Potentiating anti-tumor immunity by re-engaging immune synapse molecules.

The formation of immune synapses (ISs) between cytotoxic T cells and tumor cells is crucial for effective tumor elimination. However, the role of ISs in immune evasion and resistance to immune checkpoint blockades (ICBs) remains unclear. We demonstrate that ICAM-1, a key IS molecule activating LFA-1 signaling in T and natural killer (NK) cells, is often expressed at low levels in cancers.

Prediction Model and Decision Analysis for Early Recognition of SDNS/FRNS in Children.

Purpose: This study identified factors that identification of progression-predicting utility from steroid-sensitive nephrotic syndrome(SSNS) to steroid-dependent or frequently relapsing nephrotic syndrome (SDNS/FRNS) in patients and developed a corresponding predictive model.

Patients And Methods: This retrospective study analyzed clinical data from 756 patients aged 1 to 18 years, diagnosed with SSNS, who received treatment at the Department of Nephrology, Children's Hospital of Chongqing Medical University, between November 2007 and May 2023. We developed a shrinkage and selection operator (LASSO) - logistic regression model, which was visualized using a nomogram.

Molecular Basis of the Recognition of the Active Rab8a by Optineurin.

Optineurin (OPTN), a multifunctional adaptor protein in mammals, plays critical roles in many cellular processes, such as vesicular trafficking and autophagy. Notably, mutations in optineurin are directly associated with many human diseases, such as amyotrophic lateral sclerosis (ALS). OPTN can specifically recognize Rab8a and the GTPase-activating protein TBC1D17, and facilitate the inactivation of Rab8a mediated by TBC1D17, but with poorly understood mechanism.

Aberrant serum-derived FN1 variants bind to integrin β1 on glomerular endothelial cells contributing to thin basement membrane nephropathy.

The glomerular basement membrane (GBM) is a critical component of the glomerular filtration barrier (GFB), with its thickness directly influencing renal function. While a uniformly thinned GBM can cause hematuria while preserving normal renal function, this condition is typically diagnosed as thin basement membrane nephropathy (TBMN). However, the pathogenesis and potential progression to renal insufficiency of TBMN are not fully understood.

Mechanistic insights into the homo-dimerization of HOIL-1L and SHARPIN.

HOIL-1L and SHARPIN are two essential regulatory subunits of the linear ubiquitin chain assembly complex (LUBAC), which is the only known E3 ligase complex generating linear ubiquitin chains. In addition to their LUBAC-dependent functions, HOIL-1L and SHARPIN alone play crucial roles in many LUBAC-independent cellular processes. Importantly, deficiency of HOIL-1L or SHARPIN leads to severe disorders in humans or mice.

Klotho inhibits renal ox-LDL deposition via IGF-1R/RAC1/OLR1 signaling to ameliorate podocyte injury in diabetic kidney disease.

Objective: Diabetic kidney disease (DKD) is characterized by the abnormal deposition of oxidized low-density lipoprotein (ox-LDL), which contributes to podocyte damage. Klotho, an aging suppressor that plays a critical role in protecting podocytes in DKD, is mainly expressed in kidney tubular epithelium and secreted in the blood. However, it has not been established whether Klotho can alleviate podocyte injury by inhibiting renal ox-LDL deposition, and the potential molecular mechanisms require further investigation.

Mechanistic insights into the enzymatic activity of E3 ligase HOIL-1L and its regulation by the linear ubiquitin chain binding.

Heme-oxidized IRP2 ubiquitin ligase 1 (HOIL-1L) serves as a unique E3 ligase to catalyze the mono-ubiquitination of relevant protein or sugar substrates and plays vital roles in numerous cellular processes in mammals. However, the molecular mechanism underpinning the E3 activity of HOIL-1L and the related regulatory mechanism remain elusive. Here, we report the crystal structure of the catalytic core region of HOIL-1L and unveil the key catalytic triad residues of HOIL-1L.

A high-impact FN1 variant correlates with fibronectin-mediated glomerulopathy via decreased binding to collagen type IV.

The glomerular basement membrane (GBM) consists of laminins, collagen IV, nidogens, and fibronectin and is essential for filtration barrier integrity in the kidney. Critically, structural and functional abnormalities in the GBM are involved in chronic kidney disease (CKD) occurrence and development. Fibronectin is encoded by FN1 and is essential for podocyte-podocyte and podocyte-matrix interactions.

Novel pathogenic variants in CUBN uncouple proteinuria from renal function.

Background: Proteinuria is an unfavorable clinical condition highly associated with a risk of renal and cardiovascular disease in chronic kidney disease (CKD). However, whether all proteinuria forms are linked to renal impairment are still unclear. Cubilin is an endocytic receptor highly expressed in renal proximal tubules mediating uptake of albumin, transferrin and α1-microglobulin.

Structure of the receptor-activated human TRPC6 and TRPC3 ion channels.

TRPC6 and TRPC3 are receptor-activated nonselective cation channels that belong to the family of canonical transient receptor potential (TRPC) channels. They are activated by diacylglycerol, a lipid second messenger. TRPC6 and TRPC3 are involved in many physiological processes and implicated in human genetic diseases.

Activation of peripheral KCNQ channels relieves gout pain.

Intense inflammatory pain caused by urate crystals in joints and other tissues is a major symptom of gout. Among therapy drugs that lower urate, benzbromarone (BBR), an inhibitor of urate transporters, is widely used because it is well tolerated and highly effective. We demonstrate that BBR is also an activator of voltage-gated KCNQ potassium channels.