Centers for New Horizons

Gene duplication generates gene paralogs that may undergo diverse fates during evolution, and thus serves as a potent catalyst of biological complexity. Genetic paralogs frequently share redundant functions and may also exhibit antagonistic activities by competing for common interaction partners. Here we show that the gene paralogs NRBP1 and NRBP2 oppositely regulate long interspersed nuclear element-1 (L1) retrotransposition, via influencing integrity of the L1 ribonucleoprotein complex. We demonstrate that the opposing roles of NRBP1 and NRBP2 are not results of a competitive mechanism, but rather due to targeting NRBP1 for degradation by NRBP2, probably through heterodimer formation. Moreover, our phylogenetic analysis shows that the regulatory function of NRBP2 may be acquired later during evolution, suggesting that evolutionary pressure has favored this functional fine-tuning of NRBP1. In summary, our findings not only identify NRBP1/2 as L1 regulators and implicate their involvement in human pathogenesis, but also provide a mechanistic insight into the regulatory details arising from gene duplication.

Abstract Purpose Pediatric external hemorrhoids are rare and often misdiagnosed. This study assesses clinical presentation, risk factors, and treatment outcomes, comparing conservative management with injection sclerotherapy. Methods A retrospective cohort study (2007–2024) was conducted at a tertiary pediatric hospital, including pediatric patients treated with conservative therapy (watchful waiting) or injection sclerotherapy for external hemorrhoids. Data from medical records were analyzed for patient history, presentation, treatment outcomes, and complications. Results Forty-four patients (86.4% male) were included. Mean age at symptom onset and presentation was respectively 4.0 (range 0–11) and 5.8 (range 2–13) years, with a median diagnostic delay of 20.5 months. All reported anal protrusion/swelling during/after defecation, though this was only visible on examination in 11.4%; diagnosis was otherwise based on parent-provided photographs (63.6%) or reference images (25.0%). Additional symptoms included pain (45.5%), bleeding (18.2%), anal itching (13.6%), anxiety (9.1%) and tenesmus (6.8%). Thirty-one patients (70.5%) underwent injection sclerotherapy, with a 69.2% success rate after one, and 90.3% after two injections. Thirteen patients (29.5%) were treated conservatively with watchful waiting, with symptoms resolving within one year, although the lesion(s) persisted. Skin erosion occurred in 35.5% of patients treated with injection sclerotherapy, leading to constipation and defecation anxiety in 9.1% of patients. Conclusion Pediatric external hemorrhoids present as anal protrusion/swelling, often accompanied by anorectal pain. Diagnosis is often delayed due to its intermittent nature. Parent-provided photographs can confirm diagnosis. Both conservative management and injection sclerotherapy are viable treatments; injection sclerotherapy offers a definitive resolution but carries risks of relapse and complications.

The dNTPase activity of tetrameric SAM and HD domain containing deoxynucleoside triphosphate triphosphohydrolase 1 (SAMHD1) plays a critical role in cellular dNTP regulation. SAMHD1 also associates with stalled DNA replication forks, DNA repair foci, ssRNAand telomeres. The above functions require nucleic acid binding by SAMHD1, which may be modulated by its oligomeric state. Here we establish in cryo-EM and biochemical studies that the guanine-specific A1 activator site of each SAMHD1 monomer is used to target the enzyme to guanine nucleotides within single-stranded (ss) DNA and RNA. Remarkably, nucleic acid strands containing a single guanine base induce dimeric SAMHD1, while two or more guanines with ∼20 nucleotide spacing induce a tetrameric form. A cryo-EM structure of ssRNA-bound tetrameric SAMHD1 shows how ssRNA strands bridge two SAMHD1 dimers and stabilize the structure. This ssRNA-bound tetramer is inactive with respect to dNTPase and RNase activity.

Imaging techniques have evolved impressively lately, allowing whole new concepts like multimodal imaging, personal medicine, theranostic therapies, and molecular imaging to increase general awareness of possiblities of imaging to medicine field. Here, we have collected the selected (3D) imaging modalities and evaluated the recent findings on preclinical and clinical inflammation imaging. The focus has been on the feasibility of imaging to aid in inflammation precision medicine, and the key challenges and opportunities of the imaging modalities are presented. Some examples of the current usage in clinics/close to clinics have been brought out as an example. This review evaluates the future prospects of the imaging technologies for clinical applications in precision medicine from the pre-clinical development point of view.

With the resumption of elective ophthalmic surgery during COVID-19, revised protocols were mandated to protect both staff and patients from transmission while increasing case numbers. We discuss a widely generalizable and in-depth protocol intended to safely allow the restart of elective procedures in 2 dedicated ophthalmic ambulatory surgical centers (ASCs) using monitored anesthesia care. A single-center review of protocols and practices designed to limit COVID-19 transmission. All patients were tested within 72 hours prior to the procedure with a COVID-19 nasal swab to assess for active disease. A distance of 6 ft between each stretcher and the staff within the ASC was maintained when possible. Preoperative anesthetizing and dilating eye drops were administered from multiuse bottles without contact with surfaces. Surgical cases were restarted at a reduced capacity of a maximum of 7 per day to distance patient arrivals. Removal of waiting room chairs and the creation of new break areas allowed for social distancing. As recommendations change on the basis of an increased understanding of the COVID-19 virus, ophthalmologists and ASC staff need to tailor protocols and workflows to limit transmission of virus with resumption of ocular surgery.

An unusual finding in an adult patient with an infected urachal cyst, was treated surgically using the Da Vinci robot. A 26-year-old woman was admitted to our hospital with complaints of lower abdominal pain and burning sensation with urination. She was diagnosed with lower urinary tract infection, treatment did not help her symptoms and further evaluation of CT revealed complex enhancing mass superior to the urinary bladder. The differentials included inflammatory cause such as an abscess, neoplastic mass, urachal cyst, vitello intestinal fistula and urachal sinus. Da Vinchi robotic diagnostic laparoscopy was performed to obtain an accurate assessment and treatment. After cystoscopy followed by laparoscopic exploration of the abdominal and pelvic cavity further helped to narrow down a diagnosis of remnants of urachus. Pathology of the excised specimen showed inflammation without evidence of malignancy and confirmed Urachal cyst. The patient had an uneventful post-operative course.

Slit guidance ligand 2 (SLIT2) is a large, secreted protein that binds roundabout (ROBO) receptors on multiple cell types, including neurons and kidney podocytes. SLIT2-ROBO-mediated signaling regulates neuronal migration and ureteric bud (UB) outgrowth during kidney development as well as glomerular filtration in adult kidneys. Additionally, SLIT2 binds Gremlin, an antagonist of bone morphogenetic proteins (BMPs), and BMP-Gremlin signaling also regulates UB formation. However, direct cross-talk between the ROBO2-SLIT2 and BMP-Gremlin signaling pathways has not been established. Here, we report the discovery of negative feedback between the SLIT2 and BMP-Gremlin signaling pathways. We found that the SLIT2-Gremlin interaction inhibited both SLIT2-ROBO2 signaling in neurons and Gremlin antagonism of BMP activity in myoblasts and fibroblasts. Furthermore, BMP2 down-regulated SLIT2 expression and promoter activity through canonical BMP signaling. Gremlin treatment, BMP receptor inhibition, and SMAD family member 4 (SMAD4) knockdown rescued BMP-mediated repression of SLIT2. BMP2 treatment of nephron progenitor cells derived from human embryonic stem cells decreased SLIT2 expression, further suggesting an interaction between the BMP2-Gremlin and SLIT2 pathways in human kidney cells. In conclusion, our study has revealed direct negative cross-talk between two pathways, previously thought to be unassociated, that may regulate both kidney development and adult tissue maintenance.

The objective of this study was to assess the adverse health symptoms experienced by adult subjects who were exposed to benzene after a flaring disaster at the BP refinery in Texas City, Texas. A total of 2162 adults aged 18 years or older and exposed to benzene were included. Using the patients' medical charts, we collected and analyzed data on health complaints as well as the patients' serum levels of beta-2-microglobulin and urinary excretion of phenol. A total of 11,368 health symptom complaints were reported in 2162 adults exposed to benzene. Neurological symptoms occurred most frequently (174%), followed upper respiratory symptoms (115%), cough (31%), painful joints (30%), cardiac symptoms (28%), dermatological symptoms (28%), gastrointestinal symptoms (27%), diarrhea (25%), vision symptoms (21%), and nausea/vomiting (19%). Logistic regression analysis indicated that urinary symptoms (R2=0.65) and painful joints (R2=0.44) were positively associated with increasing age in benzene-exposed subjects. Adult subjects exposed to benzene experience a range of adverse health symptoms and an altered profile of urinary phenol, thus indicating they are at high risk of developing serious future health complications. (Disaster Med Public Health Preparedness. 2018;12:232-240).