Fatty acid nitroalkenes - Multi-target agents for the treatment of sickle cell disease.

Sickle cell disease (SCD) is a hereditary hematological disease with high morbidity and mortality rates worldwide. Despite being monogenic, SCD patients display a plethora of disease-associated complications including anemia, oxidative stress, sterile inflammation, vaso-occlusive crisis-related pain, and vasculopathy, all of which contribute to multiorgan dysfunction and failure. Over the past decade, numerous small molecule drugs, biologics, and gene-based interventions have been evaluated; however, only four disease-modifying drug therapies are presently FDA approved.

HIC2 controls developmental hemoglobin switching by repressing BCL11A transcription.

The fetal-to-adult switch in hemoglobin production is a model of developmental gene control with relevance to the treatment of hemoglobinopathies. The expression of transcription factor BCL11A, which represses fetal β-type globin (HBG) genes in adult erythroid cells, is predominantly controlled at the transcriptional level but the underlying mechanism is unclear. We identify HIC2 as a repressor of BCL11A transcription.

Identification and characterization of RBM12 as a novel regulator of fetal hemoglobin expression.

The fetal-to-adult hemoglobin transition is clinically relevant because reactivation of fetal hemoglobin (HbF) significantly reduces morbidity and mortality associated with sickle cell disease (SCD) and β-thalassemia. Most studies on the developmental regulation of the globin genes, including genome-wide genetics screens, have focused on DNA binding proteins, including BCL11A and ZBTB7A/LRF and their cofactors. Our understanding of RNA binding proteins (RBPs) in this process is much more limited.

Cell-Based Therapies for Trabecular Meshwork Regeneration to Treat Glaucoma.

Glaucoma is clinically characterized by elevated intraocular pressure (IOP) that leads to retinal ganglion cell (RGC) and optic nerve damage, and eventually blindness if left untreated. Even in normal pressure glaucoma patients, a reduction of IOP is currently the only effective way to prevent blindness, by either increasing aqueous humor outflow or decreasing aqueous humor production. The trabecular meshwork (TM) and the adjacent Schlemm's canal inner wall play a key role in regulating IOP by providing resistance when aqueous humor drains through the tissue.

Alteration of genome folding via contact domain boundary insertion.

Animal chromosomes are partitioned into contact domains. Pathogenic domain disruptions can result from chromosomal rearrangements or perturbation of architectural factors. However, such broad-scale alterations are insufficient to define the minimal requirements for domain formation.

The HRI-regulated transcription factor ATF4 activates BCL11A transcription to silence fetal hemoglobin expression.

Reactivation of fetal hemoglobin remains a critical goal in the treatment of patients with sickle cell disease and β-thalassemia. Previously, we discovered that silencing of the fetal γ-globin gene requires the erythroid-specific eIF2α kinase heme-regulated inhibitor (HRI), suggesting that HRI might present a pharmacologic target for raising fetal hemoglobin levels. Here, via a CRISPR-Cas9-guided loss-of-function screen in human erythroblasts, we identify transcription factor ATF4, a known HRI-regulated protein, as a novel γ-globin regulator.

Understanding heterogeneity of fetal hemoglobin induction through comparative analysis of F and A erythroblasts.

Reversing the developmental switch from fetal hemoglobin (HbF, α2γ2) to adult hemoglobin (HbA, α2β2) is an important therapeutic approach in sickle cell disease (SCD) and β-thalassemia. In healthy individuals, SCD patients, and patients treated with pharmacologic HbF inducers, HbF is present only in a subset of red blood cells known as F cells. Despite more than 50 years of observations, the cause for this heterocellular HbF expression pattern, even among genetically identical cells, remains unknown.

Evolvement of transgenic male-sterility and fertility-restoration system in rice for production of hybrid varieties.

We have developed a unique male-sterility and fertility-restoration system in rice by combining Brassica napus cysteine-protease gene (BnCysP1) with anther-specific P12 promoter of rice for facilitating production of hybrid varieties. In diverse crop plants, male-sterility has been exploited as a useful approach for production of hybrid varieties to harness the benefits of hybrid vigour. The promoter region of Os12bglu38 gene of rice has been isolated from the developing panicles and was designated as P12.

Phytochemical analysis of Jatropha curcas L. during different seasons and developmental stages and seedling growth of wheat (Triticum aestivum L) as affected by extracts/leachates of Jatropha curcas L.

Jatropha curcas shows invasive characters and is a significant source of many phytochemicals with varying biological activities. Different plant parts of Jatropha curcas L exhibited variation in their phytochemical constituents. Leaves and ovary walls were found to contain higher contents of total phenols, tannins and phytic acid whereas free amino acids were greater in leaves.

Hysteroscopy: a technique for all? Analysis of 5,000 outpatient hysteroscopies.

Objective: 1) To investigate the relationship between operator experience and the success of outpatient hysteroscopy; and 2) to determine if the introduction of normal saline and the use of narrow-caliber hysteroscopes and vaginoscopic approach are associated with a lower failure rate.

Design: Retrospective study.

Setting: Teaching-hospital based outpatient hysteroscopy clinic.

A new technique for temporary ovarian suspension: temporarily displacing the ovaries anterior to the uterus facilitates pelvic side wall access in the laparoscopic treatment of endometriosis.

The adnexa frequently hinder access to the pelvic side wall during laparoscopic surgery for endometriosis. An innovative tactic can facilitate dissection.

Digital recording of surgical procedures using a personal computer.

Objective: To develop a system for recording surgical procedure digitally using a personal computer with real-time compression of the video signal.

Study Design: We built the system around a modern personal computer with a large hard disk to allow recording of over 250 h of continuous surgery. Digital capture from the camera was achieved using a standard external analogue-digital converter linked to the computer via a firewire cable.

Surgical and radiological management of uterine fibroids--a UK survey of current consultant practice.

Background: The aim of this study was to determine the current surgical and radiological management of uterine fibroids by consultants working in the UK.

Methods: A structured questionnaire was posted to all 1439 UK consultants. Non-responders were sent one reminder.

Chronic ectopic pregnancy diagnosed incidentally in an infertile woman: a case report.

Background: Chronic ectopic pregnancy is an enigma. The clinical presentation can be mild, with absent or subtle symptoms. The high incidence of negative pregnancy tests and the poor specificity of sonographic patterns can be misleading, and the correct diagnosis is sometimes established only at surgery or even histopathologically after the operation.

A new device for "no touch" biopsy at "no touch" hysteroscopy: the H Pipelle.

A new device for endometrial biopsy at "no touch" hysteroscopy has been developed based on the Pipelle. The modification (H Pipelle) facilitates endometrial sampling after hysteroscopy without the need to insert additional instruments into the vagina.