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The Vârghiș Gorges karst system (Perșani Mountains, Eastern Carpathians) constituted a point of interest for speleologists, paleontologists and archaeologists since the second half of the 19th century. Their efforts succeeded in highlighting the notable archaeological potential of the area, although the actual research results were not always thoroughly reported. Since 2014, our team reunited specialists from 10 different institutions and various fields of research and initiated archaeological excavations, coupled with achaeozoological, sedimentological and chronometric investigations, in several caves within the Vârghiș Gorges. As the paper below will show, although the results obtained so far are definitively informative, further investigation are clearly needed, in order to accurately clarify aspects pertaining to the intricate cultural and chronological framework.

Introduction. Studies regarding antibiotics administration during pregnancy and atopic dermatitis (AD) in children are only few. In this context, the objective of our study was to investigate the potential association between the timing of intrauterine exposure to antibiotics or prenatal antibiotic administration in general and AD occurrence in children.

Objective: Non-Hodgkin's lymphomas (NHL) are malignant tumors that develop from lymphoid tissue. They are one of the most common malignancies and they represent one of the most complicated problems of oncohematology. The age group that is mostly affected by NHL in the Republic of Moldova is the patients over 60 years, and the disorder in most cases starts in lymph nodes. This study aims to determine the particularities of elderly patients with NHL with primary involvement of peripheral lymph nodes(l/n). Methodology: A retrospective study of a group of 78 NHL patients with primary lymph node involvement was performed. The average age of study participants ranged from 60 to 84 years. Results: NHL more often developed primarily in the peripheral l/n (84.7%), less frequently in the mediastinal l/n (6.4%) and abdominal l/n(8.9%). Aggressive NHL predominated (59.0%), but indolent NHL also developed quite frequently (41.0%), which were more frequent in cases of primary affection to the cervical l/n (47.4%), inguinal l/n(41.7%), and abdominal l/n(42.9%). The 5-year survival of NHL patients with primary lymph node involvement aged over 60 years was low and amounted to 31.2%; Conclusion: NHL occurred more often in the peripheral lymph nodes (84.7%), less frequently in the mediastinum (6.4%), and abdominal lymph nodes (8.9%). The frequency of aggressive NHL was 59.0%. Indolent NHL was diagnosed in 41% of cases. The 5-year survival rate in the study group constitutes 31,2%, lower compared with younger patients treated in the same center.

The revolution of minimally invasive techniques from the last two decades lead to minimally invasive aortic valve replacement. Minimal "J" shaped sternotomy extended in to the 4 intercostal space provides good access to the aortic root and the possibility to connect the patient to the extracorporeal circulation machine without the use of new instruments. We present a 69-year-old patient that presents in to our clinic with degenerative aortic valve disease with severe stenosis and mild regurgitation. Minimally invasive aortic valve replacement was performed with success in our clinic, being a safe and efficient procedure. This technique could become the standard procedure for isolated aortic valve replacement, with substantial benefits regarding respiratory function. [ABSTRACT FROM AUTHOR]

Multiple strategies for tandem severe carotid artery stenosis are reported: bilateral carotid artery endarterectomy (CEA), bilateral carotid artery stenting (CAS), and hybrid procedures (CEA and CAS). The management is controversial, considering the reported high risk of periprocedural stroke, hemodynamic distress, and cerebral hyperperfusion syndrome. We present the case of a 64-year-old patient with severe symptomatic bilateral internal carotid artery stenosis (95% stenosis on the left internal carotid artery with recent ipsilateral watershed anterior cerebral artery-medial cerebral artery (ACA-MCA) and medial cerebral artery-posterior cerebral artery (MCA-PCA) ischemic strokes and 90% stenosis on the right internal carotid artery with chronic ipsilateral frontal ischemic stroke) managed successfully with staged CEA within a 3-day interval. The patient had a history of coronary angioplasty and stenting. Strategies for brain protection included shunt placement after the evaluation of carotid stump pressure, internal carotid backflow, and near-infrared spectroscopy. A collagen and silver-coated polyester patch was used to complete the endarterectomy using a 6.0 polypropylene continuous suture in both instances. Management also included neurological consults after extubation, dual antiplatelet therapy, head CT between the two surgeries, myocardial ischemia monitoring, and general anesthesia. Staged CEA with a small time interval between surgeries can be an option to treat tandem symptomatic carotid artery stenosis in highly selected patients. The decision should be tailored according to the patient's characteristics and should also be made by a cardiology specialist, a neurology specialist, and an anesthesia and intensive care physician., Competing Interests: The authors declare no conflicts of interest.

Introduction: Reconstruction surgery of the proximal aorta in most cases involves the use of an aortic conduit, followed by reimplantation of the coronary ostia. Although uncommon, the origin of the coronary arteries in certain anatomical variants poses additional difficulties when performing surgery on the aortic root and requires a different treatment rationale. Case report: We hereby present the case of a 60-year-old patient with multiple cardiovascular risk factors (smoking, arterial hypertension and dyslipidemia), suffering from severe degenerative stenosis of a bicuspid aortic valve, associated with ascending aorta aneurysm and a significant extrinsic stenosis of the left coronary artery caused by the aneurysm. The patient presented with severe degenerative bicuspid aortic valve stenosis associated with ascending aorta aneurysm and a significant extrinsic stenosis of the left coronary artery caused by the aneurysm. Following the preoperative assessment, it was decided that the best course of action was to perform surgery on the aortic valve and ascending aorta. During the surgery, the origin of the right and left coronary ostia were found at the level of the left coronary cusp, both forming a common coronary button. Due to this particular anatomical variant, it was decided to reimplant them as a common button onto the main conduit by means of an interposed No.10 PTFE (Polytetrafluoroethylene) vascular prosthesis. Conclusion: A rare case of aortic root surgery associated with coronary ostia origin variant "shotgun barrel", which required a different method of reimplantation: modified Cabrol technique., (Celsius.)

The surgical management of aortic coarctation in newborns needs to ensure postoperative evolution and long-term results as much as possible. Patients with a Gothic arch have a higher rate of postoperative hypertension, while newborns with a bovine arch have higher rates of restenosis and, thus, an additional risk of mortality. Late hypertension, even in anatomically successfully repaired patients, confers a high risk for cardiovascular events. This review of the literature focuses on the management of aortic coarctations associated with hypoplastic arch and particular arch anatomies, focusing on surgical techniques and their outcomes.

Secondary aortoesophageal fistula (AEF) is defined as a communication between the aorta and the esophagus, occurring after aortic disease treatment or esophageal procedures, associating very high mortality rates with treatment and being fatal without it. Several treatment strategies have been described in the literature, combining open surgery or endovascular aortic repair with surgical or endoscopic management of the esophageal lesion. We present the case of a 53-year-old patient with a history of open aortic surgery for a giant descending thoracic aortic pseudoaneurysm complicated with secondary AEF, successfully managed using emergency transiliac TEVAR (thoracic endovascular aortic repair), extensive antibiotic therapy associated with nutritional replenishment, and rehabilitation therapy. Novel endovascular and endoscopic devices have been developed, offering less invasive treatment strategies with improved outcomes, especially for high risk surgical patients. This case highlights the importance of a multidisciplinary approach to personalized medicine to manage such complex situations.

Aberrant right subclavian artery (ARSA) causing dysphagia, the so-called "dysphagia lusoria", is a frequent embryologic anomaly of the aortic arch. In symptomatic patients, studies report several management options including surgical, hybrid, and totally endovascular strategies. Hybrid techniques have the advantage of no chest opening with reduced morbidity, but the problem of the ARSA stump causing recurrent or persistent dysphagia remains challenging in some cases. We conducted a literature review on the management strategies of ARSA and presented the case of a 72-year-old female patient with ARSA and dysphagia managed with thoracic endovascular repair of the aorta (TEVAR) and bilateral carotid-subclavian artery bypass. This technique was chosen because of the severe calcifications at the level of ARSA origin that would make surgical ligation difficult, or if an occluder device not suitable. We think that a patient-tailored approach should be considered in cases of dysphagia lusoria, considering that a multitude of strategies are reported.

Background and objectives: The relationship between cerebral perfusion and new postoperative ischemic stroke in obese patients is not well defined. The aim of this study was to investigate the association between selective bilateral anterograde cerebral perfusion and new postoperative ischemic stroke in obese patients with emergency surgery for acute type A aortic dissection. Materials and methods: A total of 292 patients with emergency surgery for acute type A aortic dissection were included in this study. Patients with hemorrhagic stroke or ischemic stroke with severe neurological dysfunction at admission that were not candidates for surgery; patients who died in the first 48 h after intensive care admission and patients with incomplete medical records were excluded. Results: The mean age was 59.42 ± 10.68 years and the mean Euroscore was 9.12 ± 1.63. Obesity was present in 76.4%, the incidence of new postoperative ischemic stroke was 27.5%, and the postoperative mortality rate was 26.7%. The mean cardiopulmonary bypass time was 206.81 ± 75.48 min, the aortic cross-clamp time was 118.2 ± 46.42 min, and 90% of cases required cerebral perfusion. The mean cerebral perfusion time was 30.8 ± 24.41 min. Obese patients had a higher frequency of in-hospital death ( p = 0.009), smoking ( p = 0.036), hypertension ( p = 0.023), left common carotid artery dissection ( p < 0.001), right common carotid artery dissection ( p = 0.029), femoral artery cannulation ( p = 0.026), aortic root replacement ( p = 0.009), aortic valve replacement ( p = 0.005) and early reintervention for bleeding ( p = 0.004). Using logistic regression, selective bilateral anterograde cerebral perfusion over 40 min in obese patients was independently associated with new postoperative ischemic stroke (OR = 2.35; 95%CI = 1.36-4.86; p = 0.021). Conclusions: A patient-tailored strategy for cerebral perfusion should be considered in obese patients, considering the high atheromatous burden of the supra-aortic vessels in these patients and the potential risk of atheromatous embolization associated with this technique.

Paleo-archives are essential for our understanding of species responses to climate warming, yet such archives are extremely rare in the Arctic. Here, we combine morphological analyses and bulk-bone metabarcoding to investigate a unique chronology of bone deposits sealed in the high-latitude Storsteinhola cave system (68°50' N 16°22' E) in Norway. This deposit dates to a period of climate warming from the end of the Late Glacial [~13 thousand calibrated years before the present (ka cal B.P.)] to the Holocene thermal maximum (~5.6 ka cal B.P.). Paleogenetic analyses allow us to exploit the 1000s of morphologically unidentifiable bone fragments resulting in a high-resolution sequence with 40 different taxa, including species not previously found here. Our record reveals borealization in both the marine and terrestrial environments above the Arctic Circle as a naturally recurring phenomenon in past periods of warming, providing fundamental insights into the ecosystem-wide responses that are ongoing today.

Background and Objectives : Postoperative neurological complications (NCs) are an important cause of mortality in patients with acute type A aortic dissection (ATAAD). The aim of the study was to determine the association between intraoperative risk factors and newly developed postoperative NCs in patients after emergency surgery for ATAAD. Materials and Methods : A total of 203 patients requiring emergency surgery were included in the study. Patients with preoperative neurological dysfunction, deceased on the operating table or within the first 48 h after intensive care admission, with uncertain postoperative neurologic status or with incomplete records were excluded. Results : Mean age was 57.61 ± 12.27 years. Hyperlipidemia was the most frequent comorbidity (69%). A bicuspid aortic valve was present in 12.8% of cases, severe acute aortic regurgitation was present in 29.1% of patients, and cardiac tamponade was present in 27.1% of cases. The innominate artery was the most frequently dissected supra-aortic artery in 27.1% of cases. In 65% of cases, the primary entry tear was at the level of the ascending aorta. The incidence of newly developed postoperative NCs was 39.4%. The most common surgical technique performed was supra-coronary ascending aorta and hemiarch replacement, in 53.2% of patients. Using logistic regression, cardiopulmonary bypass time (OR = 1.01; 95% CI = 1.01-1.02; p < 0.001), aortic cross-clamp time over 3 h (OR = 2.71, 95% CI = 1.43-5.14, p = 0.002) and cerebral perfusion time (OR = 1.02; 95% CI = 1.002-1.03; p = 0.027) were independently associated with newly developed postoperative NCs. Conclusions : Based on the results of the study, all efforts should be made to reduce operative times. Using a simple surgical technique, like the supra-coronary ascending aorta and hemiarch technique, whenever possible, and using a simpler technique for cerebral perfusion like unilateral cerebral perfusion via the right axillary artery, could reduce operating times.

Background: Coronary artery bypass grafting has evolved from all venous grafts to bilateral mammary artery (BIMA) grafting. This was possible due to the long-term patency of the left and right internal mammary demonstrated in angiography studies compared to venous grafts. However, despite higher survival rates when using bilateral mammary arteries, multiple studies report a higher rate of surgical site infections, most notably deep sternal wound infections, a so-called "never event"., Methods: We designed a prospective study between 1 January 2022 and 31 December 2022 and included all patients proposed for total arterial myocardial revascularization in order to investigate the rate of surgical site infections (SSI). Chest closure in all patients was performed using a three-step protocol. The first step refers to sternal closure. If the patient's BMI is below 35 kg/m 2 , sternal closure is achieved using the "butterfly" technique with standard steel wires. If the patient's BMI exceeds 35 kg/m 2 , we use nitinol clips or hybrid wire cable ties according to the surgeon's preference for sternal closure. The main advantages of these systems are a larger implant-to-bone contact with a reduced risk of bone fracture. The second step refers to presternal fat closure with two resorbable monofilament sutures in a way that the edges of the skin perfectly align at the end. The third step is skin closure combined with negative pressure wound therapy., Results: This system was applied to 217 patients. A total of 197 patients had bilateral mammary artery grafts. We report only 13 (5.9%) superficial SSI and only one (0.46%) deep SSI. The preoperative risk of major wound infection was 3.9 +/- 2.7. Bilateral mammary artery grafting was not associated with surgical site infection in a univariate analysis., Conclusions: We believe this strategy of sternal wound closure can reduce the incidence of deep surgical site infection when two mammary arteries are used in coronary artery bypass surgery.

Next generation sequencing (NGS) is a technology that broadens the horizon of knowledge of several somatic pathologies, especially in oncological and oncohematological pathology. In the case of NHL, the understanding of the mechanisms of tumorigenesis, tumor proliferation and the identification of genetic markers specific to different lymphoma subtypes led to more accurate classification and diagnosis. Similarly, the data obtained through NGS allowed the identification of recurrent somatic mutations that can serve as therapeutic targets that can be inhibited and thus reducing the rate of resistant cases. The article's purpose is to offer a comprehensive overview of the best ways of integrating of next-generation sequencing technologies for diagnosis, prognosis, classification, and selection of optimal therapy from the perspective of tailor-made medicine., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tomacinschii, Mosquera Orgueira, Santos, Robu, Buruiana and Fraga Rodriguez.)

Acute type A aortic dissection (ATAAD) is a surgical emergency with a mortality of 1-2% per hour. Since its discovery over 200 years ago, surgical techniques for repairing a dissected aorta have evolved, and with the introduction of hypothermic circulatory arrest and cerebral perfusion, complex techniques for replacing the entire aortic arch were possible. However, postoperative neurological complications contribute significantly to mortality in this group of patients. The aim of this study was to determine the association between different bilateral selective antegrade cerebral perfusion (ACP) times and the incidence of postoperative ischemic stroke in patients with emergency surgery for ATAAD. Patients with documented hemorrhagic or ischemic stroke, clinical signs of stroke or neurological dysfunction prior to surgery, that died on the operating table or within 48 h after surgery, from whom the postoperative neurological status could not be assessed, and with incomplete medical records were excluded from this study. The diagnosis of postoperative stroke was made using head computed tomography imaging (CT) when clinical suspicion was raised by a neurologist in the immediate postoperative period. For selective bilateral antegrade cerebral perfusion, we used two balloon-tipped cannulas inserted under direct vision into the innominate artery and the left common carotid artery. Each cannula is connected to a separate pump with an independent pressure line. Near-infrared spectroscopy was used in all cases for cerebral oxygenation monitoring. The circulatory arrest was initiated after reaching a target core temperature of 25-28 °C. In total, 129 patients were included in this study. The incidence of postoperative ischemic stroke documented on a head CT was 24.8% (31 patients), and postoperative death was 20.9% (27 patients). The most common surgical technique performed was supravalvular ascending aorta and Hemiarch replacement with a Dacron graft in 69.8% (90 patients). The mean cardiopulmonary bypass time was 210 +/- 56.874 min, the mean aortic cross-clamp time was 114.775 +/- 34.602 min, and the mean cerebral perfusion time was 37.837 +/- 18.243 min. Using logistic regression, selective ACP of more than 40 min was independently associated with postoperative ischemic stroke (OR = 3.589; 95%CI = 1.418-9.085; p = 0.007). Considering the high incidence of postoperative stroke in our study population, we concluded that bilateral selective ACP should be used with caution, especially in patients with severely calcified ascending aorta and/or aortic arch and supra-aortic vessels. All efforts should be made to minimize the duration of circulatory arrest when using bilateral selective ACP with a target of less than 30 min, in hypothermia, at a body temperature of 25-28 °C.

Context-aware decision support in the operating room can foster surgical safety and efficiency by leveraging real-time feedback from surgical workflow analysis. Most existing works recognize surgical activities at a coarse-grained level, such as phases, steps or events, leaving out fine-grained interaction details about the surgical activity; yet those are needed for more helpful AI assistance in the operating room. Recognizing surgical actions as triplets of ‹instrument, verb, target› combination delivers more comprehensive details about the activities taking place in surgical videos. This paper presents CholecTriplet2021: an endoscopic vision challenge organized at MICCAI 2021 for the recognition of surgical action triplets in laparoscopic videos. The challenge granted private access to the large-scale CholecT50 dataset, which is annotated with action triplet information. In this paper, we present the challenge setup and the assessment of the state-of-the-art deep learning methods proposed by the participants during the challenge. A total of 4 baseline methods from the challenge organizers and 19 new deep learning algorithms from the competing teams are presented to recognize surgical action triplets directly from surgical videos, achieving mean average precision (mAP) ranging from 4.2% to 38.1%. This study also analyzes the significance of the results obtained by the presented approaches, performs a thorough methodological comparison between them, in-depth result analysis, and proposes a novel ensemble method for enhanced recognition. Our analysis shows that surgical workflow analysis is not yet solved, and also highlights interesting directions for future research on fine-grained surgical activity recognition which is of utmost importance for the development of AI in surgery., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

The ubiquitin-proteasome axis has been extensively explored at a system-wide level, but the impact of deubiquitinating enzymes (DUBs) on the ubiquitinome remains largely unknown. Here, we compare the contributions of the proteasome and DUBs on the global ubiquitinome, using UbiSite technology, inhibitors and mass spectrometry. We uncover large dynamic ubiquitin signalling networks with substrates and sites preferentially regulated by DUBs or by the proteasome, highlighting the role of DUBs in degradation-independent ubiquitination. DUBs regulate substrates via at least 40,000 unique sites. Regulated networks of ubiquitin substrates are involved in autophagy, apoptosis, genome integrity, telomere integrity, cell cycle progression, mitochondrial function, vesicle transport, signal transduction, transcription, pre-mRNA splicing and many other cellular processes. Moreover, we show that ubiquitin conjugated to SUMO2/3 forms a strong proteasomal degradation signal. Interestingly, PARP1 is hyper-ubiquitinated in response to DUB inhibition, which increases its enzymatic activity. Our study uncovers key regulatory roles of DUBs and provides a resource of endogenous ubiquitination sites to aid the analysis of substrate specific ubiquitin signalling., (© 2022. The Author(s).)

Purpose: Surgical workflow estimation techniques aim to divide a surgical video into temporal segments based on predefined surgical actions or objectives, which can be of different granularity such as steps or phases. Potential applications range from real-time intra-operative feedback to automatic post-operative reports and analysis. A common approach in the literature for performing automatic surgical phase estimation is to decouple the problem into two stages: feature extraction from a single frame and temporal feature fusion. This approach is performed in two stages due to computational restrictions when processing large spatio-temporal sequences., Methods: The majority of existing works focus on pushing the performance solely through temporal model development. Differently, we follow a data-centric approach and propose a training pipeline that enables models to maximise the usage of existing datasets, which are generally used in isolation. Specifically, we use dense phase annotations available in Cholec80, and sparse scene (i.e., instrument and anatomy) segmentation annotation available in CholecSeg8k in less than 5% of the overlapping frames. We propose a simple multi-task encoder that effectively fuses both streams, when available, based on their importance and jointly optimise them for performing accurate phase prediction., Results and Conclusion: We show that with a small fraction of scene segmentation annotations, a relatively simple model can obtain comparable results than previous state-of-the-art and more complex architectures when evaluated in similar settings. We hope that this data-centric approach can encourage new research directions where data, and how to use it, plays an important role along with model development., (© 2022. The Author(s).)

Background and objective Myxomas are the most common cardiac tumors. This study aimed to analyze the possible risk factors associated with late mortality in this group of patients and assess long-term survival. Methods A retrospective study was conducted among patients who underwent myxomas resection between January 2008 and July 2019 in our service. The patients' preoperative, intraoperative, and postoperative data were analyzed. Multivariate logistic regression was performed to identify predictors of mortality at five years. The Kaplan-Meier curve and Cox proportion-adjusted survival curves were used to assess mortality at five and 10 years. Results A total of 108 patients with cardiac myxomas were identified. All cardiac tumors resected were confirmed as myxomas on histopathological examination. Ninety-six patients presented with left-side myxomas (94 left-atria and two left-ventricle) and 12 with right-side myxomas (11 right-atria, one right-ventricle); 78 of the tumors were capsulated, and 30 were sessile-papillary. The mean dimensions were 37 ±6.1 mm on the left side and 41 ±6.7 mm on the right side. Surgical excision was successful in all cases, with 25% requiring interatrial septum patch repair. Recurrence occurred in 2.77% of the patients. Multivariate logistic regression showed chronic kidney disease (CKD) (OR: 7.96, 95% CI: 1.469-43.125, p=0,016) to be an independent predictor for five-year mortality. The mean follow-up period was 7.13 ±2.965 years, and the Kaplan-Meier curve cumulative proportion survival of patients at five years and 10 years were 100% and 88.8%, respectively. There was no statistically significant difference in late-term survival between patients with and without CKD in the Cox proportion-adjusted survival curve (p=0.275). Conclusions Patients with myxomas have a good long-term prognosis following surgical resection. The multivariate logistic regression showed CKD to be an independent predictor of five-year mortality., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Tulin et al.)

Nucleotide excision repair (NER) is the most versatile DNA repair pathway that removes a wide variety of DNA lesions caused by different types of physical and chemical agents, such as ultraviolet radiation (UV), environmental carcinogen benzo[a]pyrene and anti-cancer drug carboplatin. The mammalian NER utilizes more than 30 proteins, in a multi-step process that begins with the lesion recognition within seconds of DNA damage to completion of repair after few hours to several days. The core proteins and their biochemical reactions are known from in vitro DNA repair assays using purified proteins, but challenge was to understand the dynamics of their rapid recruitment and departure from the lesion site and their coordination with other proteins and post-translational modifications to execute the sequential steps of repair. Here, we provide a brief overview of various techniques developed by different groups over last 20 years to overcome these challenges. However, more work is needed for a comprehensive knowledge of all aspects of mammalian NER. With this aim, here we provide detailed protocols of three simple yet innovative methods developed by many teams that range from local UVC irradiation to in situ extraction and sub-cellular fractionation that will permit study of endogenous as well as exogenous NER proteins in any cellular model. These methods do not require unique reagents or specialized instruments, and will allow many more laboratories to explore this repair pathway in different models. These techniques would reveal intracellular movement of these proteins to the DNA lesion site, their interactions with other proteins during repair and the effect of post-translational modifications on their functions. We also describe how these methods led us to identify hitherto unexpected role of poly(ADP-ribose) polymerase-1 (PARP1) in NER. Collectively these three simple techniques can provide an initial assessment of the functions of known and unknown proteins in the core or auxiliary events associated with mammalian NER. The results from these techniques could serve as a solid foundation and a justification for more detailed studies in NER using specialized reagents and more sophisticated tools. They can also be suitably modified to study other cellular processes beyond DNA repair., (Copyright © 2020 Robu, Shah and Shah.)

Heavy reliance on plants is rare in Carnivora and mostly limited to relatively small species in subtropical settings. The feeding behaviors of extinct cave bears living during Pleistocene cold periods at middle latitudes have been intensely studied using various approaches including isotopic analyses of fossil collagen. In contrast to cave bears from all other regions in Europe, some individuals from Romania show exceptionally high δ 15 N values that might be indicative of meat consumption. Herbivory on plants with high δ 15 N values cannot be ruled out based on this method, however. Here we apply an approach using the δ 15 N values of individual amino acids from collagen that offsets the baseline δ 15 N variation among environments. The analysis yielded strong signals of reliance on plants for Romanian cave bears based on the δ 15 N values of glutamate and phenylalanine. These results could suggest that the high variability in bulk collagen δ 15 N values observed among cave bears in Romania reflects niche partitioning but in a general trophic context of herbivory.

SnappySonic provides an ultrasound acquisition replay simulator designed for public engagement and training. It provides a simple interface to allow users to experience ultrasound acquisition without the need for specialist hardware or acoustically compatible phantoms. The software is implemented in Python, built on top of a set of open source Python modules targeted at surgical innovation. The library has high potential for reuse, most obviously for those who want to simulate ultrasound acquisition, but it could also be used as a user interface for displaying high dimensional images or video data., Competing Interests: Competing Interests The authors have no competing interests to declare.

The current phylogeographic pattern of European brown bears ( Ursus arctos ) has commonly been explained by postglacial recolonization out of geographically distinct refugia in southern Europe, a pattern well in accordance with the expansion/contraction model. Studies of ancient DNA from brown bear remains have questioned this pattern, but have failed to explain the glacial distribution of mitochondrial brown bear clades and their subsequent expansion across the European continent. We here present 136 new mitochondrial sequences generated from 346 remains from Europe, ranging in age between the Late Pleistocene and historical times. The genetic data show a high Late Pleistocene diversity across the continent and challenge the strict confinement of bears to traditional southern refugia during the last glacial maximum (LGM). The mitochondrial data further suggest a genetic turnover just before this time, as well as a steep demographic decline starting in the mid-Holocene. Levels of stable nitrogen isotopes from the remains confirm a previously proposed shift toward increasing herbivory around the LGM in Europe. Overall, these results suggest that in addition to climate, anthropogenic impact and inter-specific competition may have had more important effects on the brown bear's ecology, demography, and genetic structure than previously thought., Competing Interests: None declared.

Xeroderma pigmentosum C (XPC) protein initiates the global genomic subpathway of nucleotide excision repair (GG-NER) for removal of UV-induced direct photolesions from genomic DNA. The XPC has an inherent capacity to identify and stabilize at the DNA lesion sites, and this function is facilitated in the genomic context by UV-damaged DNA-binding protein 2 (DDB2), which is part of a multiprotein UV-DDB ubiquitin ligase complex. The nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP1) has been shown to facilitate the lesion recognition step of GG-NER via its interaction with DDB2 at the lesion site. Here, we show that PARP1 plays an additional DDB2-independent direct role in recruitment and stabilization of XPC at the UV-induced DNA lesions to promote GG-NER. It forms a stable complex with XPC in the nucleoplasm under steady-state conditions before irradiation and rapidly escorts it to the damaged DNA after UV irradiation in a DDB2-independent manner. The catalytic activity of PARP1 is not required for the initial complex formation with XPC in the nucleoplasm but it enhances the recruitment of XPC to the DNA lesion site after irradiation. Using purified proteins, we also show that the PARP1-XPC complex facilitates the handover of XPC to the UV-lesion site in the presence of the UV-DDB ligase complex. Thus, the lesion search function of XPC in the genomic context is controlled by XPC itself, DDB2, and PARP1. Our results reveal a paradigm that the known interaction of many proteins with PARP1 under steady-state conditions could have functional significance for these proteins., Competing Interests: The authors declare no conflict of interest.

The existing methodologies for studying robust responses of poly (ADP-ribose) polymerase-1 (PARP-1) to DNA damage with strand breaks are often not suitable for examining its subtle responses to altered DNA without strand breaks, such as UV-damaged DNA. Here we describe two novel assays with which we characterized the interaction of PARP-1 with UV-damaged DNA in vivo and in vitro. Using an in situ fractionation technique to selectively remove free PARP-1 while retaining the DNA-bound PARP-1, we demonstrate a direct recruitment of the endogenous or exogenous PARP-1 to the UV-lesion site in vivo after local irradiation. In addition, using the model oligonucleotides with single UV lesion surrounded by multiple restriction enzyme sites, we demonstrate in vitro that DDB2 and PARP-1 can simultaneously bind to UV-damaged DNA and that PARP-1 casts a bilateral asymmetric footprint from -12 to +9 nucleotides on either side of the UV-lesion. These techniques will permit characterization of different roles of PARP-1 in the repair of UV-damaged DNA and also allow the study of normal housekeeping roles of PARP-1 with undamaged DNA.

In 1965, Ciur-Izbuc Cave in the Carpathian Mountains of Romania was discovered to contain about 400 ancient human footprints. At that time, researchers interpreted the footprints to be those of a man, woman and child who entered the cave by an opening which is now blocked but which was usable in antiquity. The age of the prints (≈10-15 ka BP) was based partly on their association with cave bear (Ursus spelaeus) footprints and bones, and the belief that cave bears became extinct near the end of the last ice age. Since their discovery, the human and bear evidence and the cave itself have attracted spelunkers and other tourists, with the result that the ancient footprints are in danger of destruction by modern humans. In an effort to conserve the footprints and information about them and to reanalyze them with modern techiques, Ciur-Izbuc Cave was restudied in summer of 2012. Modern results are based on fewer than 25% of the originally described human footprints, the rest having been destroyed. It is impossible to confirm some of the original conclusions. The footprints do not cluster about three different sizes, and the number of individuals is estimated to be six or seven. Two cases of bears apparently overprinting humans help establish antiquity, and C-14 dates suggest a much greater age than originally thought. Unfortunately, insufficient footprints remain to measure movement variables such as stride length. However, detailed three-dimensional mapping of the footprints does allow a more precise description of human movements within the cave., (© 2014 Wiley Periodicals, Inc.)