Search

Cdc48 (VCP/p97) is a major AAA-ATPase involved in protein quality control, along with its canonical cofactors Ufd1 and Npl4 (UN). Here, we present novel structural insights into the interactions within the Cdc48-Npl4-Ufd1 ternary complex. Using integrative modeling, we combine subunit structures with crosslinking mass spectrometry (XL-MS) to map the interaction between Npl4 and Ufd1, alone and in complex with Cdc48. We describe the stabilization of the UN assembly upon binding with the N-terminal-domain (NTD) of Cdc48 and identify a highly conserved cysteine, C115, at the Cdc48-Npl4-binding interface which is central to the stability of the Cdc48-Npl4-Ufd1 complex. Mutation of Cys115 to serine disrupts the interaction between Cdc48-NTD and Npl4-Ufd1 and leads to a moderate decrease in cellular growth and protein quality control in yeast. Our results provide structural insight into the architecture of the Cdc48-Npl4-Ufd1 complex as well as its in vivo implications., Competing Interests: Declaration of interests The authors state that no competing financial interests exist., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Current approaches to characterizing deficits in upper limb movements after stroke typically focus either on changes in a functional measure, for example, how well a patient can complete a task, or changes in impairment, for example, isolated measurements of joint range of motion. However, there can be notable dissociations between static measures of impairment versus those of function., Objective: We develop a method to measure upper limb joint angles during performance of a functional task and use measurements to characterize joint impairment in the context of a functional task., Methods: We developed a sensorized glove that can precisely measure select finger, hand, and arm joints while participants complete a functional reach-to-grasp task involving manipulation of a sensorized object., Results: We first characterized the accuracy and precision of the glove's joint angle measurements. We then measured joint angles in neurologically intact participants (n = 4 participants, 8 limbs) to define the expected distribution of joint angle variation during task execution. These distributions were used to normalize finger, hand, and arm joint angles in stroke participants (n = 6) as they performed the task. We present a participant-specific visualization of functional joint angle variance which illustrated that stroke participants with nearly identical clinical scores exhibited unique patterns of joint angle variation., Conclusions: Overall, measuring individual joint angles in the context of a functional task may inform whether changes in functional scores over recovery or rehabilitation are driven by changes in impairment or the development of compensatory strategies, and provide a quantified path toward personalized rehabilitative therapy.

Background: With the outbreak of the COVID-19 pandemic, the need arose to maintain treatment continuity for religious Jewish Ultra-Orthodox young women with eating disorders (EDs) previously hospitalized in the ED department at the Ultra-Orthodox "Mayanei Hayeshua" medical center in Israel. This need led to the development of home-based online treatment channels, previously unfamiliar, and unaccepted in this population. The implementation of this model had to take into consideration many of the difficulties inherent in the use of online treatment in Jewish Ultra-Orthodox mental health patients. Aims: We sought to investigate our online home-based treatment model implemented during the COVID-19 pandemic in previously hospitalized young Ultra-Orthodox women with EDs. Method: We briefly review the literature on: (1) The Jewish Israeli Ultra-Orthodox culture; (2) Young women in Ultra-Orthodox society; and (3) EDs in Jewish Israeli Ultra-Orthodox women. We then present the inpatient ED department for Ultra-Orthodox young women and describe the online treatment model adapted to this population during the COVID-19 pandemic. We highlight the difficulties, dilemmas, and advantages of our online model with the description of three patients. Findings: Online therapy can serve as a barrier to treatment in some cases, due to physical (lack of suitable online devices except phones), familial (over-crowded families), and religious circumstances, as well as because of the patients' reluctance to take part in this treatment. In other cases, virtual home-based treatment can lead to a positive change. This may be the case in patients who find the distancing online model suitable for them, and in parents who are committed to treatment, using their greater physical and emotional presence at home during the COVID-19 pandemic for the good if their ill-daughters. Discussion: This paper highlights the difficulties and possibilities inherent in a virtual home-based treatment during the COVID-19 pandemic for Ultra-Orthodox young women previously hospitalized because of an ED. This model can be effective for some patients and families if undertaken by a multidisciplinary team that is not only knowledgeable about the treatment of EDs and the use of online strategies but also knowledgeable and culturally sensitive to the specific needs and codes of Ultra-Orthodox populations., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Latzer, Herman, Ashkenazi, Atias, Laufer, Biran Ovadia, Oppenheim, Shimoni, Uziel and Stein.)

Protein homeostasis is an essential component of proper cellular function; however, sustaining protein health is a challenging task, especially during the aerobic lifestyle. Natural cellular oxidants may be involved in cell signaling and antibacterial defense; however, imbalanced levels can lead to protein misfolding, cell damage, and death. This merges together the processes of protein homeostasis and redox regulation. At the heart of this process are redox-regulated proteins or thiol-based switches, which carefully mediate various steps of protein homeostasis across folding, localization, quality control, and degradation pathways. In this review, we discuss the "redox code" of the proteostasis network, which shapes protein health during cell growth and aging. We describe the sources and types of thiol modifications and elaborate on diverse strategies of evolving antioxidant proteins in proteostasis networks during oxidative stress conditions. We also highlight the involvement of cysteines in protein degradation across varying levels, showcasing the importance of cysteine thiols in proteostasis at large. The individual examples and mechanisms raised open the door for extensive future research exploring the interplay between the redox and protein homeostasis systems. Understanding this interplay will enable us to re-write the redox code of cells and use it for biotechnological and therapeutic purposes.

We report the use of near-field electrospinning (NFES) as a route to fabricate composite electrodes. Electrodes made of composite fibers of multi-walled carbon nanotubes in polyethylene oxide (PEO) are formed via liquid deposition, with precise control over their configuration. The electromechanical properties of free-standing fibers and fibers deposited on elastic substrates are studied in detail. In particular, we examine the elastic deformation limit of the resulting free-standing fibers and find, similarly to bulk PEO composites, that the plastic deformation onset is below 2% of tensile strain. In comparison, the apparent deformation limit is much improved when the fibers are integrated onto a stretchable, elastic substrate. It is hoped that the NFES fabrication protocol presented here can provide a platform to direct-write polymeric electrodes, and to integrate both stiff and soft electrodes onto a variety of polymeric substrates.

Hypothalamic hamartomas (HHs) are associated with treatment-resistant epilepsy. Many patients also experience severe and sometimes disabling psychiatric problems. The most common behavioral symptoms consist of paroxysms of uncontrolled anger related to poor frustration tolerance. These can include violence, resulting in disrupted family or school relationships, and legal consequences including incarceration. In a large cohort of patients undergoing surgical resection of HHs for refractory epilepsy, 88% of families described an improvement in overall behavioral functioning [1]. Here, we describe four patients (three males, mean age=11.9 years) who underwent surgical resection of HHs largely for behavioral indications. Three patients had relatively well controlled seizures, and one had no history of epilepsy. All patients had striking improvement in their psychiatric comorbidity. HH resection can result in significant improvement in behavioral functioning, even in patients with relatively infrequent seizures. Further investigation under approved human research protocols is warranted., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Protein fibrils are emerging as a novel class of functional bionanomaterials. In this paper we make use of their rigidity by combining lysozyme fibrils with a silicone elastomer and demonstrating that at a filling ratio of 10%, the protein fibril composite is at minimum 2 times stiffer than a CNT elastomeric composite of the same filling ratio. We also show that when the elastomer is patterned such that the lysozyme fibrils can be spatially modulated within the elastomer, anisotropic moduli varying by a factor of 2 is produced. By using shear mixing as the fabrication process, the modulus of a 2 wt.% insulin fibril composite is equivalent to a CNT composite with the same filling ratio. In conclusion, we have presented the fabrication and mechanical characterisation of a class of elastomer/protein fibril composite material., (Copyright 2009 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

The incidence of residual neoplastic cells on prostatic biopsy following conventional external beam radiotherapy is reported to range from 40-90%. As a result, it has been stated that current modalities of radiotherapy may carry an unacceptable local failure rate even in patients irradiated for low stage disease. In order to assess the potential benefits of three-dimensional (3-D) treatment planning, an unselected, consecutive group of patients with localized adenocarcinoma of the prostate was evaluated. This study was designed to determine the frequency of residual cancer in the prostate two years following definitive external beam radiotherapy designed, using a 3-D planning system. Between February 1988 and February 1989, 30 consecutive patients with localized (Stage T1-T3NxMo) adenocarcinoma of the prostate received definitive external beam radiotherapy. All treatment fields were designed with a computed tomography (CT)-based 3-D treatment planning system, resulting in a static conformal radiotherapy plan. The minimum dose delivered to the target volume, which included the prostate, periprostatic tissues, and a 1 cm margin, was between 65 and 69 cGy. Twenty-six patients had Stage T1, T2NxMo primary tumors and four were T3NxMo. Two years following the completion of treatment, all patients underwent digital rectal examination, transrectal ultrasound examination of the prostate with multiple biopsies, bone scan, and serum prostate specific antigen (PSA) determinations. Residual prostate cancer was proven by biopsy in six of 30 patients (20%). Four of 26 (15%) with Stage T1 and T2 tumors had a positive biopsy. However, two of the four Stage T3 tumors had postradiation biopsies positive for cancer (50%). Only one patient with a positive biopsy had an abnormal rectal examination. Five of the eight patients with elevated serum PSA levels after two years had residual neoplasia identified on biopsy. One of six patients with an abnormal postradiation ultrasound had residual tumor. Only one of the 22 patients (5%) with a normal serum PSA at two years had a positive postradiation biopsy. In patients with localized prostate cancer, the use of 3-D static conformal radiotherapy followed by multiple ultrasound guided biopsies confirmed the efficacy of external beam radiotherapy in low stage disease. We believe that the low incidence of positive biopsies in this study resulted from the benefits of 3-D treatment planning as well as the fact that all patients were evaluated, whereas past studies have been in selected patient groups when suspicion of residual disease existed prior to biopsy.(ABSTRACT TRUNCATED AT 400 WORDS)