Discovery and Optimization of First-in-Class Molecular Glue Degraders of the WIZ Transcription Factor for Fetal Hemoglobin Induction to Treat Sickle Cell Disease.

Sickle cell disease (SCD) is a prevalent, life-threatening condition with few treatment options, attributed to a heritable mutation in β-hemoglobin. Therapeutic induction of fetal hemoglobin (HbF) with small molecules has been pursued as a treatment to ameliorate many disease complications but with limited success. Herein, we report the discovery of , a novel, potent, and selective molecular glue degrader of the transcription factor WIZ that robustly induces HbF expression as a potential treatment for SCD.

Quantification of heat shock proteins in the posterior interosseous nerve among subjects with type 1 and type 2 diabetes compared to healthy controls.

Introduction: Diabetic peripheral neuropathy (DPN) is a common complication of both type 1 (T1D) and type 2 diabetes (T2D). No cure for DPN is available, but several potential targets have been proposed for treatment. Heat shock proteins (HSPs) are known to respond to both hyper- and hypoglycemia.

Identification of Brain-Penetrant ATP-Competitive mTOR Inhibitors for CNS Syndromes.

The allosteric inhibitor of the mechanistic target of rapamycin (mTOR) everolimus reduces seizures in tuberous sclerosis complex (TSC) patients through partial inhibition of mTOR functions. Due to its limited brain permeability, we sought to develop a catalytic mTOR inhibitor optimized for central nervous system (CNS) indications. We recently reported an mTOR inhibitor () that is able to block mTOR functions in the mouse brain and extend the survival of mice with neuronal-specific ablation of the 1 gene.

HIV envelope antibodies and TLR7 agonist partially prevent viral rebound in chronically SHIV-infected monkeys.

A key challenge for the development of a cure to HIV-1 infection is the persistent viral reservoir established during early infection. Previous studies using Toll-like receptor 7 (TLR7) agonists and broadly neutralizing antibodies (bNAbs) have shown delay or prevention of viral rebound following antiretroviral therapy (ART) discontinuation in simian-human immunodeficiency virus (SHIV)-infected rhesus macaques. In these prior studies, ART was initiated early during acute infection, which limited the size and diversity of the viral reservoir.

Reconstruction of the Distal Oblique Bundle for DRUJ Instability.

 Treatment algorithm for disruption of the triangular fibrocartilage complex (TFCC) from the ulnar fovea includes direct TFCC repair, tendon reconstruction of the radioulnar ligaments, or a salvage procedure in cases with painful distal radioulnar joint (DRUJ) degeneration.  We describe our surgical technique for reconstruction of the distal oblique bundle (DOB), to attain DRUJ stability in a young man, after failed attempts of direct TFCC reinsertion and radioulnar ligament reconstruction with the Adams procedure.  Reconstruction of the central band of the interosseous membrane is well recognized for Essex-Lopresti injuries that demonstrate longitudinal forearm instability.

Pregnancy and postpartum psychiatric episodes in fathers: A population-based study on treatment incidence and prevalence.

Background: For women, the perinatal period confers an increased risk of severe psychiatric disorders, but similar evidence for fathers is lacking. We examined rates of first-time and recurrent psychiatric disorders in men before and after becoming fathers.

Methods: A descriptive prospective study design was applied using information from the Danish National registers.

Evaluation of Broadly Neutralizing Antibody Sensitivity by Genotyping and Phenotyping for Qualifying Participants to HIV Clinical Trials.

Background: HIV envelope (env) diversity represents a significant challenge for the use of broadly neutralizing antibodies (bNAbs) in HIV treatment and cure studies. Screening for viral sensitivity to bNAbs to select eligible trial participants will be important to improve clinical efficacy; however, no universal approach has been established.

Methods: Pre-antiretroviral therapy plasma virus from participants in the Zurich Primary HIV Infection (ZPHI) study was genotyped and phenotyped for sensitivity to the bNAbs elipovimab (EVM, formerly GS-9722) and 3BNC117.

Quantitative proteomic analysis of human peripheral nerves from subjects with type 2 diabetes.

Aims: Diabetic peripheral neuropathy (DPN) is a common and severe complication to type 2 diabetes. The pathogenesis of DPN is not fully known, but several pathways and gene polymorphisms contributing to DPN are described. DPN can be studied using nerve biopsies, but studies on the proteome of the nerve itself, and its surrounding tissue as a whole, are lacking.

Vibrotactile sense 5 years after carpal tunnel release in people with diabetes: A prospective study with matched controls.

Aim: To compare vibrotactile sense, 5 years after carpal tunnel release in people with and without diabetes.

Methods: Out of 35 people with diabetes and carpal tunnel syndrome, age- and gender-matched with 31 people without diabetes but with idiopathic carpal tunnel syndrome, 27 and 30 people, respectively, participated in this prolonged follow-up. Vibration perception threshold of the index and little finger (median and ulnar nerve, respectively), 5 years after surgery, was measured at seven different frequencies (8, 16, 32, 64, 125, 250 and 500 Hz).

Epidemiology of scaphoid fractures and non-unions: A systematic review.

Background: The scaphoid is the most commonly fractured carpal bone in adults as well as in children. Previous studies have reported a wide range of fracture incidences. Scaphoid fractures and non-unions in children have been sparsely investigated.

Outcome of carpal tunnel release in patients with normal nerve conduction studies.

Background: We evaluated outcome after carpal tunnel release (CTR) in patients with clinically diagnosed carpal tunnel syndrome (CTS) but normal results in nerve conduction studies (NCS), and compared these results with those from a prospective group of patients with NCS-verified CTS.

Methods: Over a 5-year period, we prospectively included 103 patients with clinical CTS. NCS were done at inclusion, with surgeon and patient being kept blind regarding the result.

Three-dimensional architecture of human diabetic peripheral nerves revealed by X-ray phase contrast holographic nanotomography.

A deeper knowledge of the architecture of the peripheral nerve with three-dimensional (3D) imaging of the nerve tissue at the sub-cellular scale may contribute to unravel the pathophysiology of neuropathy. Here we demonstrate the feasibility of X-ray phase contrast holographic nanotomography to enable 3D imaging of nerves at high resolution, while covering a relatively large tissue volume. We show various subcomponents of human peripheral nerves in biopsies from patients with type 1 and 2 diabetes and in a healthy subject.

Discovery of a Brain-Penetrant ATP-Competitive Inhibitor of the Mechanistic Target of Rapamycin (mTOR) for CNS Disorders.

Recent clinical evaluation of everolimus for seizure reduction in patients with tuberous sclerosis complex (TSC), a disease with overactivated mechanistic target of rapamycin (mTOR) signaling, has demonstrated the therapeutic value of mTOR inhibitors for central nervous system (CNS) indications. Given that everolimus is an incomplete inhibitor of the mTOR function, we sought to develop a new mTOR inhibitor that has improved properties and is suitable for CNS disorders. Starting from an in-house purine-based compound, optimization of the physicochemical properties of a thiazolopyrimidine series led to the discovery of the small molecule , a potent and selective brain-penetrant ATP-competitive mTOR inhibitor.

Evaluation of small nerve fiber dysfunction in type 2 diabetes.

Objectives: To assess potential correlations between intraepidermal nerve fiber densities (IENFD), graded with light microscopy, and clinical measures of peripheral neuropathy in elderly male subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes (T2DM), respectively.

Materials And Methods: IENFD was assessed in thin sections of skin biopsies from distal leg in 86 men (71-77 years); 24 NGT, 15 IGT, and 47 T2DM. Biopsies were immunohistochemically stained for protein gene product (PGP) 9.

Integrated Use of Biochemical, Native Mass Spectrometry, Computational, and Genome-Editing Methods to Elucidate the Mechanism of a Salmonella deglycase.

Salmonellais a foodborne pathogen that causes annually millions of cases of salmonellosis globally, yet Salmonella-specific antibacterials are not available. During inflammation, Salmonella utilizes the Amadori compound fructose-asparagine (F-Asn) as a nutrient through the successive action of three enzymes, including the terminal FraB deglycase. Salmonella mutants lacking FraB are highly attenuated in mouse models of inflammation due to the toxic build-up of the substrate 6-phosphofructose-aspartate (6-P-F-Asp).

[Scaphoid fractures - Guidelines for diagnosis and treatment].

This article suggests algorithms for diagnosis and treatment of scaphoid fractures. A clinical suspected scaphoid fracture without signs of fracture on conventional radiographs should have a supplementary MRI done within 5-7 days. Displaced fractures and all proximal fractures should be classified by CT.

Accuracy of Pre- and Postcontrast, 3 T Indirect MR Arthrography Compared with Wrist Arthroscopy in the Diagnosis of Wrist Ligament Injuries.

 Magnetic resonance (MR) is the most important imaging technique to assess intra-articular pathology of the wrist. Among various MR imaging protocols, the diagnostic performance of indirect MR arthrography needs further investigation.  The purpose of this study was to assess the diagnostic performance of pre- and postcontrast, 3 T indirect MR arthrography in the diagnosis of scapholunate intrinsic ligament (SLIL) and triangular fibrocartilage complex (TFCC) injuries, using wrist arthroscopy as reference standard.

Multiple genetic variations in sodium channel subunits in a case of sudden infant death syndrome.

Background: Dysfunction of Na 1.5 encoded by SCN5A accounts for approximately half of the channelopathic SIDS cases. We investigated the functional effect of two gene variants identified in the same patient, one in SCN5A and one in SCN1Bb.

Discovery of LSZ102, a Potent, Orally Bioavailable Selective Estrogen Receptor Degrader (SERD) for the Treatment of Estrogen Receptor Positive Breast Cancer.

In breast cancer, estrogen receptor alpha (ERα) positive cancer accounts for approximately 74% of all diagnoses, and in these settings, it is a primary driver of cell proliferation. Treatment of ERα positive breast cancer has long relied on endocrine therapies such as selective estrogen receptor modulators, aromatase inhibitors, and selective estrogen receptor degraders (SERDs). The steroid-based anti-estrogen fulvestrant (5), the only approved SERD, is effective in patients who have not previously been treated with endocrine therapy as well as in patients who have progressed after receiving other endocrine therapies.

Engineering a light-activated caspase-3 for precise ablation of neurons in vivo.

The circuitry of the brain is characterized by cell heterogeneity, sprawling cellular anatomy, and astonishingly complex patterns of connectivity. Determining how complex neural circuits control behavior is a major challenge that is often approached using surgical, chemical, or transgenic approaches to ablate neurons. However, all these approaches suffer from a lack of precise spatial and temporal control.