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ABSTRACTDefective mitophagy is consistently found in postmortem brain and iPSC-derived neurons from Alzheimer disease (AD) patients. However, there is a lack of extensive examination of mitophagy status in serum or cerebrospinal fluid (CSF), and the clinical potential of mitophagy biomarkers has not been tested. We quantified biomarkers of mitophagy/autophagy and lysosomal degradation (PINK1, BNIP3L and TFEB) in CSF and serum from 246 individuals, covering mild cognitive impairment due to AD (MCI-AD, n = 100), dementia due to AD (AD-dementia, n = 100), and cognitively unimpaired individuals (CU, n = 46), recruited from the Czech Brain Aging Study. Cognitive function and brain atrophy were also assessed. Our data show that serum and CSF PINK1 and serum BNIP3L were higher, and serum TFEB was lower in individuals with AD than in corresponding CU individuals. Additionally, the magnitude of mitophagy impairment correlated with the severity of clinical indicators in AD patients. Specifically, levels of PINK1 positively correlated with phosphorylated (p)-MAPT/tau (181), total (t)-MAPT/tau, NEFL (neurofilament light chain), and NRGN (neurogranin) levels in CSF and negatively with memory, executive function, and language domain. Serum TFEB levels negatively correlated with NEFL and positively with executive function and language. This study reveals mitophagy impairment reflected in biofluid biomarkers of individuals with AD and associated with more advanced AD pathology.Abbreviation:Aβ: amyloid beta; AD: Alzheimer disease; AVs: autophagic vacuoles; BNIP3L: BCL2 interacting protein 3 like; CU: cognitively unimpaired; CSF: cerebrospinal fluid; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCI: mild cognitive impairment; NRGN: neurogranin; NEFL: neurofilament light chain; p-MAPT/tau: phosphorylated microtubule associated protein tau; PINK1: PTEN induced kinase 1; t-MAPT/tau: total microtubule associated protein tau; TFEB: transcription factor EB; TMT: Trail Making Test.

The synthesis, structures, and reactivity of the first unsaturated AlSi2three-membered ring systems were described. Reactions of dilithiodisilene [(NHB)LiSi═SiLi(NHB)] (1, NHB = diazaborolyl) with aluminum halides AlCl3, Ar(SiMe3)NAlCl2(Ar = 2,6-iPr2C6H3), Cp*AlBr2(Cp* = C5Me5), and TipAlBr2·Et2O (Tip = 2,4,6-iPr3C6H2) led to the formation of AlSi2three-membered ring species, solvated (NHBSi)2AlCl(OEt2) (2) and solvent-free (NHBSi)2AlN(SiMe3) Ar (3), (NHBSi)2AlCp* (4), and (NHBSi)2AlTip (5), in good yields. X-ray diffraction studies and DFT calculations disclosed delocalized AlSi22π electron systems. Methanolysis of 4aresulted in cleavage of the Al–Si σ and Si–Si π bonds, giving trihydrodisilane (NHB)H(MeO)SiSiH2(NHB) (6). Reaction of 4bwith 4 equiv of N2O and H2C═CH2resulted in the insertion of four oxygen atoms and four H2C═CH2π bonds into all of the Al–Si and Si–Si bonds, yielding the O- and CH2CH2-bridged polycyclic species 7and 8, demonstrating the synergistic reactivity of the Al–Si and Si–Si bonds in the AlSi2ring system.

•Off-the-shelf FLT3 CAR_sIL-15 NK cells secrete IL-15, preferentially lyse human FLT3+AML, and activate T cells.•FLT3 CAR_sIL-15 NK cells expressing soluble IL-15 prolong survival of FLT3+AML–bearing mice without toxicity to normal hematopoiesis.

The synthesis, structures, and reactivity of the first neutral 2π-aromatic Si4rings [LSiSiAr(X)]2(3: X = Br; 4: X = Cl; L = PhC(NtBu)2, Ar = 2,4,6-Me3C6H2) were described. Compounds 3and 4were obtained by 1,3-halogenation of tetrasilacyclobutadiene (LSiSiAr)2(2), which was prepared by the reductive cross-coupling of trisilane (ArSiCl2)2SiHAr with two equiv of chlorosilylene LSiCl. The reaction of 3with two equiv of PhLi yielded the corresponding substitution Si4ring [LSiSiAr(Ph)]2(5). Single-crystal X-ray diffraction analysis of 3disclosed that it adopts both puckered (3a) and planar (3b) structures in the solid state, whereas 4and 5exhibit only a puckered structure. DFT calculations suggested that the puckered 3afeatures almost the same electronic structure with fully delocalized 2π planar 3b. The dominant 2π-aromaticity of 3in a σ-frame has been demonstrated by DFT calculations, providing the first example of aromatics featuring both planar and puckered structures.

Despite tumor-associated macrophages (TAMs) playing a key role in shaping the tumor microenvironment (TME), the mechanisms by which TAMs influence the TME and contribute to cancer progression remain unclear. Here, we show that the N6-methyladenosine reader YTHDF2 regulates the antitumor functions of TAMs. YTHDF2 deficiency in TAMs suppressed tumor growth by reprogramming TAMs toward an antitumoral phenotype and increasing their antigen cross-presentation ability, which in turn enhanced CD8+T cell-mediated antitumor immunity. YTHDF2 deficiency facilitated the reprogramming of TAMs by targeting interferon-γ−STAT1 signaling. The expression of YTHDF2 in TAMs was regulated by interleukin-10−STAT3 signaling. Selectively targeting YTHDF2 in TAMs using a Toll-like receptor 9 agonist-conjugated small interfering RNA reprogrammed TAMs toward an antitumoral phenotype, restrained tumor growth and enhanced the efficacy of PD-L1 antibody therapy. Collectively, our findings describe the role of YTHDF2 in orchestrating TAMs and suggest that YTHDF2 inhibition is an effective approach to enhance cancer immunotherapy.

The immune pathways that define treatment response and non-response in lupus nephritis (LN) are unknown. To characterize these intra-kidney pathways, transcriptomic analysis was done on protocol kidney biopsies obtained at flare (initial biopsy (Bx1)) and after treatment (second biopsy (Bx2)) in 58 patients with LN. Glomeruli and tubulointerstitial compartments were isolated using laser microdissection. RNA was extracted and analyzed by nanostring technology with transcript expression from clinically complete responders, partial responders and non-responders compared at Bx1 and Bx2 and to the healthy controls. Top transcripts that differentiate clinically complete responders from non-responders were validated at the protein level by confocal microscopy and urine ELISA. At Bx1, cluster analysis determined that glomerular integrin, neutrophil, chemokines/cytokines and tubulointerstitial chemokines, T cell and leukocyte adhesion genes were able to differentiate non-responders from clinically complete responders. At Bx2, glomerular monocyte, extracellular matrix, and interferon, and tubulointerstitial interferon, complement, and T cell transcripts differentiated non-responders from clinically complete responders. Protein analysis identified several protein products of overexpressed glomerular and tubulointerstitial transcripts at LN flare, recapitulating top transcript findings. Urine complement component 5a and fibronectin-1 protein levels reflected complement and fibronectin expression at flare and after treatment. Thus, transcript analysis of serial LN kidney biopsies demonstrated how gene expression in the kidney changes with clinically successful and unsuccessful therapy. Hence, these insights into the molecular landscape of response and non-response may help align LN management with the pathogenesis of kidney injury.

Type I innate lymphoid cells (ILC1s) are critical regulators of inflammation and immunity in mammalian tissues. However, their function in cancer is mostly undefined. Here, we show that a high density of ILC1s induces leukemia stem cell (LSC) apoptosis in mice. At a lower density, ILC1s prevent LSCs from differentiating into leukemia progenitors and promote their differentiation into non-leukemic cells, thus blocking the production of terminal myeloid blasts. All of these effects, which require ILC1s to produce interferon-γ after cell–cell contact with LSCs, converge to suppress leukemogenesis in vivo. Conversely, the antileukemia potential of ILC1s wanes when JAK–STAT or PI3K–AKT signaling is inhibited. The relevant antileukemic properties of ILC1s are also functional in healthy individuals and impaired in individuals with acute myeloid leukemia (AML). Collectively, these findings identify ILC1s as anticancer immune cells that might be suitable for AML immunotherapy and provide a potential strategy to treat AML and prevent relapse of the disease.

Due to the limitations of autologous chimeric antigen receptor (CAR)-T cells, alternative sources of cellular immunotherapy, including CAR macrophages, are emerging for solid tumors. Human induced pluripotent stem cells (iPSCs) offer an unlimited source for immune cell generation. Here, we develop human iPSC-derived CAR macrophages targeting prostate stem cell antigen (PSCA) (CAR-iMacs), which express membrane-bound interleukin (IL)-15 and truncated epidermal growth factor receptor (EGFR) for immune cell activation and a suicide switch, respectively. These allogeneic CAR-iMacs exhibit strong antitumor activity against human pancreatic solid tumors in vitroand in vivo, leading to reduced tumor burden and improved survival in a pancreatic cancer mouse model. CAR-iMacs appear safe and do not exhibit signs of cytokine release syndrome or other in vivotoxicities. We optimized the cryopreservation of CAR-iMac progenitors that remain functional upon thawing, providing an off-the-shelf, allogeneic cell product that can be developed into CAR-iMacs. Overall, our preclinical data strongly support the potential clinical translation of this human iPSC-derived platform for solid tumors, including pancreatic cancer.

The N-heterocyclic germylenes and stannylenes LSi(NAr)2EX (L = PhC(NtBu)2, Ar = 2,6-iPr2C6H3; E = Ge, Sn; X = Cl, CF3SO3, BPh4) supported by the bulky silaamidinate ligand [LSi(NAr)2]−have been synthesized and fully characterized. The germylene triflate LSi(NAr)2GeOTf (3b) and dimeric borate [LSi(NAr)2Ge]2ClBPh4(3a) enabled highly regio- and chemoselective catalytic hydroboration of pyridines and may represent the most active catalytic system for the transformation. DFT calculations disclosed that the cationic germylene [LSi(NAr)2Ge]+with a low-lying LUMO energy initiated the catalytic process. In contrast, the analogous amidinate germylene triflates are almost inactive, indicating the silaamidinate ligand is essential for the stabilization of cationic species.

The first examples of cyclic (alkyl)(amino)carbene (CAAC) lanthanide (Ln) complexes were synthesized from the reaction of CAAC with Yb[N(SiMe3)2]2and Eu[N(SiMe3)2]2(THF)2(THF = tetrahydrofuran). The structures of (CAAC)Yb[N(SiMe3)2]2(2) and (CAAC)Eu[N(SiMe3)2]2(THF) (3) were determined by X-ray diffraction analysis. Density functional theory calculations of 2revealed the predominantly ionic bond between the Ln ion and CAAC. Complex 3enabled catalytic hydrosilylation of aryl- and silylalkenes with primary and secondary silanes in high yields and Markovnikov selectivity.

The reactions of NHB-stabilized disilyne (NHB)Si≡Si(NHB) (1, NHB = [ArN(CMe)2NAr]B, Ar = 2,6-iPr2C6H3) with internal alkynes were described. Reaction of disilyne 1with one equivalent of bis(trimethylsilyl)acetylene led to a reversible [1 + 2] cycloaddition of one of the Si atoms with the alkyne and the insertion of the other Si into one of Ar rings with the formation of a silirenyl–silepin 2, whereas reaction of 1with two equivalents of Me3SiCCSiMe3resulted in the formal addition of the Csp–Si bond to the Si≡Si triple bond to give disilene (NHB)(Me3Si)Si=Si(CCSiMe3)(NHB). Reaction of 1with 1,3-diyne Me3SiCCCCSiMe3yielded a 1,2-disilacyclobut-3-ene via cycloaddition, ring expansion, and NHB 1,2-shift sequence. The initial [1 + 2] cycloaddition of one of the silicon atoms with an alkyne was strongly supported by DFT calculations. The results demonstrated the significant bis(silylene) character and rich synthetic potential of bis(boryl) disilyne 1.

The well-defined NHC-copper phosphides [(NHC)CuPPh2]3(1, NHC = 1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene (IiPr); 2, NHC = N,N-di-tert-butylimidazol-2-ylidene (ItBu)) have been prepared by the reaction of simple copper halides with HPPh2in the presence of N-heterocyclic carbenes (NHCs). Complexes 1and 2enabled catalytic double hydrophosphination of alkyl and aryl terminal alkynes to yield 1,2-diphosphinoethanes selectively in good yields. On the basis of these results, the most efficient and pratical in situ CuCl2/NHC catalyst has been developed. It catalyzes the selective double hydrophosphination of the alkynes with high efficiency and a wide substrate scope and exhibits even better performance than the well-defined NHC-Cu phosphides. The mechanistic studies disclosed that the formation of a copper acetylide in the catalytic cycle played an important role in the acceleration of the catalytic process.

Employing fluorinated solid-state polymer electrolytes (SPEs) has emerged as a promising strategy to form stable solid-electrolyte interphase (SEI) on Li metal, which can regulate the behavior of Li deposition during cycling. However, in-situ polymerization of excessively fluorinated monomers suffers from weak polymerization kinetics and a low degree of polymerization. Herein, a partially fluorinated SPEs with meltblown cloth reinforcement was proposed and synthesized via UV-curing. The partially fluorinated meltblown cloth reinforced SPE (PFMC-SPE) showed significantly improved performances due to the enhanced mechanical properties from meltblown cloth and optimized electrochemical performances from the partial fluorination strategy. The PFMC-SPE possesses both a superior room temperature ionic conductivity (1.0 mS cm−1) and a wide electrochemical stability window (up to 5 V). Furthermore, the Li//LiFePO4cell can stably work for more than 750 cycles at 1.0 C rate with a capacities retention of 84.7% from 141.2 mAh g−1to 119.6 mAh g−1at 30 °C. Both employing the reliable and inexpensive meltblown cloth based separators for solid-state electrolytes and the partial fluorination strategy is very promising in developing next-generation ultrastable solid-state lithium batteries.

Flexible Zinc-Air batteries (FZABs) have been extensively investigated by researchers due to their exceptional safety and high energy density. The sandwich structure employed in FZABs imposes stringent demands on the electrolyte, necessitating good electrical conductivity and alkali resistance. In this paper, a carboxylation@Lignocellulose-based hydrogel polymer electrolyte with high ionic conductivity and excellent alkali resistance has designed and applied in FZABs. The carboxylation@lignocellulose is dissolved in a sodium hydroxide/urea/water system, followed by the incorporation of acrylamide monomers into the lignocellulose solution to prepare the hydrogel polymer electrolyte. The results combined suggest that the solid electrolyte exhibits improved ion conductivity, liquid absorption capability, and alkali resistance. Therefore, it has been confirmed that carboxyl functional groups have a positive effect on the performance of solid electrolytes. These characteristics enable the lignocellulose-based hydrogel polymer electrolyte FZAB to have an open-circuit voltage (1.34 V), a peak power density (141.55 mW cm−2), and a cycle lifetime to 65 h (555 cycles). Compared to FZABs based polyacrylamide-KOH hydrogel polymer electrolyte-based, FZABs utilizing lignocellulose-based hydrogel polymer electrolyte prepared in this paper demonstrate excellent performance.

Hepatocellular carcinoma (HCC) is the most common subtype of primary liver cancer and one of the leading causes of cancer-related death worldwide. To gain more insights into the transcriptomic landscape and molecular mechanism of HCC, we performed TMT-labelled tandem mass spectrometry (n= 4) and whole-transcriptome sequencing (n= 3) based on HCC tumour (T) and adjacent normal (N) tissues from seven HCC patients. To comprehensively evaluate the gene-regulatory circuits in HCC, differential expression and enrichment analyses were performed on the differentially expressed proteins (DEPs), genes (DEGs), miRNAs (555), lncRNAs (29) and circRNAs (895). A total of 977 proteins and 243 genes were found to be differentially expressed in HCC tumours compared with adjacent normal tissues. HCC data from The Cancer Genome Atlas were used to validate the results. Combined with the results above, 56 DEP-DEGs with common changes in relative quantity were identified. Functional pathway analysis showed that the DEP-DEGs were mainly enriched in the spliceosome and various metabolic processes. Bioinformatics analysis showed that hsa-miR-1266-5p, hsa-miR-128-1-5p, hsa-miR-139-5p, hsa-miR-34b-3p and hsa-miR-570-3p were involved in the regulation of the hub genes mentioned above. The crucial coexpression (lncRNA–mRNA, circRNA–mRNA) and competing endogenous RNA interaction axes showed the possible functions of the lncRNAs and circRNAs. We explored potential cancer biomarkers by combining proteomic and transcriptomic studies. Our study provides a valuable resource for understanding regulatory mechanisms at the RNA level and may ultimately further assist in the development of diagnostic and/or therapeutic targets for HCC.

Reduction of (boryl)dibromosilane (boryl)SiHBr2(1; boryl = B(NArCH)2, Ar = 2,6-iPr2C6H3) with 2 equiv of potassium graphite in DME at low temperature led to the isolation of bis(boryl)disilane (boryl)SiH2SiH2(boryl) (3) as a colorless solid, whereas reduction of (boryl)SiPhBr2(2) in THF gave the boryl-substituted disilene (boryl)PhSi═SiPh(boryl) (4) as a yellow solid. The reaction of 1with 1,3-diisopropyl-4,5-dimethylimidazol-2-ylidene (IiPr) unexpectedly led to the formation of the cationic species [(boryl)SiHBr(IiPr)]+Br–(6). These products were characterized by spectroscopic methods as well as by X-ray single-crystal analysis.

Background: Tendinopathy is a debilitating tendon disorder that affects millions of Americans and costs billions of health care dollars every year. High mobility group box 1 (HMGB1), a known tissue damage signaling molecule, has been identified as a mediator in the development of tendinopathy due to mechanical overloading of tendons in mice. Metformin (Met), a drug approved by the Food and Drug Administration used for the treatment of type 2 diabetes, specifically inhibits HMGB1. This study tested the hypothesis that Met would prevent mechanical overloading-induced tendinopathy in a mouse model of tendinopathy created by intensive treadmill running (ITR).Methods: C57BL/6J mice (female, 3 months old) were equally separated into 4 groups and treated for 24 weeks as follows: group 1 had cage control activities, group 2 received a single intraperitoneal injection of Met (50 mg/kg body weight) daily, group 3 underwent ITR to induce tendinopathy, and group 4 received daily Met injection along with ITR to inhibit HMGB1. Tendinopathic changes were assessed in Achilles tendons of all mice using histology, immunohistochemistry, and enzyme-linked immunosorbent assays.Results: ITR induced HMGB1 release into the tendon matrix and developed characteristics of tendinopathy as evidenced by the expression of macrophage marker CD68, proinflammatory molecules (COX-2, PGE2), cell morphological changes from normal elongated cells to round cells, high levels of expression of chondrogenic markers (SOX-9, collagen type II), and accumulation of proteoglycans in tendinopathic tendons. Daily injection of Met inhibited HMGB1 release and decreased these degenerative changes in ITR tendons.Conclusions: Inhibition of HMGB1 by injections of Met prevented tendinopathy development due to mechanical overloading in the Achilles tendon in mice.Clinical Relevance: Met may be able to be repurposed as a therapeutic option for preventing the development of tendinopathy in high-risk patients.

Herein we report the first synthesis of a 1-magnesium-2,3-disilacyclopropene and a related bis(disilenide). Reduction of (boryl)tribromosilane (1, boryl = (HCArN)2B, Ar = 2,6-iPr2C6H3) with magnesium in THF afforded boryl-substituted magnesium complex [(boryl)Si]2Mg(THF)3(2) in good yield, whereas reduction of (boryl)trichlorosilane (3) with KC8in THF led to the isolation of bridged alkoxy alkyl bis(disilenide) (THF)K(boryl)Si═Si(boryl)O(CH2)4(boryl)Si═Si(boryl)K(THF) (4) via ring opening of a THF molecule. X-ray diffraction analysis of 2confirmed the presence of the novel Si2Mg three-membered ring as well as the Si═Si double bond, which existed in a noticeably twisted B–Si–Si–B array. Complex 2also represents the first reported example of a stable disilyne dianion.

Background: This study compares the impact of open (OIHR) versus laparoscopic (LIHR) inguinal hernia repair on healthcare spending and postoperative outcomes. Methods: The TRUVEN database was queried using ICD9 procedure codes for open, laparoscopic, and robotic-assisted IHR, from 2012 to 2013. Patients > 18 years of age and continuously enrolled for 12 months postoperatively were included. Demographics, patient comorbidities, postoperative complications, pain medication use, length of hospital stay, missed work hours, postoperative visits, and overall expenditure were collected, and assessed at time of surgery and at 30-, 60-, 90-, 180-, and 365-days postoperatively. Statistical analysis was conducted using SAS, with α= 0.05. Results: 66,116 patients were included (LIHR: N = 23,010; OIHR: N = 43,106). Robotic-assisted procedures were excluded due to small sample size (N= 61). The largest demographic was males between 55 and 64 years. LIHR had fewer surgical wound complications than OIHR (LIHR: 0.3%; OIHR: 0.5%, p = 0.007), less utilization of pain medication (LIHR: 23.3%; OIHR: 28.5%; p < 0.001), and fewer outpatient visits. In the 90-day postoperative period, LIHR had significantly fewer missed work hours (LIHR: 12.1 ± 23.2 h; OIHR: 12.9 ± 26.7 h, p = 0.023). LIHR had higher postoperative urinary complications (LIHR: 0.2%; OIHR: 0.1%; p < 0.001), consistent with the current literature. LIHR expenditures ($15,030 ± $25,906) were higher than OIHR ($13,303 ± 32,014), p < 0.001. Conclusions: The results highlight the benefits of laparoscopic repair with regard to surgical wound complications, postoperative pain, outpatient visits, and missed work hours. These improved outcomes with respect to overall healthcare spending and employee absenteeism support the paradigm shift toward laparoscopic inguinal hernia repairs, in spite of higher overall expenditures.

A series of novel bis-BN-naphthalene-fused oxepin derivatives were synthesized via a Pd-catalyzed tandem reaction from brominated 2,1-borazaronaphthalenes and cis-bis(boryl)alkenes. X-ray crystallographic analysis revealed that bis-BN-naphthalene-fused oxepins feature a planar framework. The electronic and photophysical properties of the novel BN-naphthalene-fused oxepins were investigated by UV–vis and fluorescence spectroscopies and density functional theory (DFT) calculations, which disclosed the distinct electronic and photophysical properties of the analogous hydrocarbon system. Interestingly, dual-fluorescent emissions were observed upon dissolving N-substituted derivatives 10–14in dimethyl sulfoxide. Tunable emission colors especially for white-light emissions can be achieved by controlling the ratio of solvents, concentration, or temperature using only a single-molecule compound.

ABSTRACTCanine parvovirus (CPV) has been used in cancer control as a drug delivery vehicle or anti-tumor reagent due to its multiple natural advantages. However, potential host cell cycle arrest induced by virus infection may impose a big challenge to CPV associated cancer control as it could prevent host cancer cells from undergoing cell lysis and foster them regain viability once the virotherapy was ceased. To explore CPV-induced cell cycle arrest and the underlying mechanism toward improved virotherapeutic design, we focus on epidermal growth factor receptor (EGFR), a cellular receptor interacting with TfR that mediates CPV-host interactions, and alterations on its tyrosine phosphorylation sites in response to CPV infection. We found that CPV could trigger host G1/S cell cycle arrest via the EGFR (Y1086)/p27 and EGFR (Y1068)/STAT3/cyclin D1 axes, and EGFR inhibitor could not reverse this process. Our results contribute to our understandings on the mechanism of CPV-induced host cellular response and can be used in the onco-therapeutic design utilizing CPV by preventing host cancer cells from entering cell cycle arrest.

ABSTRACTWith the high pervasiveness of viral diseases, the battle against viruses has never ceased. Here we discuss five cellular processes, namely “autophagy”, “programmed cell death”, “immune response”, “cell cycle alteration”, and “lipid metabolic reprogramming”, that considerably guide viral replication after host infection in an orchestrated manner. On viral infection, “autophagy” and “programmed cell death” are two dynamically synchronized cell survival programs; “immune response” is a cell defense program typically suppressed by viruses; “cell cycle alteration” and “lipid metabolic reprogramming” are two altered cell housekeeping programs tunable in both directions. We emphasize on their functionalities in modulating viral replication, strategies viruses have evolved to tune these processes for their benefit, and how these processes orchestrate and govern cell fate upon viral infection. Understanding how viruses hijack host networks has both academic and industrial values in providing insights toward therapeutic strategy design for viral disease control, offering useful information in applications that aim to use viral vectors to improve human health such as gene therapy, and providing guidelines to maximize viral particle yield for improved vaccine production at a reduced cost.

Moyamoya disease belongs to rare diseases which are arousing public awareness of its importance in China. In order to investigate the clinical features of inpatients diagnosed Moyamoya disease, the study was conducted to collect clinical information data of subjects on demographic information and clinical characteristics in Henan, China.

Herein, we describe the first synthesis of anionic silaketenimines and the coupling product with an isocyanide. Treatment of boryl silanorcaradienyllithium [CH2(L)N]2BSiLi (where L = B[N(Ar)CH]2and Ar = 2,6-iPr2C6H3) with isocyanides afforded silaketenimine anions [CH2(R)N]2BSi(Li)═C═NR featuring a Si═C═N allenic structure. X-ray diffraction studies and density functional theory calculations strongly support the presence of an anionic silicon atom and a strong π bond between the silicon and carbon atoms. One of the silaketenimine anions underwent a formal [2 + 2] cycloaddition reaction with a second molecule of isocyanide to give a novel silacyclopropyl anion with a delocalized anionic skeleton. These reactions demonstrated that the bonding nature of the boryl lithiosilylene was distinct from that of common silylenes.

The combination of venetoclax with hypomethylating agents (VEN-HMAs) showed promising activity in newly diagnosed and relapsed/refractory (r/r) acute myeloid leukemia (AML). Treatment with VEN-HMAs results in prolonged cytopenia, thereby exposing patients to invasive fungal infections (IFIs). Here, we retrospectively studied a cohort of 119 AML patients treated with VEN-HMAs and analyzed the occurrence of IFIs, as well as our practice of antifungal prophylaxis, with the aim to identify the nature and risk factors for IFIs and their association with the type of antifungal prophylaxis used. The intended antifungal prophylaxis was micafungin in 38% of patients, azoles in 41% of patients, and none in 21% of patients. Older age was associated with no antifungal prophylaxis or micafungin use and lesser use of azoles (P = .043). We recorded 15 (12.6%) patients who developed probable or proven IFIs, with a median onset of 72 days (range, 35-281) after starting therapy. IFIs were more common among nonresponders compared with responders to VEN-HMA therapy (22% vs 6%, P = .0132) and in r/r compared with newly diagnosed AML (19% vs 5%, P = .0498); however, the antifungal prophylaxis used, patient age, hypomethylating agent schedule, history of prior allogeneic transplant, and initial neutropenia duration did not influence the development of IFIs during therapy. We conclude that the overall risk of IFIs during VEN-HMA therapy is low. The risk of IFIs is higher in nonresponders and in those who were treated in the r/r setting; these patients need reevaluation of their antifungal prophylaxis to minimize the risk of IFIs during therapy.

Background: Aberrant overexpression of pro-survival Bcl-2 family proteins is one mechanism by which leukemic cells circumvent apoptosis. BCL-2 overexpression is common in various subtypes of B-acute lymphocytic leukemia (ALL), including Philadelphia (Ph)-like ALL. Ph-like ALL is a chemotherapy-resistant disease associated with higher rates of induction failure and persistent measurable residual disease (MRD), and poor overall survival (OS) outcomes with frontline chemotherapy regimens, compared to other subtypes. Venetoclax (VEN) is a selective BCL2 inhibitor, and its addition to pediatric-type frontline regimens could improve response and long-term outcomes for B-ALL, including Ph-like subtype.

Background:Mutations in FLT3 (FLT3m), either internal tandem duplication (ITD) or tyrosine kinase domain (TKD) are found in approximately 25% of AML patients. The current standard of care for eligible patients is induction chemotherapy with 7 + 3 regimen with the addition of multikinase inhibitor midostaurin, based on CALGB 10603 which enrolled patients up to 59 years of age (Stone et al; NEJM 2017). Quizartinib recently demonstrated improved overall survival (OS) compared to placebo when combined with standard 7+3 induction in patients up to 75 years of age, although the benefit in patients 60 and above was less clear (Erba et al; Lancet Oncol 2023). We sought to review the clinical outcomes among patients 60 years of age or greater at our institution for who received midostaurin with 7+3 for newly diagnosed (ND) FLT3m AML.

Background

Acute myeloid leukemia (AML) is a devastating disease with a median 5-year survival of only 40-45% for patients younger than age 65 who are treated with standard chemotherapy. Although in some cases allogeneic stem cell transplantation has proven to be curative, the treatment-related mortality and the risk for disease relapse due to persistence of leukemia stem cells (LSCs) remains relatively high. Therefore, safer and more effective novel therapeutic approaches are needed to improve the clinical outcomes of patients with AML. Innate lymphoid cell (ILC) is critical in mediating immune responses and regulating tissue homeostasis and inflammation. We recently reported that mouse ILC1s contribute to the control of AML by eliminating LSCs and inhibiting their differentiation into myeloid blasts, and functional impairment of mouse ILC1s in AML leads to the outgrowth of LSCs and disease relapse (Li et al., Nature Immunology. 2022). However, the full role and mechanistic characterization of humanILC1s in anti-tumor responses to AML remains to be fully explored.

There are known constitutional mutations associated with bone marrow failure and progression to malignancy, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). For the majority of the defects associated with clonal hematopoiesis and progression to MDS/AML, there are no specific treatments. We sought to determine if messenger RNA (mRNA) transfer can restore expression of the normal proteins, modulate abnormal proliferation and differentiation, and enhance response to chemotherapy and targeted agents.

Innate lymphoid cells (ILCs) are tissue-resident innate immune cells that respond rapidly to infection and secrete inflammatory mediators. Group 1 includes ILC1s and NK cells. Both cell types produce IFN-γ and require T-BET for their function; however, at least in mice, ILC1s do not express EOMES while NK cells do. The NKp46 receptor, encoded by the Ncr1gene, plays an important role in NK cells. Non-NK immune cells, including ILC1s also express NKp46. However, the role of NKp46 in these non-NK immune cells remains largely unknown. We previously reported that NKp46 deficiency reduces both the percentages and numbers of ILC1s in mice but not the proportions of NK cells, ILC2s, and ILC3s (Wang et al., Plos Biology, 2018), suggesting that NKp46 may play a unique role in ILC1s. However, the precise mechanism by which NKp46 regulates ILC1s is yet to be determined.

Reaction of the bulky N-heterocyclic silylene Si[NB(NArCH)2CH2]2(3; Ar = 2,6-iPr2C6H3) with BCl3resulted in ring expansion with formation of the six-membered C2N2SiB heterocycle 4. Reduction of 4with lithium afforded the first silanorcaradienyllithium 5, which presumably formed by intramolecular cyclopropanation of a lithium-substituted borylsilylene intermediate with one of the aryl C═C bonds. Treatment of 5with MeOTf and Et3NHCl led to electrophilic substitution accompanied by the SiC2ring expansion to give silacycloheptatrienes (silepins) 6and 7, respectively. The addition of 1,3,4,5-tetramethylimidazol-2-ylidene (NHCMe) to silepin 7yielded the NHC-stabilized hydrosilylene 8with the silicon atom free from the silepin ring. The formation of 5could be attributed to the unique electronic structure of the lithium-substituted silylene, which has been predicted to be in a triplet ground state with a relatively large singlet–triplet energy gap by theoretical calculations.

Opioids are a mainstay for postsurgical pain management, but have associated complications and costs, and contribute to the opioid epidemic. While efforts to reduce opioid use exist, little study has been done on opioid utilization and its impact across surgical approaches. Our goal was to evaluate the impact of opioid utilization on quality measures and costs after open and laparoscopic colorectal surgery. The Premier database was reviewed for inpatient colorectal procedures from January 01, 2014, to September 30, 2015. Procedures were stratified into open and laparoscopic approaches, then “opioid” and “opioid-free” groups within each approach. Univariate analysis compared demographics, outcomes, and cost by opioid use and surgical approach. In the “opioid” groups, opioid consumption and duration were assessed across platforms. Multivariate regression analyzed the association between opioid use and surgical approach on costs and quality outcomes. 50,098 procedures were evaluated—40.4% laparoscopic and 59.6% open. 6.6% of laparoscopic and 5.3% of open cases were “opioid free.” Across both approaches, patients over 65 were most likely opioid free, while the obese and cancer patients were most likely to use opioids. Length of stay was shorter, and post-discharge nursing needs and total costs were lower in the “opioid-free” group in both approaches (all p< 0.001). The median daily and total opioid consumption were lower with a laparoscopic approach (p< 0.001), which also had a shorter duration of use versus open cases (p< 0.001). Opioids were 20% more likely in open cases. Total costs were 16% greater with opioids and 24% greater in open surgery. Complications were 89% more likely in open surgery. Readmissions were increased by 14% with both opioid use and open surgery. Opioid-free colorectal surgery results in improved outcomes, and laparoscopy further improves these results. Continued efforts to increase laparoscopy are key for reducing opioids and improving outcomes as we transition to value-based care.

Interleukin 15 (IL-15) is one of the most important cytokines that regulate the biology of natural killer (NK) cells1. Here we identified a signaling pathway—involving the serine-threonine kinase AKT and the transcription factor XBP1s, which regulates unfolded protein response genes2,3—that was activated in response to IL-15 in human NK cells. IL-15 induced the phosphorylation of AKT, which led to the deubiquitination, increased stability and nuclear accumulation of XBP1s protein. XBP1s bound to and recruited the transcription factor T-BET to the gene encoding granzyme B, leading to increased transcription. XBP1s positively regulated the cytolytic activity of NK cells against leukemia cells and was also required for IL-15-mediated NK cell survival through an anti-apoptotic mechanism. Thus, the newly identified IL-15–AKT–XBP1s signaling pathway contributes to enhanced effector functions and survival of human NK cells.

Abstract

Introduction of the category III CPT code (0437T) for prophylactic mesh augmentation (PMA) highlights efforts to reduce incisional hernia (IH). PMA’s value in the context of value-based care requires understanding both the cost of IH development and the savings from prevention. We hypothesized large healthcare costs with IH development. Appreciating which subsets of patients are at highest risk for IH, and the subsets who have the costliest care is essential in targeting interventions for hernia prevention. Retrospective cohort study utilizing data from Truven Health Analytic MarketScan Commercial Claims and Encounters Database from calendar years 2011–2014. Adults undergoing open abdominal operations with continued enrollment 3-year post-surgery were included. Inpatient and outpatient claims were tracked over 3 years to identify IH. Quantile regression estimated the association between conditional distribution of total cost and IH. A generalized linear model with gamma distribution estimated the association of conditional mean of total cost and IH. Models were adjusted for confounding cost covariates (e.g., age, gender, obesity, smoking, cancer). 14,290 patients were identified, 1294 (9.1%) developed IH, 48% within 1-year, 33% at 1–2 years, and 19% at 2–3 years post-surgery. 515 underwent stoma creation, 4579 colon resection, 2263 liver/kidney, 3890 peritoneal, 3043 other (foregut, appendectomy, cholecystectomy). Rate of IH formation was 25, 13, 5.9, 6.3, and 6.3%, respectively. The difference in median expenditures for IH development versus no IH was ostomies: $26,098, colorectal: $21,211, liver/kidney: $23,811, peritoneal: $25,554, others: $28,870 (p< 0.0.01). IH within 1 year was more expensive than within 3 years in the following categories: colorectal ($16,034, p= 0.0385), liver/kidney ($27,145, p= 0.0004), and ostomy ($18,992, p= 0.0035). IH is a common occurrence imposing significant healthcare burden. Higher costs occur when IH occurs within 1 year versus 3 years from the index-procedure. This highlights the importance of hernia prevention techniques and the question of whether temporizing closure adjuncts  are appropriate in high-risk patients.

Targeted inhibition of oncogenic miRNA-21 has been proposed to treat glioblastoma by rescuing tumor suppressors, PTEN and PDCD4. However, systemic delivery of anti-miR-21 sequences requires a robust and efficient delivery platform to successfully inhibit this druggable target. Three-way-junction (3WJ)-based RNA nanoparticles (RNP), artificially derived from pRNA of bacteriophage phi29 DNA packaging motor, was recently shown to target glioblastoma. Here, we report that multi-valent folate (FA)-conjugated 3WJ RNP constructed to harbor anti-miR-21 LNA sequences (FA-3WJ-LNA-miR21) specifically targeted and delivered anti-miR-21 LNA and knocked down miR-21 expression in glioblastoma cells in vitro and in vivo with favorable biodistribution. Systemically injected FA-3WJ-LNA-miR21 RNP efficiently rescued PTEN and PDCD4, resulting in glioblastoma cell apoptosis and tumor growth regression. Overall survival rate was also significantly improved by FA-3WJ-LNA-miR21 RNP. These results are indicative of the clinical benefit of FA-3WJ RNP-based gene therapy for the successful targeted therapy of developing and even recurring glioblastoma.

To reduce the production cost and improve the performance of new membranes a high permeability porous mullite membrane material was directly synthesized by designing a mesh structure formed from needle-like mullite. The kaolin powder with 65% Al2O3content served as the precursor material for the porous mullite support, the powder doped 5 wt% AlF3with 60% Al2O3content served as the precursor material of the needle like mullite crystal layer. A thin layer of the precursor material of the needle like mullite crystal layer was coated on the support precursor. In the co-sintering preparation of the membrane the free SiO2in the kaolin was consumed by the alumina precursors, AlF3as additive promoted the formation of mullite whiskers, so that a mesh structure was formed in-situ, which imparted suitable permeability and selectivity to the final structure. The growth of mullite whiskers has a positive impact on the improvement of porosity and permeability of ceramic membranes. The water flux of the membrane increased by 1.2–2 times compared to the existing microporous membranes of the similar pore size. The porosity of the samples was greater than 47% between 1250°C and 1400°C as the sintering temperature was increased. This preparation process simplified the preparation of the bilayer membrane, and greatly decreased the cost of raw material and production time and improved the performance of the membrane product. The bilayer membrane developed in this study may be used as a microfiltration membrane, particularly in high-throughput water treatment applications.

The glymphatic system (GS) is a perivascular fluid exchange pathway, that is crucial for maintaining brain homeostasis, and may contribute to ischemic edema. Tissue Kallikrein treatment provides cerebral infarction patients with vasodilatory activity, which may facilitate the kinetics in GS. We hypothesized that Tissue Kallikrein could attenuate early ischemic edema following blood interruption by altering the kinetics of the GS. In this study, we evaluated the effects of Tissue Kallikrein on mice acute ischemic edema in pMCAO mice. A fluorescent tracer was injected into the striatum of mice, and the proportion of area infused by the fluorescent tracer in the brain parenchyma was measured to assess the kinetics of the GS. The effect of Tissue Kallikrein on edema was determined by DWI/T2 mismatch, ischemic edema progression was indicated by a mismatch between diffusion-weighted imaging (DWI) and T2-weighted imaging (T2WI), that is, an acute ischemic lesion on DWI without a corresponding lesion on T2WI. Concurrently, correlation analysis was performed for the kinetics and the time windows of DWI/T2 mismatch. Our results indicated that Tissue Kallikrein attenuated brain edema was associated with improved GS kinetics in mice with pMCAO. In brief, this study shows the neuroprotective effects of Tissue Kallikrein in ischemic edema for the first time in pMCAO mice by boosting the GS kinetics.

The pupal stage of six Blapsspecies occurring in the northwest China are described and illustrated in detail: Blaps kiritshenkoiSemenov and Bogatchev, 1936, B. rugosaGebler, 1825, B. miliariaFischer von Waldheim, 1844, B. gobiensisFrivaldszky, 1889, B. caraboides caraboidesAllard, 1882, and B. femoralisFischer von Waldheim, 1844. A key to the pupae of Blapsis provided.

This study investigated the degradation performance and mechanism of extracellular antibiotic resistance genes (eARGs) by nematodes using batch degradation experiments, mutant strain validation, and phylogenetic tree construction. Caenorhabditis elegans, a representative nematode, effectively degraded approximately 99.999% of eARGs (tetMand kan) in 84 h and completely deactivated them within a few hours. Deoxyribonuclease (DNase) II encoded by nuc-1in the excretory and secretory products of nematodes was the primary mechanism. A neighbor-joining phylogenetic tree indicated the widespread presence of homologs of the NUC-1 protein in other nematodes, such as Caenorhabditis remaneiand Caenorhabditis brenneri, whose capabilities of degrading eARGs were then experimentally confirmed. C. elegansremained effective in degrading eARGs under the effects of natural organic matter (5, 10, and 20 mg/L, 5.26–6.22 log degradation), cation (2.0 mM Mg2+and 2.5 mM Ca2+, 5.02–5.04 log degradation), temperature conditions (1, 20, and 30 °C, 1.21–5.26 log degradation), and in surface water and wastewater samples (4.78 and 3.23 log degradation, respectively). These findings highlight the pervasive but neglected role of nematodes in the natural decay of eARGs and provide novel approaches for antimicrobial resistance mitigation biotechnology by introducing nematodes to wastewater, sludge, and biosolids.

The support for the membrane is the basis for the preparation and application of the zeolite membrane. Moreover, its cost and properties directly determine the performance of the zeolite membrane and its industrial applications. A novel porous silicon carbide (SiC) support for zeolite membrane bonded with needle-like mullite (3Al2O3·2SiO2) was prepared using SiC powders as the raw material and kaolin, Al(OH)3, and AlF3as the needle-like mullite precursor additives via an in situ high-temperature reactions in an air atmosphere. Effects of the support material composition and the sintering temperature on the sintering behavior, pore structure, permeability, and microstructure of the resultant supports were extensively investigated. The needle-like mullite formation consumed silicon oxide (SiO2) and generated a rigid skeleton structure with a good pore structure and bonding phase. Hence, the porous SiC support exhibited high porosity, with relatively large pore size and mechanical strength, which helped improve the support performance. Notably, the porous SiC support sintered at 1480 °C with in situ inter-particle needle-like mullite bonding exhibited excellent filtration and permeability performance. The porous support materials and methods used in this work are suitable for designing and preparing a novel porous SiC support for zeolite membranes.