Food system actor perspectives on future-proofing European food systems through plant breeding.

Crop improvement is a key innovation area in the pursuit of sustainable food systems. However, realising its potential requires integration of the needs and priorities of all agri-food chain stakeholders. In this study, we provide a multi-stakeholder perspective on the role of crop improvement in future-proofing the European food system. We engaged agri-business, farm- and consumer-level stakeholders, and plant scientists through an online survey and focus groups. Four of each group's top five priorities were shared and related to environmental sustainability goals (water, nitrogen and phosphorus efficiency, and heat stress). Consensus was identified on issues including considering existing alternatives to plant breeding (e.g. management strategies), minimising trade-offs, and addressing geographical variation in needs. We conducted a rapid evidence synthesis on the impacts of priority crop improvement options, highlighting the urgent need for further research examining downstream sustainability impacts to identify concrete targets for plant breeding innovation as a food systems solution.

Germline Pathogenic Variants in the Ataxia Telangiectasia Mutated (ATM) Gene are Associated with High and Moderate Risks for Multiple Cancers.

Pathogenic variants (PVs) in ATM are relatively common, but the scope and magnitude of risk remains uncertain. This study aimed to estimate ATM PV cancer risks independent of family cancer history. This analysis included patients referred for hereditary cancer testing with a multi-gene panel (N = 627,742). Cancer risks for ATM PV carriers (N = 4,607) were adjusted for family history using multivariable logistic regression and reported as ORs with 95% confidence intervals (CIs). Subanalyses of the c.7271T>G missense PV were conducted. Moderate-to-high risks for pancreatic (OR, 4.21; 95% CI, 3.24-5.47), prostate (OR, 2.58; 95% CI, 1.93-3.44), gastric (OR, 2.97; 95% CI, 1.66-5.31), and invasive ductal breast (OR, 2.03; 95% CI, 1.89-2.19) cancers were estimated for ATM PV carriers. Notably, c.7271T>G was associated with higher invasive ductal breast cancer risk (OR, 3.76; 95% CI, 2.76-5.12) than other missense and truncating ATM PVs. Low-to-moderate risks were seen for ductal carcinoma in situ (OR, 1.80; 95% CI, 1.61-2.02), male breast cancer (OR, 1.72; 95% CI, 1.08-2.75), ovarian cancer (OR, 1.57; 95% CI, 1.35-1.83), colorectal cancer (OR, 1.49; 95% CI, 1.24-1.79), and melanoma (OR, 1.46; 95% CI, 1.18-1.81). ATM PVs are associated with multiple cancer risks and, while professional society guidelines support that carriers are eligible for increased breast and pancreatic cancer screening, increased screening for prostate and gastric cancer may also be warranted. c.7271T>G is associated with high risk for breast cancer, with a 3- to 4-fold risk increase that supports consideration of strategies for prevention and/or early detection. PREVENTION RELEVANCE: This study estimated risks for multiple cancers associated with ATM pathogenic variants independent of family history. These results indicate that some common variants may be associated with higher breast cancer risks than previously appreciated and increased screening for prostate and gastric cancer may be warranted for carriers of ATM pathogenic variants.

Skin manifestations of COVID-19 in children: Part 1.

The current COVID-19 pandemic is caused by the SARS-CoV-2 coronavirus. The initial recognized symptoms were respiratory, sometimes culminating in severe respiratory distress requiring ventilation, and causing death in a percentage of those infected. As time has passed, other symptoms have been recognized. The initial reports of cutaneous manifestations were from Italian dermatologists, probably because Italy was the first European country to be heavily affected by the pandemic. The overall clinical presentation, course and outcome of SARS-CoV-2 infection in children differ from those in adults as do the cutaneous manifestations of childhood. In this review, we summarize the current knowledge on the cutaneous manifestations of COVID-19 in children after thorough and critical review of articles published in the literature and from the personal experience of a large panel of paediatric dermatologists in Europe. In Part 1, we discuss one of the first and most widespread cutaneous manifestation of COVID-19, chilblain-like lesions. In Part 2, we review other manifestations, including erythema multiforme, urticaria and Kawasaki disease-like inflammatory multisystemic syndrome, while in Part 3, we discuss the histological findings of COVID-19 manifestations, and the testing and management of infected children, for both COVID-19 and any other pre-existing conditions.

Skin manifestations of COVID-19 in children: Part 2.

The current COVID-19 pandemic is caused by the SARS-CoV-2 coronavirus. The initial recognized symptoms were respiratory, sometimes culminating in severe respiratory distress requiring ventilation, and causing death in a percentage of those infected. As time has passed, other symptoms have been recognized. The initial reports of cutaneous manifestations were from Italian dermatologists, probably because Italy was the first European country to be heavily affected by the pandemic. The overall clinical presentation, course and outcome of SARS-CoV-2 infection in children differ from those in adults, as do the cutaneous manifestations of childhood. In this review, we summarize the current knowledge on the cutaneous manifestations of COVID-19 in children after thorough and critical review of articles published in the literature and from the personal experience of a large panel of paediatric dermatologists in Europe. In Part 1, we discussed one of the first and most widespread cutaneous manifestations of COVID-19, chilblain-like lesions. In this part of the review, we describe other manifestations, including erythema multiforme, urticaria and Kawasaki disease-like inflammatory multisystemic syndrome. In Part 3, we discuss the histological findings of COVID-19 manifestations, and the testing and management of infected children for both COVID-19 and any other pre-existing conditions.

Skin manifestations of COVID-19 in children: Part 3.

The current COVID-19 pandemic is caused by the SARS-CoV-2 coronavirus. The initial recognized symptoms were respiratory, sometimes culminating in severe respiratory distress requiring ventilation, and causing death in a percentage of those infected. As time has passed, other symptoms have been recognized. The initial reports of cutaneous manifestations were from Italian dermatologists, probably because Italy was the first European country to be heavily affected by the pandemic. The overall clinical presentation, course and outcome of SARS-CoV-2 infection in children differ from those in adults as do the cutaneous manifestations of childhood. In this review, we summarize the current knowledge on the cutaneous manifestations of COVID-19 in children after thorough and critical review of articles published in the literature and from the personal experience of a large panel of paediatric dermatologists in Europe. In Part 1, we discuss one of the first and most widespread cutaneous manifestations of COVID-19, chilblain-like lesions, and in Part 2 we expanded to other manifestations, including erythema multiforme, urticaria and Kawasaki disease-like inflammatory multisystemic syndrome. In this part of the review, we discuss the histological findings of COVID-19 manifestations, and the testing and management of infected children for both COVID-19 and any other pre-existing conditions.

Flightless anchors IQGAP1 and R-ras to mediate cell extension formation and matrix remodeling.

Tractional remodeling of collagen fibrils by fibroblasts requires long cell extensions that mediate fibril alignment. The formation of these cell extensions involves flightless I (FliI), an actin-binding protein that contains a leucine-rich-repeat (LRR), which binds R-ras and may regulate cdc42. We considered that FliI interacts with small GTPases and their regulators to mediate assembly of cell extensions. Mass spectrometry analyses of FliI immunoprecipitates showed abundant Ras GTPase-activating-like protein (IQGAP1), which in immunostained samples colocalized with FliI at cell adhesions. Knockdown of IQGAP1 reduced the numbers of cell extensions and the alignment of collagen fibrils. In experiments using dominant negative mutants, cdc42 activity was required for the formation of short extensions while R-ras was required for the formation of long extensions. Immunoprecipitation of wild-type and mutant constructs showed that IQGAP1 associated with cdc42 and R-ras; this association required the GAP-related domain (1004-1237 aa) of IQGAP1. In cells transfected with FliI mutants, the LRR of FliI, but not its gelsolin-like domains, mediated association with cdc42, R-ras, and IQGAP1. We conclude that FliI interacts with IQGAP1 and co-ordinates with cdc42 and R-ras to control the formation of cell extensions that enable collagen tractional remodeling.

A Compendium of Mutational Signatures of Environmental Agents.

Whole-genome-sequencing (WGS) of human tumors has revealed distinct mutation patterns that hint at the causative origins of cancer. We examined mutational signatures in 324 WGS human-induced pluripotent stem cells exposed to 79 known or suspected environmental carcinogens. Forty-one yielded characteristic substitution mutational signatures. Some were similar to signatures found in human tumors. Additionally, six agents produced double-substitution signatures and eight produced indel signatures. Investigating mutation asymmetries across genome topography revealed fully functional mismatch and transcription-coupled repair pathways. DNA damage induced by environmental mutagens can be resolved by disparate repair and/or replicative pathways, resulting in an assortment of signature outcomes even for a single agent. This compendium of experimentally induced mutational signatures permits further exploration of roles of environmental agents in cancer etiology and underscores how human stem cell DNA is directly vulnerable to environmental agents. VIDEO ABSTRACT.

Misdiagnosis of X-linked retinitis pigmentosa in a choroideremia patient with heavily pigmented fundi.

Inherited retinal diseases are thought to be the leading cause of sight loss in the working age population. Mutations found in the RPGR and CHM genes cause retinitis pigmentosa (RP) and choroideremia, respectively. In the first instance, an X-linked family history of visual field loss commonly raises the suspicion of one of these two genes. In choroideremia, the classic description of a white fundal reflex secondary to the widespread chorioretinal degeneration was made over a hundred years ago in Caucasians. But, it is not so obvious in heavily pigmented fundi. Hence, the clinical diagnosis of CHM in non-Caucasian patients may be challenging in the first stages of the disease. Here we report a case of a Southeast Asian gentleman who has a family history of X-linked retinal degeneration and was found to have a confirmed in-frame deletion of 12 DNA nucleotides in exon 15 of the RPGR gene. Later in life, however, his fundal appearance showed unusual areas of circular pigment hypertrophy and clumping. He was therefore tested for carrying a disease-causing mutation in the CHM gene and a null mutation was found. Since gene therapy trials are ongoing for both of these conditions, it has now become critically important to establish the correct genetic diagnosis in order to recruit suitable candidates. Moreover, this case demonstrates the necessity to remain vigilant in the interpretation of genetic results which are inconsistent with clinical features.

Mechano-electrical feedback in the clinical setting: Current perspectives.

Mechano-electric feedback (MEF) is an established mechanism whereby myocardial deformation causes changes in cardiac electrophysiological parameters. Extensive animal, laboratory and theoretical investigation has demonstrated that abnormal patterns of cardiac strain can induce alteration of electrical excitation and recovery through MEF, which can potentially contribute to the establishment of dangerous arrhythmias. However, the clinical relevance of MEF in patients with heart disease remains to be established. This paper reviews up-to date experimental evidence describing the response to different types of mechanical stimuli in the intact human heart with the support of new data collected during cardiac surgery. It discusses modulatory effects of MEF that may contribute to increase the vulnerability to arrhythmia and describes MEF interaction with clinical conditions where mechanically induced changes in cardiac electrophysiology are likely to be more relevant. Finally, directions for future studies, including the need for in-vivo human data providing simultaneous assessment of the distribution of structural, functional and electrophysiological parameters at the regional level, are identified.

Hepatoprotective Mongolian prescription II enhances the antitumor effects of chemotherapeutics in hepatocellular carcinoma xenografts.

Hepatoprotective Mongolian prescription II (MPII), a mixture of 18 different medicinal herbs, significantly inhibited the growth of human liver cancer cell lines Huh-7 and HepG2 in vitro with different concentrations; MPII (6mg/mL) inhibited cell proliferation by 80.48%. MPII induced apoptosis in both cell lines, which was observed by light microscopy and flow cytometry. MPII-induced apoptosis and G0/G1 cell cycle arrest were quantified by Annexin V-FITC/PI staining and flow cytometry. At the molecular level, MPII induced caspase-3, caspase-8, caspase-9, and cytochrome c gene expression. In vivo, MPII dramatically inhibited human liver tumor growth in a xenograft model in Kunming mice with no apparent cytotoxicity to the hosts. Apoptotic genes (Bcl-2 and Bax) are up-regulated, suggesting that the ratio of Bcl-2/Bax was statistically significant, indicating that the drugs had affected the expression of apoptosis genes, especially on induce apoptosis gene Bax. We also observed an attenuated effect when MPII was used in combination with chemotherapy drug 5-fluorouracil (5-FU). The mice treated with 5-FU alone did not show a concentration-dependent effect, but 5-FU in combination with MPII displayed concentration-dependent effects on liver cancer cells. Our study suggests that MPII works by inducing apoptosis and cell cycle arrest, and has the potential to be a powerful anticancer agent.

Erratum: Management of neglected sacral fracture with cauda equina syndrome: report of two cases with review of literature.

[This corrects the article DOI: 10.1038/scsandc.2015.20.][This corrects the article DOI: 10.1038/scsandc.2015.20.].

Autologous bone marrow cell transplantation in acute spinal cord injury--an Indian pilot study.

STUDY DESIGN: Phase- I/II, prospective, randomized, single-blind, controlled pilot study. PRIMARY OBJECTIVE: To determine the safety and feasibility of autologous bone marrow transplantation in patients with acute spinal cord injury (SCI) via two routes of transplantation as compared with controls. SETTING: Indian Spinal Injuries Center, New Delhi. METHODS: Twenty-one subjects with acute, American Spinal Injury Association Impairment Scale (AIS) A (complete), traumatic SCI with neurological level T1-T12, were recruited and randomized into three groups of seven subjects each. Two groups underwent cell transplantation through the intrathecal or intralesional route, whereas the third served as control. Participants were assessed at baseline and followed up at 6 months and 12-months post enrollment. Safety and tolerability were evaluated by monitoring for any adverse events. Efficacy was assessed through neurological, functional and psychological evaluation, as well as through electrophysiological studies and urodynamics. RESULTS: Surgery was tolerated well by all participants. There were no significant adverse events attributable to the procedure. There was no significant improvement in the neurological, electrophysiological or urodynamic efficacy variables. A statistically significant improvement in functional scores as evaluated by the Spinal Cord Independence Measure and International Spinal Cord Injury Scale was observed in all groups. CONCLUSIONS: The procedure is safe and feasible in AIS A participants with thoracic-level injuries at 12-months follow-up. No efficacy could be demonstrated that could be attributed to the procedure.