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We use ab initiomodeling (CASTEP) to help elucidate the crystallization phenomena and chemistry behind kidney stone composition and formation. To explore the stone formation process, we have constructed a surface model of calcium oxalate dihydrate─the mineral most commonly found in patients with hypercalciuria and modeled stone growth, by simulating further calcium oxalate adsorption onto the surface (−7.446 eV, −0.065 eV/atom). Furthermore, urine analysis of kidney stone patients has previously revealed that their urine contains higher concentrations of phospholipids compared to healthy individuals. Therefore, to investigate the interactions between urinary macromolecules and the growing crystal surfaces at an atomic level, we have performed ab initiomolecular dynamics simulations of phosphocholine adsorption on calcium oxalate surfaces. We have shown that the phosphocholine headgroups become entrapped within the growing crystal and the lowest energy structures (−18.008 eV, −0.0396 eV/atom) are those where the calcium oxalate dihydrate surfaces have become disrupted, with reorganization of their crystallographic structure. Urinary calculi (kidney stones) are a common ailment affecting around 10% of the world’s population and resulting in nearly 90,000 finished consultant episodes (FCE) each year in the United Kingdom [Hospital Episode Statistics, Admitted Patient Care─England, 2011–12 NHS Digital, 2021–2022. https://digital.nhs.uk/data-and-information/publications/statistical/hospital-admitted-patient-care-activity/hospital-episode-statistics-admitted-patient-care-england-2011-12].

This study reports the following: (1) frequency of TP53comutation within each component of the European LeukemiaNet 2022 acute myeloid leukemia risk classification, (2) relevance of TP53mutated variant allelic fraction <10%, (3) prognostic impact of −7, −5/del(5q), −17/abn(17p), complex karyotype/monosomal karyotype, or myelodysplasia-related gene mutations with/without mutated TP53.

Randomized trials in acute myeloid leukemia (AML) have demonstrated improved survival by the BCL-2 inhibitor venetoclax combined with azacitidine in older patients, and clinical trials are actively exploring the role of venetoclax in combination with intensive chemotherapy in fitter patients with AML. As most patients still develop recurrent disease, improved understanding of relapse mechanisms is needed. We find that 17% of patients relapsing after venetoclax-based therapy for AML have acquired inactivating missense or frameshift/nonsense mutations in the apoptosis effector gene BAX. In contrast, such variants were rare after genotoxic chemotherapy. BAX variants arose within either leukemic or preleukemic compartments, with multiple mutations observed in some patients. In vitro, AML cells with mutated BAX were competitively selected during prolonged exposure to BCL-2 antagonists. In model systems, AML cells rendered deficient for BAX, but not its close relative BAK, displayed resistance to BCL-2 targeting, whereas sensitivity to conventional chemotherapy was variable. Acquired mutations in BAX during venetoclax-based therapy represent a novel mechanism of resistance to BH3-mimetics and a potential barrier to the long-term efficacy of drugs targeting BCL-2 in AML.

•Acquired BAXmutations represent a novel mechanism of adaptive resistance to venetoclax-based therapy for patients with AML.•Defective BAX enhances resistance to BH3-mimetics targeting diverse BCL-2 family prosurvival proteins in AML.

Almost all interactions and reactions that occur in living organisms involve proteins. The various biological roles of proteins include, but are not limited to, signal transduction, gene transcription, cell death, immune function, structural support, and catalysis of all the chemical reactions that enable organisms to survive. The varied roles of proteins have led to them being dubbed ‘the workhorses of all living organisms’. This article discusses the functions of proteins and how protein function is studied in a laboratory setting. In this article, we begin by examining the functions of protein domains, followed by a discussion of some of the major classes of proteins based on their function. We consider protein binding in detail, which is central to protein function. We then examine how protein function can be altered through various mechanisms including post-translational modification, and changes to environment, oligomerisation and mutations. Finally, we consider a handful of the techniques employed in the laboratory to understand and measure the function of proteins.

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a clear genetic component. While most SLE patients carry rare gene variants in lupus risk genes, little is known about their contribution to disease pathogenesis. Amongst them, SH2B3—a negative regulator of cytokine and growth factor receptor signaling—harbors rare coding variants in over 5% of SLE patients. Here, we show that unlike the variant found exclusively in healthy controls, SH2B3 rare variants found in lupus patients are predominantly hypomorphic alleles, failing to suppress IFNGR signaling via JAK2-STAT1. The generation of two mouse lines carrying patients’ variants revealed that SH2B3 is important in limiting the number of immature and transitional B cells. Furthermore, hypomorphic SH2B3 was shown to impair the negative selection of immature/transitional self-reactive B cells and accelerate autoimmunity in sensitized mice, at least in part due to increased IL-4R signaling and BAFF-R expression. This work identifies a previously unappreciated role for SH2B3 in human B cell tolerance and lupus risk.

Progressive multifocal leukoencephalopathy is a rare condition caused by the polyomavirus JC (JCV) affecting almost exclusively immunosuppressed individuals. Treatment strategies are limited and generally focus on immune reconstitution. Inhibition of Programmed cell death protein 1 (PD-1) has been associated with reduced CSF JC viral load and clinical stabilisation or improvement in 5 of 8 patients reported in a previous case series (Cortese et al., 2019)[i]. Here, we report three cases of PML in patients without HIV or immunosuppressive treatment who were treated with the checkpoint inhibitor pembrolizumab in an attempt to increase CD4+ and CD8+ T-cell activity against JCV. At time of submission, disease progression had halted in 2 of 3 patients (median follow-up=10months, 1-22months). We will detail presentation and disease course and discuss challenges experienced in the management of these patients.[i] Cortese I, Muranski P, Enose-Akahata Y, Ha SK, Smith B, Monaco M, Ryschkewitsch C, Major EO, Ohayon J, Schindler MK, Beck E, Reoma LB, Jacobson S, Reich DS, Nath A. Pembrolizumab Treatment for Pro- gressive Multifocal Leukoencephalopathy. N Engl J Med. 2019 Apr 25;380(17):1597-1605. doi: 10.1056/NEJMoa1815039. Epub 2019 Apr 10. PMID: 30969503.