Defective Cell Research Articles

The N-glycosylation defect in Lec5 and Lec9 CHO cells is caused by absence of the DHRSX gene.

Glycosylation-deficient Chinese hamster ovary (CHO) cell lines have been instrumental in the discovery of N-glycosylation machinery. Yet, the molecular causes of the glycosylation defects in the Lec5 and Lec9 mutants have been elusive, even though for both cell lines a defect in dolichol formation from polyprenol was previously established. We recently found that dolichol synthesis from polyprenol occurs in three steps consisting of the conversion of polyprenol to polyprenal by DHRSX, the reduction of polyprenal to dolichal by SRD5A3 and the reduction of dolichal to dolichol, again by DHRSX. This led us to investigate defective dolichol synthesis in Lec5 and Lec9 cells. Both cell lines showed increased levels of polyprenol and its derivatives, concomitant with decreased levels of dolichol and derivatives, but no change in polyprenal levels, suggesting DHRSX deficiency. Accordingly, N-glycan synthesis and changes in polyisoprenoid levels were corrected by complementation with human DHRSX but not with SRD5A3. Furthermore, the typical polyprenol dehydrogenase and dolichal reductase activities of DHRSX were absent in membrane preparations derived from Lec5 and Lec9 cells, while the reduction of polyprenal to dolichal, catalyzed by SRD5A3, was unaffected. Long-read whole genome sequencing of Lec5 and Lec9 cells did not reveal mutations in the ORF of SRD5A3, but the genomic region containing DHRSX was absent. Lastly, we established the sequence of Chinese hamster DHRSX and validated that this protein has similar kinetic properties to the human enzyme. Our work therefore identifies the basis of the dolichol synthesis defect in CHO Lec5 and Lec9 cells.

Substituent engineering in tertiary phosphine oxides for passivating defects of perovskite solar cells

AbstractDefect passivation based on Lewis acid–base chemistry has been regarded as an effective strategy to improve the photovoltaic performance and stability of perovskite solar cells (PSCs). Here, we report on tertiary phosphine oxides (R3PO) as materials for defect passivation, where photovoltaic performance was investigated depending on the substituents R. Electron‐donating ability of the substituents in R3PO was found to play an important role in passivation. Cyclohexyl substituent was better in achieving photovoltaic performance than linear hexyl substituent. The heterocyclic morpholine substituent bearing oxygen and nitrogen in cyclohexyl form further improved photovoltaic performance due to its enhanced electron‐donating ability. Compared with an untreated PSC, the trimorpholinophosphine oxide (TMPPO)‐treated PSC improved the power conversion efficiency from 21.95% to 23.72%. Additionally, the dark‐storage stability test with an unencapsulated device showed that the TMPPO‐treated device maintained 92.7% of its initial PCE after 1250 h, while 86.8% was maintained for the untreated device. Three hundred hour‐light‐soaking of the encapsulated devices revealed that the operational stability of the TMPPO‐treated PSC was superior to the untreated device.image

Hepatocyte growth factor and insulin-like growth factor-1 were used to repair bone-cartilage defects in bone marrow mesenchymal stem cells in a rabbit model of postmenopausal

In postmenopausal osteoporosis (PMOP), an imbalance exists in the differentiation of bone marrow mesenchymal stem cells (BMSCs), with a decrease in osteogenic differentiation and an increase in adipogenic differentiation. This imbalance leads to bone marrow adiposity, bone loss, bone fragility, and a substantial rise in fracture risk. After a patient experiences an osteochondral defect due to trauma, it struggles to heal naturally, presenting a clinical challenge for treatment. Our study delved into the abnormal differentiation of BMSCs in PMOP by conducting transcriptome sequencing on BMSCs from a PMOP model (PMOP-BMSCs) and a healthy control model (Normal-BMSCs). We identified insulin-like growth factor 1 (IGF-1) and hepatocyte growth factor (HGF) genesas significantly low-expressed protein-coding genes during the osteogenic cartilage differentiation process of PMOP-BMSCs. Due to the downregulation of its expression, it leads to the deletion of the proteins it encodes IGF-1 and HGF. In order to verify the sequencing results, the feasibility of co-culture the above two growth factors with PMOP-BMSCs to repair osteochondral defects was discussed. The findings indicated that the inclusion of elements enhanced the DNA replication activity and extracellular matrix mineralization of PMOP-BMSCs. It also promoted the construction of tissue-engineered bone in vitro and the up- regulation of Runx2, BMP4, OCN, ACAN, collagen type Ⅰ, II, and Sox9 osteochondral differentiation markers. In the rabbit model of knee osteochondral injury with PMOP, the group treated with both growth factors and PMOP-BMSCs showed superior outcomes in repairing cartilage and subchondral bone defects compared to the other groups. We suggest that the addition of HGF and IGF-1 increases the expression of osteoblast and cartilage-related genes and proteins, promoting the proliferation and differentiation of osteochondrous bone in PMOP-BMSCs. These findings could offer a novel cell therapy strategy for treating postmenopausal osteoporosis, utilizing growth factors.

SIIF: Semantic information interactive fusion network for photovoltaic defect segmentation

Any defects or damage on photovoltaic panels significantly reduce photoelectric conversion efficiency and service life. Therefore, the refined defect segmentation technology is the key to the quality inspection of photovoltaic equipment. However, the existing methods ignore the information interaction between multi-levels, causing semantic features to be easily lost and difficult to fuse. In this paper, we propose a segmentation network based on an interactive fusion of semantic information for solar cell defect identification, which can effectively interact with multi-level rich information and enhance the positioning capabilities of high-level semantics. Specifically, we propose a novel Multi-Level Pyramid Strategy (MLPS) to reduce the information gap between multi-level features. MLPS adopts a pooling distribution mechanism to enable multi-level features to interact effectively in the feature pyramid. In addition, to effectively integrate high-level positioning semantics into the neighbor level, we design a new Neighbor Attention Fusion module (NAF) to propagate high-level semantic information gradually. NAF learns spatial neighbor-level similarity combined with high-level attention to balance location information and contextual features. We perform comprehensive experiments to demonstrate the advancement of our approach. Our method achieves 84.3% MIOU on our solar cell dataset, outperforming existing state-of-the-art (SOTA) methods. To verify the generalization ability of our network, we train and evaluate the PSCDE dataset. The results show that our model achieves an excellent 98.35%MIOU.

DNA demethylase Tet2 promotes the terminal maturation of natural killer cells.

The cytotoxicity feature to eliminate malignant cells makes natural killer (NK) cells a candidate for tumor immunotherapy. However, this scenario is currently hampered by inadequate understanding of the regulatory mechanisms of NK cell development. Ten-Eleven-Translocation 2 (Tet2) is a demethylase whose mutation was recently shown to cause phenotypic defects in NK cells. However, the role of Tet2 in the development and maturation of NK cells is not entirely clear. Here we studied the modulatory role of Tet2 in NK cell development and maturation by generating hematopoietic Tet2 knockout mice and mice with Tet2 conditional deletion in NKp46+ NK cells. The results showed that both hematopoietic and NK cell conditional deletion of Tet2 had no effect on the early steps of NK cell development, but impaired the terminal maturation of NK cells defined by CD11b, CD43, and KLRG1 expression. In the liver, Tet2 deletion not only prevented the terminal maturation of NK cells, but also increased the proportion of type 1 innate lymphoid cells (ILC1s) and reduced the proportion of conventional NK cells (cNK). Moreover, hematopoietic deletion of Tet2 lowered the protein levels of perforin in NK cells. Furthermore, hematopoietic deletion of Tet2 downregulated the protein levels of Eomesodermin (Eomes), but not T-bet, in NK cells. In conclusion, our results demonstrate that Tet2 plays an important role in the terminal maturation of NK cells, and the Eomes transcription factor may be involved.

Correction of age-associated defects in dendritic cells enables CD4+ T cells to eradicate tumors

Defective host defenses later in life are associated with changes in immune cell activities, suggesting that age-specific considerations are needed in immunotherapy approaches. In this study, we found that PD-1 and CTLA4-based cancer immunotherapies are unable to eradicate tumors in elderly mice. This defect in anti-tumor activity correlated with two known age-associated immune defects: diminished abundance of systemic naive CD8+ Tcells and weak migratory activities of dendritic cells (DCs). We identified a vaccine adjuvant, referred to as a DC hyperactivator, which corrects DC migratory defects in the elderly. Vaccines containing tumor antigens and DC hyperactivators induced T helper type 1 (TH1) CD4+ Tcells with cytolytic activity that drive anti-tumor immunity in elderly mice. When administered early in life, DC hyperactivators were the only adjuvant identified that elicited anti-tumor CD4+ Tcells that persisted into old age. These results raise the possibility of correcting age-associated immune defects through DC manipulation.

MCM8 interacts with DDX5 to promote R-loop resolution

MCM8 has emerged as a core gene in reproductive aging and is crucial for meiotic homologous recombination repair. It also safeguards genome stability by coordinating the replication stress response during mitosis, but its function in mitotic germ cells remains elusive. Here we found that disabling MCM8 in mice resulted in proliferation defects of primordial germ cells (PGCs) and ultimately impaired fertility. We further demonstrated that MCM8 interacted with two known helicases DDX5 and DHX9, and loss of MCM8 led to R-loop accumulation by reducing the retention of these helicases at R-loops, thus inducing genome instability. Cells expressing premature ovarian insufficiency-causative mutants of MCM8 with decreased interaction with DDX5 displayed increased R-loop levels. These results show MCM8 interacts with R-loop-resolving factors to prevent R-loop-induced DNA damage, which may contribute to the maintenance of genome integrity of PGCs and reproductive reserve establishment. Our findings thus reveal an essential role for MCM8 in PGC development and improve our understanding of reproductive aging caused by genome instability in mitotic germ cells.

Defective mesenchymal Bmpr1a-mediated BMP signaling causes congenital pulmonary cysts.

Abnormal lung development can cause congenital pulmonary cysts, the mechanisms of which remain largely unknown. Although the cystic lesions are believed to result directly from disrupted airway epithelial cell growth, the extent to which developmental defects in lung mesenchymal cells contribute to abnormal airway epithelial cell growth and subsequent cystic lesions has not been thoroughly examined. In the present study using genetic mouse models, we dissected the roles of bone morphogenetic protein (BMP) receptor 1a (Bmpr1a)-mediated BMP signaling in lung mesenchyme during prenatal lung development and discovered that abrogation of mesenchymal Bmpr1a disrupted normal lung branching morphogenesis, leading to the formation of prenatal pulmonary cystic lesions. Severe deficiency of airway smooth muscle cells and subepithelial elastin fibers were found in the cystic airways of the mesenchymal Bmpr1a knockout lungs. In addition, ectopic mesenchymal expression of BMP ligands and airway epithelial perturbation of the Sox2-Sox9 proximal-distal axis were detected in the mesenchymal Bmpr1a knockout lungs. However, deletion of Smad1/5, two major BMP signaling downstream effectors, from the lung mesenchyme did not phenocopy the cystic abnormalities observed in the mesenchymal Bmpr1a knockout lungs, suggesting that a Smad-independent mechanism contributes to prenatal pulmonary cystic lesions. These findings reveal for the first time the role of mesenchymal BMP signaling in lung development and a potential pathogenic mechanism underlying congenital pulmonary cysts.

Defective mesenchymal Bmpr1a-mediated BMP signaling causes congenital pulmonary cysts

Abnormal lung development can cause congenital pulmonary cysts, the mechanisms of which remain largely unknown. Although the cystic lesions are believed to result directly from disrupted airway epithelial cell growth, the extent to which developmental defects in lung mesenchymal cells contribute to abnormal airway epithelial cell growth and subsequent cystic lesions has not been thoroughly examined. In the present study using genetic mouse models, we dissected the roles of bone morphogenetic protein (BMP) receptor 1a (Bmpr1a)-mediated BMP signaling in lung mesenchyme during prenatal lung development and discovered that abrogation of mesenchymal Bmpr1a disrupted normal lung branching morphogenesis, leading to the formation of prenatal pulmonary cystic lesions. Severe deficiency of airway smooth muscle cells and subepithelial elastin fibers were found in the cystic airways of the mesenchymal Bmpr1a knockout lungs. In addition, ectopic mesenchymal expression of BMP ligands and airway epithelial perturbation of the Sox2-Sox9 proximal-distal axis were detected in the mesenchymal Bmpr1a knockout lungs. However, deletion of Smad1/5, two major BMP signaling downstream effectors, from the lung mesenchyme did not phenocopy the cystic abnormalities observed in the mesenchymal Bmpr1a knockout lungs, suggesting that a Smad-independent mechanism contributes to prenatal pulmonary cystic lesions. These findings reveal for the first time the role of mesenchymal BMP signaling in lung development and a potential pathogenic mechanism underlying congenital pulmonary cysts.

Screening of Functional Small Molecules via Modified Machine Learning Strategy toward Efficient All-Inorganic Perovskite Solar Cells.

Organic small molecules are proven to be capable of passivating the bulk/interfacial defects in inorganic perovskite solar cells. Considering the burdensome situation to screen the functional small molecules, we employ a modified machine learning (ML) strategy to guide screening suitable small molecules toward efficient solar cells through three modified ML algorithms to construct the prediction model: (i) random forest algorithm (RF), (ii) support vector machine algorithm (SVR), and (iii) XGBoost. Among them, the XGBoost algorithm displays a better overall predictive performance, whereby the R2 index reaches 0.939. Accordingly, eight small molecules are selected to modify the interface of perovskite films, and both the theoretical and experimental results certify that the difluorobenzylamine with additional fluorine atoms has a better interface modification effect among the small molecules containing functional groups, e.g., the benzene ring and amino group. The high accuracy of the modified machine learning model enables us to simplify the small-molecule screening process and form an important step for ongoing developments in perovskite solar cells and other optoelectronic devices.

FDA-approved PDE4 inhibitors reduce the dominant toxicity of ALS-FTD-associated CHCHD10 S59L.

Mutations in coiled-coil-helix-coiled-coil-helix domain containing 10( CHCHD10 ) have been identified as a genetic cause of amyotrophic lateral sclerosis and/or frontotemporal dementia(ALS-FTD). In our previous studies using in vivo Drosophila model expressing C2C10H S81L , and human cell models expressing CHCHD10 S59L , we have identified that the PINK1/Parkin pathway is activated and causes cellular toxicity. Furthermore, we demonstrated that pseudo-substrate inhibitors for PINK1 and mitofusin2 agonists mitigated the cellular toxicity of CHCHD10 S59L . Evidences using in vitro/ in vivo genetic and chemical tools indicate that inhibiting PINK1 would be the most promising treatment for CHCHD10 S59L -induced diseases. Therefore, we have investigated cellular pathways that can modulate the PINK1/Parkin pathway and reduce CHCHD10 S59L -induced cytotoxicity. Here, we report that FDA-approved PDE4 inhibitors reduced CHCHD10 S59L -induced morphological and functional mitochondrial defects in human cells and an in vivo Drosophila model expressing C2C10H S81L . Multiple PDE4 inhibitors decreased PINK1 accumulation and downstream mitophagy induced by CHCHD10 S59L . These findings suggest that PDE4 inhibitors currently available in the market may be repositioned to treat CHCHD10 S59L -induced ALS-FTD and possibly other related diseases.

Neuroinflammation and Lysosomal Abnormalities Characterise the Essential Role for Oxidation Resistance 1 in the Developing and Adult Cerebellum.

Loss-of-function mutations in the TLDc family of proteins cause a range of severe childhood-onset neurological disorders with common clinical features that include cerebellar neurodegeneration, ataxia and epilepsy. Of these proteins, oxidation resistance 1 (OXR1) has been implicated in multiple cellular pathways related to antioxidant function, transcriptional regulation and cellular survival; yet how this relates to the specific neuropathological features in disease remains unclear. Here, we investigate a range of loss-of-function mouse model systems and reveal that constitutive deletion of Oxr1 leads to a rapid and striking neuroinflammatory response prior to neurodegeneration that is associated with lysosomal pathology. We go on to show that neuroinflammation and cell death in Oxr1 knockouts can be completely rescued by the neuronal expression of Oxr1, suggesting that the phenotype is driven by the cell-intrinsic defects of neuronal cells lacking the gene. Next, we generate a ubiquitous, adult inducible knockout of Oxr1 that surprisingly displays rapid-onset ataxia and cerebellar neurodegeneration, establishing for the first time that the distinctive pathology associated with the loss of Oxr1 occurs irrespective of developmental stage. Finally, we describe two new homozygous human pathogenic variants in OXR1 that cause neurodevelopmental delay, including a novel stop-gain mutation. We also compare functionally two missense human pathogenic mutations in OXR1, including one newly described here, that cause different clinical phenotypes but demonstrate partially retained neuroprotective activity against oxidative stress. Together, these data highlight the essential role of Oxr1 in modulating neuroinflammatory and lysosomal pathways in the mammalian brain and support the hypothesis that OXR1 protein dosage may be critical for pathological outcomes in disease.

Nur77 as a novel regulator of Paneth cell differentiation and function

Serving as a part of intestinal innate immunity, Paneth cells play an important role in intestinal homeostasis maintenance via their multiple functions. However, the regulation of Paneth cells has been proven to be complex and diverse. Here, we identified nuclear receptor Nur77 as a novel regulator of Paneth cell differentiation and function. Nur77 deficiency led to the loss of Paneth cells in murine ileal crypts. Intestinal tissues or organoids with Nur77 deficiency exhibited the impaired intestinal stem cell niche and failed to enhance antimicrobial peptide expression after Paneth cell degranulation. The defects in Paneth cells and antimicrobial peptides in Nur7-/- mice led to intestinal microbiota disorders. Nur77 deficiency rendered postnatal mice susceptible to necrotizing enterocolitis. Mechanistically, Nur77 transcriptionally inhibited Dact1 expression to activate Wnt signaling activity, thus promoting Paneth cell differentiation and function. Taken together, our data suggest the regulatory role of Nur77 in Paneth cell differentiation and function and reveal a novel Dact1-mediated Wnt inhibition mechanism in Paneth cell development.

TANGO2 deficiency disease is predominantly caused by a lipid imbalance.

TANGO2 deficiency disease (TDD) is a rare genetic disorder estimated to affect ∼8000 individuals worldwide. It causes neurodegeneration often accompanied by potentially lethal metabolic crises that are triggered by diet or illness. Recent work has demonstrated distinct lipid imbalances in multiple model systems either depleted for or devoid of the TANGO2 protein, including human cells, fruit flies and zebrafish. Importantly, vitamin B5 supplementation has been shown to rescue TANGO2 deficiency-associated defects in flies and human cells. The notion that vitamin B5 is needed for synthesis of the lipid precursor coenzyme A (CoA) corroborates the hypothesis that key aspects of TDD pathology may be caused by lipid imbalance. A natural history study of 73 individuals with TDD reported that either multivitamin or vitamin B complex supplementation prevented the metabolic crises, suggesting this as a potentially life-saving treatment. Although recently published work supports this notion, much remains unknown about TANGO2 function, the pathological mechanism of TDD and the possible downsides of sustained vitamin supplementation in children and young adults. In this Perspective, we discuss these recent findings and highlight areas for immediate scientific attention.

Chronic granulomatous disease: A single-center experience in Central Anatolia

BackgroundChronic granulomatous disease (CGD), one of the phagocytic cell defects, is the primary immunodeficiency caused by dysfunction of the NADPH oxidase complex in neutrophils. MethodsThe clinical, demographic and laboratory findings of 17 CGD patients who were followed-up between 2002 and 2021 were obtained retrospectively from the records of the patients. ResultsThe number of male and female patients was 10/7. The median age at diagnosis was 5.3 months (range 4–120) for 3 patients with X-CGD, and 42.4 months (range 8–350) for 14 patients with AR-CGD. We have investigated rare CYBA exon 3–6 deletion in 7 patients and hotspot mutation with delGT at the beginning of exon 2 of NCF1 in 5 patients. The most common clinical findings were pneumonia and lymphadenitis with recurrent fever, respectively (41.2%, 35.3%). A total of 154 microbial infections requiring hospital admission (27 in 3 XL and 127 in 14 AR patients) were detected in the follow-up of the patients and median infection number for a patient was 9 in both groups. Eight of 17 patients had stem cell transplantation and the survival rate was 87.5%. ConclusionsX-CGD patients are more rapidly recognized by family history and severe infections than those with AR-CGD and early prophylaxis may decrease infectious episodes. We have investigated the large deletion suggesting a possible founder effect for CYBA exon 3–6 deletion in Central Anatolia. Additionally, HSCT transplantation leads to a high survival rate for the patients with CGD.

Alkali Metal Pretreatment for Precise Na Doping and Voc Improvement in CIGS Thin-Film Solar Cells.

The pretreatment of the Cu(In,Ga)Se2 (CIGS) absorption layer using an alkali element can effectively improve the photoelectric conversion efficiency (PCE) of CIGS solar cells. Here, we propose using NaF layer pretreatment below the CIGS absorption layer deposited by a three-stage process. Sodium ions in NaF can effectively suppress the diffusion of Ga elements and form a steep gradient backscatter layer on the back of the CIGS absorption layer, thereby passivating solar cell defects, inhibiting carrier recombination, promoting carrier transmission and collection, improving open circuit voltage (VOC), short circuit current (Jsc), and filling factor (FF), and further improving the PCE.

A proposed hybrid model of ANN and KNN for solar cell defects detection and temperature prediction using fuzzy image segmentation

This paper presents a novel hybrid model employing Artificial Neural Networks (ANN) and Mathematical Morphology (MM) for the effective detection of defects in solar cells. Focusing on issues such as broken corners and black edges caused by environmental factors like broken glass cover, dust, and temperature variations. This study utilizes a hybrid model of ANN and K-Nearest Neighbor (KNN) for temperature prediction. This hybrid approach leverages the strengths of both models, potentially opening up new avenues for improved accuracy in temperature forecasting, which is critical for solar energy applications. The significance lies in the interconnectedness of temperature fluctuations and solar cell efficiency, leading to defects. The proposed model aims to predict temperatures accurately, providing insights into potential solar cell efficiency problems. Subsequently, this work studies the transitions to defect detection using Fuzzy C-Means (FCM) clustering and MM techniques. The hybrid model demonstrates accurate temperature prediction with Mean Absolute Percentage Error (MAPE) values of 0.92 %, 0.72 %, and 1.3 % for average, maximum, and minimum temperatures, respectively. The defect detection process yields a detection accuracy (CR) of 96 % and sensitivity of detection (SD) of 89 %. This work is validated compared to the literature work done and by using K-fold cross validation technique. The proposed work emphasizes the improvement in defect detection accuracy and the overall quality enhancement of solar cells.

#821 Kibra mediates the activation of hippo by classic signal pathway related to NPHP1 defect

Abstract Background and Aims Nephronophthisis (NPH) is an autosomal recessive cystic kidney disease, which is the most common genetic cause of end-stage renal disease (ESRD) in children. The pathogenesis of NPH has not been clear yet. There are more than 20 different pathogenic genes identified at present, among which NPHP1 is the most prevalent one. Hippo signal pathway has been suggested to be involved in the pathogenesis of NPH cause by NPHP4 and NPHP9 defects, respectively. In the present study, we attempted to explore the state of hippo signal pathway in NPHP1 defect in both MDCK cells and C57/6j mice. Method NPHP1 knockout (NPHP1KO) MDCK cells and NPHP1KO C57BL/6J mice were constructed by CRISPR/Cas9 technology. Recombined kibra knockdown siRNA, kibra knockdown AAV9 (AAV9-Kibra-KD) and NPHP1 overexpress AAV9 construct (AAV9-NPHP1-OE) were constructed, respectively. The expression and phosphorylation of core molecules of hippo pathway in different group of MDCK cells and the kidney C57BL/6J mice were investigated through Real-time Quantitative PCR, western blotting, immunofluorescence. The renal pathology of the mice kidney was also observed. Results In NPHP1KO MDCK cells and the kidney of NPHP1KO mice, the expression of KIBRA, p-MST, p-LATS and p-Yap were increased, which indicates the activation of hippo signal pathway. The activation of hippo pathway could be suppressed partially by NPHP1 re-expression both in NPHP1KO MDCK cells and the kidney of NPHP1KO mice, which means the activation of hippo pathway was related to NPHP1 defect both in vitro and in vivo. Moreover, the kidney pathological changes were improved by NPHP1 re-expression. Kibra is the upper regulator of hippo signal pathway, we observed that kibra knockdown inhibited the activation of hippo pathway both in NPHP1KO MDCK cells and the kidney of NPHP1KO mice, which indicates that kibra mediates the activation of hippo pathway related to NPHP1 defect both in vitro and in vivo. As well, kibra knockdown ameliorated renal fibrosis CTGF expression, interstitial inflammation and renal cyst formation in NPHP1KO mice. Conclusion We conclude that NPHP1 defect activates hippo pathway which involves in the pathogenesis of NPH. Kibra mediates the activation of hippo related to NPHP1 defect by classic signal pathway. Hippo signal maybe a target for the treatment of NPHP1 defect NPH.

BET inhibition reforms the immune microenvironment and alleviates T cell dysfunction in chronic lymphocytic leukemia.

Redundant tumor microenvironment (TME) immunosuppressive mechanisms and epigenetic maintenance of terminal T cell exhaustion greatly hinder functional antitumor immune responses in chronic lymphocytic leukemia (CLL). Bromodomain and extraterminal (BET) proteins regulate key pathways contributing to CLL pathogenesis and TME interactions, including T cell function and differentiation. Herein, we report that blocking BET protein function alleviates immunosuppressive networks in the CLL TME and repairs inherent CLL T cell defects. The pan-BET inhibitor OPN-51107 reduced exhaustion-associated cell signatures resulting in improved T cell proliferation and effector function in the Eμ-TCL1 splenic TME. Following BET inhibition (BET-i), TME T cells coexpressed significantly fewer inhibitory receptors (IRs) (e.g., PD-1, CD160, CD244, LAG3, VISTA). Complementary results were witnessed in primary CLL cultures, wherein OPN-51107 exerted proinflammatory effects on T cells, regardless of leukemic cell burden. BET-i additionally promotes a progenitor T cell phenotype through reduced expression of transcription factors that maintain terminal differentiation and increased expression of TCF-1, at least in part through altered chromatin accessibility. Moreover, direct T cell effects of BET-i were unmatched by common targeted therapies in CLL. This study demonstrates the immunomodulatory action of BET-i on CLL T cells and supports the inclusion of BET inhibitors in the management of CLL to alleviate terminal T cell dysfunction and potentially enhance tumoricidal T cell activity.

A Novel Homozygous RHOH Variant Associated with T Cell Dysfunction and Recurrent Opportunistic Infections.

RHOH, an atypical small GTPase predominantly expressed in hematopoietic cells, plays a vital role in immune function. A deficiency in RHOH has been linked to epidermodysplasia verruciformis, lung disease, Burkitt lymphoma and T cell defects. Here, we report a novel germline homozygous RHOH c.245G > A (p.Cys82Tyr) variant in a 21-year-old male suffering from recurrent, invasive, opportunistic infections affecting the lungs, eyes, and brain. His sister also succumbed to a lung infection during early adulthood. The patient exhibited a persistent decrease in CD4+ T, B, and NK cell counts, and hypoimmunoglobulinemia. The patient's T cell showed impaired activation upon in vitro TCR stimulation. In Jurkat T cells transduced with RHOHC82Y, a similar reduction in activation marker CD69 up-regulation was observed. Furthermore, the C82Y variant showed reduced RHOH protein expression and impaired interaction with the TCR signaling molecule ZAP70. Together, these data suggest that the newly identified autosomal-recessive RHOH variant is associated with T cell dysfunction and recurrent opportunistic infections, functioning as a hypomorph by disrupting ZAP70-mediated TCR signaling.