Exceptional sperm cooperation in the wood mouse

Spermatozoa from a single male will compete for fertilization of ova with spermatozoa from another male when present in the female reproductive tract at the same time. Close genetic relatedness predisposes individuals towards altruism, and as haploid germ cells of an ejaculate will have genotypic similarity of 50%, it is predicted that spermatozoa may display cooperation and altruism to gain an advantage when inter-male sperm competition is intense. We report here the probable altruistic behaviour of spermatozoa in an eutherian mammal. Spermatozoa of the common wood mouse, Apodemus sylvaticus, displayed a unique morphological transformation resulting in cooperation in distinctive aggregations or 'trains' of hundreds or thousands of cells, which significantly increased sperm progressive motility. Eventual dispersal of sperm trains was associated with most of the spermatozoa undergoing a premature acrosome reaction. Cells undergoing an acrosome reaction in aggregations remote from the egg are altruistic in that they help sperm transport to the egg but compromise their own fertilizing ability

An Anti-Human ICAM-1 Antibody Inhibits Rhinovirus-Induced Exacerbations of Lung Inflammation

Human rhinoviruses (HRV) cause the majority of common colds and acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). Effective therapies are urgently needed, but no licensed treatments or vaccines currently exist. Of the 100 identified serotypes, ∼90% bind domain 1 of human intercellular adhesion molecule-1 (ICAM-1) as their cellular receptor, making this an attractive target for development of therapies; however, ICAM-1 domain 1 is also required for host defence and regulation of cell trafficking, principally via its major ligand LFA-1. Using a mouse anti-human ICAM-1 antibody (14C11) that specifically binds domain 1 of human ICAM-1, we show that 14C11 administered topically or systemically prevented entry of two major groups of rhinoviruses, HRV16 and HRV14, and reduced cellular inflammation, pro-inflammatory cytokine induction and virus load in vivo. 14C11 also reduced cellular inflammation and Th2 cytokine/chemokine production in a model of major group HRV-induced asthma exacerbation. Interestingly, 14C11 did not prevent cell adhesion via human ICAM-1/LFA-1 interactions in vitro, suggesting the epitope targeted by 14C11 was specific for viral entry. Thus a human ICAM-1 domain-1-specific antibody can prevent major group HRV entry and induction of airway inflammation in vivo

A multi-gene signature predicts outcome in patients with pancreatic ductal adenocarcinoma.

© 2014 Haider et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Improved usage of the repertoires of pancreatic ductal adenocarcinoma (PDAC) profiles is crucially needed to guide the development of predictive and prognostic tools that could inform the selection of treatment options

Comparative genomics of isolates of a pseudomonas aeruginosa epidemic strain associated with chronic lung infections of cystic fibrosis patients

Pseudomonas aeruginosa is the main cause of fatal chronic lung infections among individuals suffering from cystic fibrosis (CF). During the past 15 years, particularly aggressive strains transmitted among CF patients have been identified, initially in Europe and more recently in Canada. The aim of this study was to generate high-quality genome sequences for 7 isolates of the Liverpool epidemic strain (LES) from the United Kingdom and Canada representing different virulence characteristics in order to: (1) associate comparative genomics results with virulence factor variability and (2) identify genomic and/or phenotypic divergence between the two geographical locations. We performed phenotypic characterization of pyoverdine, pyocyanin, motility, biofilm formation, and proteolytic activity. We also assessed the degree of virulence using the Dictyostelium discoideum amoeba model. Comparative genomics analysis revealed at least one large deletion (40-50 kb) in 6 out of the 7 isolates compared to the reference genome of LESB58. These deletions correspond to prophages, which are known to increase the competitiveness of LESB58 in chronic lung infection. We also identified 308 non-synonymous polymorphisms, of which 28 were associated with virulence determinants and 52 with regulatory proteins. At the phenotypic level, isolates showed extensive variability in production of pyocyanin, pyoverdine, proteases and biofilm as well as in swimming motility, while being predominantly avirulent in the amoeba model. Isolates from the two continents were phylogenetically and phenotypically undistinguishable. Most regulatory mutations were isolate-specific and 29% of them were predicted to have high functional impact. Therefore, polymorphism in regulatory genes is likely to be an important basis for phenotypic diversity among LES isolates, which in turn might contribute to this strain's adaptability to varying conditions in the CF lung

Lack of Detectable HIV-1 Molecular Evolution during Suppressive Antiretroviral Therapy

A better understanding of changes in HIV-1 population genetics with combination antiretroviral therapy (cART) is critical for designing eradication strategies. We therefore analyzed HIV-1 genetic variation and divergence in patients' plasma before cART, during suppression on cART, and after viral rebound. Single-genome sequences of plasma HIV-1 RNA were obtained from HIV-1 infected patients prior to cART (N = 14), during suppression on cART (N = 14) and/or after viral rebound following interruption of cART (N = 5). Intra-patient population diversity was measured by average pairwise difference (APD). Population structure was assessed by phylogenetic analyses and a test for panmixia. Measurements of intra-population diversity revealed no significant loss of overall genetic variation in patients treated for up to 15 years with cART. A test for panmixia, however, showed significant changes in population structure in 2/10 patients after short-term cART (<1 year) and in 7/10 patients after long-term cART (1-15 years). The changes consisted of diverse sets of viral variants prior to cART shifting to populations containing one or more genetically uniform subpopulations during cART. Despite these significant changes in population structure, rebound virus after long-term cART had little divergence from pretherapy virus, implicating long-lived cells infected before cART as the source for rebound virus. The appearance of genetically uniform virus populations and the lack of divergence after prolonged cART and cART interruption provide strong evidence that HIV-1 persists in long-lived cells infected before cART was initiated, that some of these infected cells may be capable of proliferation, and that on-going cycles of viral replication are not evident

Fecal microbiota and bile acid interactions with systemic and adipose tissue metabolism in diet-induced weight loss of obese postmenopausal women

Microbiota and bile acids in the gastrointestinal tract profoundly alter systemic metabolic processes. In obese subjects, gradual weight loss ameliorates adipose tissue inflammation and related systemic changes. We assessed how rapid weight loss due to a very low calorie diet (VLCD) affects the fecal microbiome and fecal bile acid composition, and their interactions with the plasma metabolome and subcutaneous adipose tissue inflammation in obesity. We performed a prospective cohort study of VLCD-induced weight loss of 10% in ten grades 2-3 obese postmenopausal women in a metabolic unit. Baseline and post weight loss evaluation included fasting plasma analyzed by mass spectrometry, adipose tissue transcription by RNA sequencing, stool 16S rRNA sequencing for fecal microbiota, fecal bile acids by mass spectrometry, and urinary metabolic phenotyping by H-NMR spectroscopy. Outcome measures included mixed model correlations between changes in fecal microbiota and bile acid composition with changes in plasma metabolite and adipose tissue gene expression pathways. Alterations in the urinary metabolic phenotype following VLCD-induced weight loss were consistent with starvation ketosis, protein sparing, and disruptions to the functional status of the gut microbiota. We show that the core microbiome was preserved during VLCD-induced weight loss, but with changes in several groups of bacterial taxa with functional implications. UniFrac analysis showed overall parallel shifts in community structure, corresponding to reduced abundance of the genus Roseburia and increased Christensenellaceae;g__ (unknown genus). Imputed microbial functions showed changes in fat and carbohydrate metabolism. A significant fall in fecal total bile acid concentration and reduced deconjugation and 7-α-dihydroxylation were accompanied by significant changes in several bacterial taxa. Individual bile acids in feces correlated with amino acid, purine, and lipid metabolic pathways in plasma. Furthermore, several fecal bile acids and bacterial species correlated with altered gene expression pathways in adipose tissue. VLCD dietary intervention in obese women changed the composition of several fecal microbial populations while preserving the core fecal microbiome. Changes in individual microbial taxa and their functions correlated with variations in the plasma metabolome, fecal bile acid composition, and adipose tissue transcriptome

A multicomponent intervention for the management of chronic pain in older adults: study protocol for a randomized controlled trial

Background: Studies have shown that physical interventions and psychological methods based on the cognitive behavioral approach are efficacious in alleviating pain and that combining both tends to yield more benefits than either intervention alone. In view of the aging population with chronic pain and the lack of evidence-based pain management programs locally, we developed a multicomponent intervention incorporating physical exercise and cognitive behavioral techniques and examined its long-term effects against treatment as usual (i.e., pain education) in older adults with chronic musculoskeletal pain in Hong Kong. Methods/design: We are conducting a double-blind, cluster-randomized controlled trial. A sample of 160 participants aged ≥ 60 years will be recruited from social centers or outpatient clinics and will be randomized on the basis of center/clinic to either the multicomponent intervention or the pain education program. Both interventions consist of ten weekly sessions of 90 minutes each. The primary outcome is pain intensity, and the secondary outcomes include pain interference, pain persistence, pain self-efficacy, pain coping, pain catastrophizing cognitions, health-related quality of life, depressive symptoms, and hip and knee muscle strength. All outcome measures will be collected at baseline, postintervention, and at 3 and 6 months follow-up. Intention-to-treat analysis will be performed using mixed-effects regression to see whether the multicomponent intervention alleviates pain intensity and associated outcomes over and above the effects of pain education (i.e., a treatment × time intervention effect). Discussion: Because the activities included in the multicomponent intervention were carefully selected for ready implementation by allied health professionals in general, the results of this study, if positive, will make available an efficacious, nonpharmacological pain management program that can be widely adopted in clinical and social service settings and will hence improve older people’s access to pain management services

Transorbital sonographic evaluation of normal optic nerve sheath diameter in healthy volunteers in Bangladesh

INTRODUCTION: Measurement of optic nerve sheath diameter (ONSD) by ultrasound is increasingly used as a marker to detect raised intracranial pressure (ICP). ONSD varies with age and there is no clear consensus between studies for an upper limit of normal. Knowledge of normal ONSD in a healthy population is essential to interpret this measurement. METHODS: In a prospective observational study, ONSD was measured using a 15 MHz ultrasound probe in healthy volunteers in Chittagong, Bangladesh. The aims were to determine the normal range of ONSD in healthy Bangladeshi adults and children, compare measurements in males and females, horizontal and vertical beam orientations and left and right eyes in the same individual and to determine whether ONSD varies with head circumference independent of age. RESULTS: 136 subjects were enrolled, 12.5% of whom were age 16 or under. Median ONSD was 4.41 mm with 95% of subjects in the range 4.25-4.75 mm. ONSD was bimodally distributed. There was no relationship between ONSD and age (≥4 years), gender, head circumference, and no difference in left vs right eye or horizontal vs vertical beam. CONCLUSIONS: Ultrasonographic ONSD in Bangladeshi healthy volunteers has a narrow bimodal distribution independent of age (≥4 years), gender and head circumference. ONSD >4.75 mm in this population should be considered abnormal

Kesempatan Belajar Dan Melakukan Penelitian Ikut Menentukan Pilihan Lokasi Kerja Lulusan Dokter di Daerah Tertinggal

Objective: Memahami alasan lulusan dokter memilih daerah tertinggal sebagai lokasi kerja. Methods: Penelitian kualitatif dengan pendekatan fenomenologi. Focused group discussion (FGD) dilakukan di Kota Kupang dan 2 pulau tertinggal lain di Nusa Tenggara Timur (NTT) dengan karakteristik yang berbeda. Penelitian diikuti oleh 24 orang lulusan dokter yang direkrut secara purposive dan bekerja di enam kabupaten yang berbeda. Transkripsi hasil wawancara dianalisis secara tematik oleh dua orang peneliti dengan dibantu program OpenCode 4.03. Results: Upaya intervensi yang telah dilakukan oleh pemerintah selama ini melalui berbagai program seperti beasiswa dengan ikatan kerja, insentif dan perhitungan beban kerja, peningkatan keamanan, fasilitas, dan aksesibilitas daerah tertinggal, serta promosi daerah tertinggal sebagai lokasi wisata merupakan hal yang terbukti sangat mendukung pemilihan daerah tertinggal sebagai lokasi kerja lulusan dokter. Beberapa hal yang telah dipertimbangkan dalam perekrutan dan penempatan tenaga medis di daerah tertinggal (internship, PTT, maupun Nusantara Sehat) pun terbukti berperan besar, misalnya: rural origin (asal daerah dan adanya keluarga di daerah), adanya rekomendasi otoritas setempat yang menunjukkan adanya teman atau kolega di daerah yang dituju. Hal baru yang ditambahkan oleh penelitian ini adalah lokasi yang menyediakan kesempatan dan pendamping untuk belajar lebih lanjut, termasuk melakukan penelitian, dengan disertai adanya otonomi dan kemandirian dalam bertindak mendapatkan prioritas. Manajemen institusi yang mendukung dan mampu menciptakan suasana kerja yang menyenangkan, serta budaya dan politik setempat pun ikut memberikan warna dalam pengambilan keputusan pilihan lokasi kerja. Conclusion: Banyak faktor yang berperan dalam pilihan lokasi kerja telah diintervensi dan berhasil menarik minat lulusan dokter untuk masuk dan bekerja di daerah tertinggal. Keputusan lulusan dalam memberikan prioritas pilihan terhadap daerah yang mampu menyediakan pendamping dokter spesialis dan memberikan kesempatan dan otonomi untuk belajar serta melakukan penelitian perlu mendapatkan perhatian dan memberikan arah bagi pengembangan program intervensi pemerataan tenaga medis ke daerah tertinggal selanjutnya.Objective: Memahami alasan lulusan dokter memilih daerah tertinggal sebagai lokasi kerja.Methods: Penelitian kualitatif dengan pendekatan fenomenologi. Focused group discussion (FGD) dilakukan di Kota Kupang dan 2 pulau tertinggal lain di Nusa Tenggara Timur (NTT) dengan karakteristik yang berbeda. Penelitian diikuti oleh 24 orang lulusan dokter yang direkrut secara purposive dan bekerja di enam kabupaten yang berbeda. Transkripsi hasil wawancara dianalisis secara tematik oleh dua orang peneliti dengan dibantu program OpenCode 4.03.Results: Upaya intervensi yang telah dilakukan oleh pemerintah selama ini melalui berbagai program seperti beasiswa dengan ikatan kerja, insentif dan perhitungan beban kerja, peningkatan keamanan, fasilitas, dan aksesibilitas daerah tertinggal, serta promosi daerah tertinggal sebagai lokasi wisata merupakan hal yang terbukti sangat mendukung pemilihan daerah tertinggal sebagai lokasi kerja lulusan dokter. Beberapa hal yang telah dipertimbangkan dalam perekrutan dan penempatan tenaga medis di daerah tertinggal (internship, PTT, maupun Nusantara Sehat) pun terbukti berperan besar, misalnya: rural origin (asal daerah dan adanya keluarga di daerah), adanya rekomendasi otoritas setempat yang menunjukkan adanya teman atau kolega di daerah yang dituju. Hal baru yang ditambahkan oleh penelitian ini adalah lokasi yang menyediakan kesempatan dan pendamping untuk belajar lebih lanjut, termasuk melakukan penelitian, dengan disertai adanya otonomi dan kemandirian dalam bertindak mendapatkan prioritas. Manajemen institusi yang mendukung dan mampu menciptakan suasana kerja yang menyenangkan, serta budaya dan politik setempat pun ikut memberikan warna dalam pengambilan keputusan pilihan lokasi kerja.Conclusion: Banyak faktor yang berperan dalam pilihan lokasi kerja telah diintervensi dan berhasil menarik minat lulusan dokter untuk masuk dan bekerja di daerah tertinggal. Keputusan lulusan dalam memberikan prioritas pilihan terhadap daerah yang mampu menyediakan pendamping dokter spesialis dan memberikan kesempatan dan otonomi untuk belajar serta melakukan penelitian perlu mendapatkan perhatian dan memberikan arah bagi pengembangan program intervensi pemerataan tenaga medis ke daerah tertinggal selanjutnya

Biogeographical venom variation in the Indian spectacled cobra (Naja naja) underscores the pressing need for pan-India efficacious snakebite therapy

Background: Snake venom composition is dictated by various ecological and environmental factors, and can exhibit dramatic variation across geographically disparate populations of the same species. This molecular diversity can undermine the efficacy of snakebite treatments, as antivenoms produced against venom from one population may fail to neutralise others. India is the world’s snakebite hotspot, with 58,000 fatalities and 140,000 morbidities occurring annually. Spectacled cobra (Naja naja) and Russell’s viper (Daboia russelii) are known to cause the majority of these envenomations, in part due to their near country-wide distributions. However, the impact of differing ecologies and environment on their venom compositions has not been comprehensively studied. Methods: Here, we used a multi-disciplinary approach consisting of venom proteomics, biochemical and pharmacological analyses, and in vivo research to comparatively analyse N. naja venoms across a broad region (>6000 km; seven populations) covering India’s six distinct biogeographical zones. Findings: By generating the most comprehensive pan-Indian proteomic and toxicity profiles to date, we unveil considerable differences in the composition, pharmacological effects and potencies of geographically-distinct venoms from this species and, through the use of immunological assays and preclinical experiments, demonstrate alarming repercussions on antivenom therapy. We find that commercially-available antivenom fails to effectively neutralise envenomations by the pan-Indian populations of N. naja, including a complete lack of neutralisation against the desert Naja population. Conclusion: Our findings highlight the significant influence of ecology and environment on snake venom composition and potency, and stress the pressing need to innovate pan-India effective antivenoms to safeguard the lives, limbs and livelihoods of the country’s 200,000 annual snakebite victims