Histone H1 loss drives lymphoma by disrupting 3D chromatin architecture.

Linker histone H1 proteins bind to nucleosomes and facilitate chromatin compaction1, although their biological functions are poorly understood. Mutations in the genes that encode H1 isoforms B-E (H1B, H1C, H1D and H1E; also known as H1-5, H1-2, H1-3 and H1-4, respectively) are highly recurrent in B cell lymphomas, but the pathogenic relevance of these mutations to cancer and the mechanisms that are involved are unknown. Here we show that lymphoma-associated H1 alleles are genetic driver mutations in lymphomas. Disruption of H1 function results in a profound architectural remodelling of the genome, which is characterized by large-scale yet focal shifts of chromatin from a compacted to a relaxed state. This decompaction drives distinct changes in epigenetic states, primarily owing to a gain of histone H3 dimethylation at lysine 36 (H3K36me2) and/or loss of repressive H3 trimethylation at lysine 27 (H3K27me3). These changes unlock the expression of stem cell genes that are normally silenced during early development. In mice, loss of H1c and H1e (also known as H1f2 and H1f4, respectively) conferred germinal centre B cells with enhanced fitness and self-renewal properties, ultimately leading to aggressive lymphomas with an increased repopulating potential. Collectively, our data indicate that H1 proteins are normally required to sequester early developmental genes into architecturally inaccessible genomic compartments. We also establish H1 as a bona fide tumour suppressor and show that mutations in H1 drive malignant transformation primarily through three-dimensional genome reorganization, which leads to epigenetic reprogramming and derepression of developmentally silenced genes.

Mechanisms by which the cystic fibrosis transmembrane conductance regulator may influence SARS-CoV-2 infection and COVID-19 disease severity.

Patients with cystic fibrosis (CF) exhibit pronounced respiratory damage and were initially considered among those at highest risk for serious harm from SARS-CoV-2 infection. Numerous clinical studies have subsequently reported that individuals with CF in North America and Europe-while susceptible to severe COVID-19-are often spared from the highest levels of virus-associated mortality. To understand features that might influence COVID-19 among patients with cystic fibrosis, we studied relationships between SARS-CoV-2 and the gene responsible for CF (i.e., the cystic fibrosis transmembrane conductance regulator, CFTR). In contrast to previous reports, we found no association between CFTR carrier status (mutation heterozygosity) and more severe COVID-19 clinical outcomes. We did observe an unexpected trend toward higher mortality among control individuals compared with silent carriers of the common F508del CFTR variant-a finding that will require further study. We next performed experiments to test the influence of homozygous CFTR deficiency on viral propagation and showed that SARS-CoV-2 production in primary airway cells was not altered by the absence of functional CFTR using two independent protocols. On the contrary, experiments performed in vitro strongly indicated that virus proliferation depended on features of the mucosal fluid layer known to be disrupted by absent CFTR in patients with CF, including both low pH and increased viscosity. These results point to the acidic, viscous, and mucus-obstructed airways in patients with cystic fibrosis as unfavorable for the establishment of coronaviral infection. Our findings provide new and important information concerning relationships between the CF clinical phenotype and severity of COVID-19.

From terminal ileum to terminal diagnosis: The critical role of terminal ileum intubation in diagnosing langerhans cell histiocytosis in a patient with TAR syndrome.

The co-occurrence of Thrombocytopenia with Absent Radius (TAR) syndrome and Langerhans Cell Histiocytosis (LCH) is exceedingly rare, with scant documentation in existing medical literature. This case report aims to shed light on this unique intersection of conditions, emphasizing the diagnostic and therapeutic challenges it presents. A 27-year-old female with a history of TAR syndrome presented with microcytic anemia, hip pain, and gastrointestinal symptoms. Terminal ileum intubation during colonoscopy revealed superficial ulcerations, leading to a biopsy that confirmed LCH. Subsequent radiologic investigations, including CT and MRI, showed multiple osseous lesions in the pelvis, sacrum, and skull. A treatment plan involving IV Cytarabine was initiated due to concerns of CNS involvement, as indicated by mastoid air cell involvement and symptoms of dizziness and ear fullness. The case highlights the diagnostic value of terminal ileum intubation during colonoscopy, which was pivotal in diagnosing LCH in this patient. It also discusses the use of IV cytarabine, a chemotherapy drug that inhibits DNA synthesis, as a suitable treatment option given the suspected CNS involvement. The case adds to the limited literature on the natural history and management of adult patients with LCH, particularly in the context of TAR syndrome. This case report serves as a compelling addition to medical literature, highlighting the diagnostic complexities and treatment considerations in a patient with both TAR syndrome and LCH. It emphasizes the importance of comprehensive diagnostic approaches, including terminal ileum intubation during colonoscopy, and introduces IV cytarabine as a viable treatment option for cases with suspected CNS involvement.

Design and Implementation of an Instrumented Data Glove that measures Kinematics and Dynamics of Human Hand.

Human hands are versatile biomechanical architectures that can perform simple movements such as grasping to complicated movements such as playing a musical instrument. Such extremely dependable and useful parts of the human body can be debilitated due to movement disorders such as Parkinson's disease, stroke, spinal cord injury, multiple sclerosis and cerebral palsy. In such cases, precisely measuring the residual or abnormal hand function becomes a critical assessment to help clinicians and physical therapists in diagnosis, treatment and in prescribing appropriate prosthetics or rehabilitation therapies. The current methodologies used to measure abnormal or residual hand function are either paperbased scales that are prone to human error or expensive motion tracking systems. The cost and complexity restrict the usability of these methods in clinical environments. In this paper we present a low-cost instrumented glove that can measure kinematics and dynamics of human hand, by leveraging the recent advances in 3D printing technologies and flexible sensors.

Dietary Interventions to Prevent or Delay Alzheimer's Disease: What the Evidence Shows.

PURPOSE OF REVIEW: A variety of potentially modifiable risk factors have been investigated in an attempt to delay/prevent Alzheimer's disease (AD). Among these, dietary regimens and nutritional supplements have been most extensively studied. The purpose of this article is to critically review recent evidence for the Mediterranean/MIND diets along with the use of various vitamins and popular herbal supplements, including curcumin, Ginkgo biloba, and fish oil, among others. RECENT FINDINGS: The Mediterranean and MIND diets are supported by observational studies performed in community settings, especially in the group with high adherence to the Mediterranean diet and with moderate-high adherence to the MIND diet. Randomized controlled trials of various vitamins and supplements have, in general, not shown statistically significant results, although there has been some promising evidence for vitamin D supplementation and curcumin use. There is sufficient data to recommend the Mediterranean and MIND diets to delay the onset of AD. It is judicious to supplement vitamin D, especially in deficient patients, and to consider the use of curcumin to improve cognitive performance. Future research should focus on larger, controlled trials in diverse populations.

Acute shortness of breath due to reoccurrence of an intrapericardial bronchogenic cyst.

A 71-year-old woman presented with dysphagia and acute shortness of breath. Surgical history included a prior thoracotomy overseas for a bronchogenic mesothelial cyst 19 years before. Computed tomography demonstrated a mass within the posterior mediastinum measuring 69 × 70 × 74 mm. A median sternotomy was performed, and after removal of the cyst, repair of the left atrium and pulmonary vessels was undertaken due to the invading nature of the cyst. Intrapericardial bronchogenic cysts are a rare form of congenital cysts arising from the primitive foregut. The cardiac primordia are in close proximity to the foregut and primitive tracheobronchial tree, and thus, abnormal budding of the tracheobronchial tree can arise in a myocardial location. Irrespective of the method of approach in redo surgery, complete resection must be performed in order to minimize the chance of recurrence, relieve symptoms, eliminate risk of infection, and prevent malignant degeneration.

Discovery of Stromal Regulatory Networks that Suppress Ras-Sensitized Epithelial Cell Proliferation.

Mesodermal cells signal to neighboring epithelial cells to modulate their proliferation in both normal and disease states. We adapted a Caenorhabditis elegans organogenesis model to enable a genome-wide mesodermal-specific RNAi screen and discovered 39 factors in mesodermal cells that suppress the proliferation of adjacent Ras pathway-sensitized epithelial cells. These candidates encode components of protein complexes and signaling pathways that converge on the control of chromatin dynamics, cytoplasmic polyadenylation, and translation. Stromal fibroblast-specific deletion of mouse orthologs of several candidates resulted in the hyper-proliferation of mammary gland epithelium. Furthermore, a 33-gene signature of human orthologs was selectively enriched in the tumor stroma of breast cancer patients, and depletion of these factors from normal human breast fibroblasts increased proliferation of co-cultured breast cancer cells. This cross-species approach identified unanticipated regulatory networks in mesodermal cells with growth-suppressive function, exposing the conserved and selective nature of mesodermal-epithelial communication in development and cancer.

LASIK for hyperopia with the WaveLight excimer laser.

PURPOSE: To evaluate the safety and efficacy of the ALLEGRETTO WAVE excimer laser system (WaveLight Laser Technologie AG, Erlangen, Germany) in LASIK for hyperopia and hyperopic astigmatism. METHODS: One hundred twenty consecutive LASIK cases for hyperopia with or without astigmatism treated with the ALLEGRETTO WAVE excimer laser were prospectively evaluated up to 12 months postoperatively. Patients were allocated into three groups according to their refractive sphere and cylinder: a low hyperopia group, with up to +3.00 diopters (D) sphere and astigmatism < or = +1.00 D (n = 52); a moderate hyperopia group with +3.25 to +5.00 D sphere and astigmatism of < or = +1.00 D (n = 45); and a high hyperopia/toric group with sphere > or = +5.25 D or cylinder > or = +1.25.D (n = 23). Flaps were created with the Moria M2 microkeratome (Moria, Antony, France). Parameters evaluated were pre- and postoperative refractive error, uncorrected visual acuity, best spectacle-corrected visual acuity (BSCVA), higher order aberration change, and contrast sensitivity. RESULTS: One hundred twelve eyes (93%) were available for follow-up at 12 months. Of the eyes in the low hyperopia group, 92% were within +/- 0.50 D of the refractive goal. For the moderate sphere group and the high hyperopia/toric group, 79% and 71% of eyes, respectively, were within +/- 0.50 D of the refractive goal. No eye lost > or = 2 lines of BSCVA. An increase in higher order aberrations was noted in the high hyperopia/toric group from 0.47 microm (+/- 0.096) to 0.94 microm (+/- 0.167) (P < .001). No significant changes in higher order aberrations were noted in the low and moderate hyperopia groups. CONCLUSIONS: Hyperopic LASIK using the WaveLight ALLEGRETTO WAVE excimer laser appears to be safe and effective in the correction of low, moderate, and high hyperopia and hyperopic astigmatism.

FoxD3 regulates cranial neural crest EMT via downregulation of tetraspanin18 independent of its functions during neural crest formation.

The scaffolding protein tetraspanin18 (Tspan18) maintains epithelial cadherin-6B (Cad6B) to antagonize chick cranial neural crest epithelial-to-mesenchymal transition (EMT). For migration to take place, Tspan18 must be downregulated. Here, we characterize the role of the winged-helix transcription factor FoxD3 in the control of Tspan18 expression. Although we previously found that Tspan18 mRNA persists several hours past the stage it would normally be downregulated in FoxD3-deficient neural folds, we now show that Tspan18 expression eventually declines. This indicates that while FoxD3 is crucial for initial downregulation of Tspan18, other factors subsequently impact Tspan18 expression. Remarkably, the classical EMT transcription factor Snail2 is not one of these factors. As in other vertebrates, FoxD3 is required for chick cranial neural crest specification and migration, however, FoxD3 has surprisingly little impact on chick cranial neural crest cell survival. Strikingly, Tspan18 knockdown rescues FoxD3-dependent neural crest migration defects, although neural crest specification is still deficient. This indicates that FoxD3 promotes cranial neural crest EMT by eliciting Tspan18 downregulation separable from its Tspan18-independent activity during neural crest specification and survival.