Ronin is essential for embryogenesis and the pluripotency of mouse embryonic stem cells.

Pluripotency is a unique biological state that allows cells to differentiate into any tissue type. Here we describe a candidate pluripotency factor, Ronin, that possesses a THAP domain, which is associated with sequence-specific DNA binding and epigenetic silencing of gene expression. Ronin is expressed primarily during the earliest stages of murine embryonic development, and its deficiency in mice produces periimplantational lethality and defects in the inner cell mass. Conditional knockout of Ronin prevents the growth of ES cells while forced expression of Ronin allows ES cells to proliferate without differentiation under conditions that normally do not promote self-renewal. Ectopic expression also partly compensates for the effects of Oct4 knockdown. We demonstrate that Ronin binds directly to HCF-1, a key transcriptional regulator. Our findings identify Ronin as an essential factor underlying embryogenesis and ES cell pluripotency. Its association with HCF-1 suggests an epigenetic mechanism of gene repression in pluripotent cells.

Transverse Myelitis Associated with Cryptococcus neoformans in an Immunocompetent Patient.

Cryptococcus neoformans is a microscopic fungus that despite its pervasiveness in the environment rarely causes infection in immunocompetent patients. In immunosuppressed patients, infections involving the central nervous system (CNS) usually present as meningitis or meningoencephalitis. Cryptococcal infections are known to cause significant morbidity and mortality in immunosuppressed patients as it is difficult to eradicate even with adequate antifungal treatment. A 44-year-old Hispanic male presented to the hospital with headache, progressive urinary retention, neck and back pain, and right upper and bilateral lower extremity weakness for five days. Imaging revealed small foci in the white matter and revealed diffuse abnormal signal involving the cervical medullary junction extending up to the thoracic spine. Analysis of cerebral spinal fluid (CSF) obtained via lumbar puncture was positive for the Streptococcus antigen with cultures also growing Cryptococcus neoformans. Upon evaluation, patient was not found to be immunocompromised. This report works to highlight an atypical presentation of a cryptococcal CNS infection to raise awareness amongst clinicians hoping to prevent a delay in diagnosis of this disease given its high mortality.

Pisiform Bone Dislocation in a Pediatric Patient: What is the Best Treatment? Case Report and Review of the Literature.

Traumatic dislocation of the pisiform bone (PB) is a rare injury of the carpal bones, especially in pediatric patients. A few cases were reported, and there is no consensus about the treatment. Each author supports his own method, such as an open reduction internal fixation (ORIF) approach or a closed reduction. However, failures of both techniques with recurrent dislocation of the PB have been reported in the literature. In this article, a fracture dislocation of the PB was treated with ORIF in an 11-year-old boy with a greenstick radial fracture. In addition, a review of the literature about pisiform fracture dislocation in children has been made.

Chronic active Epstein-Barr exacerbated by COVID-19 co-infection.

A 60-year-old Hispanic female was admitted with recurrent fevers, altered mental status, lymphadenopathy, hepatosplenomegaly, and pancytopenia. Initially, sepsis was presumed because of recurrent urinary tract infection with extended-spectrum beta-lactamase Escherichia coli. Despite appropriate therapy, her clinical condition continued to decline. An extensive workup was obtained to determine the source of her ailments. Bone marrow biopsy was negative for leukemia, lymphoma, and myelodysplastic syndrome; fluorescence in situ hybridization and a cytogenetic panel were normal; a lumbar puncture was negative. However, peripheral blood was remarkable for elevated titers for Epstein-Barr virus (EBV) consistent with chronic active EBV. Treatment with valganciclovir showed early positive results, but the patient became co-infected with COVID-19, and her EBV titer increased again, resulting in a precipitous health decline and death.

Rad23 as a reciprocal agent for stimulating or repressing immune responses.

The proteasome degrades cellular proteins and provides peptides for major histocompatibility complex (MHC) class I molecules to drive CD8+ T-cell responses to kill intracellular pathogens. Rad23 plays a role in protein degradation by targeting polyubiquitinated substrates to the proteasome via an N-terminal ubiquitin-like (UbL) domain that binds the proteasome and two C-terminal ubiquitin-associated (UBA) domains that bind ubiquitinated proteins. We demonstrate here that fusion of Rad23 or its UBA domain to the green fluorescent protein (GFP) targets this antigen to the proteasome for increased degradation in mammalian cells and enhanced antigen-specific CD8+ T-cell responses in BALB/c mice. Conversely, we show that coexpression of unfused Rad23 with destabilized GFP inhibits degradation of the reporter protein and attenuates in vivo CD8+ T-cell responses. Rad23 therefore holds promise as a useful agent either to enhance or attenuate cellular immune responses to suit the reciprocal immunologic needs of both gene therapy and genetic vaccine applications.

Oral immunization of rhesus macaques with adenoviral HIV vaccines using enteric-coated capsules.

Targeted delivery of vaccine candidates to the gastrointestinal (GI) tract holds potential for mucosal immunization, particularly against mucosal pathogens like the human immunodeficiency virus (HIV). Among the different strategies for achieving targeted release in the GI tract, namely the small intestine, pH sensitive enteric coating polymers have been shown to protect solid oral dosage forms from the harsh digestive environment of the stomach and dissolve relatively rapidly in the small intestine by taking advantage of the luminal pH gradient. We developed an enteric polymethacrylate formulation for coating hydroxy-propyl-methyl-cellulose (HPMC) capsules containing lyophilized Adenoviral type 5 (Ad5) vectors expressing HIV-1 gag and a string of six highly-conserved HIV-1 envelope peptides representing broadly cross-reactive CD4(+) and CD8(+) T cell epitopes. Oral immunization of rhesus macaques with these capsules primed antigen-specific mucosal and systemic immune responses and subsequent intranasal delivery of the envelope peptide cocktail using a mutant cholera toxin adjuvant boosted cellular immune responses including, antigen-specific intracellular IFN-gamma-producing CD4(+) and CD8(+) effector memory T cells in the intestine. These results suggest that the combination of oral adenoviral vector priming followed by intranasal protein/peptide boosting may be an effective mucosal HIV vaccination strategy for targeting viral antigens to the GI tract and priming systemic and mucosal immunity.