Jefferson Village Downtown District Plan

Jefferson Village is an incorporated municipality in Northeastern Ohio, with a population in 2000 of about 4000 residents. Originally founded in 1803 and incorporated in 1836, the Village has been the county seat for Ashtabula County since 1807. The Village is centrally located in Ashtabula County, 10 miles south of Lake Erie, and 10 miles west of the Pennsylvania border. Interstate highway 90 runs parallel to the lake shore, about 6 miles north of the village; and State Route 11 is a major north-south connector located about 2 miles east of the village. The primary employment locations in the Village are the downtown County administration and the independent professional offices that serve county-related needs, and a light industrial park to the southeast of downtown. The County fairground is also located within the village limits. While residential, commercial and retail growth have occurred over the years, the village still retains much of its original Western Reserve town character. Over 25% of the buildings in the downtown district have historic merit, and both Chestnut and Jefferson Streets are lined with older brick commercial buildings, as well as large, well-kept residences of Western Reserve, Georgian and Victorian architectural styles. Village administration is still based in the original Town Hall, and residents take much pride in the small town charm of the community. In 2006, new commercial development was proposed for Chestnut Street that would have required removal of a residence of historic character, replacing it with a new, generic commercial structure and a typical street-frontage parking lot. Residents were concerned, and public discourse in the local newspaper and at Town Hall led to withdrawal of the proposal. Village leadership felt that it was time to explore the historic character and economic future of the downtown district, and establish policy that could guide future decision making for the downtown

Jefferson Village Downtown District Plan

Jefferson Village is an incorporated municipality in Northeastern Ohio, with a population in 2000 of about 4000 residents. Originally founded in 1803 and incorporated in 1836, the Village has been the county seat for Ashtabula County since 1807. The Village is centrally located in Ashtabula County, 10 miles south of Lake Erie, and 10 miles west of the Pennsylvania border. Interstate highway 90 runs parallel to the lake shore, about 6 miles north of the village; and State Route 11 is a major north-south connector located about 2 miles east of the village. The primary employment locations in the Village are the downtown County administration and the independent professional offices that serve county-related needs, and a light industrial park to the southeast of downtown. The County fairground is also located within the village limits. While residential, commercial and retail growth have occurred over the years, the village still retains much of its original Western Reserve town character. Over 25% of the buildings in the downtown district have historic merit, and both Chestnut and Jefferson Streets are lined with older brick commercial buildings, as well as large, well-kept residences of Western Reserve, Georgian and Victorian architectural styles. Village administration is still based in the original Town Hall, and residents take much pride in the small town charm of the community. In 2006, new commercial development was proposed for Chestnut Street that would have required removal of a residence of historic character, replacing it with a new, generic commercial structure and a typical street-frontage parking lot. Residents were concerned, and public discourse in the local newspaper and at Town Hall led to withdrawal of the proposal. Village leadership felt that it was time to explore the historic character and economic future of the downtown district, and establish policy that could guide future decision making for the downtown

Glycogen Synthase Kinase 3 Inactivation Drives T-bet-Mediated Downregulation of Co-receptor PD-1 to Enhance CD8(+) Cytolytic T Cell Responses.

Despite the importance of the co-receptor PD-1 in T cell immunity, the upstream signaling pathway that regulates PD-1 expression has not been defined. Glycogen synthase kinase 3 (GSK-3, isoforms α and β) is a serine-threonine kinase implicated in cellular processes. Here, we identified GSK-3 as a key upstream kinase that regulated PD-1 expression in CD8(+) T cells. GSK-3 siRNA downregulation, or inhibition by small molecules, blocked PD-1 expression, resulting in increased CD8(+) cytotoxic T lymphocyte (CTL) function. Mechanistically, GSK-3 inactivation increased Tbx21 transcription, promoting enhanced T-bet expression and subsequent suppression of Pdcd1 (encodes PD-1) transcription in CD8(+) CTLs. Injection of GSK-3 inhibitors in mice increased in vivo CD8(+) OT-I CTL function and the clearance of murine gamma-herpesvirus 68 and lymphocytic choriomeningitis clone 13 and reversed T cell exhaustion. Our findings identify GSK-3 as a regulator of PD-1 expression and demonstrate the applicability of GSK-3 inhibitors in the modulation of PD-1 in immunotherapy.C.E.R. was supported by Wellcome Trust 092627/Z/10/Z, J.A.H. by an Irvington Institute Postdoctoral Fellowship from the Cancer Research Institute (New York), and E.I.Z. by a Leukemia and Lymphoma Society Scholar Award and a grant from the NIH AI081923. We thank Dr. Graham Lord (King’s College London) for the kind gift of the Ifng CNS-12 promoter.This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.immuni.2016.01.01

Functional changes through the usage of 3D-printed transitional prostheses in children

Introduction: There is limited knowledge on the use of 3 D-printed transitional prostheses, as they relate to changes in function and strength. Therefore, the purpose of this study was to identify functional and strength changes after usage of 3 D-printed transitional prostheses for multiple weeks for children with upper-limb differences. Materials and methods: Gross manual dexterity was assessed using the Box and Block Test and wrist strength was measured using a dynamometer. This testing was conducted before and after a period of 24 ± 2.61 weeks of using a 3 D-printed transitional prosthesis. The 11 children (five girls and six boys; 3–15 years of age) who participated in the study, were fitted with a 3 D-printed transitional partial hand (n = 9) or an arm (n = 2) prosthesis. Results: Separate two-way repeated measures ANOVAs were performed to analyze function and strength data. There was a significant hand by time interaction for function, but not for strength. Conclusion and relevance to the study of disability and rehabilitation: The increase in manual gross dexterity suggests that the Cyborg Beast 2 3 D-printed prosthesis can be used as a transitional device to improve function in children with traumatic or congenital upper-limb differences. Implications for Rehabilitation Children’s prosthetic needs are complex due to their small size, rapid growth, and psychosocial development. Advancements in computer-aided design and additive manufacturing offer the possibility of designing and printing transitional prostheses at a very low cost, but there is limited knowledge on the function of this type of devices. The use of 3D printed transitional prostheses may improve manual gross dexterity in children after several weeks of using it

Brain lateralization in children with upper‑limb reduction deficiency

Background: The purpose of the current study was to determine the influence of upper-limb prostheses on brain activity and gross dexterity in children with congenital unilateral upper-limb reduction deficiencies (ULD) compared to typically developing children (TD). Methods: Five children with ULD (3 boys, 2 girls, 8.76 ± 3.37 years of age) and five age- and sex-matched TD children (3 boys, 2 girls, 8.96 ± 3.23 years of age) performed a gross manual dexterity task (Box and Block Test) while measuring brain activity (functional near-infrared spectroscopy; fNIRS). Results: There were no significant differences (p = 0.948) in gross dexterity performance between the ULD group with prosthesis (7.23 ± 3.37 blocks per minute) and TD group with the prosthetic simulator (7.63 ± 5.61 blocks per minute). However, there was a significant (p = 0.001) difference in Laterality Index (LI) between the ULD group with prosthesis (LI = − 0.2888 ± 0.0205) and TD group with simulator (LI = 0.0504 ± 0.0296) showing in a significant ipsilateral control for the ULD group. Thus, the major finding of the present investigation was that children with ULD, unlike the control group, showed significant activation in the ipsilateral motor cortex on the non-preferred side using a prosthesis during a gross manual dexterity task. Conclusions: This ipsilateral response may be a compensation strategy in which the existing cortical representations of the non-affected (preferred) side are been used by the affected (non-preferred) side to operate the prosthesis. This study is the first to report altered lateralization in children with ULD while using a prosthesis. Trial registration The clinical trial (ClinicalTrial.gov ID: NCT04110730 and unique protocol ID: IRB # 614-16-FB) was registered on October 1, 2019 (https ://clini caltr ials.gov/ct2/show/NCT04 11073 0) and posted on October 1, 2019. The study start date was January 10, 2020. The first participant was enrolled on January 14, 2020, and the trial is scheduled to be completed by August 23, 2023. The trial was updated January 18, 2020 and is currently recruitin

A Potent Peptidomimetic Inhibitor of Botulinum Neurotoxin Serotype A Has a Very Different Conformation than SNAP-25 Substrate

SummaryBotulinum neurotoxin serotype A is the most lethal of all known toxins. Here, we report the crystal structure, along with SAR data, of the zinc metalloprotease domain of BoNT/A bound to a potent peptidomimetic inhibitor (Ki = 41 nM) that resembles the local sequence of the SNAP-25 substrate. Surprisingly, the inhibitor adopts a helical conformation around the cleavage site, in contrast to the extended conformation of the native substrate. The backbone of the inhibitor's P1 residue displaces the putative catalytic water molecule and concomitantly interacts with the “proton shuttle” E224. This mechanism of inhibition is aided by residue contacts in the conserved S1′ pocket of the substrate binding cleft and by the induction of new hydrophobic pockets, which are not present in the apo form, especially for the P2′ residue of the inhibitor. Our inhibitor is specific for BoNT/A as it does not inhibit other BoNT serotypes or thermolysin