One-dimensional semiconductor in a polar solvent: Solvation and low-frequency dynamics of an excess charge carrier

Due to solvation, excess charge carriers on 1d semiconductor nanostructures immersed in polar solvents undergo self-localization into polaronic states. Using a simplified theoretical model for small-diameter structures, we study low-frequency properties of resulting 1d adiabatic polarons. The combined microscopic dynamics of the electronic charge density and the solvent leads to macroscopic Langevin dynamics of a polaron and to the appearance of local dielectric relaxation modes. Polaron mobility is evaluated as a function of system parameters. Numerical estimates indicate that the solvated carriers can have mobilities orders of magnitude lower than the intrinsic values.Comment: Typo in Eq.(12) has been correcte

Year-round shellfish exploitation in the Levant and implications for Upper Palaeolithic hunter-gatherer subsistence

Recent studies have shown that the use of aquatic resources has greater antiquity in hominin diets than pre- viously thought. At present, it is unclear when hominins started to habitually consume marine resources. This study examines shellfish exploitation from a behavioural ecology perspective, addressing how and when past hunter-gatherers from the Levant used coastal resources for subsistence purposes. We investigate the seasonality of shellfish exploitation in the Levantine Upper Palaeolithic through oxygen isotope analysis on shells of the intertidal rocky shore mollusc Phorcus (Osilinus) turbinatus from the key site Ksâr ‘Akil (Lebanon). At this rockshelter, multi-layered archaeological deposits contained remains of both marine and terrestrial molluscs in relatively large quantities, which were consumed and used as tools and ornaments by the occupants of the site. Our results indicate that at the start of the Initial Upper Palaeolithic (IUP), there is no evidence for shellfish consumption. Humans started to take fresh shellfish to the rockshelter from the second half of the IUP onward, albeit in low quantities. During the Early Upper Palaeolithic (EUP) shellfish exploitation became increasingly frequent. Oxygen isotope data show that shellfish exploitation was practised in every season throughout most of the Upper Palaeolithic (UP), with an emphasis on the colder months. This suggests that coastal resources had a central role in early UP foraging strategies, rather than a seasonally restricted supplementary one. Year-round shellfish gathering, in turn, suggests that humans occupied the rockshelter at different times of the year, al- though not necessarily continuously. Our oxygen isotope data is complemented with broader-scale exploitation patterns of faunal resources, both vertebrate and invertebrate, at the site. The inclusion of coastal marine re- sources signifies a diversification of the human diet from the EUP onward, which is also observed in foraging practices linked to the exploitation of terrestrial fauna.H2020 Marie Skłodowska-Curie fellowship “EU-BEADS”, project number: 656325 and the Max Planck Society

Decreased expression of miR-146a and miR-155 contributes to an abnormal Treg phenotype in patients with rheumatoid arthritis

Objectives: MicroRNAs (miRNAs) have been implicated in the pathogenesis of autoimmune diseases, not least for their critical role in the regulation of regulatory T cell (Treg) function. Deregulated expression of miR-146a and miR-155 has been associated with rheumatoid arthritis (RA). We therefore investigated miR-146a and miR-155 expression in Tregs of patients with RA and their possible impact on Treg function and disease activity. Methods: Expression of miR-146a and miR-155 was assessed in RA patients and controls. MiRNA expression was correlated with disease activity and expression of target genes. Interference with biological activity of miRNAs was evaluated in functional Treg assays. Results: Diminished upregulation of miR-146a and miR-155 in response to T cell stimulation was found in Tregs of RA patients. Diminution of miR-146a expression was observed in particular in patients with active disease, and correlated with joint inflammation. In patients with active RA, Tregs demonstrated a pro-inflammatory phenotype characterised by inflammatory cytokine expression. This was due to an augmented expression and activation of signal transducer and activator transcription 1 (STAT1), a direct target of miR-146a. Conclusions: Our results suggest that in RA miR-146a facilitates a pro-inflammatory phenotype of Tregs via increased STAT1 activation, and contributes thereby to RA pathogenesis

Chemotherapy in patients with unresected pancreatic cancer in Australia: A population-based study of uptake and survival

1 Aim Palliative chemotherapy improves symptom control and prolongs survival in patients with unresectable pancreatic cancer, but there is a paucity of data describing its use and effectiveness in everyday practice. We explored patterns of chemotherapy use in patients with unresected pancreatic cancer in Australia and the impact of use on survival. 2 Methods We reviewed the medical records of residents of New South Wales or Queensland, Australia, diagnosed with unresectable pancreatic adenocarcinoma between July 2009 and June 2011. Associations between receipt of chemotherapy and sociodemographic, clinical and health service factors were evaluated using logistic regression. We used Cox proportional hazards models to analyze associations between chemotherapy use and survival. 3 Results Data were collected for 1173 eligible patients. Chemotherapy was received by 44% (n = 184/414) of patients with localized pancreatic cancer and 53% (n = 406/759) of patients with metastases. Chemotherapy receipt depended on clinical factors, such as performance status and comorbidity burden, and nonclinical factors, such as age, place of residence, multidisciplinary team review and the type of specialist first encountered. Consultation with an oncologist mitigated most of the sociodemographic and service‐related disparities in chemotherapy use. The receipt of chemotherapy was associated with prolonged survival in patients with inoperable pancreatic cancer, including after adjusting for common prognostic factors. 4 Conclusions These findings highlight the need to establish referral pathways to ensure that all patients have the opportunity to discuss treatment options with a medical oncologist. This is particularly relevant for health care systems covering areas with a geographically dispersed population

Advertising in Medical Journals: Should Current Practices Change?

Fugh-Berman and colleagues surveyed medical journals' policies and practices on advertising. Pharmaceutical products, they say, dominate journals' advertising pages, creating conflicts of interests

Biallelic variants in ADARB1, encoding a dsRNA-specific adenosine deaminase, cause a severe developmental and epileptic encephalopathy

Background: Adenosine-to-inosine RNA editing is a co-transcriptional/post-transcriptional modification of double-stranded RNA, catalysed by one of two active adenosine deaminases acting on RNA (ADARs), ADAR1 and ADAR2. ADARB1 encodes the enzyme ADAR2 that is highly expressed in the brain and essential to modulate the function of glutamate and serotonin receptors. Impaired ADAR2 editing causes early onset progressive epilepsy and premature death in mice. In humans, ADAR2 dysfunction has been very recently linked to a neurodevelopmental disorder with microcephaly and epilepsy in four unrelated subjects. / Methods: We studied three children from two consanguineous families with severe developmental and epileptic encephalopathy (DEE) through detailed physical and instrumental examinations. Exome sequencing (ES) was used to identify ADARB1 mutations as the underlying genetic cause and in vitro assays with transiently transfected cells were performed to ascertain the impact on ADAR2 enzymatic activity and splicing. / Results: All patients showed global developmental delay, intractable early infantile-onset seizures, microcephaly, severe-to-profound intellectual disability, axial hypotonia and progressive appendicular spasticity. ES revealed the novel missense c.1889G>A, p.(Arg630Gln) and deletion c.1245_1247+1 del, p.(Leu415PhefsTer14) variants in ADARB1 (NM_015833.4). The p.(Leu415PhefsTer14) variant leads to incorrect splicing resulting in frameshift with a premature stop codon and loss of enzyme function. In vitro RNA editing assays showed that the p.(Arg630Gln) variant resulted in a severe impairment of ADAR2 enzymatic activity. / Conclusion: In conclusion, these data support the pathogenic role of biallelic ADARB1 variants as the cause of a distinctive form of DEE, reinforcing the importance of RNA editing in brain function and development

Biallelic variants in ADARB1, encoding a dsRNA-specific adenosine deaminase, cause a severe developmental and epileptic encephalopathy.

BACKGROUND: Adenosine-to-inosine RNA editing is a co-transcriptional/post-transcriptional modification of double-stranded RNA, catalysed by one of two active adenosine deaminases acting on RNA (ADARs), ADAR1 and ADAR2. ADARB1 encodes the enzyme ADAR2 that is highly expressed in the brain and essential to modulate the function of glutamate and serotonin receptors. Impaired ADAR2 editing causes early onset progressive epilepsy and premature death in mice. In humans, ADAR2 dysfunction has been very recently linked to a neurodevelopmental disorder with microcephaly and epilepsy in four unrelated subjects. METHODS: We studied three children from two consanguineous families with severe developmental and epileptic encephalopathy (DEE) through detailed physical and instrumental examinations. Exome sequencing (ES) was used to identify ADARB1 mutations as the underlying genetic cause and in vitro assays with transiently transfected cells were performed to ascertain the impact on ADAR2 enzymatic activity and splicing. RESULTS: All patients showed global developmental delay, intractable early infantile-onset seizures, microcephaly, severe-to-profound intellectual disability, axial hypotonia and progressive appendicular spasticity. ES revealed the novel missense c.1889G>A, p.(Arg630Gln) and deletion c.1245_1247+1 del, p.(Leu415PhefsTer14) variants in ADARB1 (NM_015833.4). The p.(Leu415PhefsTer14) variant leads to incorrect splicing resulting in frameshift with a premature stop codon and loss of enzyme function. In vitro RNA editing assays showed that the p.(Arg630Gln) variant resulted in a severe impairment of ADAR2 enzymatic activity. CONCLUSION: In conclusion, these data support the pathogenic role of biallelic ADARB1 variants as the cause of a distinctive form of DEE, reinforcing the importance of RNA editing in brain function and development

Lentiviral Vector Delivery of Human Interleukin-7 (hIL-7) to Human Immune System (HIS) Mice Expands T Lymphocyte Populations

Genetically modified mice carrying engrafted human tissues provide useful models to study human cell biology in physiologically relevant contexts. However, there remain several obstacles limiting the compatibility of human cells within their mouse hosts. Among these is inadequate cross-reactvitiy between certain mouse cytokines and human cellular receptors, depriving the graft of important survival and growth signals. To circumvent this problem, we utilized a lentivirus-based delivery system to express physiologically relevant levels of human interleukin-7 (hIL-7) in Rag2-/-γc-/- mice following a single intravenous injection. hIL-7 promoted homeostatic proliferation of both adoptively transferred and endogenously generated T-cells in Rag2-/-γc-/- Human Immune System (HIS) mice. Interestingly, we found that hIL-7 increased T lymphocyte numbers in the spleens of HIV infected HIS mice without affecting viral load. Taken together, our study unveils a versatile approach to deliver human cytokines to HIS mice, to both improve engraftment and determine the impact of cytokines on human diseases

Re-evaluating early breast neoplasia

Historically, histomorphological and epidemiological data suggested that atypical ductal hyperplasia and ductal carcinoma in situ are the earliest recognizable neoplastic stages of breast cancer progression. Over the past several years, detailed high-throughput molecular genetic, gene expression and epigenetic analyses have enhanced our understanding of these early neoplastic lesions and have re-shaped our view of human breast cancer progression to include multiple distinct pathways of evolution