mRNA export factors store nascent transcripts within nuclear speckles as an adaptive response to transient global inhibition of transcription.

Several transcription inhibitors have been developed as cancer therapies. However, they show modest clinical activity, highlighting that our understanding of the cellular response to transcriptional inhibition remains incomplete. Here we report that potent inhibitors of transcription not only impact mRNA output but also markedly impair mRNA transcript localization and nuclear export.

Peripheral contributions to resting state brain dynamics.

The correlational structure of brain activity dynamics in the absence of stimuli or behavior is often taken to reveal intrinsic properties of neural function. To test the limits of this assumption, we analyzed peripheral contributions to resting state activity measured by fMRI in unanesthetized, chemically immobilized male rats that emulate human neuroimaging conditions. We find that perturbation of somatosensory input channels modifies correlation strengths that relate somatosensory areas both to one another and to higher-order brain regions, despite the absence of ostensible stimuli or movements.

Calciphylaxis: A Case Report and Review of the Role of Sodium Thiosulphate and Other Treatment Modalities.

Calciphylaxis is a rare and serious disorder almost exclusively seen in patients on dialysis or those with advanced chronic kidney disease (CKD) not on dialysis and is associated with very high mortality. We present the case of a 50-year-old male with a background of end-stage renal disease (ESRD) compliant with dialysis, parathyroid adenoma, secondary hyperparathyroidism, and high body mass index (BMI). Whilst receiving 31 doses of intravenous sodium thiosulphate (STS) over an 11-week period, the patient underwent surgical debridement of multiple painful ulcerative lesions in his lower abdomen and left thigh and then subsequently a subtotal parathyroidectomy at 70 days from admission.

Catalytic inhibition of KAT6/KAT7 enhances the efficacy and overcomes primary and acquired resistance to Menin inhibitors in MLL leukaemia.

Understanding the molecular pathogenesis of MLL fusion oncoprotein (MLL-FP) leukaemia has spawned epigenetic therapies that have improved clinical outcomes in this often-incurable disease. Using genetic and pharmacological approaches, we define the individual and combined contribution of KAT6A, KAT6B and KAT7, in MLL-FP leukaemia. Whilst inhibition of KAT6A/B is efficacious in some pre-clinical models, simultaneous targeting of KAT7, with the novel inhibitor PF-9363, increases the therapeutic efficacy.

Acute resistance to BET inhibitors remodels compensatory transcriptional programs via p300 coactivation.

Initial clinical trials with drugs targeting epigenetic modulators - such as bromodomain and extraterminal protein (BET) inhibitors - demonstrate modest results in acute myeloid leukemia (AML). A major reason for this involves an increased transcriptional plasticity within AML, which allows cells to escape the therapeutic pressure. In this study, we investigated immediate epigenetic and transcriptional responses following BET inhibition and could demonstrate that BET inhibitor-mediated release of BRD4 from chromatin is accompanied by an acute compensatory feedback that attenuates down-regulation, or even increases expression, of specific transcriptional modules.