Synthesis of arylidene-β-lactams via exo-selective matsuda-heck arylation of methylene-β-lactams

exo-Methylene-β-lactams were synthesized in two steps from commercially available 3-bromo-2-(bromomethyl)propionic acid and reacted with arene diazonium salts in a Heck-type arylation in the presence of catalytic amounts of Pd(OAc)2 under ligand-free conditions. The products, arylidene-β-lactams, were obtained in high yields as single isomers. The β-hydride elimination step of the Pd-catalyzed coupling reaction proceeds with high exo-regioselectivity and E-stereoselectivity. With aryl iodides, triflates, or bromides, the coupling products were isolated only in low yields, due to extensive decomposition of the starting material at elevated temperatures. This underlines that arene diazonium salts can be superior arylating reagents in Heck-type reactions and yield coupling products in synthetically useful yields and selectivities when conventional conditions fail

Single domain antibodies: promising experimental and therapeutic tools in infection and immunity

Antibodies are important tools for experimental research and medical applications. Most antibodies are composed of two heavy and two light chains. Both chains contribute to the antigen-binding site which is usually flat or concave. In addition to these conventional antibodies, llamas, other camelids, and sharks also produce antibodies composed only of heavy chains. The antigen-binding site of these unusual heavy chain antibodies (hcAbs) is formed only by a single domain, designated VHH in camelid hcAbs and VNAR in shark hcAbs. VHH and VNAR are easily produced as recombinant proteins, designated single domain antibodies (sdAbs) or nanobodies. The CDR3 region of these sdAbs possesses the extraordinary capacity to form long fingerlike extensions that can extend into cavities on antigens, e.g., the active site crevice of enzymes. Other advantageous features of nanobodies include their small size, high solubility, thermal stability, refolding capacity, and good tissue penetration in vivo. Here we review the results of several recent proof-of-principle studies that open the exciting perspective of using sdAbs for modulating immune functions and for targeting toxins and microbes

Outdoor education through the lens of peace philosophy: exploring the inherent peace educating potential of outdoor education and how outdoor practitioners can use it for enhancing their work

This theory-generating research explores the otherwise academically seldom acknowledged interface of outdoor education and peace philosophy, employing educational science as an overarching frame. Building on a theoretical framework that shows how educational forms of Erziehung, formal education, derive from modern understandings of peace while forms of Bildung, non-formal education, derive from transrational approaches to peace outdoor education is analysed for these different educational components that allow conclusions about the peace-fostering potential of outdoor education. The inductive, exploratory investigation uses two semi-structured expert interviews, one expert of outdoor education and one of peace philosophy, to define five distinctive features of outdoor education that foster peace: (1) being movement-oriented, (2) regarding conflict as a motor for personal development, (3) exemplary training how to cope with it, (4) being relationship-oriented and (5) providing group and community experiences; and to find four aspects of outdoor educational practices that stand in the way to unfolding this inherent peace-fostering potential of outdoor education even more: (6) overly focusing on conflicts instead of peace experiences, (7) losing sight of the central importance of relationship-work within outdoor education, (8) pushing participants for presentable learning outcomes and (9) facilitators not seeking broad enough training

Reduction of Risk Factors for Pedophilic Sexual Offending

Introduction: Exploratory analysis of characteristics and reduction of risk factors for child sexual abuse (CSA) in a sample treated in the Prevention Projects Dunkelfeld Hannover and Regensburg. Aim: To evaluate a treatment program aimed at reducing dynamic risk factors (DRF) for CSA. Methods: Using a psychometric test battery based on self-report questionnaires, intergroup analysis between treatment group (TG, n = 35), treatment refusers (TR, n = 51), and drop-out group (DO, n = 14) was conducted with pretreatment data. Intragroup analysis compared data of TG from pre- and posttreatment. The test battery included sociodemographic and sociosexual data, as well as questionnaires measuring DRF. Main Outcome Measure: This study investigated effects of treatment on pedophilic men who are at risk for offending and observed reductions in important risk factors for CSA. Results: TG, TR (consisting of persons who were offered but refused therapy), and DO did not differ regarding sociodemographic and sociosexual variables before therapy. There were no significant differences in education, relationship status, living solitarily, and being a father/stepfather. TR and DO lived farther away from treatment site than TG. In the TG, a reduction in offense-supportive attitudes, coping self-efficacy deficits, and child identification were revealed at second assessment. In TG no participants started the consumption of child abuse content during the course of the study. Clinical Implications: Future treatment concepts should focus on the reduction of empirically relevant risk factors for child sexual offending. Strength & Limitations: The present article is the first that compares TG to TR and DO before assessment regarding DRF and sociosexual variables. Moreover, it is only the second study that investigated treatment effects on a population of pedophilic men who are at risk for offending. These preliminary findings are limited by moderate group size and a missing control group. Conclusion: A reduction in some but not all assessed risk factors for sexual offending against minors could be seen within the time frame of therapy. Findings are in line with results from a previous evaluation study. Copyright (C) 2018, International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved

An Optical Absolute Frequency Reference For A Sounding Rocket Mission Based On Iodine

We present a compact absolute optical frequency reference based on hyperfine transitions in molecular iodine for application on a sounding rocket mission. It is based on a micro-integrated extended cavity diode laser at 1064 nm with integrated optical amplifier, fiber pigtailed second harmonic generation wave-guide modules, and a quasi-monolithic spectroscopy setup with operating electronics. This frequency reference is scheduled for launch end of 2017 aboard the TEXUS 54 sounding rocket as an important qualification step towards space application of iodine frequency references and related technologies. We aim for a fractional frequency instability of better than 3 × 10−14. The payload will operate autonomously and its optical frequency will be compared to an optical frequency comb during its space flight

Engineered skeletal muscle recapitulates human muscle development, regeneration and dystrophy

Abstract Background Human pluripotent stem cell‐derived muscle models show great potential for translational research. Here, we describe developmentally inspired methods for the derivation of skeletal muscle cells and their utility in skeletal muscle tissue engineering with the aim to model skeletal muscle regeneration and dystrophy in vitro. Methods Key steps include the directed differentiation of human pluripotent stem cells to embryonic muscle progenitors followed by primary and secondary foetal myogenesis into three‐dimensional muscle. To simulate Duchenne muscular dystrophy (DMD), a patient‐specific induced pluripotent stem cell line was compared to a CRISPR/Cas9‐edited isogenic control line. Results The established skeletal muscle differentiation protocol robustly and faithfully recapitulates critical steps of embryonic myogenesis in two‐dimensional and three‐dimensional cultures, resulting in functional human skeletal muscle organoids (SMOs) and engineered skeletal muscles (ESMs) with a regeneration‐competent satellite‐like cell pool. Tissue‐engineered muscle exhibits organotypic maturation and function (up to 5.7 ± 0.5 mN tetanic twitch tension at 100 Hz in ESM). Contractile performance could be further enhanced by timed thyroid hormone treatment, increasing the speed of contraction (time to peak contraction) as well as relaxation (time to 50% relaxation) of single twitches from 107 ± 2 to 75 ± 4 ms (P < 0.05) and from 146 ± 6 to 100 ± 6 ms (P < 0.05), respectively. Satellite‐like cells could be documented as largely quiescent PAX7+ cells (75 ± 6% Ki67−) located adjacent to muscle fibres confined under a laminin‐containing basal membrane. Activation of the engineered satellite‐like cell niche was documented in a cardiotoxin injury model with marked recovery of contractility to 57 ± 8% of the pre‐injury force 21 days post‐injury (P < 0.05 compared to Day 2 post‐injury), which was completely blocked by preceding irradiation. Absence of dystrophin in DMD ESM caused a marked reduction of contractile force (−35 ± 7%, P < 0.05) and impaired expression of fast myosin isoforms resulting in prolonged contraction (175 ± 14 ms, P < 0.05 vs. gene‐edited control) and relaxation (238 ± 22 ms, P < 0.05 vs. gene‐edited control) times. Restoration of dystrophin levels by gene editing rescued the DMD phenotype in ESM. Conclusions We introduce human muscle models with canonical properties of bona fide skeletal muscle in vivo to study muscle development, maturation, disease and repair

WORKING GROUP ON BIOLOGICAL PARAMETERS (WGBIOP)

The main objective of the Working Group on Biological Parameters (WGBIOP) is to review the status, issues, developments, and quality assurance of biological parameters for use in assess-ments and management that are in line with the requirements of end-users. In this final year of the three-year term, WGBIOP operated under challenging circumstances due to COVID-19 measures. The initial action plan was replaced by a more flexible one, where online plenary and subgroup meetings were spread over the year with intersessional work to finalize the proposed deliverables. WGBIOP continued the review of past exchanges and workshops under the remit of the working group. Since 2019, these calibrations on age, maturity, and larvae identification have been carried out in SmartDots, an online platform for sharing images and facilitating the reading of otoliths, staging of gonads, and identification of early life stages. Developments are underway to include an improved calculation of modal age and error matrices in the SmartDots standard report. WGBIOP investigated ways to incorporate error matrices into assessments and studied the effect of this inclusion together with stock assessors. Requests for new exchanges and workshops were reviewed, with a focus on stocks to be bench-marked in the coming years. Issue lists were scrutinized, problems identified, and information provided to stock coordinators via regular channels and through the Stock Identification Data-base (SID). Despite close cooperation with stock assessors and continued efforts, it has not been possible to further streamline the WGBIOP workflow with the benchmark process. This will be addressed with the Advisory Committee. The need for validation studies was stressed by the repeated low levels of agreement between readers of some stocks and recurring issues and recommendations to WGBIOP. Lack of resources is the main obstacle. As a first step for measures to prioritize validation studies, WGBIOP iden-tified precision, trueness, and feasibility of validation methods (as well as the urgency for the assessment). WGBIOP continued investigations into new life-history parameters for integrated assessment and advice in cooperation with end-users (Working Group on Integrative, Physical-biological and Ecosystem Modelling-WGIPEM and Regional Coordination Groups-RCGs). This included a standardization and quality assurance action plan for stomach sampling. Efforts have also been taken to streamline data and workflows across databases and groups. A step has been taken in the standardization of quality assurance procedures at the regional level. Institute-level overviews of methods and quality assurance protocols used for ageing and maturity are now available. Also, a new method for quality grading was developed, tested, and implemented in SmartDots