Fine Selmer Groups and Isogeny Invariance

We investigate fine Selmer groups for elliptic curves and for Galois representations over a number field. More specifically, we discuss Conjecture A, which states that the fine Selmer group of an elliptic curve over the cyclotomic extension is a finitely generated $\mathbb{Z}_p$-module. The relationship between this conjecture and Iwasawa's classical $\mu=0$ conjecture is clarified. We also present some partial results towards the question whether Conjecture A is invariant under isogenies.Comment: 20 page

Programmed DNA destruction by miniature CRISPR-Cas14 enzymes.

CRISPR-Cas systems provide microbes with adaptive immunity to infectious nucleic acids and are widely employed as genome editing tools. These tools use RNA-guided Cas proteins whose large size (950 to 1400 amino acids) has been considered essential to their specific DNA- or RNA-targeting activities. Here we present a set of CRISPR-Cas systems from uncultivated archaea that contain Cas14, a family of exceptionally compact RNA-guided nucleases (400 to 700 amino acids). Despite their small size, Cas14 proteins are capable of targeted single-stranded DNA (ssDNA) cleavage without restrictive sequence requirements. Moreover, target recognition by Cas14 triggers nonspecific cutting of ssDNA molecules, an activity that enables high-fidelity single-nucleotide polymorphism genotyping (Cas14-DETECTR). Metagenomic data show that multiple CRISPR-Cas14 systems evolved independently and suggest a potential evolutionary origin of single-effector CRISPR-based adaptive immunity

On the non-abelian Brumer-Stark conjecture and the equivariant Iwasawa main conjecture

We show that for an odd prime p, the p-primary parts of refinements of the (imprimitive) non-abelian Brumer and Brumer-Stark conjectures are implied by the equivariant Iwasawa main conjecture (EIMC) for totally real fields. Crucially, this result does not depend on the vanishing of the relevant Iwasawa mu-invariant. In combination with the authors' previous work on the EIMC, this leads to unconditional proofs of the non-abelian Brumer and Brumer-Stark conjectures in many new cases.Comment: 33 pages; to appear in Mathematische Zeitschrift; v3 many minor updates including new title; v2 some cohomological arguments simplified; v1 is a revised version of the second half of arXiv:1408.4934v

A framework for interpreting genome-wide association studies of psychiatric disorders

Genome-wide association studies (GWAS) have yielded a plethora of new findings in the past 3 years. By early 2009, GWAS on 47 samples of subjects with attention-deficit hyperactivity disorder, autism, bipolar disorder, major depressive disorder and schizophrenia will be completed. Taken together, these GWAS constitute the largest biological experiment ever conducted in psychiatry (59 000 independent cases and controls, 7700 family trios and >40 billion genotypes). We know that GWAS can work, and the question now is whether it will work for psychiatric disorders. In this review, we describe these studies, the Psychiatric GWAS Consortium for meta-analyses of these data, and provide a logical framework for interpretation of some of the conceivable outcomes

Infection prevention and control interventions in the first outbreak of methicillin-resistant Staphylococcus aureus infections in an equine hospital in Sweden

<p>Abstract</p> <p>Background</p> <p>The first outbreak of methicillin-resistant <it>Staphylococcus aureus </it>(MRSA) infection in horses in Sweden occurred in 2008 at the University Animal Hospital and highlighted the need for improved infection prevention and control. The present study describes interventions and infection prevention control in an equine hospital setting July 2008 - April 2010.</p> <p>Method</p> <p>This descriptive study of interventions is based on examination of policy documents, medical records, notes from meetings and cost estimates. MRSA cases were identified through clinical sampling and telephone enquiries about horses post-surgery. Prospective sampling in the hospital environment with culture for MRSA and genotyping of isolates by <it>spa</it>-typing and pulsed-field gel electrophoresis (PFGE) were performed.</p> <p>Results</p> <p>Interventions focused on interruption of indirect contact spread of MRSA between horses via staff and equipment and included: Temporary suspension of elective surgery; and identification and isolation of MRSA-infected horses; collaboration was initiated between authorities in animal and human public health, human medicine infection control and the veterinary hospital; extensive cleaning and disinfection was performed; basic hygiene and cleaning policies, staff training, equipment modification and interior renovation were implemented over seven months.</p> <p>Ten (11%) of 92 surfaces sampled between July 2008 and April 2010 tested positive for MRSA <it>spa</it>-type 011, seven of which were from the first of nine sampling occasions. PFGE typing showed the isolates to be the outbreak strain (9 of 10) or a closely related strain. Two new cases of MRSA infection occurred 14 and 19 months later, but had no proven connections to the outbreak cases.</p> <p>Conclusions</p> <p>Collaboration between relevant authorities and the veterinary hospital and formation of an infection control committee with an executive working group were required to move the intervention process forward. Support from hospital management and the dedication of staff were essential for the development and implementation of new, improved routines. Demonstration of the outbreak strain in the environment was useful for interventions such as improvement of cleaning routines and interior design, and increased compliance with basic hygienic precautions. The interventions led to a reduction in MRSA-positive samples and the outbreak was considered curbed as no new cases occurred for over a year.</p

High Log-Scale Expansion of Functional Human Natural Killer Cells from Umbilical Cord Blood CD34-Positive Cells for Adoptive Cancer Immunotherapy

Immunotherapy based on natural killer (NK) cell infusions is a potential adjuvant treatment for many cancers. Such therapeutic application in humans requires large numbers of functional NK cells that have been selected and expanded using clinical grade protocols. We established an extremely efficient cytokine-based culture system for ex vivo expansion of NK cells from hematopoietic stem and progenitor cells from umbilical cord blood (UCB). Systematic refinement of this two-step system using a novel clinical grade medium resulted in a therapeutically applicable cell culture protocol. CD56+CD3− NK cell products could be routinely generated from freshly selected CD34+ UCB cells with a mean expansion of >15,000 fold and a nearly 100% purity. Moreover, our protocol has the capacity to produce more than 3-log NK cell expansion from frozen CD34+ UCB cells. These ex vivo-generated cell products contain NK cell subsets differentially expressing NKG2A and killer immunoglobulin-like receptors. Furthermore, UCB-derived CD56+ NK cells generated by our protocol uniformly express high levels of activating NKG2D and natural cytotoxicity receptors. Functional analysis showed that these ex vivo-generated NK cells efficiently target myeloid leukemia and melanoma tumor cell lines, and mediate cytolysis of primary leukemia cells at low NK-target ratios. Our culture system exemplifies a major breakthrough in producing pure NK cell products from limited numbers of CD34+ cells for cancer immunotherapy

Influenza pandemic preparedness: motivation for protection among small and medium businesses in Australia

<p>Abstract</p> <p>Background</p> <p>Community-wide preparedness for pandemic influenza is an issue that has featured prominently in the recent news media, and is currently a priority for health authorities in many countries. The small and medium business sector is a major provider of private sector employment in Australia, yet we have little information about the preparedness of this sector for pandemic influenza. This study aimed to investigate the association between individual perceptions and preparedness for pandemic influenza among small and medium business owners and managers.</p> <p>Methods</p> <p>Semi-structured face-to-face interviews were conducted with 201 small and medium business owners or managers in New South Wales and Western Australia. Eligible small or medium businesses were defined as those that had less than 200 employees. Binomial logistic regression analysis was used to identify the predictors of having considered the impact of, having a plan for, and needing help to prepare for pandemic influenza.</p> <p>Results</p> <p>Approximately 6 per cent of participants reported that their business had a plan for pandemic influenza, 39 per cent reported that they had not thought at all about the impact of pandemic influenza on their business, and over 60 per cent stated that they required help to prepare for a pandemic. Beliefs about the severity of pandemic influenza and the ability to respond were significant independent predictors of having a plan for pandemic influenza, and the perception of the risk of pandemic influenza was the most important predictor of both having considered the impact of, and needing help to prepare for a pandemic.</p> <p>Conclusion</p> <p>Our findings suggest that small and medium businesses in Australia are not currently well prepared for pandemic influenza. We found that beliefs about the risk, severity, and the ability to respond effectively to the threat of pandemic influenza are important predictors of preparedness. Campaigns targeting small and medium businesses should emphasise the severity of the consequences to their businesses if a pandemic were to occur, and, at the same time, reassure them that there are effective strategies capable of being implemented by small and medium businesses to deal with a pandemic.</p

Unilateral optic neuropathy following subdural hematoma: a case report

<p>Abstract</p> <p>Introduction</p> <p>Unilateral optic neuropathy is commonly due to a prechiasmatic affliction of the anterior visual pathway, while losses in visual hemifields result from the damage to brain hemispheres. Here we report the unusual case of a patient who suffered from acute optic neuropathy following hemispherical subdural hematoma. Although confirmed up to now only through necropsy studies, our case strongly suggests a local, microcirculatory deficit identified through magnetic resonance imaging <it>in vivo</it>.</p> <p>Case presentation</p> <p>A 70-year-old Caucasian German who developed a massive left hemispheric subdural hematoma under oral anticoagulation presented with acute, severe visual impairment on his left eye, which was noticed after surgical decompression. Neurologic and ophthalmologic examinations indicated sinistral optic neuropathy with visual acuity reduced nearly to amaurosis. Ocular pathology such as vitreous body hemorrhage, papilledema, and central retinal artery occlusion were excluded. An orbital lesion was ruled out by means of orbital magnetic resonance imaging. However, cerebral diffusion-weighted imaging and T2 maps of magnetic resonance imaging revealed a circumscribed ischemic lesion within the edematous, slightly herniated temporomesial lobe within the immediate vicinity of the affected optic nerve. Thus, the clinical course and morphologic magnetic resonance imaging findings suggest the occurrence of pressure-induced posterior ischemic optic neuropathy due to microcirculatory compromise.</p> <p>Conclusion</p> <p>Although lesions of the second cranial nerve following subdural hematoma have been reported individually, their pathogenesis was preferentially proposed from autopsy studies. Here we discuss a dual, pressure-induced and secondarily ischemic pathomechanism on the base of <it>in vivo </it>magnetic resonance imaging diagnostics which may remain unconsidered by computed tomography.</p

Agent based modelling helps in understanding the rules by which fibroblasts support keratinocyte colony formation

Background: Autologous keratincoytes are routinely expanded using irradiated mouse fibroblasts and bovine serum for clinical use. With growing concerns about the safety of these xenobiotic materials, it is desirable to culture keratinocytes in media without animal derived products. An improved understanding of epithelial/mesenchymal interactions could assist in this. Methodology/Principal Findings: A keratincyte/fibroblast o-culture model was developed by extending an agent-based keratinocyte colony formation model to include the response of keratinocytes to both fibroblasts and serum. The model was validated by comparison of the in virtuo and in vitro multicellular behaviour of keratinocytes and fibroblasts in single and co-culture in Greens medium. To test the robustness of the model, several properties of the fibroblasts were changed to investigate their influence on the multicellular morphogenesis of keratinocyes and fibroblasts. The model was then used to generate hypotheses to explore the interactions of both proliferative and growth arrested fibroblasts with keratinocytes. The key predictions arising from the model which were confirmed by in vitro experiments were that 1) the ratio of fibroblasts to keratinocytes would critically influence keratinocyte colony expansion, 2) this ratio needed to be optimum at the beginning of the co-culture, 3) proliferative fibroblasts would be more effective than irradiated cells in expanding keratinocytes and 4) in the presence of an adequate number of fibroblasts, keratinocyte expansion would be independent of serum. Conclusions: A closely associated computational and biological approach is a powerful tool for understanding complex biological systems such as the interactions between keratinocytes and fibroblasts. The key outcome of this study is the finding that the early addition of a critical ratio of proliferative fibroblasts can give rapid keratinocyte expansion without the use of irradiated mouse fibroblasts and bovine serum

The contribution of genetic variants to disease depends on the ruler

Our understanding of the genetic basis of disease has evolved from descriptions of overall heritability or familiality to the identification of large numbers of risk loci. One can quantify the impact of such loci on disease using a plethora of measures, which can guide future research decisions. However, different measures can attribute varying degrees of importance to a variant. In this Analysis, we consider and contrast the most commonly used measures-specifically, the heritability of disease liability, approximate heritability, sibling recurrence risk, overall genetic variance using a logarithmic relative risk scale, the area under the receiver-operating curve for risk prediction and the population attributable fraction-and give guidelines for their use that should be explicitly considered when assessing the contribution of genetic variants to disease