structure, large porosity, and extraordinary redox capacity of COFs. Thanks to the heterointerface optimization, the MXene@COF heterostructure exhibits a very stable cycling performance over 100 CDI cycles with a maximum NaCl adsorption capacity of 53.1 mg g-1 in oxygenated saline water, among the state-of-the-art values for CDI electrodes and also exceeding those of most MXene-based or 2D materials. This study highlights the importance of heterointerface optimization in MXene-organic 2D heterostructures to promote CDI of natural (oxygenated) saline water.

The AdcR-regulated AdcA and AdcAII contribute additively to zinc acquisition and virulence in Streptococcus suis.

Metals are necessary elements for bacteria. Typically, vertebrate hosts restrict invading bacterial pathogens from accessing metals. Therefore, bacteria have evolved high-affinity metal importers to acquire metals. Streptococcus suis is a major swine pathogen and an emerging zoonotic agent that endangers the swine industry and human health worldwide. Herein, we aimed to identify the zinc acquisition systems in S. suis and evaluate their roles in bacterial virulence. Bioinformatic analyses revealed that S. suis encodes homologues of AdcA and AdcAII, two well-characterised Zn-binding lipoproteins in certain streptococci. Quantitative reverse transcription PCR (qRT-PCR) analysis revealed that the expressions of adcA and adcAII were significantly upregulated in response to Zn limitation, with a higher expression level of adcAII than adcA. Gene deletion mutants and complementation strains were constructed; their growth characteristics under Zn-deficient and Zn-replete conditions indicated that AdcA and AdcAII have overlapping functionality in Zn acquisition. A mouse infection model was used to evaluate the roles of AdcA and AdcAII in S. suis virulence. Mice infected with the double mutant ΔadcAΔadcAII exhibited a significantly higher survival rate, decreased bacterial burden, and lower production of inflammatory cytokines compared to those infected with the wild type (WT) strain. Furthermore, ΔadcAΔadcAII showed reduced competitiveness in infection establishment compared with the WT strain. RNA sequencing, qRT-PCR, and electrophoretic mobility shift assays revealed that AdcR negatively regulates the expressions of adcA and adcAII. Collectively, our results demonstrated that AdcA and AdcAII, which are negatively regulated by AdcR, contribute additively to zinc acquisition and virulence in S. suis.

Interlayer-Expanded MoS2 Nanoflowers Vertically Aligned on MXene@Dual-Phased TiO2 as High-Performance Anode for Sodium-Ion Batteries.

As a promising energy-storage and conversion anode material for high-power sodium-ion batteries operated at room temperature, the practical application of layered molybdenum disulfide (MoS2) is hindered by volumetric expansion during cycling. To address this issue, a rational design of MoS2 with enlarged lattice spacing aligned vertically on hierarchically porous Ti3C2Tx MXene nanosheets with partially oxidized rutile and anatase dual-phased TiO2 (MoS2@MXene@D-TiO2) composites via one-step hydrothermal method without following anneal process is reported. This unique "plane-to-surface" structure accomplishes hindering MoS2 from aggregating and restacking, enabling sufficient electrode/electrolyte interaction simultaneously. Meanwhile, the heterogeneous structure among dual-phased TiO2, MoS2, and MXene could constitute a built-in electric field, promoting high Na+ transportation. As a result, the as-constructed 3D MoS2@MXene@D-TiO2 heterostructure delivers admirable high-rate reversible capacity (359.6 mAh g-1 up to 5 A g-1) at room temperature, excellent cycling stability (about 200 mAh g-1) at a low temperature of -30 °C, and superior electrochemical performance in Na+ full batteries by coupling with a Na3V2(PO4)3 cathode. This ingenious design is clean and facile to inspire the potential of advanced low-dimensional heterogeneous structure electrode materials in the application of high-performance sodium-ion batteries.

The DmeRF System Is Involved in Maintaining Cobalt Homeostasis in Vibrio parahaemolyticus.

Although cobalt (Co) is indispensable for life, it is toxic to cells when accumulated in excess. The DmeRF system is a well-characterized metal-response system that contributes to Co and nickel resistance in certain bacterial species. The Vibrio parahaemolyticus RIMD 2210633 genome also harbors a dmeRF operon that encodes a multiple antibiotic resistance regulator family transcriptional regulator and a cation diffusion facilitator family protein. Quantitative real-time PCR, growth curves analysis, inductively coupled plasma-mass spectrometry, ß-galactosidase activity assays, electrophoretic mobility shift assays, and a mouse infection experiment were performed to characterize the function of the DmeRF system in V. parahaemolyticus. Zinc, copper, and Co significantly increase dmeF expression, with Co inducing the greatest increase. DmeF promotes V. parahaemolyticus growth under high-Co conditions. Additionally, increased accumulation of cellular Co in the ΔdmeF mutant indicates that DmeF is potentially involved in Co efflux. Moreover, DmeR represses the dmeRF operon by binding directly to its promoter in the absence of Co. Finally, the DmeRF system was not required for V. parahaemolyticus virulence in mice. Collectively, our data indicate that the DmeRF system is involved in maintaining Co homeostasis in V. parahaemolyticus and DmeR functioning as a repressor of the operon.

IgM Plasma Cell Myeloma.

OBJECTIVES: Immunoglobulin M plasma cell myeloma (IgMPCM) is a rare entity that is difficult to distinguish from other IgM-related neoplasms. The study aims to characterize the clinicopathologic features of IgMPCM, including MYD88 L265P and CXCR4 mutations. METHODS: From our institutional archives, bone marrow biopsy specimens from January 1, 2008, to December 1, 2018, with monotypic plasma cells (PCs) expressing IgM that met current International Myeloma Working Group/World Health Organization criteria for PCM were included. Sanger sequencing was used to test for MYD88 L265P and WHIM-like CXCR4 mutations. RESULTS: Nine cases of IgMPCM were identified. Serum IgM paraproteins were detected in eight cases. CD138-positive PC burden averaged 41.9% (5%-80%). In four cases, PCs had lymphoplasmacytic morphology with cyclin D1 expression by immunohistochemistry. Three of four tested cases were positive for t(11;14) by fluorescence in situ hybridization, one with monosomy 13. The remaining case was positive for del13q14. All were negative for MYD88 L265P and WHIM-like CXCR4 mutations. Eight patients received immunochemotherapy, with four receiving autologous hematopoietic stem cell transplant. Median follow-up was 61 months (range, 11-120). All patients were alive except one. CONCLUSIONS: Distinguishing IgMPCM from other IgM-related disorders requires correlation with clinical, laboratory, and radiologic findings. Exclusion of MYD88 L265P and WHIM-like CXCR4 mutations may be useful to diagnose IgMPCM.

Application evaluation of virtual reality technology in dental implant training: a new dental implant training system: A CONSORT-compliant trial.

ABSTRACT: To evaluate the application of virtual reality technology in a dental implant training system.A 3-dimensional model of mandible was established by Mimics17.0 software based on the Digital Imaging and Communications in Medicine data obtained from cone beam computed tomography scanning of the patient in mandibular. Thirty physicians were divided into 2 groups. The virtual reality dental implant training system was used for group A, while conventional theoretical knowledge training and clinical demonstration were performed in group B. All young physicians have a 1-month study. After training, all the physicians in groups A and B would conduct a questionnaire survey according to the training situation, which was compared between the 2 groups. The success rate of the operation was also evaluated and compared.The median scores in the 5 dimensions of postoperative assessment of group A was 9/9/9/8/8, and of group B was 6/7/6/7/7. The scores of the 5 dimensions were significantly higher than those of group B (P < .05), indicating that group A has a better grasp of the simulator. After the training of simulated mandibular implants in group A, the deviations in the 4 dimensions of mesiodistal, buccal and tongue, depth, and angle were significantly lower than those of group B (P < .05). Group A has smaller deviations in each of the 4 dimensions than those in group B, indicating group A has a higher operation success rate.We independently develop a set of virtual surgery system for dental implant training, which can be used for teaching and training, with good operability and predictability, to achieve a breakthrough in dental implant surgery training.

Decreased BIM expression in BCL2-negative follicular lymphoma: a potential mechanism for resistance to apoptosis.

Follicular lymphoma (FL) is characterized by t(14; 18)(q32; q21), leading to overexpression of the antiapoptotic molecule BCL2; however, a subset of FLs lack BCL2 rearrangement and BCL2 expression as analyzed by immunohistochemistry (IHC). In this study, we evaluated expression of antiapoptotic (MCL1 and BCL-XL) and proapoptotic proteins (BIM) by IHC in both BCL2(-) and BCL2(+) FLs. FLs diagnosed between 2009 and 2019 were reviewed to identify BCL2(-) cases by IHC (assessed by clone 124). Immunohistochemical analyses for BCL2 (EP36), MCL1, BIM, BCL-XL, and Ki-67 were performed on tissue microarrays or whole slides. BCL2 (EP36) was interpreted as positive (≥10%) or negative (<10%). Ki-67 was interpreted on tumor cells in 10% increments. The remaining immunohistochemical analysis results were scored on tumor cells in 10% increments, and intensity was interpreted as weak, moderate, or strong to derive an H-score. Twenty-four BCL2(-) FLs were initially identified, but on further testing with BCL2(EP36) immunohistochemical staining, 5 of 24 were reclassified as BCL2(+), leaving 19 BCL2(-) FLs. Thirty-three BCL2(+) FLs were selected with sufficient tissue for additional immunohistochemical analyses. There was no significant difference in expression of antiapoptotic BCL-XL or MCL1 between BCL2(-) and BCL2(+) FLs (p = 0.75 and 0.28, respectively). However, proapoptotic BIM expression was significantly lower in BCL2(-) FLs than in BCL2(+) FLs (p = 0.002). In our study, 21% of putative BCL2(-) FLs were BCL2(+) when tested with alternative clones, supporting the practice of having more than one BCL2 clone in immunohistochemical laboratories. Decreased BIM expression in BCL2(-) FLs could have an overall antiapoptotic effect and represent an alternate mechanism for cell survival in BCL2(-) FLs.

Inhibition of cyclin-dependent kinase 9 synergistically enhances venetoclax activity in mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an aggressive and largely incurable subtype of non-Hodgkin's lymphoma. Venetoclax has demonstrated efficacy in MCL patients with relapsed or refractory disease, however response is variable and less durable than CLL. This may be the result of co-expression of other anti-apoptotic proteins such as MCL-1, which is associated with both intrinsic and acquired resistance to venetoclax in B-cell malignancies. One strategy for neutralizing MCL-1 and other short-lived survival factors is to inhibit CDK9, which plays a key role in transcription. Here, we report the response of MCL cell lines and primary patient samples to the combination of venetoclax and novel CDK9 inhibitors. Primary samples represented de novo patients and relapsed disease, including relapse after ibrutinib failure. Despite the diverse responses to each single agent, possibly due to variable expression of the BCL-2 family members, venetoclax plus CDK9 inhibitors synergistically induced apoptosis in MCL cells. The synergistic effect was also confirmed via venetoclax plus a direct MCL-1 inhibitor. Murine xenograft studies demonstrated potent in vivo efficacy of venetoclax plus CDK9 inhibitor that was superior to each agent alone. Together, this study supports clinical investigation of this combination in MCL, including in patients who have progressed on ibrutinib.

A Multi-Wall Sn/SnO2 @Carbon Hollow Nanofiber Anode Material for High-Rate and Long-Life Lithium-Ion Batteries.

Multi-wall Sn/SnO2 @carbon hollow nanofibers evolved from SnO2 nanofibers are designed and programable synthesized by electrospinning, polypyrrole coating, and annealing reduction. The synthesized hollow nanofibers have a special wire-in-double-wall-tube structure with larger specific surface area and abundant inner spaces, which can provide effective contacting area of electrolyte with electrode materials and more active sites for redox reaction. It shows excellent cycling stability by virtue of effectively alleviating pulverization of tin-based electrode materials caused by volume expansion. Even after 2000 cycles, the wire-in-double-wall-tube Sn/SnO2 @carbon nanofibers exhibit a high specific capacity of 986.3 mAh g-1 (1 A g-1 ) and still maintains 508.2 mAh g-1 at high current density of 5 A g-1 . This outstanding electrochemical performance suggests the multi-wall Sn/SnO2 @ carbon hollow nanofibers are great promising for high performance energy storage systems.

A novel CDK9 inhibitor increases the efficacy of venetoclax (ABT-199) in multiple models of hematologic malignancies.

MCL-1 is one of the most frequently amplified genes in cancer, facilitating tumor initiation and maintenance and enabling resistance to anti-tumorigenic agents including the BCL-2 selective inhibitor venetoclax. The expression of MCL-1 is maintained via P-TEFb-mediated transcription, where the kinase CDK9 is a critical component. Consequently, we developed a series of potent small-molecule inhibitors of CDK9, exemplified by the orally active A-1592668, with CDK selectivity profiles that are distinct from related molecules that have been extensively studied clinically. Short-term treatment with A-1592668 rapidly downregulates RNA pol-II (Ser 2) phosphorylation resulting in the loss of MCL-1 protein and apoptosis in MCL-1-dependent hematologic tumor cell lines. This cell death could be attenuated by either inhibiting caspases or overexpressing BCL-2 protein. Synergistic cell killing was also observed between A-1592668 or the related analog A-1467729, and venetoclax in a number of hematologic cell lines and primary NHL patient samples. Importantly, the CDK9 inhibitor plus venetoclax combination was well tolerated in vivo and demonstrated efficacy superior to either agent alone in mouse models of lymphoma and AML. These data indicate that CDK9 inhibitors could be highly efficacious in tumors that depend on MCL-1 for survival or when used in combination with venetoclax in malignancies dependent on MCL-1 and BCL-2.