Sweeping away barriers to interdisciplinary research:recommendations based on X-Net project outcomes - March 2024

X-Net is an interdisciplinary research network whose main aim is to understand barriers to interdisciplinary research, before offering solutions to overcome them. X-Net recommends a 13-step programme of targeted multi-level interventions drawn from evidence gathered by the network in 2022- 2023. The 13 interventions would deeply weave interdisciplinarity into UK scientific research culture and free the flow of ideas and expertise across traditional disciplinary boundaries and sectors

Overcoming barriers to cross-disciplinary research

Interdisciplinary research can create many scientific opportunities but may also face challenges and barriers. X-Net’s main objective is helping interdisciplinary scientists to overcome those barriers providing guidance and resources, particularly to early career researchers. We organised an online workshop “Overcoming barriers to cross-disciplinary research” (6th July, 2022) with the purpose of identifying the main obstacles of interdisciplinary research (IDR) in the UK. The workshop incorporated a pre-workshop anonymous survey that allowed participants to identify and share some of their personal experiences of cross-disciplinary research. The workshop then used these experiences to find themes or challenges in common. It also allowed participants to consider, through action learning, what specific cross-disciplinary barrier(s) they sought advice on. The survey questionnaire was designed to focus on the opinions of individual scientists regarding the barriers or incentives for interdisciplinary research and to receive diverse perspectives. Researchers with early or ongoing experience in interdisciplinarity entering biomedical sciences from STEM were approached for their opinions

Cell cycle stage-specific roles of Rad18 in tolerance and repair of oxidative DNA damage

The E3 ubiquitin ligase Rad18 mediates tolerance of replication fork-stalling bulky DNA lesions, but whether Rad18 mediates tolerance of bulky DNA lesions acquired outside S-phase is unclear. Using synchronized cultures of primary human cells, we defined cell cycle stage-specific contributions of Rad18 to genome maintenance in response to ultraviolet C (UVC) and H2O2-induced DNA damage. UVC and H2O2 treatments both induced Rad18-mediated proliferating cell nuclear antigen mono-ubiquitination during G0, G1 and S-phase. Rad18 was important for repressing H2O2-induced (but not ultraviolet-induced) double strand break (DSB) accumulation and ATM S1981 phosphorylation only during G1, indicating a specific role for Rad18 in processing of oxidative DNA lesions outside S-phase. However, H2O2-induced DSB formation in Rad18-depleted G1 cells was not associated with increased genotoxin sensitivity, indicating that back-up DSB repair mechanisms compensate for Rad18 deficiency. Indeed, in DNA LigIV-deficient cells Rad18-depletion conferred H2O2-sensitivity, demonstrating functional redundancy between Rad18 and non-homologous end joining for tolerance of oxidative DNA damage acquired during G1. In contrast with G1-synchronized cultures, S-phase cells were H2O2-sensitive following Rad18-depletion. We conclude that although Rad18 pathway activation by oxidative lesions is not restricted to S-phase, Rad18-mediated trans-lesion synthesis by Polη is dispensable for damage-tolerance in G1 (because of back-up non-homologous end joining-mediated DSB repair), yet Rad18 is necessary for damage tolerance during S-phase

Genomic and Transcriptional Co-Localization of Protein-Coding and Long Non-Coding RNA Pairs in the Developing Brain

Besides protein-coding mRNAs, eukaryotic transcriptomes include many long non-protein-coding RNAs (ncRNAs) of unknown function that are transcribed away from protein-coding loci. Here, we have identified 659 intergenic long ncRNAs whose genomic sequences individually exhibit evolutionary constraint, a hallmark of functionality. Of this set, those expressed in the brain are more frequently conserved and are significantly enriched with predicted RNA secondary structures. Furthermore, brain-expressed long ncRNAs are preferentially located adjacent to protein-coding genes that are (1) also expressed in the brain and (2) involved in transcriptional regulation or in nervous system development. This led us to the hypothesis that spatiotemporal co-expression of ncRNAs and nearby protein-coding genes represents a general phenomenon, a prediction that was confirmed subsequently by in situ hybridisation in developing and adult mouse brain. We provide the full set of constrained long ncRNAs as an important experimental resource and present, for the first time, substantive and predictive criteria for prioritising long ncRNA and mRNA transcript pairs when investigating their biological functions and contributions to development and disease

Publisher Correction:Parent of origin genetic effects on methylation in humans are common and influence complex trait variation

In the original version of this Article, the legend in the upper panel of Figure 2 incorrectly read ‘paternal imprinting’ and should have read ‘maternal imprinting’. This has been corrected in both the PDF and HTML versions of the Article

Effects of Exercise Interventions on Quality of Life and Cancer-Related Fatigue in Patients Undergoing Chemotherapy: A Systematic Literature Review

Motivation: Cancer is a debilitating and life-threatening array of diseases that present many health challenges, including cancer-related fatigue (CRF) and reduced quality of life (QoL). These challenges can occur throughout the disease process, become exacerbated during chemotherapy treatment, and persist into survivorship. While there is evidence that exercise can safely help to mitigate these challenges in cancer survivors, there remains a gap as to whether exercise during chemotherapy has both immediate and long-term effects. Problem Statement: The objective of this review is to identify evidence on exercise interventions during chemotherapy treatment and their impact on CRF and QoL. Methods: Articles were selected using six different electronic databases; Ovid MEDLINE, PsycINFO, Cochrane, PEDro, CINAHL, and Web of Science (WoS). Studies selected for review measured the impacts of exercise interventions on CRF and QoL for adults undergoing chemotherapy treatment. The quality and level of evidence for each study was assessed using OCEBM and PEDro. Main research results were summarized into recommendations that were graded using OCEBM. Results: Ten randomized controlled trials were selected for inclusion in this review. The most common range of intervention was 12-16 weeks, and interventions consisted of aerobic training, resistance training, or a combination of the two. Preliminary results show that exercise-based programs were better than usual care at preventing further declines in certain subcategories of QoL and CRF in participants undergoing chemotherapy. One longitudinal study showed that a combined resistance and aerobic exercise program prevented an increase in CRF both during chemotherapy and 2 years post-intervention. Conclusions: A combined resistance and aerobic training program, implemented early during chemotherapy treatment, can minimize the immediate and long-term burden of CRF and reduced QoL when compared to usual care

Cell cycle stage-specific roles of Rad18 in tolerance and repair of oxidative DNA damage

The E3 ubiquitin ligase Rad18 mediates tolerance of replication fork-stalling bulky DNA lesions, but whether Rad18 mediates tolerance of bulky DNA lesions acquired outside S-phase is unclear. Using synchronized cultures of primary human cells, we defined cell cycle stage-specific contributions of Rad18 to genome maintenance in response to ultraviolet C (UVC) and H(2)O(2)-induced DNA damage. UVC and H(2)O(2) treatments both induced Rad18-mediated proliferating cell nuclear antigen mono-ubiquitination during G(0), G(1) and S-phase. Rad18 was important for repressing H(2)O(2)-induced (but not ultraviolet-induced) double strand break (DSB) accumulation and ATM S1981 phosphorylation only during G(1), indicating a specific role for Rad18 in processing of oxidative DNA lesions outside S-phase. However, H(2)O(2)-induced DSB formation in Rad18-depleted G1 cells was not associated with increased genotoxin sensitivity, indicating that back-up DSB repair mechanisms compensate for Rad18 deficiency. Indeed, in DNA LigIV-deficient cells Rad18-depletion conferred H(2)O(2)-sensitivity, demonstrating functional redundancy between Rad18 and non-homologous end joining for tolerance of oxidative DNA damage acquired during G(1). In contrast with G(1)-synchronized cultures, S-phase cells were H(2)O(2)-sensitive following Rad18-depletion. We conclude that although Rad18 pathway activation by oxidative lesions is not restricted to S-phase, Rad18-mediated trans-lesion synthesis by Polη is dispensable for damage-tolerance in G(1) (because of back-up non-homologous end joining-mediated DSB repair), yet Rad18 is necessary for damage tolerance during S-phase