KLHL24 is an E3 ubiquitin ligase. Variants in the start codon of KLHL24 result in truncated KLHL24 protein lacking the initial 28 amino acids (KLHL24-ΔN28). KLHL24-ΔN28 is more stable than wild-type ...KLHL24 and causes excessive degradation of keratin 14, leading to epidermolysis bullosa. Patients with KLHL24-related epidermolysis bullosa usually develop alopecia, which is uncommon in patients with epidermolysis bullosa. The mechanisms by which KLHL24 variants cause alopecia is currently unclear. In this study, we show that KLHL24 regulates hair maintenance by mediating the stability of keratin 15. Using a Klhl24
knock-in mouse model, we identify that KLHL24-ΔN28 disrupts the structure of hair follicle stem cells (HFSCs). Destructed HFSCs cannot anchor hairs and cause premature hair loss. Long-term destruction of HFSCs causes their exhaustion and hair follicle degeneration. Mechanically, KLHL24 mediates the ubiquitination and proteasomal degradation of keratin 15, an intermediate filament composing the HFSC cytoskeleton network. Keratin 15 is dramatically decreased in the skin of Klhl24
mice and in patients with KLHL24-related epidermolysis bullosa. These findings show that KLHL24 plays a role in hair maintenance by regulating the cytoskeleton structure of HFSCs and highlight the importance of the ubiquitin‒proteasome system in the stability of HFSCs.
Nagashima-type palmoplantar keratoderma (NPPK) is the most prevalent hereditary palmoplantar keratoderma (PPK) in China, but there is a paucity of epidemiological data on the Chinese population. To ...explore the clinical and genetic characteristics, evaluate the demographic distribution, and estimate the burden of disease of NPPK. A total of 234 Chinese patients with NPPK were enrolled from two medical centers and an online PPK support group. Next-generation sequencing and Sanger sequencing were performed to screen out and confirm pathogenic mutations in SERPINB7. Clinical features and quality of life (QOL) were evaluated using self-completed questionnaires. In total, 14 pathogenic mutations were identified in SERPINB7 from the cohort. The top four recurrent mutations were c.796C>T (355, 75.9%), c.522dupT (66, 14.1%), c.650_653delCTGT (24, 5.1%), and c.455G>T (12, 2.6%), accounting for 97.6% of Chinese NPPK patients. Other mutations (11, 2.4%) include c.455-1G>T, c.336+2T>G, c.635delG and seven novel mutations c.2T>C, c.434delG, c.455-16A>G, c.656T>C, c.745-553T>G, c.832C>T, c.1036G>T. The estimated prevalence of NPPK in China was found to be 0.975/10 000 based on Chinese databases. Clinically, there were no apparent genotype-phenotype correlations in NPPK patients. Pediatric patients mainly presented with palmoplantar peeling, while adults presented with scale (p < 0.001). The most common comorbidities in NPPK patients were onychomycosis (40.0%), eczema (36.8%), and tinea pedis (30.3%). As for burden of disease, NPPK patients' QOL was decreased by a moderate degree. In this study, pathogenic mutations' allele frequencies in SERPINB7 were updated, and prevalence of NPPK in China was estimated. This large-scale cohort study provides evidence-based recommendations for patient management. Identification of new mutations are important for timely diagnosis of NPPK. Palmoplantar peeling in children can be used as a hallmark for early recognition of NPPK.
To accurately assess onshore deep oil and gas resources, this study proposed a design scheme for a new in-situ pressure-preserved coring (IPP-Coring) tool with a pressure-preserving capacity of ...70 MPa and extensively elucidated its pressure-preserving mechanism. This tool can complete the pressure-preserving operation using the hydraulic lifting force of the drilling fluid. The pressure-preserving mechanism of this tool was attributed to the combined action of the fixed sealing structure, separate sealing structure, and pressure controller sealing structure. Using theoretical calculations and CFD simulations, the structural parameters and operation technology of this tool were elaborately determined. To demonstrate the IPP-Coring performance, laboratory and field tests were conducted. Four core samples 0.6 m, 0.92 m, 0.3 m, and 0.8 m long were obtained during laboratory coring experiments, and the average recovery of the core was 75 %. Notably, the IPP-Coring tool formed a stable sealing chamber that could maintain pressure at 70 MPa for at least 2 h in a downhole drilling fluid environment. In addition, an in-situ core sample of 1.4 m was obtained at 9 MPa in a real drilling field. This study offers a theoretical framework and design standards for the creation of analogous pressure coring technologies.
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•Design scheme of a new in-situ pressure-preserved tool was proposed.•Pressure-preserving mechanisms were clarified by theoretical analysis.•The structure and technological parameters were elaborately determined.•It has utilization potential due to a high pressure-preserving capacity of 70 MPa.
Natural killer (NK) cells can eliminate malignant cells and play a vital role in immunosurveillance. Administration of natural compounds represents a promising approach for antitumor immunotherapy, ...which may enhance the NK cell activity via multiple mechanisms.
Establishing approaches to evaluate the effect of select natural products on NK cell-mediated cytotoxicity.
We selected a natural product library containing 2880 pure compounds, which was provided by the National Centre for Drug Screening of China. 0.1% DMSO was employed as a negative control, and 100 U/mL human recombinant IL-2 was employed as a positive control. To evaluate the % of tumour cells which were killed by NK cells, expanded NK cells were co-cultured with tumour cells and then treated with natural products at the concentration of 10 μM. After 24-h co-incubation, luminescent signal was detected and percent lysis was calculated.
We report on the results of a three-round high-throughput screening effort that identified 20-deoxyingenol 3-angelate (DI3A) and its analogue ingenol 3-angelate (I3A) as immuno enhancers which boosts NK cell-mediated killing of non-small cell lung cancer cells (NSCLCs). Biophotonic cytotoxicity assay and calcein release assay were used as two well-established NK cell cytotoxicity detection assays to validate the immuno-enhancing effects of DI3A and I3A, which was achieved by increasing degranulation and interferon-gamma secretion of NK cells.
Our newly established ATP-based method was a valuable and information-rich screening tool to investigate the biological effects of natural products on both NK cells and tumour cells.
To provide a more accurate evaluation of the scale of deep underground resources, a new pressure coring system was carefully developed and its strength and safety of the engineering were verified by ...theoretical analyses and numerical simulation. The designed pressure coring system can obtain cores with length of 3 m and diameter of 50 mm at 70 MPa. The results of the ball-drop operation experiment demonstrate that differential motion assembly can effectively cut a safety pin by applying a tensile force of 4852 N, and it can lift the core tube through the center pole to complete a series of mechanical actions to seal the pressure. Additionally, by maintaining pressures at 70 MPa for 30 min, the pressure sealing capacity of the system was proven. Furthermore, a core sample with a diameter of 50 mm was obtained through a core drilling experiment and the coring performance of the pressure coring system was verified. This study can not only enrich the existing onshore coring technology but also provide a theoretical guide and design criteria for the development of similar pressure coring systems to meet the demand for deeper underground exploration.
Glutamine is crucial for the activation and efficacy of T cells, and may play a role in regulating the immune environment. This study aimed to investigate the potential role of glutamine in the ...activation and proliferation of induced regulatory T cells (iTregs).
CD4+CD45RA+T cells were sorted from peripheral blood mononuclear cells and cultured to analyze iTreg differentiation. Glutamine was then added to the culture system to evaluate the effects of glutamine on iTregs by determining oxidative phosphorylation (OXPHOS), apoptosis, and cytokine secretion. Additionally, a humanized murine graft-versus-host disease (GVHD) model was constructed to confirm the efficacy of glutamine-treated iTregs in vivo.
After being cultured in vitro, glutamine significantly enhanced the levels of Foxp3, CTLA-4, CD39, CD69, IL-10, TGF-β, and Ki67 (CTLA-4, IL-10, TGF-β are immunosuppressive markers of iTregs) compared with that of the control iTregs (P < 0.05). Furthermore, the growth curve showed that the proliferative ability of glutamine-treated iTregs was better than that of the control iTregs (P < 0.01). Compared with the control iTregs, glutamine supplementation significantly increased oxygen consumption rates and ATP production (P < 0.05), significantly downregulated Annexin V and Caspase 3, and upregulated BCL2 (P < 0.05). However, GPNA significantly reversed the effects of glutamine (P < 0.05). Finally, a xeno-GVHD mouse model was successfully established to confirm that glutamine-treated iTregs increased the mice survival rate, delayed weight loss, and alleviated colon injury.
Glutamine supplementation can improve the activity and immunosuppressive action of iTregs, and the possible mechanisms by which this occurs are related to cell proliferation, apoptosis, and OXPHOS.
We comprehensively investigate the interannual variability of multi‐scale motions in the northern South China Sea (NSCS) and associated influences from the terrestrial, atmospheric, and oceanic ...processes over the period 1994–2018 based on observations and a numerical simulation. We find that the interannual variabilities of the NSCS circulation and hydrographic properties, in the form of a cross‐scale interactive dynamic system, are sensitive to the tropical climate variability represented by the El Niño–Southern Oscillation (ENSO). In coastal areas with less than 30 m depth, the anomalous warm (cold) and less (more) saline waters are regulated by the rate of Pearl River discharge due to the predominant precipitation (evaporation) and positive (negative) heat‐flux anomaly in the Pearl River catchment in El Niño (La Niña) years. Controlled by the interannual variabilities of slope current and atmospheric forcings, the shelf current at 30–200 m depth responds asymmetrically to the ENSO, which establishes a stronger northeastward flow anomaly in El Niño years than the southwestward flow anomaly in La Niña years. We further show that the interannual variability of the slope current is jointly governed by the atmospheric and oceanic processes that tend to offset each other in interannual timescales. In particular, the weakened (strengthened) cyclonic wind stress curl over the ocean basin tends to moderate (intensify) the slope current in the NSCS, while this process is mitigated by the stronger (weaker) Kuroshio intrusion in El Niño (La Niña) years.
Plain Language Summary
The oceanic circulations and biogeochemical processes of shelf seas of the world's oceans have long been recognized to be concurrently impacted by the terrestrial, oceanic, and atmospheric forcings. However, the climatic controls and respective function of those forcings in regulating the interannual variability of shelf circulations in the northern South China Sea (NSCS) have not been thoroughly investigated. This research comprehensively studies the interannual variabilities and joint functions of those forcings in the NSCS. This research relies on valuable long‐term observations and well‐validated numerical simulation, and demonstrates that hydrographic properties in the coastal seas to the west of the Pearl River Estuary (PRE) are sensitive to the interannual variability of terrestrial forcings sourced from the Pearl River catchment. A large volume of warm and fresh waters is established when the extensive air‐sea‐land interactions in and around the southern China notably elevate the riverine discharges in El Niño years. Shelf circulations are mainly influenced by interannual changes of the prevailing winds, which drive northeastward shelf current anomalies in El Niño years. The slope current illustrates a southwestward anomaly, elevates the shoreward cross‐shelf pressure gradient force and strengthens the northeastward anomaly of shelf current in El Niño years.
Key Points
Shelf current in the northern South China Sea shows extensive interannual variability
Terrestrial forcings determines interannual variability of hydrographic properties of coastal oceans to the west of Pearl River Estuary
The shelf current shows notable asymmetric responses to interannual changes of winds over the shelf
Autologous stem cell transplantation (autoHCT) is considered standard of care for newly diagnosed multiple myeloma (MM). Although most patients eventually progress after autoHCT, a small proportion ...achieve a durable response. In this retrospective study we included 1576 patients, 244 (15%) of whom were long-term responders (LTR), defined as having a progression-free survival (PFS) of ≥8 years after transplant. Patients in the LTR group were younger than the non-LTR group (median age 58.4 vs. 59.5 years; p = 0.012), less likely to have high-risk cytogenetics (4% vs. 14%; p < 0.001), more often had <50% bone marrow plasma cells (67% vs. 58%; p = 0.018) and R-ISS stage I disease (43% vs. 34%). More patients in the LTR group received post-transplant maintenance (63% vs. 52%; p = 0.002). Patients in the LTR group had higher rates of complete response (CR) at day100 (41% vs. 27%; p < 0.001) and at best post-transplant response (70% vs. 37%; p < 0.001), compared to the non-LTR group. Patients in the LTR groups had a median PFS of 169.3 months and the median overall survival (OS) had not been reached. The leading cause of death in the LTR was disease progression. In conclusion, 15% of patients in the cohort were LTR after upfront autoHCT, with distinct characteristics and a median PFS of more than 14 years.
Background: The second revision of the International Staging System (R2-ISS) is a new and simple tool to risk stratify newly diagnosed multiple myeloma (NDMM) patients. Our aim in this study was to ...evaluate the utility of R2-ISS in NDMM patients who received upfront autologous hematopoietic stem cell transplantation (auto-HCT). Methods: We conducted a retrospective analysis of all NDMM patients who underwent upfront auto-HCT between 1988 and 2021 at MD Anderson Cancer Center and had available data for calculation of R2-ISS, including albumin, β-2 microglobulin, LDH, and fluorescence in-situ hybridization (FISH) analysis at diagnosis. High-risk cytogenetic abnormalities (HRCA) were t(4;14), del(17p), and 1q21 gain or amplification, as detected by FISH. The primary endpoints were progression-free survival (PFS) and overall survival (OS), and the secondary endpoint was hematological response after auto-HCT. Results: A total of 1291 patients were included, with a median age of 62 years (range 29 - 83) and 60% were male. Four hundred-and-nineteen patients (32%) had HRCA. Most patients received either bortezomib, lenalidomide, and dexamethasone (VRD) (34%) or carfilzomib, lenalidomide, and dexamethasone (KRD) (25%) induction regimens, and most patients (95%) received melphalan based conditioning. The distribution of R2-ISS stages in our cohort was as follows: 123 (10%) stage I, 471 (36%) stage II, 566 (44%) stage III, and 131 (10%) stage IV. A total of 1027 (80%) patients received post auto-HCT maintenance, mostly lenalidomide with or without dexamethasone (n = 785, 61%) (Table 1). With a median follow-up of 42.2 months (range 0.3 - 181.0) for the entire cohort, the median PFS was 73.0, 65.2, 44.0, and 24.8 months ( P < .001) and the median OS was 130.8, 128.5, 94.2, and 61.4 months ( P < .001) for patients with R2-ISS stages I, II, III, and IV, respectively (Figure 1). On multivariable analysis (MVA) for PFS, using R2-ISS stage I as the reference group, there was no significant difference for R2-ISS stage II (hazard ratio 95% CI, 1.11 0.76-1.63; P = .59), but there was a significant worsening in PFS for R2-ISS stage III (1.55 1.05-2.29; P = .028) and R2-ISS stage IV (2.04 1.24-3.36; P = .005). On MVA for OS, again using R2-ISS stage I as the reference group, there was no significant difference for R2-ISS stage II (1.33 0.74-2.40; P = .34) or R2-ISS stage III (1.75 0.97-3.17; P = .06), but there was a significant worsening in OS for R2-ISS stage IV (2.43 1.18-5.01; P = .017). On MVA, other measures significantly associated with worsening PFS were year of auto-HCT < 2010, lambda light chain disease subtype, presence of HRCA, prior MRD/response other than negative/≥CR, and not achieving MRD negative/≥ CR post auto-HCT. For OS, other measures significantly associated with worsening survival on MVA were presence of HRCA, HCT-CI > 3, having at least one bone lesion, not achieving CR at best response, and not receiving post auto-HCT maintenance therapy. Conclusion: Our study demonstrates that R2-ISS is a reliable prognostic tool for NDMM in a large cohort of patients who received standard anti-myeloma treatment, including modern induction regimens, upfront auto-HCT, and post-transplant maintenance.
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