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Graphical Abstract Osteogenesis imperfecta (OI) is a hereditary skeletal disorder primarily affecting collagen type I structure and function, causing bone fragility and occasionally versatile extraskeletal symptoms. This study expands the spectrum of OI‐causing TAPT1 mutations and links extracellular matrix changes to signaling regulation.

Mitochondrial membranes define distinct structural and functional compartments. Cristae of the inner mitochondrial membrane (IMM) function as independent bioenergetic units that undergo rapid and transient remodelling, but the significance of this compartmentalized organization is unknown1. Using super-resolution microscopy, here we show that cytosolic IMM vesicles, devoid of outer mitochondrial membrane or mitochondrial matrix, are formed during resting state. These vesicles derived from the IMM (VDIMs) are formed by IMM herniation through pores formed by voltage-dependent anion channel 1 in the outer mitochondrial membrane. Live-cell imaging showed that lysosomes in proximity to mitochondria engulfed the herniating IMM and, aided by the endosomal sorting complex required for transport machinery, led to the formation of VDIMs in a microautophagy-like process, sparing the remainder of the organelle. VDIM formation was enhanced in mitochondria undergoing oxidative stress, suggesting their potential role in maintenance of mitochondrial function. Furthermore, the formation of VDIMs required calcium release by the reactive oxygen species-activated, lysosomal calcium channel, transient receptor potential mucolipin 1, showing an interorganelle communication pathway for maintenance of mitochondrial homeostasis. Thus, IMM compartmentalization could allow for the selective removal of damaged IMM sections via VDIMs, which should protect mitochondria from localized injury. Our findings show a new pathway of intramitochondrial quality control.We show that cytosolic inner mitochondrial membrane vesicles, devoid of outer mitochondrial membrane or mitochondrial matrix, are formed during resting state and directly herniate into lysosomes through pores formed by voltage-dependent anion channel 1 in the outer mitochondrial membrane, thereby allowing their selective removal. [ABSTRACT FROM AUTHOR]

Breast cancer is the most frequently diagnosed cancer in females globally. However, we know relatively little about trends in males. This study describes United Kingdom (UK) secular trends in breast cancer from 2000 to 2021 for both sexes. We describe a population-based cohort study using UK primary care Clinical Practice Research Datalink (CPRD) GOLD and Aurum databases. There were 5,848,436 eligible females and 5,539,681 males aged 18+ years, with ≥ one year of prior data availability in the study period. We estimated crude breast cancer incidence rates (IR), prevalence and survival probability at one-, five- and 10-years after diagnosis using the Kaplan–Meier method. Analyses were further stratified by age. Crude IR of breast cancer from 2000 to 2021 was 194.4 per 100,000 person-years for females and 1.16 for males. Crude prevalence in 2021 was 2.1% for females and 0.009% for males. Both sexes have seen around a 2.5-fold increase in prevalence across time. Incidence increased with age for both sexes, peaking in females aged 60–69 years and males 90+. There was a drop in incidence for females aged 70–79 years. From 2003–2019, incidence increased > twofold in younger females (aged 18–29: IR 2.12 in 2003 vs. 4.58 in 2018); decreased in females aged 50–69 years; and further declined from 2015 onwards in females aged 70–89 years. Survival probability for females after one-, five-, and ten-years after diagnosis was 95.1%, 80.2%, and 68.4%, and for males 92.9%, 69.0%, and 51.3%. Survival probability at one-year increased by 2.08% points, and survival at five years increased by 5.39% from 2000–2004 to 2015–2019 for females, particularly those aged 50–70 years. For males, there were no clear time-trends for short-term and long-term survival probability. Changes in incidence of breast cancer in females largely reflect the success of screening programmes, as rates rise and fall in synchronicity with ages of eligibility for such programmes. Overall survival from breast cancer for females has improved from 2000 to 2021, again reflecting the success of screening programmes, early diagnosis, and improvements in treatments. Male breast cancer patients have worse survival outcomes compared to females, highlighting the need to develop male-specific diagnosis and treatment strategies to improve long-term survival in line with females. [ABSTRACT FROM AUTHOR]

Effective prevention strategies for post-COVID complications are crucial for patients, clinicians, and policy makers to mitigate their cumulative burden. This study evaluated the association of modifiable lifestyle factors (smoking, alcohol intake, BMI, physical activity, sedentary time, sleep duration, and dietary habits) with COVID-19 multisystem sequelae, death, and hospitalization in the UK Biobank cohort (n = 68,896). A favorable lifestyle (6-10 healthy factors; 46.4%) was associated with a 36% lower risk of multisystem sequelae (HR, 0.64; 95% CI, 0.58-0.69; ARR at 210 days, 7.08%; 95% CI, 5.98-8.09) compared to an unfavorable lifestyle (0-4 factors; 12.3%). Risk reductions spanned all 10 organ systems, including cardiovascular, coagulation, metabolic, gastrointestinal, kidney, mental health, musculoskeletal, respiratory disorders, and fatigue. This beneficial effect was largely attributable to direct lifestyle impacts independent of corresponding pre-infection comorbidities (71% for any sequelae). A favorable lifestyle was also related to the risk of post-COVID death (HR 0.59, 0.52-0.66) and hospitalization (HR 0.78, 0.73-0.84). These associations persisted across acute and post-acute infection phases, irrespective of hospitalization status, vaccination, or SARS-CoV-2 variant. These findings underscore the clinical and public health importance of adhering to a healthy lifestyle in mitigating long-term COVID-19 adverse impacts and enhancing future pandemic preparedness. The impact of modifiable lifestyle factors on the risk of post-COVID-19 sequelae is not well understood. Here, the authors perform a prospective cohort study amongst UK Biobank participants and show that a healthy lifestyle is associated with lower risk of post-COVID-19 sequelae across multiple organ systems. [ABSTRACT FROM AUTHOR]

Worldwide, over 2 billion children under the age of 5 experience stunting, wasting, or are underweight. Malnutrition contributes to 45% of all deaths in this age group (approximately 3.1 million deaths) [1]. Poverty, food insecurity, suboptimal feeding practices, climate change, and conflict are all contributing factors. Malnutrition causes significant respiratory problems, including increased risk of respiratory infections, impaired lung function, and increased risk of subsequent adult respiratory disease, including asthma, COPD, and lung cancer. Childhood malnutrition not only has serious consequences for children's health but it also has numerous consequences on wellbeing and educational attainment. Childhood malnutrition is a complex and multifaceted problem. However, by understanding and addressing the underlying causes, and investing in prevention and treatment programs, it is possible to maximize children's health and wellbeing on a global scale. This narrative review will focus on the impact of childhood malnutrition on lung development, the consequent respiratory disease, and what actions can be taken to reduce the burden of malnutrition on lung health. [ABSTRACT FROM AUTHOR]

A two-stage model is proposed for investigating remodelling characteristics in bone over time and distance to the growth plate. The first stage comprises a partial differential equation (PDE) for bone density as a function of time and distance from the growth plate. This stage clarifies the contributions to changes in bone density due to remodelling and growth processes and tracks the rate at which new bone emanates from the growth plate. The second stage consists of simulating the remodelling process to determine remodelling characteristics. Implementing the second stage requires the rate at which bone moves away from the growth plate computed during the first stage. The second stage is also needed to confirm that remodelling characteristics predicted by the first stage may be explained by a realistic model for remodelling and to compute activation frequency. The model is demonstrated on microCT scans of tibia of juvenile female rats in three experimental groups: sham-operated control, oestrogen deprived, and oestrogen deprived followed by treatment. Model predictions for changes in bone density and remodelling characteristics agree with the literature. In addition, the model provides new insight into the role of treatment on the density of new bone emanating from the growth plate and provides quantitative descriptions of changes in remodelling characteristics beyond what has been possible to ascertain by experimentation alone. [ABSTRACT FROM AUTHOR]

Background/objective: With increasing obesity prevalence in children globally, accurate and practical methods for quantifying body fat are critical for effective monitoring and prevention, particularly in high-risk settings. No population is at higher risk of obesity than Pacific Islanders, including children living in the independent nation of Samoa. We developed and validated sex-specific prediction models for fat mass in Samoan children. Subjects/methods: Dual X-ray absorptiometry (DXA) assessments of fat mass and weight, height, circumferences, and skinfolds were obtained from 356 children aged 7–9 years old in the Ola Tuputupua'e "Growing Up" study. Sex-specific models were developed from a randomly selected model development sample (n = 118 females, n = 120 males) using generalized linear regressions. In a validation sample (n = 59 females; n = 59 males), Lin's concordance and Bland-Altman limits-of-agreement (LoA) of DXA-derived and predicted fat mass from this study and other published models were examined to assess precision and accuracy. Results: Models to predict fat mass in kilograms were: e^[(−0.0034355 * Age8 − 0.0059041 * Age9 + 1.660441 * ln (Weight (kg))−0.0087281 * Height (cm) + 0.1393258 * ln[Suprailiac (mm)] − 2.661793)] for females and e^[−0.0409724 * Age8 − 0.0549923 * Age9 + 336.8575 * [Weight (kg)]−2 − 22.34261 * ln (Weight (kg)) [Weight (kg)]−1 + 0.0108696 * Abdominal (cm) + 6.811015 * Subscapular (mm)−2 − 8.642559 * ln (Subscapular (mm)) Subscapular (mm)−2 − 1.663095 * Tricep (mm)−1 + 3.849035]for males, where Age8 = Age9 = 0 for children at age 7 years, Age8 = 1 and Age9 = 0 at 8 years, Age8 = 0 and Age9 = 1 at 9 years. Models showed high predictive ability, with substantial concordance (ρC > 0.96), and agreement between DXA-derived and model-predicted fat mass (LoA female = −0.235, 95% CI:−2.924–2.453; male = −0.202, 95% CI:−1.977–1.572). Only one of four existing models, developed in a non-Samoan sample, accurately predicted fat mass among Samoan children. Conclusions: We developed models that predicted fat mass in Samoans aged 7–9 years old with greater precision and accuracy than the majority of existing models that were tested. Monitoring adiposity in children with these models may inform future obesity prevention and interventions. [ABSTRACT FROM AUTHOR]

Rapid development of antisense therapies can enable on-demand responses to new viral pathogens and make personalized medicine for genetic diseases practical. Antisense phosphorodiamidate morpholino oligomers (PMOs) are promising candidates to fill such a role, but their challenging synthesis limits their widespread application. To rapidly prototype potential PMO drug candidates, we report a fully automated flow-based oligonucleotide synthesizer. Our optimized synthesis platform reduces coupling times by up to 22-fold compared to previously reported methods. We demonstrate the power of our automated technology with the synthesis of milligram quantities of three candidate therapeutic PMO sequences for an unserved class of Duchenne muscular dystrophy (DMD). To further test our platform, we synthesize a PMO that targets the genomic mRNA of SARS-CoV-2 and demonstrate its antiviral effects. This platform could find broad application not only in designing new SARS-CoV-2 and DMD antisense therapeutics, but also for rapid development of PMO candidates to treat new and emerging diseases. PMOs (phosphorodiamidate morpholino oligomers) have huge potential for antisense therapy but complex and slow synthesis limits application. Here, the authors report the development of automated flow synthesis methods which reduce nucleobase coupling times from hours to minutes removing human errors and allow for high-throughput production. [ABSTRACT FROM AUTHOR]

Intimate partner violence includes psychological aggression, physical violence, sexual violence, and stalking from a current or former intimate partner. Past research suggests that exposure to intimate partner violence can impact cognitive and psychological functioning, as well as neurological outcomes. These seem to be compounded in those who suffer a brain injury as a result of trauma to the head, neck or body due to physical and/or sexual violence. However, our understanding of the neurobehavioral and neurobiological effects of head trauma in this population is limited due to factors including difficulty in accessing/recruiting participants, heterogeneity of samples, and premorbid and comorbid factors that impact outcomes. Thus, the goal of the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium Intimate Partner Violence Working Group is to develop a global collaboration that includes researchers, clinicians, and other key community stakeholders. Participation in the working group can include collecting harmonized data, providing data for meta- and mega-analysis across sites, or stakeholder insight on key clinical research questions, promoting safety, participant recruitment and referral to support services. Further, to facilitate the mega-analysis of data across sites within the working group, we provide suggestions for behavioral surveys, cognitive tests, neuroimaging parameters, and genetics that could be used by investigators in the early stages of study design. We anticipate that the harmonization of measures across sites within the working group prior to data collection could increase the statistical power in characterizing how intimate partner violence-related head trauma impacts long-term physical, cognitive, and psychological health. [ABSTRACT FROM AUTHOR]

Food sovereignty among Inuit in Nunavut, Canada has long meant year-round harvest of country (hunted, fished, or gathered) food. In recent decades, climatic and non-climatic challenges have complicated these subsistence activities, threatening food security. We examine the meaning of country food, identify determinants of low-yield periods of country food harvest and their effects on community health, and summarize coping strategies and ideas for sustaining food security during these "leaner" periods. Thirty semi-structured interviews were conducted in July and August of 2018 with elders and/or hunters and trappers in Cambridge Bay and Pond Inlet. We found country food holds diverse meanings in the lives of our participants, including for their diet and nutrition, health, Inuit identity and traditions, practice of harvest and subsistence, and spirituality. Participants reported reduced wildlife populations, environmental or weather issues, changing wildlife migration patterns, and financial or equipment-related constraints as determinants of low-yield periods of harvest. Community health is impacted during lean periods across four interrelated dimensions: "craving" of country food, physical health, mental health, and nutrition. Due to their lifelong reliance on country food, elders were described as being particularly vulnerable and are prioritized within the traditional food sharing system. The most commonly cited coping strategies were turning to intra- or inter-community food sharing networks for country food and purchasing groceries. To support communities during low-yield periods of harvest, participants suggested increased support for Hunters and Trappers Organizations to acquire country food for community distribution, as well as greater financial and equipment support for harvesters. [ABSTRACT FROM AUTHOR]

Namibia has previously relied on external training of pharmacists but began in-country training in 2011. In response to an identified need for postgraduate clinical pharmacy development and training in the country, a Master's degree was set up at the University of Namibia in 2016. The country has a considerable health burden of HIV and TB as well as a shortage of healthcare professionals. A UK clinical diploma model was adapted to meet the specific needs of the country and wider region, ensuring students could access the course over a sparsely populated, but large geographical spread, in addition to providing work-based learning, embedding research skills for future development, and focusing on the health needs of Namibia. The course uses online learning platforms and contact sessions to cover both knowledge and skill acquisition throughout the 3 years of the course. UK and US clinical pharmacists are utilised to provide specialist input, both remotely and within student workplaces, and further support has come from collaborations, including cross-site visits, with the UK-based pharmacy school whose diploma model was adapted. Challenges have included a shortage of clinical mentors, also compounding the students' difficulty in visualising their future roles, as well as lone practitioners finding it hard to attend all contact sessions. The initial dropout rates of earlier cohorts have since reduced with greater understanding of the programme, and enthusiasm for the course remains high. The aim for the Master's is to train students to become competent clinical pharmacists, thus having the knowledge and skills to mentor future cohorts of the course, as well as expanding the specialty within the country. [ABSTRACT FROM AUTHOR]

Purpose: To explore associations between magnetic resonance imaging (MRI) features of prostate cancer and expression levels of cell cycle genes, as assessed by the Prolaris® test. Materials and methods: Retrospective analysis of 118 PCa patients with genetic testing of biopsy specimen and prostate MRI from 08/2013 to 11/2015. Associations between the cell cycle risk (CCR) score and MRI features [i.e., PI-RADSv2 score, extracapsular extension (ECE), quantitative metrics] were analyzed with Fisher's exact test, nonparametric tests, and Spearman's correlation coefficient. In 41 patients (34.7%), test results were compared to unfavorable features on prostatectomy specimen (i.e., Gleason group ≥ 3, ECE, lymph node metastases). Results: Fifty-four (45.8%), 60 (50.8%), and 4 (3.4%) patients had low-, intermediate-, and high-risk cancers according to American Urological Association scoring system. Patients with ECE on MRI had significantly higher mean CCR scores (reader 1: 3.9 vs. 3.2, p = 0.015; reader 2: 3.6 vs. 3.2, p = 0.045). PI-RADSv2 scores and quantitative MRI features were not associated with CCR scores. In the prostatectomy subset, ECE on MRI (p = < 0.001–0.001) and CCR scores (p = 0.049) were significantly associated with unfavorable histopathologic features. Conclusion: The phenotypic trait of ECE on MRI indicates a more aggressive genotype of prostate cancer. [ABSTRACT FROM AUTHOR]

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients. [ABSTRACT FROM AUTHOR]

Objectives Pacific Islanders are disproportionately burdened by poorer perinatal health outcomes with higher rates of pre-term births, low birth weight babies, infant mortality, and inadequate or no prenatal care. The aim of this study is to examine Marshallese mothers’ beliefs, perceptions, and experiences of prenatal care and to identify potential barriers. Methods Three focus groups were conducted with Marshallese mothers, who were 18 years or older, and living in Arkansas. Focus groups focused on mothers’ beliefs, perceptions, and experiences of prenatal care. A thematic qualitative analysis was conducted to identify salient themes within the data. Results The results demonstrated that negotiating health insurance, transportation, and language barriers were all major structural barriers that constrain prenatal care. The social-cultural barriers that emerged included a lack of understanding of the importance of seeking early and consistent prenatal care, as well as how to navigate the healthcare process. The more complicated challenges that emerged were the feelings of shame and embarrassment due to the perception of their age or being unmarried during pregnancy not being acceptable in American culture. Furthermore, the participants described perceived discrimination from prenatal care providers. Lastly, the participants described fear as a barrier to seeking out prenatal care. Conclusions for Practice This study identified both structural and socio-cultural barriers that can be incorporated into suggestions for policy makers to aid in alleviating maternal health disparities among Pacific Islander women. Further research is needed to address the Marshallese mothers’ perceived discrimination from maternal health care providers. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Most type 2 diabetes-associated genetic variants identified via genome-wide association studies (GWASs) appear to act via the pancreatic islet. Observed defects in insulin secretion could result from an impact of these variants on islet development and/or the function of mature islets. Most functional studies have focused on the latter, given limitations regarding access to human fetal islet tissue. Capitalising upon advances in in vitro differentiation, we characterised the transcriptomes of human induced pluripotent stem cell (iPSC) lines differentiated along the pancreatic endocrine lineage, and explored the contribution of altered islet development to the pathogenesis of type 2 diabetes.Methods: We performed whole-transcriptome RNA sequencing of human iPSC lines from three independent donors, at baseline and at seven subsequent stages during in vitro islet differentiation. Differentially expressed genes (q < 0.01, log2 fold change [FC] > 1) were assigned to the stages at which they were most markedly upregulated. We used these data to characterise upstream transcription factors directing different stages of development, and to explore the relationship between RNA expression profiles and genes mapping to type 2 diabetes GWAS signals.Results: We identified 9409 differentially expressed genes across all stages, including many known markers of islet development. Integration of differential expression data with information on transcription factor motifs highlighted the potential contribution of REST to islet development. Over 70% of genes mapping within type 2 diabetes-associated credible intervals showed peak differential expression during islet development, and type 2 diabetes GWAS loci of largest effect (including TCF7L2; log2FC = 1.2; q = 8.5 × 10−10) were notably enriched in genes differentially expressed at the posterior foregut stage (q = 0.002), as calculated by gene set enrichment analyses. In a complementary analysis of enrichment, genes differentially expressed in the final, beta-like cell stage of in vitro differentiation were significantly enriched (hypergeometric test, permuted p value <0.05) for genes within the credible intervals of type 2 diabetes GWAS loci.Conclusions/interpretation: The present study characterises RNA expression profiles during human islet differentiation, identifies potential transcriptional regulators of the differentiation process, and suggests that the inherited predisposition to type 2 diabetes is partly mediated through modulation of islet development.Data availability: Sequence data for this study has been deposited at the European Genome-phenome Archive (EGA), under accession number EGAS00001002721. [ABSTRACT FROM AUTHOR]

Objectives: To investigate changes in the Apparent Diffusion Coefficient (ADC) using diffusion-weighted imaging (DWI) in men on active surveillance for prostate cancer taking dutasteride 0.5 mg or placebo.Methods: We analysed 37 men, randomised to 6 months of daily dutasteride (n = 18) or placebo (n = 19), undergoing 3T multi-parametric Magnetic Resonance Imaging (mpMRI) scans at baseline and 6 months. Images were reviewed blind to treatment allocation and clinical information. Mean ADC of peripheral (PZ) and transition (TZ) zones, and MR-suspicious lesions were compared between groups over 6 months. Conspicuity was defined as the PZ divided by tumour ADC, and its change over 6 months was assessed.Results: A decrease in mean conspicuity in the dutasteride group (but not the controls) was seen over 6 months (1.54 vs 1.38; p = 0.025). Absolute changes in ADC and conspicuity were significantly different between placebo and dutasteride groups at 6 months: (-0.03 vs 0.08, p = 0.033) and (0.11 vs -0.16, p = 0.012), as were percentage changes in the same parameters: (-2.27% vs 8.56% p = 0.048) and (9.25% vs -9.89% p = 0.013).Conclusions: Dutasteride was associated with increased tumour ADC and reduced conspicuity. A lower threshold for triggering biopsy might be considered in men on dutasteride undergoing mpMRI for prostate cancer.Key Points: • Dutasteride increases ADC and reduces conspicuity in small mpMRI-visible prostate cancers. • Knowledge of dutasteride exposure is important in the interpretation of prostate mpMRI. • A lower threshold for triggering biopsy may be appropriate on dutasteride. [ABSTRACT FROM AUTHOR]

Lymphatic growth (lymphangiogenesis) within lymph nodes functions to promote dendritic cell entry and effector lymphocyte egress in response to infection or inflammation. Here we demonstrate a crucial role for lymphotoxin-beta receptor (LTβR) signaling to fibroblastic reticular cells (FRCs) by lymphotoxin-expressing B cells in driving mesenteric lymph node lymphangiogenesis following helminth infection. LTβR ligation on fibroblastic reticular cells leads to the production of B-cell-activating factor (BAFF), which synergized with interleukin-4 (IL-4) to promote the production of the lymphangiogenic factors, vascular endothelial growth factors (VEGF)-A and VEGF-C, by B cells. In addition, the BAFF-IL-4 synergy augments expression of lymphotoxin by antigen-activated B cells, promoting further B cell--fibroblastic reticular cell interactions. These results underlie the importance of lymphotoxin-dependent B cell--FRC cross talk in driving the expansion of lymphatic networks that function to promote and maintain immune responsiveness. [ABSTRACT FROM AUTHOR]

Objectives: To determine whether Radiofrequency Ablation (RFA) followed by Radiotherapy (RT) (RFA-RT) produces better palliation in terms of pain than RT alone in patients with osteolytic bone metastases.Methods: Patients with solitary bone metastases and a pain score of least 5 or more on the VAS scale were selected. Fifteen patients were treated with RFA-RT (20 Gy delivered in 5 fractions of 4 Gy over 1 week) and were compared with a matched group (30 subjects) treated by RT.Results: A complete response in terms of pain relief at 12 weeks was documented in 16.6% (5/30) and 53.3% (8/15) of the subjects treated by RT or RFA-RT, respectively (p = 0.027). The overall response rate at 12 weeks was 93.3% (14 patients) in the group treated by RFA-RT and 59.9% (18 patients) in the group treated by RT (p = 0.048). Although recurrent pain was documented more frequently after RT (26.6%) than after RFA-RT (6.7%) the difference did not reach statistical significance. The morbidity related to RT did not significantly differ when this treatment was associated with RFA.Conclusions: Our results suggest that RFA-RT is safe and more effective than RT. The findings described here should serve as a framework around which to design future clinical trials. [ABSTRACT FROM AUTHOR]

Exposure to naturally occurring variants of herpesviruses in clinical settings can have a dramatic impact on anti-viral immunity. Here we have evaluated the molecular imprint of variant peptide-MHC complexes on the T-cell repertoire during human cytomegalovirus (CMV) infection and demonstrate that primary co-infection with genetic variants of CMV was coincident with development of strain-specific T-cell immunity followed by emergence of cross-reactive virus-specific T-cells. Cross-reactive CMV-specific T cells exhibited a highly conserved public T cell repertoire, while T cells directed towards specific genetic variants displayed oligoclonal repertoires, unique to each individual. T cell recognition foot–print and pMHC-I structural analyses revealed that the cross-reactive T cells accommodate alterations in the pMHC complex with a broader foot-print focussing on the core of the peptide epitope. These findings provide novel molecular insight into how infection with naturally occurring genetic variants of persistent human herpesviruses imprints on the evolution of the anti-viral T-cell repertoire. [ABSTRACT FROM AUTHOR]

Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ∼150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10−6), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (−0.17 s.d., P = 4.6 × 10−4). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention. [ABSTRACT FROM AUTHOR]

Metabolites from intestinal microbiota are key determinants of host-microbe mutualism and, consequently, the health or disease of the intestinal tract. However, whether such host-microbe crosstalk influences inflammation in peripheral tissues, such as the lung, is poorly understood. We found that dietary fermentable fiber content changed the composition of the gut and lung microbiota, in particular by altering the ratio of Firmicutes to Bacteroidetes. The gut microbiota metabolized the fiber, consequently increasing the concentration of circulating short-chain fatty acids (SCFAs). Mice fed a high-fiber diet had increased circulating levels of SCFAs and were protected against allergic inflammation in the lung, whereas a low-fiber diet decreased levels of SCFAs and increased allergic airway disease. Treatment of mice with the SCFA propionate led to alterations in bone marrow hematopoiesis that were characterized by enhanced generation of macrophage and dendritic cell (DC) precursors and subsequent seeding of the lungs by DCs with high phagocytic capacity but an impaired ability to promote T helper type 2 (TH2) cell effector function. The effects of propionate on allergic inflammation were dependent on G protein-coupled receptor 41 (GPR41, also called free fatty acid receptor 3 or FFAR3), but not GPR43 (also called free fatty acid receptor 2 or FFAR2). Our results show that dietary fermentable fiber and SCFAs can shape the immunological environment in the lung and influence the severity of allergic inflammation. [ABSTRACT FROM AUTHOR]

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.

Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders and who may consequently have increased disease risk. Previous studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates. We sequenced seven genes for maturity-onset diabetes of the young (MODY) in well-phenotyped population samples (n = 4,003). We filtered rare variants according to two prediction criteria for disease-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, conserved and protein damaging). Approximately 1.5% and 0.5% of randomly selected individuals from the Framingham and Jackson Heart Studies, respectively, carry variants from these two classes. However, the vast majority of carriers remain euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a substantial fraction of individuals as being at risk for MODY or other Mendelian diseases. [ABSTRACT FROM AUTHOR]

Behçet syndrome (also known as Behçet disease) is a rare condition that is associated with considerable morbidity. Cases of Behçet syndrome have been reported worldwide, but the highest prevalence occurs in countries that border the ancient Silk Route, such as Turkey and Iran. Although oral ulceration, genital ulceration and eye disease are the classic triad of manifestations, the cardiovascular, gastrointestinal, musculoskeletal and central nervous systems can also be affected. The syndrome is chronic and relapsing with some patients having benign episodes whereas others have more serious complications, including blindness or the rupture of a pulmonary arterial aneurysm. Diagnosing Behçet syndrome, particularly outside of endemic regions, often incurs a considerable delay owing to the rarity of this condition. Furthermore, a paucity exists of data from randomized controlled trials on the optimal therapeutic approaches to use in patients, as well as a lack of informative laboratory surrogate markers to monitor disease progression. This Review discusses the issues surrounding the diagnosis and differential diagnosis of Behçet syndrome and presents the current approaches to managing patients with this complex group of disorders. [ABSTRACT FROM AUTHOR]

Objectives: In this article the state of art the of prostate cancer (Pca) imaging and non-surgical salvage treatments (STs) is surveyed in order to explore the impact of imaging findings on the identification of radiorecurrent Pca after external beam radiotherapy (EBRT).Methods: A computerised search was performed to identify all relevant studies in Medline up to 2012. Additional articles were extracted based on recommendations from an expert panel of authors.Results: Definitive EBRT for Pca is increasingly used as treatment. After radiorecurrent Pca, non-surgical STs are emerging and shifting from investigational status to more established therapeutic options. Therefore, several scientific societies have published guidelines including clinical and imaging recommendations, even if the timing, efficacy and long-term toxicity of these STs have to be established. In some measure, accurately delineating the location and the extent of cancer is critical in selecting target lesions and in identifying patients who are candidates for STs. However, there is increasing awareness that anatomical approaches based on measurements of tumour size have substantial limitations, especially for tumours of unknown activity that persist or recur following irradiationConclusions: To date, the main focus for innovations in imaging is the combination of excellence in anatomical resolution with specific biological correlates that depict metabolic processes and hallmarks at the tumour level. The emergence of new molecular markers could favour the development of methods that directly determine their presence, thereby improving tumour detection.Key Points: Imaging may influence therapeutic decisions during non-surgical STs. MRI findings correlate with parametric maps derived from multiple functional techniques. Non-surgical salvage treatments allow local tumour control in patients with radiorecurrent PCa. [ABSTRACT FROM AUTHOR]

The evolutionary importance of hybridization and introgression has long been debated. Hybrids are usually rare and unfit, but even infrequent hybridization can aid adaptation by transferring beneficial traits between species. Here we use genomic tools to investigate introgression in Heliconius, a rapidly radiating genus of neotropical butterflies widely used in studies of ecology, behaviour, mimicry and speciation. We sequenced the genome of Heliconius melpomene and compared it with other taxa to investigate chromosomal evolution in Lepidoptera and gene flow among multiple Heliconius species and races. Among 12,669 predicted genes, biologically important expansions of families of chemosensory and Hox genes are particularly noteworthy. Chromosomal organization has remained broadly conserved since the Cretaceous period, when butterflies split from the Bombyx (silkmoth) lineage. Using genomic resequencing, we show hybrid exchange of genes between three co-mimics, Heliconius melpomene, Heliconius timareta and Heliconius elevatus, especially at two genomic regions that control mimicry pattern. We infer that closely related Heliconius species exchange protective colour-pattern genes promiscuously, implying that hybridization has an important role in adaptive radiation. [ABSTRACT FROM AUTHOR]

Supergenes are tight clusters of loci that facilitate the co-segregation of adaptive variation, providing integrated control of complex adaptive phenotypes. Polymorphic supergenes, in which specific combinations of traits are maintained within a single population, were first described for 'pin' and 'thrum' floral types in Primula and Fagopyrum, but classic examples are also found in insect mimicry and snail morphology. Understanding the evolutionary mechanisms that generate these co-adapted gene sets, as well as the mode of limiting the production of unfit recombinant forms, remains a substantial challenge. Here we show that individual wing-pattern morphs in the polymorphic mimetic butterfly Heliconius numata are associated with different genomic rearrangements at the supergene locus P. These rearrangements tighten the genetic linkage between at least two colour-pattern loci that are known to recombine in closely related species, with complete suppression of recombination being observed in experimental crosses across a 400-kilobase interval containing at least 18 genes. In natural populations, notable patterns of linkage disequilibrium (LD) are observed across the entire P region. The resulting divergent haplotype clades and inversion breakpoints are found in complete association with wing-pattern morphs. Our results indicate that allelic combinations at known wing-patterning loci have become locked together in a polymorphic rearrangement at the P locus, forming a supergene that acts as a simple switch between complex adaptive phenotypes found in sympatry. These findings highlight how genomic rearrangements can have a central role in the coexistence of adaptive phenotypes involving several genes acting in concert, by locally limiting recombination and gene flow. [ABSTRACT FROM AUTHOR]

The application of MRI as a non-invasive, quantitative tool for diagnosing lumbar intervertebral disc degeneration is currently an area of active research. The objective of this study was to examine, in vitro, the efficacy of a manganese chloride phantom-based MRI technique for quantitatively assessing lumbar disc composition and degenerative condition. Sixteen human lumbar discs were imaged ex vivo using T2-weighted MRI, and assigned a quantitative grade based on the relative signal intensities of nine phantoms containing serial concentrations of manganese chloride. Discs were then graded macroscopically for degenerative condition, and water and uronic acid (glycosaminoglycan) contents were determined. MRI ranking exhibited significant and strong negative correlation with nucleus pulposus uronic acid content (r = -0.78). MRI grades were significantly higher for degenerate discs. The technique described presents immediate potential for in vitro studies requiring robust, minimally invasive and quantitative determination of lumbar disc composition and condition. Additionally, the technique may have potential as a clinical tool for diagnosing lumbar disc degeneration as it provides a standardised series of reference phantoms facilitating cross-platform consistency, requires short scan times and simple T2-weighted signal intensity measurements. [ABSTRACT FROM AUTHOR]

Sedentary species face a trade-off between the benefits of exploiting food close to their homes and the cost of defending it. In aquatic systems, it has been suggested that some sedentary grazers can increase the range of circumstances under which they are at an advantage over mobile grazers by enhancing food resources within their feeding territories through ‘gardening’. We examined this for the retreat-building sedentary larvae of the caddis Tinodes waeneri, which are often dominant in the littoral of lakes. We hypothesised that T. waeneri gardens by fertilising its retreat (a fixed ‘gallery’ on which algae and other microorganisms grow), and that gardening would be more important in lower productivity lakes. We tested this by analysing the carbon and nitrogen stable isotope ratios of larvae, their galleries and the general background epilithon, collected from rocks in the littoral zones of six lakes spread across a natural nutrient gradient. We found evidence of nutrient recycling within the Tinodes gallery community in all lakes. Galleries were 15N-depleted compared to the epilithon, suggesting that algae on galleries preferentially assimilated 14N from larval excretions that were themselves 15N-depleted relative to the larval food source. Mixing model results indicate that galleries formed an important larval carbon and nitrogen source, with mean gallery dietary contributions of over 40% in at least one sample period in all lakes studied. Gallery contributions were greater between April and October than in January and, contrary to our initial hypothesis, greater in the more productive lakes of those surveyed. Nevertheless, T. waeneri galleries do act as a fertilised garden. ‘Gardening’ appears to be widespread in this species, and may affect productivity and patterns of nitrogen retention within the stony littoral of lakes. [ABSTRACT FROM AUTHOR]

Autophagy is emerging as a crucial defense mechanism against bacteria, but the host intracellular sensors responsible for inducing autophagy in response to bacterial infection remain unknown. Here we demonstrated that the intracellular sensors Nod1 and Nod2 are critical for the autophagic response to invasive bacteria. By a mechanism independent of the adaptor RIP2 and transcription factor NF-κB, Nod1 and Nod2 recruited the autophagy protein ATG16L1 to the plasma membrane at the bacterial entry site. In cells homozygous for the Crohn's disease–associated NOD2 frameshift mutation, mutant Nod2 failed to recruit ATG16L1 to the plasma membrane and wrapping of invading bacteria by autophagosomes was impaired. Our results link bacterial sensing by Nod proteins to the induction of autophagy and provide a functional link between Nod2 and ATG16L1, which are encoded by two of the most important genes associated with Crohn's disease. [ABSTRACT FROM AUTHOR]

Elastic fibres are critical constituents of dynamic biological structures that functionally require elasticity and resilience. The network of elastic fibres in the anulus fibrosus of the intervertebral disc is extensive, however until recently, the majority of histological, biochemical and biomechanical studies have focussed on the roles of other extracellular matrix constituents such as collagens and proteoglycans. The resulting lack of detailed descriptions of elastic fibre network architecture and mechanical function has limited understanding of the potentially important contribution made by elastic fibres to healthy disc function and their possible roles in the progression of disc degeneration. In addition, it has made it difficult to postulate what the consequences of elastic fibre related disorders would be for intervertebral disc behaviour, and to develop treatments accordingly. In this paper, we review recent and historical studies which have examined both the structure and the function of the human lumbar anulus fibrosus elastic fibre network, provide a synergistic discussion in an attempt to clarify its potentially critical contribution both to normal intervertebral disc behaviour and the processes relating to its degeneration, and recommend critical areas for future research. [ABSTRACT FROM AUTHOR]

More than 500 million people worldwide are persistently infected with hepatitis B virus or hepatitis C virus. Although both viruses are poorly cytopathic, persistence of either virus carries a risk of chronic liver inflammation, potentially resulting in liver steatosis, liver cirrhosis, end-stage liver failure or hepatocellular carcinoma. Virus-specific T cells are a major determinant of the outcome of hepatitis, as they contribute to the early control of chronic hepatitis viruses, but they also mediate immunopathology during persistent virus infection. We have analyzed the role of platelet-derived vasoactive serotonin during virus-induced CD8+ T cell–dependent immunopathological hepatitis in mice infected with the noncytopathic lymphocytic choriomeningitis virus. After virus infection, platelets were recruited to the liver, and their activation correlated with severely reduced sinusoidal microcirculation, delayed virus elimination and increased immunopathological liver cell damage. Lack of platelet-derived serotonin in serotonin-deficient mice normalized hepatic microcirculatory dysfunction, accelerated virus clearance in the liver and reduced CD8+ T cell–dependent liver cell damage. In keeping with these observations, serotonin treatment of infected mice delayed entry of activated CD8+ T cells into the liver, delayed virus control and aggravated immunopathological hepatitis. Thus, vasoactive serotonin supports virus persistence in the liver and aggravates virus-induced immunopathology. [ABSTRACT FROM AUTHOR]

Enzyme inhibition through mimicry of the transition state is a major area for the design of new therapeutic agents. Emerging evidence suggests that many retaining glycosidases that are active on α- or β-mannosides harness unusual B2,5 (boat) transition states. Here we present the analysis of 25 putative β-mannosidase inhibitors, whose Ki values range from nanomolar to millimolar, on the Bacteroides thetaiotaomicron β-mannosidase BtMan2A. B2,5 or closely related conformations were observed for all tightly binding compounds. Subsequent linear free energy relationships that correlate log Ki with log Km/kcat for a series of active center variants highlight aryl-substituted mannoimidazoles as powerful transition state mimics in which the binding energy of the aryl group enhances both binding and the degree of transition state mimicry. Support for a B2,5 transition state during enzymatic β-mannosidase hydrolysis should also facilitate the design and exploitation of transition state mimics for the inhibition of retaining α-mannosidases—an area that is emerging for anticancer therapeutics. [ABSTRACT FROM AUTHOR]

One form of myotonic dystrophy, dystrophia myotonica 1 (DM1), is caused by the expansion of a (CTG)n repeat within the dystrophia myotonica-protein kinase (DMPK) gene located in chromosome region 19q13.3. Unaffected individuals carry alleles with repeat size (CTG)5–37, premutation carriers (CTG)38–49 and DM1 affected individuals (CTG)50–6000. Preferential transmission both of expanded repeats from DM1-affected parents and larger DMPK alleles in the normal-size range have been reported in live-born offspring. To determine the moment in development when transmission ratio distortion (TRD) for larger normal-size DMPK alleles is generated, the transmission from heterozygous parents with one repeat within the (CTG)5–18 range (Group I repeat) and the other within the (CTG)19–37 range (Group II repeat) to human preimplantation embryos was analysed. A statistically significant TRD of 59% (95% confidence interval of 54–64) in favour of Group II repeats from both mothers and fathers was observed in preimplantation embryos, which remained significant when female embryos were considered separately. In contrast, no significant TRD was detected for repeats from informative Group I/Group I parents. Our analysis showed that Group II repeats specifically were preferentially transmitted in human preimplantation embryos. We suggest that TRD, in Group II repeats at the DMPK locus, is likely to result from events occurring at or around the time of fertilisation.European Journal of Human Genetics (2006) 14, 299–306. doi:10.1038/sj.ejhg.5201559; published online 4 January 2006 [ABSTRACT FROM AUTHOR]

The aim of this study was to delineate the role of the Fas pathway in vaccination against Helicobacter pylori. C57BL/6 and Fas ligand-deficient (gld) mice were divided into 3 groups: control, H. pylori infected, and orally vaccinated (H. pylori whole cell sonicate and cholera toxin adjuvant). Oral vaccination prevented H. pylori colonization in 78% of C57BL/6 mice compared to only 18% of gld mice. Vaccination did not alter the degree of apoptosis in either strain of mice. Vaccination led to significant increase in interleukin (IL)-5 and IL-10 in C57BL/6 but not gld mice. H. pylori infection increased interferon (IFN)-gamma levels in C57BL/6 but not in gld mice while vaccination had no effect on IFN-gamma levels in either strain. Oral vaccination is not effective in Fas ligand-deficient mice likely owing to lack of effective cytokine responses. This indicates that the Fas pathway plays a critical role in promoting an appropriate effector response following H. pylori vaccination. [ABSTRACT FROM AUTHOR]

Autoimmune diabetes mellitus in humans is characterized by immunological destruction of pancreatic beta islet cells. We investigated the circumstances under which CD8+ T cells specific for pancreatic beta-islet antigens induce disease in mice expressing lymphocytic choriomeningitis virus (LCMV) glycoprotein (GP) as a transgene under the control of the rat insulin promoter. In contrast to infection with LCMV, immunization with LCMV-GP derived peptide did not induce autoimmune diabetes despite large numbers of autoreactive cytotoxic T cells. Only subsequent treatment with Toll-like receptor ligands elicited overt autoimmune disease. This difference was critically regulated by the peripheral target organ itself, which upregulated class I major histocompatibility complex (MHC) in response to systemic Toll-like receptor-triggered interferon-aproduction. These data identify the 'inflammatory status' of the target organ as a separate and limiting factor determining the development of autoimmune disease. [ABSTRACT FROM AUTHOR]