Highlights d The self-polymerizing HIV-1 capsid protein 'trapped' in discrete, soluble oligomers d Engineered capsid protein assemblies faithfully mimic the infectious capsid surface d Host factors MxB, TRIMCyp, TRIM5a, and FEZ1 recognize unique capsid patterns d Capsid binding by proteins and small molecules can be rapidly analyzed

No abstract

Type 2 diabetes is associated with insulin resistance, impaired pancreatic β-cell insulin secretion, and nonalcoholic fatty liver disease. Tissue-specific SWELL1 ablation impairs insulin signaling in adipose, skeletal muscle, and endothelium, and impairs β-cell insulin secretion and glycemic control. Here, we show that ICl,SWELL and SWELL1 protein are reduced in adipose and β-cells in murine and human diabetes. Combining cryo-electron microscopy, molecular docking, medicinal chemistry, and functional studies, we define a structure activity relationship to rationally-design active derivatives of a SWELL1 channel inhibitor (DCPIB/SN-401), that bind the SWELL1 hexameric complex, restore SWELL1 protein, plasma membrane trafficking, signaling, glycemic control and islet insulin secretion via SWELL1-dependent mechanisms. In vivo, SN-401 restores glycemic control, reduces hepatic steatosis/injury, improves insulin-sensitivity and insulin secretion in murine diabetes. These findings demonstrate that SWELL1 channel modulators improve SWELL1-dependent systemic metabolism in Type 2 diabetes, representing a first-in-class therapeutic approach for diabetes and nonalcoholic fatty liver disease.

Twenty-three patients with an ileal bladder substitute formed after cystectomy for invasive bladder cancer were evaluated clinically and urodynamically between 3 and 38 months post-operatively. The urodynamic measurements were compared with the clinical findings. After re-education of the patients' voiding habits the mean voiding volumes of the bladder substitutes stabilised 6-9 months post-operatively at 350 ml. The frequency of micturition was 3 to 5 times during the day and once or twice at night. The maximum functional capacity (maximum voiding volume) was about 490 ml. Ninety-one per cent of the patients were continent during the day 18 months after the operation and 82% were continent during the night. Micturition was problem-free with an average maximum flow of 25 ml/s and an average micturition time of 50 s. The mean voiding volume of ileal bladder substitutes was 50% of the measured cystometric capacity; the maximum functional capacity (= max. micturition volume) was 80% of the cystometric capacity. The average basal pressure was < 20 cm H2O from the third post-operative month onwards. Eleven of the 23 patients had contractions in the bladder substitute (average at 30 cm H2O) at 55-76% of the maximum cystometric capacity or at approximately 90% of the maximum functional capacity. Such spike waves had no clinical or radiological consequences. If the patients were shown how to increase the functional capacity of a reservoir made from only 40 cm of ileum, the clinical results were excellent.

When a urinary reservoir intended to replace the bladder is made from bowel, it should meet several requirements: good capacity, viscoelasticity and compliance, voluntary control of micturition without residual (infected) urine, a sensation of the filled state and urinary continence. In addition, there should be no major metabolic changes due to malabsorption after bowel resection or due to reabsorption of urinary constituents by the reservoir. In this review several conflicting aspects of bladder reconstruction are addressed: the persisting intestinal peristalsis and urinary incontinence, the volume of the reservoir and its metabolic impact, the bowel segment to be used and the amount that can be resected without the risk of long-term sequelae. Our clinical experience with ileal bladder substitutes in 80 patients underlines the theoretical aspects. After careful instruction, our patients increased the functional capacity of their reservoirs to 500 ml, a precondition for good urinary continence. Provided that the patients were regularly followed-up, the functional, clinical and metabolic results were good. The operative procedure was easy to perform, and no major metabolic sequelae occurred during a maximal observation time of 6 years. Nevertheless, continuing careful follow-up for the detection of potential long-term sequelae, such as disturbances in lipid metabolism or chronic bone demineralisation, are required before definitive statements on the role of intestinal bladder substitutes can be made.The therapeutic benefits of a radical cystectomy for invasive bladder cancer must be considered in the light of the impact of urinary diversion on the quality of life and the associated morbidity. Although today the ileal conduit is still considered to be the standard urinary diversion with * To whom correspondence should be addressed which any other form must be compared, the first attempt at continent urinary drainage, a case of ureterosigmoidostomy, was reported as early as in 1852 by J. Simon [40]. Various forms of intestinal segments were in use for continent urinary reservoirs and bladder substitutes at the turn of this century [46]. High rates of surgical, metabolic and infectious complications have precluded the widespread use of bladder substitutes. However, a better understanding of intestinal physiology, the metabolic implications of the use of the intestine as part 0fthe urinary tract and increasing knowledge of the urodynamic aspects of urinary continence have led to a r~ni~issance of continent diversion first in the 1950s and then again in recent years.The intestinal bladder substitute should be a low-pressure, capacious and high compliance reservoir that can be voided without residual urine as the patient desires. The state of fullness should be appreciable by the patient. The bladder should provide voluntary control of urine as well as continence. Renal functions must be preserved, but at the same time intestinal malabsorption, fluid and electrolyte imbalances and metabolic long-term sequelae caused by...