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Targeting subunits of BAF/PBAF chromatin remodeling complexes has been proposed as an approach to exploit cancer vulnerabilities. Here, we develop proteolysis targeting chimera (PROTAC) degraders of the BAF ATPase subunits SMARCA2 and SMARCA4 using a bromodomain ligand and recruitment of the E3 ubiquitin ligase VHL. High-resolution ternary complex crystal structures and biophysical investigation guided rational and efficient optimization toward ACBI1, a potent and cooperative degrader of SMARCA2, SMARCA4 and PBRM1. ACBI1 induced anti-proliferative effects and cell death caused by SMARCA2 depletion in SMARCA4 mutant cancer cells, and in acute myeloid leukemia cells dependent on SMARCA4 ATPase activity. These findings exemplify a successful biophysics- and structure-based PROTAC design approach to degrade high profile drug targets, and pave the way toward new therapeutics for the treatment of tumors sensitive to the loss of BAF complex ATPases. A structure-based design allows the development of a potent PROTAC to degrade BAF ATPase subunits SMARCA2 and SMARCA4 via recruitment of E3 ubiquitin ligase VHL and induce cancer cell death.

In the assessment of hand and upper limb function, grip strength is of major importance. Use of the JAMAR dynamometer has been an accepted test of grip strength and routinely part of the physical examination. The aim of this study was to determine by means of a median nerve block simulating a patient group if the measurement of different types of grip force can improve the quantification of impairment of the hand beyond the sole power grip measurements. In 29 healthy volunteers, grip force measurement was done by the JAMAR dynamometer for power grip and by a pinch grip dynamometer for pincer grip, precision grip, pinch grip, and palmar abduction. At the power grip, the force of digit 2-5 was measured separately by a sensor glove. For each measurement, 3 trials were recorded subsequently. A within-subject research design was used in this prospective study. Each subject served as the control by preinjection measurements of grip and pinch strength. Subsequent measurements after median nerve block were used to examine within-subject change. In power grip, there was no significant reduction of maximum grip force with median nerve block compared with grip force without block. By measuring the finger forces by a sensor glove, a reduction of force at the individual fingers was found compared with the setting with no block, although significant only at the middle finger (P < .017). With median nerve block, average grip force decreased significantly 20% in pincer grip (P < .021), 29.5% in pinch grip (P < .002), 39.5% in precision grip (P < .001), and 70.7% in palmar abduction (P < .013). These experiments suggest a minor role of the measurement of the power grip force in the diagnostics of distal median nerve block with the dynamometer, which could not be substantially improved by the digit forces and the force distribution of the individual fingers. The assessment of other grip forms, such as pincer grasp, precision grip, pinch grip, and especially palmar abduction, leads to a relevant improvement in the diagnostics of distal median nerve lesion. II.

In the version of this article originally published, several lines of text in the last paragraph of the right column on page 1 of the PDF were transposed into the bottom paragraph of the left column. The affected text of the left column should read “The ATP-dependent activities of the BAF (SWI/SNF) chromatin remodeling complexes affect the positioning of nucleosomes on DNA and thereby many cellular processes related to chromatin structure, including transcription, DNA repair and decatenation of chromosomes during mitosis 12,13 .” The affected text of the right column should read “SMARCA2/4 BD inhibitors are thus precluded from use for the treatment of SMARCA4 mutant cancers but could provide attractive ligands for PROTAC conjugation. Small molecules binding to other bromodomains have been successfully converted into PROTACs by conjugating them with structures capable of binding to the E3 ligases von Hippel−Lindau (VHL) or cereblon 5,6,10,11,25,26,27 .” The errors have been corrected in the PDF version of the paper.

In the assessment of hand and upper limb function, grip strength is of the major importance. The measurement by dynamometers has been established. In this study, the effect of a simulated ulnar nerve lesion on different grip force measurements was evaluated. In 25 healthy volunteers, grip force measurement was done by the JAMAR dynamometer (Fabrication Enterprises Inc, Irvington, NY) for power grip and by a pinch strength dynamometer for tip pinch strength, tripod grip, and key pinch strength. A within-subject research design was used in this prospective study. Each subject served as the control by preinjection measurements of grip and pinch strength. Subsequent measurements after ulnar nerve block were used to examine within-subject change. In power grip, there was a significant reduction of maximum grip force of 26.9% with ulnar nerve block compared with grip force without block (P < .0001). Larger reductions in pinch strength were observed with block: 57.5% in tip pinch strength (P < .0001), 61.0% in tripod grip (P < .0001), and 58.3% in key pinch strength (P < .0001). The effect of the distal ulnar nerve block on grip and pinch force could be confirmed. However, the assessment of other dimensions of hand strength as tip pinch, tripod pinch and key pinch had more relevance in demonstrating hand strength changes resulting from an distal ulnar nerve lesion. The measurement of tip pinch, tripod grip and key pinch can improve the follow-up in hand rehabilitation. II.

A within-subject research design was used in this study. The difference of the range of motion (ROM) with and without ulnar nerve block was analyzed. For the clinical evaluation of the functional effects of ulnar nerve palsy at the hand the relevance of clinical tests is in discussion. The aim of the study was to evaluate the predictive value of 2 clinical tests for a simulated ulnar nerve lesion by motion analysis with a sensor glove. In 28 healthy subjects, dynamic measurements of the finger joints were performed by a sensor glove with and without ulnar nerve block at the wrist. In the 0° metacarpophalangeal (MCP) stabilization test, the subjects were asked to stabilize the MCP joints actively in 0° while moving the interphalangeal joints, whereas at the 90° MCP stabilization test, the subjects stabilized the MCP joints actively in the 90° position. In the 0° MCP stabilization test, no remarkable changes of the ROM were found at the MCP joints; at the proximal interphalangeal joints 2-5, the ROM decreased with ulnar nerve block, significantly at the index, middle, and ring fingers (P < .05). In the 90° MCP stabilization test, the average ROM of the MCP joints 2-5 significantly increased with ulnar nerve block (P < .05), whereas at the PIP joints, the average ROM decreased (P < .05). The 90° MCP stabilization test had a high predictive value for the discrimination between healthy subjects and subjects with a simulated peripheral ulnar nerve lesion. The results could be relevant for the determination of the functional effect of ulnar nerve palsy and the quantification of clawing in hand rehabilitation. II.

We estimate that unemployment insurance (UI) extensions reduce reemployment wages using sharp age discontinuities in UI eligibility in Germany. We show this effect combines two key policy parameters: the effect ofUI on reservation wages and the effect of nonemployment durations on wage offers. Our framework implies if UI extensions do not affect wages conditional on duration, then reservation wages do not bind. We derive resulting instrumental variable estimates for the effect of nonemployment durations on wage offers and bounds for reservation wage effects. The effect of UI on wages we find arises mainly from substantial negative nonemployment duration effects.

One goal of extending the duration of unemployment insurance (UI) in recessions is to increase UI coverage in the face of longer unemployment spells. Although it is a common concern that such extensions may themselves raise nonemployment durations, it is not known how recessions would affect the magnitude of this moral hazard. To obtain causal estimates of the differential effects of UI in booms and recessions, this article exploits the fact that in Germany, potential UI benefit duration is a function of exact age which is itself invariant over the business cycle. We implement a regression discontinuity design separately for 20 years and correlate our estimates with measures of the business cycle. We find that the nonemployment effects of a month of additional UI benefits are, at best, somewhat declining in recessions. Yet the UI exhaustion rate, and therefore the additional coverage provided by UI extensions, rises substantially during a downturn. The ratio of these two effects represents the nonemployment response of workers weighted by the probability of being affected by UI extensions. Hence, our results imply that the effective moral hazard effect of UI extensions is significantly lower in recessions than in booms. Using a model of job search with liquidity constraints, we also find that in the absence of market-wide effects, the net social benefits from UI extensions can be expressed either directly in terms of the exhaustion rate and the nonemployment effect of UI durations, or as a declining function of our measure of effective moral hazard.

The Great Recession has renewed interest in unemployment insurance (UI) programs around the world. At the same time, there have been important advances in both theory and measurement of UI. In this review, we first use the theory to present a unified treatment of the welfare effects of UI benefit levels and durations and derive convenient expressions of the full disincentive effect of UI. We then discuss recent estimates of the effect of UI benefit levels and durations on labor supply based on newly available administrative data and quasi-experimental research designs. Although our review of the new estimates confirms the range of negative labor supply effects of the previous literature, we show, based on the model, that these estimates are imperfect proxies for the actual disincentive effects. We also discuss several active areas of research on UI. These include the effect of UI on aggregate labor market outcomes, its effect on job outcomes, its long-term effects, its effects under nonstandard behavioral assumptions, and its interactions with other programs. We isolate several additional areas in need of further research, including estimates of the social value of UI, as well as the effects of UI in less developed countries.