The structure of Mediterranean rocky reef ecosystems across environmental and human gradients, and conservation implications

Historical exploitation of the Mediterranean Sea and the absence of rigorous baselines makes it difficult to evaluate the current health of the marine ecosystems and the efficacy of conservation actions at the ecosystem level. Here we establish the first current baseline and gradient of ecosystem structure of nearshore rocky reefs at the Mediterranean scale. We conducted underwater surveys in 14 marine protected areas and 18 open access sites across the Mediterranean, and across a 31-fold range of fish biomass (from 3.8 to 118 g m(-2)). Our data showed remarkable variation in the structure of rocky reef ecosystems. Multivariate analysis showed three alternative community states: (1) large fish biomass and reefs dominated by non-canopy algae, (2) lower fish biomass but abundant native algal canopies and suspension feeders, and (3) low fish biomass and extensive barrens, with areas covered by turf algae. Our results suggest that the healthiest shallow rocky reef ecosystems in the Mediterranean have both large fish and algal biomass. Protection level and primary production were the only variables significantly correlated to community biomass structure. Fish biomass was significantly larger in well-enforced no-take marine reserves, but there were no significant differences between multi-use marine protected areas (which allow some fishing) and open access areas at the regional scale. The gradients reported here represent a trajectory of degradation that can be used to assess the health of any similar habitat in the Mediterranean, and to evaluate the efficacy of marine protected areas.     

Normal bone turnover markers in a patient with active Paget's disease of bone: response to treatment with zoledronic acid

The treatment of Paget's disease of bone (PDB) aims at the suppression of abnormal bone turnover; bisphosphonates are currently the treatment of choice. Indications for antiresorptive treatment in symptomatic patients with PDB include bone or joint pain, neurological complications, surgery planned at an active pagetic site and hypercalcaemia from immobilisation. The goals of antiresorptive treatment are clinical improvement and biochemical remission, as assessed by the normalisation of bone turnover markers. Clinical deterioration, especially bone pain, should be considered before deciding to treat patients with late sclerotic (burned-out) PDB. Bone scintigraphy may be of importance in these patients, because it depicts increased osteoblastic activity, when bone markers may not. We present a case of late sclerotic PDB with clinical deterioration but normal bone turnover markers, who experienced significant clinical improvement after treatment with zoledronic acid.     

The ubiquitin-proteasome system in glioma cell cycle control

ABSTRACT: A major determinant of cell fate is regulation of cell cycle. Tight regulation of this process is lost during the course of development and progression of various tumors. The ubiquitin-proteasome system (UPS) constitutes a universal protein degradation pathway, essential for the consistent recycling of a plethora of proteins with distinct structural and functional roles within the cell, including cell cycle regulation. High grade tumors, such as glioblastomas have an inherent potential of escaping cell cycle control mechanisms and are often refractory to conventional treatment. Here, we review the association of UPS with several UPS-targeted proteins and pathways involved in regulation of the cell cycle in malignant gliomas, and discuss the potential role of UPS inhibitors in reinstitution of cell cycle control.     

Morphometry and Contents of the Suprascapular Notch with Potential Clinical Implications: Α Cadaveric Study

Background  The suprascapular notch (SN) represents the point along the route of the suprascapular nerve (SSN) with the greatest potential risk for injury and compression. Thus, factors reducing the area of the notch have been postulated for suprascapular neuropathy development. Methods  Thirty-one fresh-frozen shoulders were dissected. The contents of the SN were described according to four types as classified by Polguj et al and the middle-transverse diameter of the notch was measured. Also, the presence of an ossified superior transverse scapular ligament (STSL) was identified. Results  The ligament was partially ossified in 8 specimens (25.8%), fully ossified in 6 (19.35%), and not ossified in the remaining 17 (54.85%). The mean middle-transverse diameter of the SN was 9.06 mm (standard deviation [SD] = 3.45). The corresponding for type-I notches was 8.64 mm (SD = 3.34), 8.86 mm (SD = 3.12) was for type-II, and 14.5 mm (SD = 1.02) was for type III. Middle-transverse diameter was shorter when an ossified ligament was present (mean = 5.10 mm, SD = 0.88 mm), comparing with a partially ossified ligament (mean =7.67 mm, SD = 2.24 mm) and a nonossified one (mean = 11.12 mm, SD = 2.92 mm). No statistically significant evidence was found that the middle-transverse diameter depends on the number of the elements, passing below the STSL. Conclusion  Our results suggest that SSN compression could be more likely to occur when both suprascapular vessels pass through the notch. Compression of the nerve may also occur when an ossified transverse scapular ligament is present, resulting to significant reduction of the notch''s area.     

Designing and implementing a research integrity promotion plan: Recommendations for research funders

Various stakeholders in science have put research integrity high on their agenda. Among them, research funders are prominently placed to foster research integrity by requiring that the organizations and individual researchers they support make an explicit commitment to research integrity. Moreover, funders need to adopt appropriate research integrity practices themselves. To facilitate this, we recommend that funders develop and implement a Research Integrity Promotion Plan (RIPP). This Consensus View offers a range of examples of how funders are already promoting research integrity, distills 6 core topics that funders should cover in a RIPP, and provides guidelines on how to develop and implement a RIPP. We believe that the 6 core topics we put forward will guide funders towards strengthening research integrity policy in their organization and guide the researchers and research organizations they fund.

Research funders are prominently placed to foster research integrity by requiring that researchers make an explicit commitment to research integrity. This Consensus View suggests 6 core topics that funders should cover in a research integrity promotion plan and provides practical recommendations for how to implement one.

To improve research quality and validity, foster responsible research cultures, and maintain public trust in science, various stakeholders have put research integrity high on their agenda. Among them, research funders are increasingly acknowledging their pivotal role in contributing to a culture of research integrity. For example, the European Commission (EC) is mandating research organizations receiving funding from the €95 billion Horizon Europe program to have, at the institutional level, policies and processes in place for research integrity covering the promotion of good practice, prevention of misconduct and questionable practices, and procedures to deal with breaches of research integrity [1]. To meet these obligations, the EC requires beneficiaries to respect the principles of research integrity as set out in the European Code of Conduct for Research Integrity (ECoC) and suggests that research organizations develop and implement a Research Integrity Promotion Plan (RIPP) [2]. In this Consensus View, we have adopted the World Conference on Research Integrity’s approach to research integrity, by having “research integrity” refer to “the principles and standards that have the purpose to ensure validity and trustworthiness of research” [3]. More specifically, we mostly adhere to the principles outlined in the ECoC: reliability, honesty, respect, and accountability. While many definitions of research integrity exist [4,5], for example, those that distinguish between the integrity of a researcher, integrity of research, and integrity of the research record, the ECoC combines these approaches in a balanced way [1].We believe that funders are prominently placed to foster a culture of research integrity by requiring that the organizations and individual researchers they support make an explicit commitment to research integrity. At the same time, funders need to adopt appropriate research integrity practices themselves. Of late, attention to research integrity among funders has gathered pace, as reflected in several initiatives around the globe that demonstrate how funders can support a culture of research integrity. For example, the US National Science Foundation (NSF) [6] requires applicants’ research organizations to provide training and oversight in the responsible conduct of research, designate individuals responsible for research integrity, and have an institutional certification to testify of its commitment. Also, in 2016, 3 Canadian federal funders joined forces to support research integrity in the Canadian Tri-Agency Framework: Responsible Conduct of Research–Harmony and Responsibility [7]. The framework was subsequently updated in 2021. This framework sets out responsible practices that research organizations and researchers should follow, including rigor, record keeping, accurate referencing, responsible authorship, and the management of conflicts of interest. It also acknowledges the responsibilities of the funders, including “helping to promote the responsible conduct of research and to assist individuals and institutions with the interpretation or implementation of this Responsible Conduct of Research (RCR) Framework”.It is not only major funding organizations in highly developed research environments that are taking steps. Smaller funders are also acting to mandate compliance with research integrity standards. The constantly growing literature on the topic is another sign of development within this area [2,3]. In the USA, research integrity recently reached the political arena, when, following a call from researchers [8], President Biden’s administration published a memorandum on restoring trust [9] that highlights the importance of integrity in research. The memorandum will be supported by the reintroduction of the Scientific Integrity Act. This act will prohibit research misconduct and the manipulation of research findings. It talks of a “culture of research integrity” and demands that funding agencies adopt and enforce research integrity policies, appoint a research integrity officer, and provide regular research integrity and ethics training. The US are not alone in their endeavors. Governments in other countries are equally gearing up to support the integrity and reproducibility of research [10]. However, so far, there is only limited evidence about the effectiveness of such initiatives, although it is generally accepted that they raise awareness among various stakeholders concerning research integrity challenges, strengthen the sense of responsibility of those stakeholders to address those challenges, and thereby ultimately contribute to fostering a culture of research integrity.In a collective effort to foster research integrity, research organizations and funders have their own, complementary roles. The Standard Operating Procedures for Research Integrity (SOPs4RI) consortium has recommended that both research organizations and funders develop a RIPP. A RIPP outlines the key responsibilities of an organization concerning research integrity and details methods and procedures to foster it. For example, in the case of research organizations, a RIPP should facilitate and stimulate a healthy research environment, proper mentoring and supervision, research ethics structures, research integrity training, high-quality dissemination practices, research collaboration, effective data management, and open and fair procedures to deal with breaches of research integrity [11]. Funders have a different role. They can support, safeguard, and incentivise, or even mandate, responsible research practices from research organizations and researchers. Equally important, funders should make sure that their internal processes live up to the highest standards of research integrity. We recognize that funders are many and varied in their scale, portfolio, disciplinary focus, and the extent to which they have procedures and governance arrangements to support research integrity. For all funders, adopting a RIPP will structure and coordinate research integrity practices, giving clarity and transparency to applicant institutions and researchers.In this Consensus View, we highlight examples of best practice of funders worldwide to foster a research integrity culture. With these examples in mind, we suggest guidelines to support funders in taking a leading role in fostering research integrity. In so doing, we acknowledge the local contexts in which funders operate, but we believe that all funders, large and small, in all parts of the world, can and should contribute to improving research validity and building and maintaining trust in science through incentivising and mandating a culture of research integrity. Our core argument is that developing a tailored RIPP will contribute to building an institutional culture of research integrity, both within funding organizations and among the research organizations and individual researchers they fund. Based on empirical work from the SOPs4RI project, we have identified 6 key research integrity topics: researchers’ compliance with research integrity standards; expectations for research organizations; selection of grant applications; declaration of interests; monitoring funded research; and dealing with internal integrity breaches (Fig 1). We recommend that these topics should be included in a RIPP and provide guidelines on developing and implementing a RIPP.Open in a separate windowFig 1Topics to be covered in a RIPP for funders.An overview of the 6 most important topics identified by the SOPs4RI to be included in research funding organization’s RIPP. RIPP, Research Integrity Promotion Plan; SOPs4RI, Standard Operating Procedures for Research Integrity.     

IgE immunotherapy: A novel concept with promise for the treatment of cancer

The importance of antibodies in activating immune responses against tumors is now better appreciated with the emergence of checkpoint blockade antibodies and with engineered antibody Fc domains featuring enhanced capacity to focus potent effector cells against cancer cells. Antibodies designed with Fc regions of the IgE class can confer natural, potent, long-lived immune surveillance in tissues through tenacious engagement of high-affinity cognate Fc receptors on distinct, often tumor-resident immune effector cells, and through ability to activate these cells under tumor-induced Th2-biased conditions. Here, we review the properties that make IgE a contributor to the allergic response and a critical player in the protection against parasites, which also support IgE as a novel anti-cancer modality. We discuss IgE-based active and passive immunotherapeutic approaches in disparate in vitro and in vivo model systems, collectively suggesting the potential of IgE immunotherapies in oncology. Translation toward clinical application is now in progress.     

Mutations in ARL2BP,Encoding ADP-Ribosylation-Factor-Like 2 Binding Protein,Cause Autosomal-Recessive Retinitis Pigmentosa

Retinitis pigmentosa (RP) is a genetically heterogeneous retinal degeneration characterized by photoreceptor death, which results in visual failure. Here, we used a combination of homozygosity mapping and exome sequencing to identify mutations in ARL2BP, which encodes an effector protein of the small GTPases ARL2 and ARL3, as causative for autosomal-recessive RP (RP66). In a family affected by RP and situs inversus, a homozygous, splice-acceptor mutation, c.101−1G>C, which alters pre-mRNA splicing of ARLBP2 in blood RNA, was identified. In another family, a homozygous c.134T>G (p.Met45Arg) mutation was identified. In the mouse retina, ARL2BP localized to the basal body and cilium-associated centriole of photoreceptors and the periciliary extension of the inner segment. Depletion of ARL2BP caused cilia shortening. Moreover, depletion of ARL2, but not ARL3, caused displacement of ARL2BP from the basal body, suggesting that ARL2 is vital for recruiting or anchoring ARL2BP at the base of the cilium. This hypothesis is supported by the finding that the p.Met45Arg amino acid substitution reduced binding to ARL2 and caused the loss of ARL2BP localization at the basal body in ciliated nasal epithelial cells. These data demonstrate a role for ARL2BP and ARL2 in primary cilia function and that this role is essential for normal photoreceptor maintenance and function.     

Menopausal hormone therapy and women’s health: An umbrella review

BackgroundThere remains uncertainty about the impact of menopausal hormone therapy (MHT) on women’s health. A systematic, comprehensive assessment of the effects on multiple outcomes is lacking. We conducted an umbrella review to comprehensively summarize evidence on the benefits and harms of MHT across diverse health outcomes.Methods and findingsWe searched MEDLINE, EMBASE, and 10 other databases from inception to November 26, 2017, updated on December 17, 2020, to identify systematic reviews or meta-analyses of randomized controlled trials (RCTs) and observational studies investigating effects of MHT, including estrogen-alone therapy (ET) and estrogen plus progestin therapy (EPT), in perimenopausal or postmenopausal women in all countries and settings. All health outcomes in previous systematic reviews were included, including menopausal symptoms, surrogate endpoints, biomarkers, various morbidity outcomes, and mortality. Two investigators independently extracted data and assessed methodological quality of systematic reviews using the updated 16-item AMSTAR 2 instrument. Random-effects robust variance estimation was used to combine effect estimates, and 95% prediction intervals (PIs) were calculated whenever possible. We used the term MHT to encompass ET and EPT, and results are presented for MHT for each outcome, unless otherwise indicated. Sixty systematic reviews were included, involving 102 meta-analyses of RCTs and 38 of observational studies, with 102 unique outcomes. The overall quality of included systematic reviews was moderate to poor. In meta-analyses of RCTs, MHT was beneficial for vasomotor symptoms (frequency: 9 trials, 1,104 women, risk ratio [RR] 0.43, 95% CI 0.33 to 0.57, p < 0.001; severity: 7 trials, 503 women, RR 0.29, 95% CI 0.17 to 0.50, p = 0.002) and all fracture (30 trials, 43,188 women, RR 0.72, 95% CI 0.62 to 0.84, p = 0.002, 95% PI 0.58 to 0.87), as well as vaginal atrophy (intravaginal ET), sexual function, vertebral and nonvertebral fracture, diabetes mellitus, cardiovascular mortality (ET), and colorectal cancer (EPT), but harmful for stroke (17 trials, 37,272 women, RR 1.17, 95% CI 1.05 to 1.29, p = 0.027) and venous thromboembolism (23 trials, 42,292 women, RR 1.60, 95% CI 0.99 to 2.58, p = 0.052, 95% PI 1.03 to 2.99), as well as cardiovascular disease incidence and recurrence, cerebrovascular disease, nonfatal stroke, deep vein thrombosis, gallbladder disease requiring surgery, and lung cancer mortality (EPT). In meta-analyses of observational studies, MHT was associated with decreased risks of cataract, glioma, and esophageal, gastric, and colorectal cancer, but increased risks of pulmonary embolism, cholelithiasis, asthma, meningioma, and thyroid, breast, and ovarian cancer. ET and EPT had opposite effects for endometrial cancer, endometrial hyperplasia, and Alzheimer disease. The major limitations include the inability to address the varying effects of MHT by type, dose, formulation, duration of use, route of administration, and age of initiation and to take into account the quality of individual studies included in the systematic reviews. The study protocol is publicly available on PROSPERO (CRD42017083412).ConclusionsMHT has a complex balance of benefits and harms on multiple health outcomes. Some effects differ qualitatively between ET and EPT. The quality of available evidence is only moderate to poor.

In an umbrella review, Guo-Qiang Zhang and colleagues comprehensively summarize evidence on the benefits and harms of menopausal hormone therapy across diverse health outcomes.