INO80C Remodeler Maintains Genomic Stability by Preventing Promiscuous Transcription at Replication Origins

The proper coordination of transcription with DNA replication and repair is central for genomic stability. We investigate how the INO80C chromatin remodeling enzyme might coordinate these genomic processes. We find that INO80C co-localizes with the origin recognition complex (ORC) at yeast replication origins and is bound to replication initiation sites in mouse embryonic stem cells (mESCs). In yeast, INO80C recruitment requires origin sequences but does not require ORC, suggesting that recruitment is independent of pre-replication complex assembly. In both yeast and ESCs, INO80C co-localizes at origins with Mot1 and NC2 transcription factors, and genetic studies suggest that they function together to promote genome stability. Interestingly, nascent transcript sequencing demonstrates that INO80C and Mot1 prevent pervasive transcription through origin sequences, and absence of these factors leads to formation of new DNA double-strand breaks. We propose that INO80C and Mot1/NC2 function through distinct pathways to limit origin transcription, maintaining genomic stability

Existence Results for Solutions of Integral Boundary Value Problems on Time Scales

This paper deals with the existence of solutions for integral boundary value problems (IBVPs) on time scales. We provide sufficient conditions for the existence of solutions by using Schauder fixed point theorem in a cone. Existence result for this problem is also given by the method of upper and lower solutions

The PDGFRα-laminin B1-keratin 19 cascade drives tumor progression at the invasive front of human hepatocellular carcinoma

Human hepatocellular carcinomas (HCCs) expressing the biliary/hepatic progenitor cell marker keratin 19 (K19) have been linked with a poor prognosis and exhibit an increase in platelet-derived growth factor receptor a (PDGFR alpha) and laminin beta 1 (LAMB1) expression. PDGFR alpha has been reported to induce de novo synthesis of LAMB1 protein in a Sjogren syndrome antigen B (La/SSB)-dependent manner in a murine metastasis model. However, the role of this cascade in human HCC remains unclear. This study focused on the functional role of the PDGFR alpha-La/SSB-LAMB1 pathway and its molecular link to K19 expression in human HCC. In surgical HCC specimens from a cohort of 136 patients, PDGFR alpha expression correlated with K19 expression, microvascular invasion and metastatic spread. In addition, PDGFR alpha expression in pre-operative needle biopsy specimens predicted poor overall survival during a 5-year follow-up period. Consecutive histological staining demonstrated that the signaling components of the PDGFR alpha-La/SSB-LAMB1 pathway were strongly expressed at the invasive front. K19-positive HCC cells displayed high levels of alpha 2 beta 1 integrin (ITG) receptor, both in vitro and in vivo. In vitro activation of PDGFR alpha signaling triggered the translocation of nuclear La/SSB into the cytoplasm, enhanced the protein synthesis of LAMB1 by activating its internal ribosome entry site, which in turn led to increased secretion of laminin-111. This effect was abrogated by the PDGFR alpha-specific inhibitor crenolanib. Importantly LAMB1 stimulated ITG-dependent focal adhesion kinase/Src proto-oncogene non-receptor tyrosine kinase signaling. It also promoted the ITG-specific downstream target Rho-associated coiled-coil containing protein kinase 2, induced K19 expression in an autocrine manner, invadopodia formation and cell invasion. Finally, we showed that the knockdown of LAMB1 or K19 in subcutaneous xenograft mouse models resulted in significant loss of cells invading the surrounding stromal tissue and reduced HepG2 colonization into lung and liver after tail vein injection. The PDGFR alpha-LAMB1 pathway supports tumor progression at the invasive front of human HCC through K19 expression

The comparision of glybenclamide and metformin-loaded bacterial cellulose/gelatin nanofibres produced by a portable electrohydrodynamic gun for diabetic wound healing

Wound dressings made from natural polymers are an important aspect of biomaterials. Protein-based materials are less likely to instigate an immunogenic response and have the capacity to degrade in vivo, also without triggering an inflammatory response. Therefore, gelatin (GEL) was chosen and combined with bacterial cellulose (BC) to produce nanofibres and the potential of an all-natural polymer construct was determined. GEL and BC were successfully electrospun with metformin (Met) and glybenclamide (Gb) using a portable, point of need electrospinning set up. The virgin fibre group exhibited a significant effect on the proliferation of L929 (mouse fibroblast) cells but all fibre samples can safely be applied on wound site without risk of cytotoxicity. According to the results obtained by animal tests, the GEL-BC-Gb group showed better recovery than the GEL-BC-Met group. Diabetic wounds treated with GEL-BC-Met were characterized by moderate re-epithelialization and partially organized granulation tissue. Moderate to complete re-epithelialization and well-formed granulation tissue were observed in diabetic wounds treated with GEL-BC-Gb. The histologic scores obtained on day 14 confirmed that the GEL-BC-Gb group played a stronger wound-healing role compared to the GEL-BC-Met group. The highest decrease of TNF-α level was observed in the GEL-BC-Gb group at the end of the experiment but there is no significant difference between drug-loaded fibre groups. Therefore, topical administration of Met and Gb in a sustained release form has a high potential for diabetic wound healing with high bioavailability and fewer systemic side effects but Gb showed better improvement according to the results of the animal tests

Do Dogs (Canis lupus familiaris) Make Counterproductive Choices Because They Are Sensitive to Human Ostensive Cues?

Dogs appear to be sensitive to human ostensive communicative cues in a variety of situations, however there is still a measure of controversy as to the way in which these cues influence human-dog interactions. There is evidence for instance that dogs can be led into making evaluation errors in a quantity discrimination task, for example losing their preference for a larger food quantity if a human shows a preference for a smaller one, yet there is, so far, no explanation for this phenomenon. Using a modified version of this task, in the current study we investigated whether non-social, social or communicative cues (alone or in combination) cause dogs to go against their preference for the larger food quantity. Results show that dogs' evaluation errors are indeed caused by a social bias, but, somewhat contrary to previous studies, they highlight the potent effect of stimulus enhancement (handling the target) in influencing the dogs' response. A mild influence on the dog's behaviour was found only when different ostensive cues (and no handling of the target) were used in combination, suggesting their cumulative effect. The discussion addresses possible motives for discrepancies with previous studies suggesting that both the intentionality and the directionality of the action may be important in causing dogs' social biases

Evidence for Irradiation Triggered Nonuniform Defect Distribution In Multiharmonic Magnetic Susceptibility of Neutron Irradiated YBa2Cu3O7-x

Multiharmonic ac-magnetic susceptibility \ch11,\chi2,chi3, of neutron irradiated Li-doped YBa2Cu3O7-x has revealed a nonmonotonic dependence of all harmonics on the neutron fluence. The irradiation has a strongly depressive influence on the intergrain connection suggesting an increase of the effective thickness of the intergranular Josephson junction at aneutron fluence of 0.98x10$^{17}$ cm$_{-2}$. Less damaged are the intragrain properties. A spectacular enhancement of the superconducting intragranular properties reflected in the characteristics of all harmonics was observed at highest fluence \Phi = 9.98x10$^{17}$ cm$_{-2}$. We assume that this effect results from the development of a space inhomogeneous distribution with alternating defectless and defect rich regions.Comment: 24 pages, 9 figures, accepted to J. Supercon

International consensus on (ICON) anaphylaxis

ICON: Anaphylaxis provides a unique perspective on the principal evidence-based anaphylaxis guidelines developed and published independently from 2010 through 2014 by four allergy/immunology organizations. These guidelines concur with regard to the clinical features that indicate a likely diagnosis of anaphylaxis -- a life-threatening generalized or systemic allergic or hypersensitivity reaction. They also concur about prompt initial treatment with intramuscular injection of epinephrine (adrenaline) in the mid-outer thigh, positioning the patient supine (semi-reclining if dyspneic or vomiting), calling for help, and when indicated, providing supplemental oxygen, intravenous fluid resuscitation and cardiopulmonary resuscitation, along with concomitant monitoring of vital signs and oxygenation. Additionally, they concur that H1-antihistamines, H2-antihistamines, and glucocorticoids are not initial medications of choice. For self-management of patients at risk of anaphylaxis in community settings, they recommend carrying epinephrine auto-injectors and personalized emergency action plans, as well as follow-up with a physician (ideally an allergy/immunology specialist) to help prevent anaphylaxis recurrences. ICON: Anaphylaxis describes unmet needs in anaphylaxis, noting that although epinephrine in 1 mg/mL ampules is available worldwide, other essentials, including supplemental oxygen, intravenous fluid resuscitation, and epinephrine auto-injectors are not universally available. ICON: Anaphylaxis proposes a comprehensive international research agenda that calls for additional prospective studies of anaphylaxis epidemiology, patient risk factors and co-factors, triggers, clinical criteria for diagnosis, randomized controlled trials of therapeutic interventions, and measures to prevent anaphylaxis recurrences. It also calls for facilitation of global collaborations in anaphylaxis research. In addition to confirming the alignment of major anaphylaxis guidelines, ICON: Anaphylaxis adds value by including summary tables and citing 130 key references. It is published as an information resource about anaphylaxis for worldwide use by healthcare professionals, academics, policy-makers, patients, caregivers, and the public

Textiloma: a case of foreign body mimicking a spinal mass

Items such as cotton or gauze pads can be mistakenly left behind during operations. Such foreign materials (called textilomas or gossypibomas) cause foreign body reaction in the surrounding tissue. The complications caused by these foreign bodies are well known, but cases are rarely published because of medico-legal implications. Some textilomas cause infection or abscess formation in the early stage, whereas others remain clinically silent for many years. Here, we describe a case of textiloma in which the patient presented with low-back pain 4 years after lumbar discectomy. Imaging revealed an abcess-like mass in the lumbar epidural space

Familiarity bias and physiological responses in contagious yawning by dogs support link to empathy

In humans, the susceptibility to yawn contagion has been theoretically and empirically related to our capacity for empathy. Because of its relevance to evolutionary biology, this phenomenon has been the focus of recent investigations in nonhuman species. In line with the empathic hypothesis, contagious yawning has been shown to correlate with the level of social attachment in several primate species. Domestic dogs (Canis familiaris) have also shown the ability to yawn contagiously. To date, however, the social modulation of dog contagious yawning has received contradictory support and alternative explanations (i.e., yawn as a mild distress response) could explain positive evidence. The present study aims to replicate contagious yawning in dogs and to discriminate between the two possible mediating mechanisms (i.e., empathic vs. distress related response). Twenty-five dogs observed familiar (dog’s owner) and unfamiliar human models (experimenter) acting out a yawn or control mouth movements. Concurrent physiological measures (heart rate) were additionally monitored for twenty-one of the subjects. The occurrence of yawn contagion was significantly higher during the yawning condition than during the control mouth movements. Furthermore, the dogs yawned more frequently when watching the familiar model than the unfamiliar one demonstrating that the contagiousness of yawning in dogs correlated with the level of emotional proximity. Moreover, subjects’ heart rate did not differ among conditions suggesting that the phenomenon of contagious yawning in dogs is unrelated to stressful events. Our findings are consistent with the view that contagious yawning is modulated by affective components of the behavior and may indicate that rudimentary forms of empathy could be present in domesticated dogs