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Proteolysis-targeting chimeras (PROTACs) have been explored for the degradation of drug targets for more than two decades. However, only a handful of E3 ligase substrate receptors have been efficiently used. Downregulation and mutation of these receptors would reduce the effectiveness of such PROTACs. We recently developed potent ligands for DCAF1, a substrate receptor of EDVP and CUL4 E3 ligases. Here, we focus on DCAF1 toward the development of PROTACs for WDR5, a drug target in various cancers. We report four DCAF1-based PROTACs with endogenous and exogenous WDR5 degradation effects and high-resolution crystal structures of the ternary complexes of DCAF1-PROTAC-WDR5. The structures reveal detailed insights into the interaction of DCAF1 with various WDR5-PROTACs, indicating a significant role of DCAF1 loops in providing needed surface plasticity, and reflecting the mechanism by which DCAF1 functions as a substrate receptor for E3 ligases with diverse sets of substrates. The authors show that DCAF1, a substrate receptor of CUL4 and EDVP E3 ligases, can be recruited by PROTACs to degrade the cancer drug target, WDR5. They also report the crystal structures of PROTAC ternary complexes that reveal a significant role for loops in DCAF1 substrate recognition, a potential mechanism behind the diverse substrate specificity of DCAF1.

Human DCAF1 is a multidomain protein that plays a critical role in protein homeostasis. Its WDR domain functions as a substrate recruitment module for RING-type CRL4 and HECT family EDVP E3 ubiquitin ligases, enabling the ubiquitination and proteasomal degradation of specific substrates. DCAF1’s activity has been implicated in cell proliferation and is documented to promote tumorigenesis. Additionally, the DCAF1 WDR domain is hijacked by lentiviral accessory proteins to induce the degradation of host antiviral factors, such as SAMHD1 and UNG2. These diverse roles make DCAF1 an attractive target for therapeutic development in oncology and antiviral strategies. It is also a promising candidate for use in targeted protein degradation. We previously reported a novel ligand, OICR-8268, that targets the DCAF1 WDR domain. In this study, we present the development of OICR-41103, a potent, selective, and cell-active small molecule chemical probe for DCAF1, derived from OICR-8268. The co-crystal structure of the DCAF1-OICR-41103 complex reveals the ligand’s binding mode within the WDR central pocket, demonstrating its potential for PROTAC design and development. Notably, OICR-41103 effectively displaces the lentiviral Vpr protein from DCAF1 in both biochemical and cellular settings, highlighting its potential for the development of HIV therapeutics. OICR-41103 is a potent, selective probe targeting the DCAF1 WDR domain and displacing viral Vpr protein. It enables new opportunities in cancer research, antiviral therapy, and targeted protein degradation via PROTACs.

Since the government of India announced a lockdown of the country from March 2020 to September 2020, all physical conferences were cancelled indefinitely, and the education of postgraduate junior doctors is now being organised through webinars and teleconferencing apps.1 A known benefit of webinars is that they can be recorded and stored which can be made available for future learning sessions.2 Recently published standard operating procedures for smooth conductance of webinars are a helpful set of instructions for the faculty who are using webinars as a teaching medium because medical education has not come to a halt even during the pandemic.3 4 While the webinars are breaking through the web space by way of several of them being held at regular intervals throughout the day, the concerns and perspectives of the members and delegates are hardly accounted for. In several of the webinars, we have seen delegates switching off their videos and logging off within few minutes. Jeremy Bailenson described the term ‘Zoom Fatigue’, which is gaining a lot of traction these days, as an exhausting feeling that individuals experienced after prolonged video chats.5 Indian dermatologists were overwhelmed with the increasing number of webinars planned every day and hence they were reluctant to attend webinars.6 Are the delegates finding the webinars useful and are the webinars a good substitute for physically conducted continued medical education (CME) events?

Lower extremity tendinopathies, including Achilles tendinopathy (AT) and Patellar tendinopathy (PT), are common musculoskeletal conditions characterized by chronic pain and impaired physical function. These conditions are particularly prevalent among athletes involved in high impact sports activities with reported incidences of 36% for AT in runners and 18-45% for PT in volleyball players. Jump and hop assessments have emerged as valuable tools for evaluating the energy storage and recoil function of the tendon in individuals with tendinopathy. Therefore, the first aim of the dissertation work was to conduct a systematic review to identify, evaluate, and summarize the existing literature on jump and hop performance in lower extremity tendinopathy. A comprehensive search was conducted in PubMed, EMBASE, CINAHL and Web of Science databases. After applying the inclusion and exclusion criteria, 25 studies were included in the review. The findings of this review indicate that individuals with lower extremity tendinopathy demonstrated altered jump performance compared to healthy controls. However, available research showed limited exploration of joint-specific contributions to these performance changes.Assessing this gap in knowledge, the second aim of this dissertation focused on analyzing single leg drop countermovement jump (DCMJ) performance in runners with AT compared to matched controls. This study involved systematic recruitment of participants into two groups: runners with midportion unilateral AT and a control group of runners matched for age, gender, and BMI for this study. The key findings of this study were (1) Runners with AT demonstrated altered single leg DCMJ performance, (2) AT may present with clinically relevant subgroups. This study identified subgroups with reduced hip extensor strength and (3) DCMJ proves to be a robust assessment tool for evaluating AT in individuals participating in high impact sports. In conclusion, this dissertation work supports the use of jump and hop assessments as a tool to assess tendon function in lower extremity tendinopathy. Furthermore, it underscores the importance of analyzing joint specific contributions during DCMJ for comprehensive assessment of AT impairments.

This paper, for the first time, compares the behaviors of nonlinear versus linear muscle networks in decoding hidden peripheral synergistic neural patterns during dynamic functional tasks. In this paper, we report a case study during which one healthy subject conducts a series of four lower limb repetitive tasks. Specifically, the paper focuses on tasks that involve the right knee joint, including walking, sit-to-stand, stepping, and drop-jump. Twelve muscles were recorded using the Delsys Trigno system. The linear muscle network was generated using coherence analysis, and the nonlinear network was generated using Spearman's correlation. The results show that the degree, clustering coefficient, and global efficiency of the muscle network have the highest value among tasks in the linear domain for the walking task, while a low linear synergistic network behavior for the sit-to-stand is observed. On the other hand, the results show that the nonlinear functional muscle network decodes high connectivity (degree) and clustering coefficient and efficiency for the sit-to-stand when compared with other tasks. We have also developed a two-dimensional functional connectivity plane composed of linear and nonlinear features and shown that it can span the lower-limb dynamic task space. The results of this paper for the first time highlight the importance of observing both linear and nonlinear connectivity patterns, especially for complex dynamic tasks. It should also be noted that through a simultaneous EEG recording (using BrainVision System), we have shown that, indeed, cortical activity may indirectly explain highly-connected nonlinear muscle network for the sit-to-stand task, highlighting the importance of nonlinear muscle network as a neurophysiological window of observation beyond the periphery.Competing Interest StatementThe authors have declared no competing interest.

Approximately 7% of all reported tuberculosis (TB) cases each year are recurrent, occurring among people who have had TB in the recent or distant past. TB recurrence is particularly common in India, which has the largest TB burden worldwide. Although patients recently treated for TB are at high risk of developing TB again, evidence around effective active case finding (ACF) strategies in this population is scarce. We will conduct a hybrid type I effectiveness-implementation non-inferiority randomized trial to compare the effectiveness, cost-effectiveness, and feasibility of two ACF strategies among individuals who have completed TB treatment and their household contacts (HHCs). We will enroll 1076 adults ([greater than or equal to] 18 years) who have completed TB treatment at a public TB unit (TU) in Pune, India, along with their HHCs (averaging two per patient, n = 2152). Participants will undergo symptom-based ACF by existing healthcare workers (HCWs) at 6-month intervals and will be randomized to either home-based ACF (HACF) or telephonic ACF (TACF). Symptomatic participants will undergo microbiologic testing through the program. Asymptomatic HHCs will be referred for TB preventive treatment (TPT) per national guidelines. The primary outcome is rate per 100 person-years of people diagnosed with new or recurrent TB by study arm, within 12 months following treatment completion. The secondary outcome is proportion of HHCs < 6 years, by study arm, initiated on TPT after ruling out TB disease. Study staff will collect socio-demographic and clinical data to identify risk factors for TB recurrence and will measure post-TB lung impairment. In both arms, an 18-month \"mop-up\" visit will be conducted to ascertain outcomes. We will use the RE-AIM framework to characterize implementation processes and explore acceptability through in-depth interviews with index patients, HHCs and HCWs (n = 100). Cost-effectiveness will be assessed by calculating the incremental cost per TB case detected within 12 months and projected for disability-adjusted life years averted based on modeled estimates of morbidity, mortality, and time with infectious TB. This novel trial will guide India's scale-up of post-treatment ACF and provide an evidence base for designing strategies to detect recurrent and new TB in other high burden settings.

Background Approximately 7% of all reported tuberculosis (TB) cases each year are recurrent, occurring among people who have had TB in the recent or distant past. TB recurrence is particularly common in India, which has the largest TB burden worldwide. Although patients recently treated for TB are at high risk of developing TB again, evidence around effective active case finding (ACF) strategies in this population is scarce. We will conduct a hybrid type I effectiveness-implementation non-inferiority randomized trial to compare the effectiveness, cost-effectiveness, and feasibility of two ACF strategies among individuals who have completed TB treatment and their household contacts (HHCs). Methods We will enroll 1076 adults (≥ 18 years) who have completed TB treatment at a public TB unit (TU) in Pune, India, along with their HHCs (averaging two per patient, n  = 2152). Participants will undergo symptom-based ACF by existing healthcare workers (HCWs) at 6-month intervals and will be randomized to either home-based ACF (HACF) or telephonic ACF (TACF). Symptomatic participants will undergo microbiologic testing through the program. Asymptomatic HHCs will be referred for TB preventive treatment (TPT) per national guidelines. The primary outcome is rate per 100 person-years of people diagnosed with new or recurrent TB by study arm, within 12 months following treatment completion. The secondary outcome is proportion of HHCs < 6 years, by study arm, initiated on TPT after ruling out TB disease. Study staff will collect socio-demographic and clinical data to identify risk factors for TB recurrence and will measure post-TB lung impairment. In both arms, an 18-month “mop-up” visit will be conducted to ascertain outcomes. We will use the RE-AIM framework to characterize implementation processes and explore acceptability through in-depth interviews with index patients, HHCs and HCWs ( n  = 100). Cost-effectiveness will be assessed by calculating the incremental cost per TB case detected within 12 months and projected for disability-adjusted life years averted based on modeled estimates of morbidity, mortality, and time with infectious TB. Discussion This novel trial will guide India’s scale-up of post-treatment ACF and provide an evidence base for designing strategies to detect recurrent and new TB in other high burden settings. Trial registration NCT04333485 , registered April 3, 2020. CTRI/2020/05/025059 [Clinical Trials Registry of India], registered May 6 2020.