Design and Characterization of a Novel Intravitreal Dual-Transgene Genetic Medicine for Neovascular Retinopathies.

Purpose: Intravitreal delivery of therapeutic transgenes to the retina via engineered viral vectors can provide sustained local concentrations of therapeutic proteins and thus potentially reduce the treatment burden and improve long-term vision outcomes for patients with neovascular (wet) age-related macular degeneration (AMD), diabetic macular edema (DME), and diabetic retinopathy.

Methods: We performed directed evolution in nonhuman primates (NHP) to invent an adeno-associated viral (AAV) variant (R100) with the capacity to cross vitreoretinal barriers and transduce all regions and layers of the retina following intravitreal injection. We then engineered 4D-150, an R100-based genetic medicine carrying 2 therapeutic transgenes: a codon-optimized sequence encoding aflibercept, a recombinant protein that inhibits VEGF-A, VEGF-B, and PlGF, and a microRNA sequence that inhibits expression of VEGF-C.

RGS10 Attenuates Systemic Immune Dysregulation Induced by Chronic Inflammatory Stress.

Regulator of G-protein signaling 10 (RGS10), a key homeostatic regulator of immune cells, has been implicated in multiple diseases associated with aging and chronic inflammation including Parkinson's Disease (PD). Interestingly, subjects with idiopathic PD display reduced levels of RGS10 in subsets of peripheral immune cells. Additionally, individuals with PD have been shown to have increased activated peripheral immune cells in cerebral spinal fluid (CSF) compared to age-matched healthy controls.

Locus coeruleus injury modulates ventral midbrain neuroinflammation during DSS-induced colitis.

Parkinson's disease (PD) is characterized by a decades-long prodrome, consisting of a collection of non-motor symptoms that emerges prior to the motor manifestation of the disease. Of these non-motor symptoms, gastrointestinal dysfunction and deficits attributed to central norepinephrine (NE) loss, including mood changes and sleep disturbances, are frequent in the PD population and emerge early in the disease. Evidence is mounting that injury and inflammation in the gut and locus coeruleus (LC), respectively, underlie these symptoms, and the injury of these systems is central to the progression of PD.

Locus coeruleus injury modulates ventral midbrain neuroinflammation during DSS-induced colitis.

Parkinson's disease (PD) is characterized by a decades-long prodrome, consisting of a collection of non-motor symptoms that emerges prior to the motor manifestation of the disease. Of these non-motor symptoms, gastrointestinal dysfunction and deficits attributed to central norepinephrine (NE) loss, including mood changes and sleep disturbances, are frequent in the PD population and emerge early in the disease. Evidence is mounting that injury and inflammation in the gut and locus coeruleus (LC), respectively, underlie these symptoms, and the injury of these systems is central to the progression of PD.

Quantification of RPE Changes in Choroideremia Using a Photoshop-Based Method.

Purpose: To develop a reliable and efficient method for quantifying the area of preserved retinal pigment epithelium (RPE), facilitating the evaluation of disease progression or response to therapy in choroideremia (CHM).

Methods: The fundus autofluorescence images of CHM patients were captured at baseline and 1 year. A Photoshop-based method was developed to allow the reliable measurement of the RPE area.

Intravenously Administered Novel Liposomes, DCL64, Deliver Oligonucleotides to Cerebellar Purkinje Cells.

Cerebellar Purkinje cells (PCs) show conspicuous damages in many ataxic disorders. Targeted delivery of short nucleic acids, such as antisense oligonucleotides, to PCs may be a potential treatment for ataxic disorders, especially spinocerebellar ataxias (SCAs), which are mostly caused by a gain of toxic function of the mutant RNA or protein. However, oligonucleotides do not cross the blood-brain barrier (BBB), necessitating direct delivery into the central nervous system (CNS) through intra-thecal, intra-cisternal, intra-cerebral ventricular, or stereotactic parenchymal administration.

A synthetic lethal screen reveals enhanced sensitivity to ATR inhibitor treatment in mantle cell lymphoma with ATM loss-of-function.

Unlabelled: Mechanisms to maintain genomic integrity are essential for cells to remain viable. Not surprisingly, disruption of key DNA damage response pathway factors, such as ataxia telangiectasia-mutated (ATM)/ataxia telangiectasia and RAD3-related (ATR) results in loss of genomic integrity. Here, a synthetic lethal siRNA-screening approach not only confirmed ATM but identified additional replication checkpoint proteins, when ablated, enhanced ATR inhibitor (ATRi) response in a high-content γ-H2AX assay.

Is there a relationship between throbbing pain and arterial pulsations?

Pain can have a throbbing quality, especially when it is severe and disabling. It is widely held that this throbbing quality is a primary sensation of one's own arterial pulsations, arising directly from the activation of localized pain-sensory neurons by closely apposed blood vessels. We examined this presumption more closely by simultaneously recording the subjective report of the throbbing rhythm and the arterial pulse in human subjects of either sex with throbbing dental pain-a prevalent condition whose pulsatile quality is widely regarded a primary sensation.

Developing novel oncolytic adenoviruses through bioselection.

Mutants of human adenovirus 5 (Ad5) with enhanced oncolytic activity were isolated by using a procedure termed bioselection. Two mutants, ONYX-201 and ONYX-203, were plaque purified from a pool of randomly mutagenized Ad5 that was repeatedly passaged in the human colorectal cancer cell line HT29, and they were subsequently characterized. ONYX-201 and ONYX-203 replicated more rapidly in HT29 cells than wild-type Ad5, and they lysed HT29 cells up to 1,000-fold more efficiently.