The natural and human-mediated expansion of a human-commensal lizard into the fringes of Southeast Asia.

BACKGROUND: Human-commensal species often display deep ancestral genetic structure within their native range and founder-effects and/or evidence of multiple introductions and admixture in newly established areas. We investigated the phylogeography of Eutropis multifasciata, an abundant human-commensal scincid lizard that occurs across Southeast Asia, to determine the extent of its native range and to assess the sources and signatures of human introduction outside of the native range. We sequenced over 350 samples of E. multifasciata for the mitochondrial ND2 gene and reanalyzed a previous RADseq population genetic dataset in a phylogenetic framework. RESULTS: Nuclear and mitochondrial trees are concordant and show that E. multifasciata has retained high levels of genetic structure across Southeast Asia despite being frequently moved by humans. Lineage boundaries in the native range roughly correspond to several major biogeographic barriers, including Wallace's Line and the Isthmus of Kra. Islands at the outer fringe of the range show evidence of founder-effects and multiple introductions. CONCLUSIONS: Most of enormous range of E. multifasciata across Southeast Asia is native and it only displays signs of human-introduction or recent expansion along the eastern and northern fringe of its range. There were at least three events of human-introductions to Taiwan and offshore islands, and several oceanic islands in eastern Indonesia show a similar pattern. In Myanmar and Hainan, there is a founder-effect consistent with post-warming expansion after the last glacial maxima or human introduction.

A new species of terrestrially-nesting fanged frog (Anura: Dicroglossidae) from Sulawesi Island, Indonesia.

Herein, we describe a new species of terrestrially-nesting fanged frog from Sulawesi Island, Indonesia. Though male nest attendance and terrestrial egg deposition is known in one other Sulawesi fanged frog (Limnonectes arathooni), the new species exhibits a derived reproductive mode unique to the Sulawesi assemblage; male frogs guard one or more clutches of eggs festooned to leaves or mossy boulders one to two meters above small slow-moving streams, trickles, or seeps. This island endemic has thus far been collected at three sites on Sulawesi: one in the Central Core of the island, and two on the Southwest Peninsula-south of the Tempe Depression (a major biogeographical boundary). The new Limnonectes has the smallest adult body size among its Sulawesi congeners-with a maximum snout-vent length of about 30 millimeters. Beyond its unique reproductive behavior and body size, the species is further diagnosed on the basis of advertisement call and genetic distance from sympatric fanged frogs. The discovery and description of the new species highlights the remarkable reproductive trait diversity that characterizes the Sulawesi fanged frog assemblage despite that most species in this radiation have yet to be formally described.

Utilisation of the Scepter Mini dual-lumen balloon - An illustrative series.

BACKGROUND: Dual-lumen balloon microcatheters can aid in the safety and efficacy of endovascular embolisation of cerebrospinal vascular malformations. The Scepter Mini dual-lumen balloon is a novel device with a smaller profile than previous balloon microcatheters, opening up new indications not only in the treatment of cerebrospinal malformations but in various other neurovascular therapeutic and diagnostic scenarios. METHODS: Following institutional ethics review board approval, a retrospective review of our prospectively maintained database of cases employing the Scepter Mini dual-lumen microballoon catheter was conducted. Five cases in particular were highlighted, demonstrating utilisation of this device, which may be of interest to the Neurointerventionalist. Patient demographics, procedure details, complications and clinical outcome data were reviewed. RESULTS: Five cases employing the Scepter Mini dual-lumen microballoon catheter are presented; trans-arterial embolisation of cerebral AVM, pre-operative tumour embolisation, diagnostic angiography, trans-venous embolisation of cerebral AVM and trans-arterial embolisation of DAVF. No intraprocedural complications were recorded, one patient had a delayed haemorrhage. CONCLUSION: Potential utilisation of the Scepter Mini lies not only in the trans-arterial embolisation of cerebrospinal vascular malformations, but in a range of other diagnostic and therapeutic indications as demonstrated.

Use of the neuroform atlas for stenting of intracranial atherosclerotic disease: Clinical and angiographic outcomes.

BACKGROUND: Intracranial atherosclerotic disease (ICAD) is a potential cause of ischemic stroke. Treatment of ICAD can include intracranial stenting. There are specifically designed stents for this use-case; however, less is known about the off-label use of the Neuroform Atlas stent. In this study, we describe the outcomes of the Neuroform Atlas stent for treatment of ICAD. METHODS: Adult patients with symptomatic ICAD failing best medical treatment undergoing elective intracranial stenting using the Neuroform Atlas stent between November 2018 and March 2021 were included. Patient demographics, procedure-related details and clinical and imaging outcomes were analyzed. RESULTS: Eighteen patients met the inclusion criteria, with a mean follow-up duration of 9.6 ± 6.8 (standard deviation) months. There were two procedure-related mortalities (one massive intracranial hemorrhage and one groin site complication with sepsis). Fifteen patients were alive at the 6-month follow-up, all with satisfactory stent patency on follow-up imaging without any new ischemic events. Modified Rankin Scale at latest follow-up was 1.9 (interquartile range 5). CONCLUSION: In this single-center consecutive series, intracranial stenting with the Neuroform Atlas stent was a safe and effective treatment for symptomatic ICAD patients failing best medical management.

Bewildering biogeography: Waves of dispersal and diversification across southern Wallacea by bent-toed geckos (genus: Cyrtodactylus).

Bent-toed Geckos, genus Cyrtodactylus, are one of the most diverse terrestrial vertebrate groups, and their range extends from South Asia into Australo-Papua and adjacent Pacific islands. Given the generally high faunal endemism on Wallacean islands, it is rather paradoxical that the diversity in these geckos appears to be so low (21 species in Wallacea, 15 in the Philippines) compared with continental shelf assemblages (>300 species on Sunda + Sahul Shelves + adjacent islands). To determine whether this shortfall was real or an artifact of historical undersampling, we analyzed mitochondrial DNA sequences of hundreds of southern Wallacean samples (Lesser Sundas + southern Maluku). After screening to guide sample selection for target capture data collection, we obtained a 1150-locus genomic dataset (1,476,505 bp) for 119 samples of southern Wallacean and closely related lineages. The results suggest that species diversity of Cyrtodactylus in southern Wallacea is vastly underestimated, with phylogenomic and clustering analyses suggesting as many as 25 candidate species, in contrast to the 8 currently described. Gene exchange between adjacent candidate species is absent or minimal across the archipelago with only one case of > 0.5 migrants per generation. Biogeographical analysis suggests that the hitherto unrecognized diversity is the result of at least three independent dispersals from Sulawesi or its offshore islands into southern Wallacea between 6 and 14 Ma, with one invasion producing small-bodied geckos and the other two or three producing larger-bodied geckos. The smaller-bodied laevigatus group appears to be able to coexist with members of either larger-bodied clade, but we have yet to find members of the two larger-bodied clades occurring in sympatry, suggesting that ecological partitioning or competitive exclusion may be shaping individual island assemblages.

Trace Actinide Signatures of a Bulk Neptunium Sample.

In nuclear forensic analyses, measurements of actinide elements in a sample can assist with identifying interdicted or unknown materials. While these radiochemical signatures have been extensively investigated in uranium materials, less is known about bulk neptunium samples. This paper describes the measurement of trace actinide concentrations and isotopic profiles in a 237Np oxide sample. Uranium, plutonium, americium, and curium concentrations and isotopic profiles in the sample were determined and deemed potentially useful for distinguishing different sources of 237Np. Several different potential radiochronometry systems were also investigated; discordant results indicate that the Np sample was never completely purified of other actinide elements, or that subsequent contamination of the sample occurred. Few prior studies of neptunium materials have been reported, and these data suggest that trace actinide constituents could provide unique signatures to identify material out of regulatory control.

Spontaneous intracranial hypotension due to CSF-venous fistula: Evaluation of renal accumulation of contrast following decubitus myelography and maintained decubitus CT to improve fistula localization.

PURPOSE: Presented here is a strategy of sequential lateral decubitus digital subtraction myelography (LDDSM) followed closely by lateral decubitus CT (LDCT) to facilitate cerebrospinal fluid (CSF)-venous fistula (CVF) localization. MATERIALS AND METHODS: This is a retrospective analysis of patients referred to our institution for evaluation of CSF leak. Patients with Type 1 and Type 2 leaks, and those not displaying MR brain stigmata of intracranial hypotension were excluded. All patients underwent consecutive LDDSM and LDCT. If the CVF was not localized on the first LDDSM-LDCT pair the patient returned for contralateral examinations. Images were reviewed for CVF and for accumulation of contrast within the renal pelvises expressed as a renal pelvis contrast score (RPCS) in Hounsfield units (HU). RESULTS: Twenty-two patients were included in this study. In 21 of 22 patients (95%) a CVF was identified yielding an RPCS for the LDDSM-LDCT pair ipsilateral to the CVF ranging from 71 to 423 with an average of 146 HU. An RPCS of the negative side LDDSM-LDCT pair contralateral to a CVF was available in 8 patients and averaged 51 HU. In 4 patients the initial bilateral LDDSM-LDCT pairs did not reveal the location of the CVF however in 3 of these 4 cases the CVF was revealed on a third LDDSM repeated ipsilateral to the higher RPCS. CONCLUSION: The strategy of sequential LDDSM-LDCT coupled with evaluation of renal accumulation of contrast agent appears to improve the rate of CVF localization and warrants further evaluation.

Species Delimitation, Phylogenomics, and Biogeography of Sulawesi Flying Lizards: A Diversification History Complicated by Ancient Hybridization, Cryptic Species, and Arrested Speciation.

The biota of Sulawesi is noted for its high degree of endemism and for its substantial levels of in situ biological diversification. While the island's long period of isolation and dynamic tectonic history have been implicated as drivers of the regional diversification, this has rarely been tested in the context of an explicit geological framework. Here, we provide a tectonically informed biogeographical framework that we use to explore the diversification history of Sulawesi flying lizards (the Draco lineatus Group), a radiation that is endemic to Sulawesi and its surrounding islands. We employ a framework for inferring cryptic speciation that involves phylogeographic and genetic clustering analyses as a means of identifying potential species followed by population demographic assessment of divergence-timing and rates of bi-directional migration as means of confirming lineage independence (and thus species status). Using this approach, phylogenetic and population genetic analyses of mitochondrial sequence data obtained for 613 samples, a 50-SNP data set for 370 samples, and a 1249-locus exon-capture data set for 106 samples indicate that the current taxonomy substantially understates the true number of Sulawesi Draco species, that both cryptic and arrested speciations have taken place, and that ancient hybridization confounds phylogenetic analyses that do not explicitly account for reticulation. The Draco lineatus Group appears to comprise 15 species-9 on Sulawesi proper and 6 on peripheral islands. The common ancestor of this group colonized Sulawesi ~11 Ma when proto-Sulawesi was likely composed of two ancestral islands, and began to radiate ~6 Ma as new islands formed and were colonized via overwater dispersal. The enlargement and amalgamation of many of these proto-islands into modern Sulawesi, especially during the past 3 Ma, set in motion dynamic species interactions as once-isolated lineages came into secondary contact, some of which resulted in lineage merger, and others surviving to the present. [Genomics; Indonesia; introgression; mitochondria; phylogenetics; phylogeography; population genetics; reptiles.].

Thoracolumbar spinal dural arteriovenous fistulae present with longer arteriovenous transit compared to cranial and cervical dural fistulae.

BACKGROUND: Thoraco-lumbar spinal dural arteriovenous fistulae represent a rare subset of central nervous system vascular malformations. One of the unique features of spinal dural arteriovenous fistulae is their extremely low propensity to cause hemorrhage (either parenchymal or subarachnoid), with a distinct clinical presentation of myelopathy secondary to spinal venous congestion. The exact mechanism for this unique presentation is still unclear. METHODS: Following institutional review board approval, we retrospectively analyzed our prospectively maintained database of spinal dural arteriovenous fistulae and cranial (cr) DAVF cases presenting between 2008 and 2021. For all cases, angiograms were reviewed and arteriovenous transit times were calculated. Patient demographics, angiographic features, and clinical and radiological outcomes were assessed. RESULTS: In total, 66 patients presenting with confirmed thoracolumbar spinal dural arteriovenous fistulaes were identified and compared to patients presenting with cervical spinal dural arteriovenous fistulaes (n = 10), ruptured crDAVFs (n = 32) and unruptured crDAVFs (n = 20). Mean age in the target group was 66 ± 13 versus 57-62 in the other groups, p < 0.05 on one-way analysis of variance; with 80% males versus 50%-65% in other groups. Mean arteriovenous transit time in the thoracolumbar group measured 1.98 s ± 0.96 versus 0.25-0.5 s range in other groups (p < 0.0001 on one-way analysis of variance). CONCLUSION: Prolonged arteriovenous transit times may represent a distinct feature of thoracolumbar spinal dural arteriovenous fistulaes. This may, amongst other factors, play a role in the observed lesser likelihood of hemorrhagic complications compared to other dural arteriovenous shunts.

Phylogenetic relationships of southern Wallacean ranid frogs (Anura: Ranidae: Hylarana).

Frogs in the family Ranidae are diverse in Asia and are thought to have dispersed to the Sahul Shelf approximately 10 million years ago, where they radiated into more than a dozen species. Ranid species in the intervening oceanic islands of Wallacea, such as Hylarana florensis and H. elberti from the Lesser Sundas and H. moluccana from eastern Wallacea, are assumed to belong to the subgenus Papurana, yet this has not been confirmed with molecular data. We analyzed mitochondrial DNA of Hylarana species from five islands spanning the reported ranges of H. florensis and H. elberti and compared them to confirmed Papurana species and closely related subgenera within Hylarana. We find that the Lesser Sunda H. florensis and H. elberti form a clade that is sister to the rest of the Australo-Papuan Papurana assemblage. Species delimitation analyses and divergence time estimates suggest that populations of H. florensis on Lombok may be distinct from those on Flores at the species level. Likewise, populations of H. elberti on Sumba and Timor may be distinct from each other and from those on Wetar, tshe type locality of H. elberti. Samples from Babar Island thought to be members of H. elberti in fact belong to the wide-ranging H. daemeli, which occurs in northern Australia, across New Guinea, and on the neighboring island of Tanimbar. These results suggest that the Lesser Sundas may have served as a stepping-stone for colonization of the Sahul Shelf and that species diversity of Papurana frogs is underestimated in the Lesser Sundas.

Diverge and Conquer: Phylogenomics of southern Wallacean forest skinks (Genus: Sphenomorphus) and their colonization of the Lesser Sunda Archipelago.

The archipelagos of Wallacea extend between the Sunda and Sahul Shelves, serving as a semipermeable two-way filter influencing faunal exchange between Asia and Australo-Papua. Forest skinks (Genus Sphenomorphus) are widespread throughout southern Wallacea and exhibit complex clinal, ontogenetic, sexual, and seasonal morphological variation, rendering species delimitation difficult. We screened a mitochondrial marker for 245 Sphenomorphus specimens from this area to inform the selection of 104 samples from which we used targeted sequence capture to generate a dataset of 1154 nuclear genes (∼1.8 Mb) plus complete mitochondrial genomes. Phylogenomic analyses recovered many deeply divergent lineages, three pairs of which are now sympatric, that began to diversify in the late Miocene shortly after the oldest islands are thought to have become emergent. We infer a complex and nonstepping-stone pattern of island colonization, with the group having originated in the Sunda Arc islands before using Sumba as a springboard for colonization of the Banda Arcs. Estimates of population structure and gene flow across the region suggest total isolation except between two Pleistocene Aggregate Island Complexes that become episodically land-bridged during glacial maxima. These historical processes have resulted in at least 11 Sphenomorphus species in the region, nine of which require formal description. This fine-scale geographic partitioning of undescribed species highlights the importance of utilizing comprehensive genomic studies for defining biodiversity hotspots to be considered for conservation protection.

Recognition of the variant type of spinal dural arteriovenous fistula: a rare but important consideration.

OBJECTIVE: Spinal dural arteriovenous fistulas (SDAVFs) typically represent abnormal shunts between a radiculomeningeal artery and radicular vein, with the point of fistulization classically directly underneath the pedicle of the vertebral body, at the dural sleeve of the nerve root. However, SDAVFs can also develop in atypical locations or have more than one arterial feeder, which is a variant of SDAVF. The aim of this study was to describe the incidence and multidisciplinary treatment of variant SDAVFs in a single-center case series. METHODS: Following institutional review board approval, the authors retrospectively analyzed their prospectively maintained database of patients with SDAVFs who presented between 2008 and 2020. For all patients, spinal digital subtraction angiograms were reviewed and variant SDAVFs were identified. Variant types of SDAVFs were defined as cases in which the fistulous point was not located underneath the pedicle. Patient demographics, angiographic features, clinical outcomes, and treatment modalities were assessed. RESULTS: Of 59 patients with SDAVFs treated at the authors' institution, 4 patients (6.8%) were identified as having a variant location of the shunt zone, pinpointed on the dura mater at the intervertebral level, further posteriorly within the spinal canal. In 3 cases (75%), a so-called bimetameric arterial supply was demonstrated. CONCLUSIONS: Recognition of the variant type of SDAVF is crucial for management, as correct localization of the fistulous point and bimetameric supply are critical for successful surgical disconnection, preventing delay in achieving definitive treatment.

Towards an FDA-cleared basophil activation test.

Food allergy is a global health problem affecting up to 10% of the world population. Accurate diagnosis of food allergies, however, is still a major challenge in medical offices and for patients seeking alternative avenues of diagnosis. A flawless test to confirm or rule out a food allergy does not exist. The lack of optimum testing methods to establish precise clinical correlations remains a major obstacle to effective treatment. Certain IgE measurement methods, including component testing, have received FDA clearance, but they have been used primarily as an analytical tool and not to establish clinical correlations. Most allergy tests are still carried out within the laboratory, and skin tests outside a laboratory setting that are used for food allergy diagnosis rely on non-standardized allergens, according to the FDA definition. Epitope mapping and basophil activation test (BAT) have recently been proposed as a means of establishing better clinical correlations. Yet neither have received FDA clearance for widespread distribution. Of the two methods, the BAT has the advantage of being a functional assay. Over the past few years, several large private practice groups in the United States, have developed BAT as a clinical assay and have started using it in patient care. Given this clinical experience, the vast number of papers published on BAT (more than 1,400 as of 2022) and the trend toward increasing FDA regulation, it is essential to understand the roadmap for regulatory clearance of this assay.

Acute Esophageal Necrosis Secondary to a Paraesophageal Hernia.

Acute esophageal necrosis (AEN) or "black esophagus" is a rare clinical entity caused by necrosis of distal esophageal mucosa stemming from esophageal ischemia. Possible etiologies are broad but most commonly include possible triggers of low-flow vascular states in the esophagus, including infections, broad-spectrum antibiotic use, and gastric volvulus, among others. Patients most commonly present clinically with acute onset hematemesis and melena. Here, we describe a patient who initially presented with multiple nonspecific gastrointestinal symptoms, including abdominal pain and nausea, that progressed over a 10-day period, culminating in multiple episodes of hematemesis prior to presentation. Endoscopic evaluation confirmed the diagnosis of AEN and unveiled a possible paraesophageal hernia (PEH) as the causative factor. A subsequent videofluoroscopic barium swallow was utilized to better characterize the upper gastrointestinal anatomy and confirmed the PEH as a likely etiology. Esophagogastroduodenoscopy (EGD) can often identify PEH independently, but in patients with AEN secondary to a possible, but unclear, PEH on EGD, a videofluoroscopic barium swallow is an appropriate and useful next step in confirming the diagnosis. While treatment of AEN traditionally involves fluid resuscitation, intravenous protein pump inhibitors, and total parenteral nutrition, surgical intervention is often indicated in patients who have a contributing and symptomatic PEH.

High-throughput kinome-RNAi screen identifies protein kinase R activator (PACT) as a novel genetic modifier of CUG foci integrity in myotonic dystrophy type 1 (DM1).

Myotonic Dystrophy Type 1 (DM1) is the most common form of adult muscular dystrophy (~1:8000). In DM1, expansion of CTG trinucleotide repeats in the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene results in DMPK mRNA hairpin structures which aggregate as insoluble ribonuclear foci and sequester several RNA-binding proteins. The resulting sequestration and misregulation of important splicing factors, such as muscleblind-like 1 (MBNL1), causes the aberrant expression of fetal transcripts for several genes that contribute to the disease phenotype. Previous work has shown that antisense oligonucleotide-mediated disaggregation of the intranuclear foci has the potential to reverse downstream anomalies. To explore whether the nuclear foci are, to some extent, controlled by cell signalling pathways, we have performed a screen using a small interfering RNA (siRNA) library targeting 518 protein kinases to look at kinomic modulation of foci integrity. RNA foci were visualized by in situ hybridization of a fluorescent-tagged (CAG)10 probe directed towards the expanded DMPK mRNA and the cross-sectional area and number of foci per nuclei were recorded. From our screen, we have identified PACT (protein kinase R (PKR) activator) as a novel modulator of foci integrity and have shown that PACT knockdown can both increase MBNL1 protein levels; however, these changes are not suffcient for significant correction of downstream spliceopathies.

Phylogenomic Analysis Reveals Dispersal-Driven Speciation and Divergence with Gene Flow in Lesser Sunda Flying Lizards (Genus Draco).

The Lesser Sunda Archipelago offers exceptional potential as a model system for studying the dynamics of dispersal-driven diversification. The geographic proximity of the islands suggests the possibility for successful dispersal, but this is countered by the permanence of the marine barriers and extreme intervening currents that are expected to hinder gene flow. Phylogenetic and species delimitation analyses of flying lizards (genus Draco) using single mitochondrial genes, complete mitochondrial genomes, and exome-capture data sets identified 9-11 deeply divergent lineages including single-island endemics, lineages that span multiple islands, and parapatrically distributed nonsister lineages on the larger islands. Population clustering and PCA confirmed these genetic boundaries with isolation-by-distance playing a role in some islands or island sets. While gdi estimates place most candidate species comparisons in the ambiguous zone, migration estimates suggest 9 or 10 species exist with nuclear introgression detected across some intra-island contact zones. Initial entry of Draco into the archipelago occurred at 5.5-7.5 Ma, with most inter-island colonization events having occurred between 1-3 Ma. Biogeographical model testing favors scenarios integrating geographic distance and historical island connectivity, including an initial stepping-stone dispersal process from the Greater Sunda Shelf through the Sunda Arc as far eastward as Lembata Island. However, rather than reaching the adjacent island of Pantar by dispersing over the 15-km wide Alor Strait, Draco ultimately reached Pantar (and much of the rest of the archipelago) by way of a circuitous route involving at least five overwater dispersal events. These findings suggest that historical geological and oceanographic conditions heavily influenced dispersal pathways and gene flow, which in turn drove species formation and shaped species boundaries. [Biogeography; genomics, Indonesia; lizards; phylogeography; reptiles].

Late-Stage Carbon Isotope Exchange of Aryl Nitriles through Ni-Catalyzed C-CN Bond Activation.

A facile one-pot strategy for 13CN and 14CN exchange with aryl, heteroaryl, and alkenyl nitriles using a Ni phosphine catalyst and BPh3 is described. This late-stage carbon isotope exchange (CIE) strategy employs labeled Zn(CN)2 to facilitate enrichment using the nonlabeled parent compound as the starting material, eliminating de novo synthesis for precursor development. A broad substrate scope encompassing multiple pharmaceuticals is disclosed, including the preparation of [14C] belzutifan to illustrate the exceptional functional group tolerance and utility of this labeling approach. Preliminary experimental and computational studies suggest the Lewis acid BPh3 is not critical for the oxidative addition step and instead plays a role in facilitating CN exchange on Ni. This CIE method dramatically reduces the synthetic steps and radioactive waste involved in preparation of 14C labeled tracers for clinical development.

Evaluation of a Low-Toxicity PARP Inhibitor as a Neuroprotective Agent for Parkinson's Disease.

Repurposing PARP-1 inhibitors (PARPi) for non-oncological applications offers an attractive therapeutic strategy for pathological conditions characterized by PARP-1 hyperactivity. In the context of Parkinson's disease (PD), PARP-1 hyperactivity has been linked to neuronal death and disease progression. From a therapy perspective, the evaluation of PARPi as neuroprotective agents may offer a new therapeutic alternative for neurodegenerative disorders. An ideal PARPi needs to inhibit PARP-1 hyperactivity while also limiting downstream DNA damage and cellular toxicity-an effect that is attractive in cancer but far from ideal in neurological disease applications. Consequently, in this study, we set out to evaluate the neuroprotective properties of a previously reported low-toxicity PARPi (10e) using in vitro neuronal models of PD. 10e is a structural analogue of FDA-approved PARPi olaparib, with high PARP-1 affinity and selectivity. Our studies revealed that 10e protects neuronal cells from oxidative stress and DNA damage. In addition, 10e exhibits neuroprotective properties against α-synuclein pre-formed fibrils (αSyn PFF) mediated effects, including reduction in the levels of phosphorylated αSyn and protection against abnormal changes in NAD+ levels. Our in vitro studies with 10e provide support for repurposing high-affinity and low-toxicity PARPi for neurological applications and lay the groundwork for long-term therapeutic studies in animal models of PD.

A Chemical Approach for Programmable Protein Outputs Based on Engineered Cell Interactions.

Cell-cell interactions and communication are crucial to the proper function of complex mammalian physiology including neurocognitive and immune system functions. While many tools are available for observing and perturbing intracellular processes, relatively few exist to probe intercellular processes. Current techniques for studying interactions often rely on direct protein contact, and few can manipulate diverse, functional outputs with tunable protein expression. To address these limitations, we have developed a small-molecule approach based on a trimethoprim prodrug-enzyme pair capable of reporting the presence of two different engineered cell populations with programmable protein outputs. The approach relies on bacterial nitroreductase enzyme catalysis, which is orthogonal to normal mammalian biology, and diffusion of trimethoprim from "activator" cells to "receiver" cells. We test this strategy, which can theoretically regulate many different types of proteins, using biochemical and in vitro culture assays with optical and cytokine protein readouts. This describes the first small-molecule approach capable of detecting and controlling engineered cell-cell outputs, and we anticipate future applications that are especially relevant to the field of immuno-oncology.