Atomistic description of the OCTN1 recognition mechanism via in silico methods.

The Organic Cation Transporter Novel 1 (OCTN1), also known as SLC22A4, is widely expressed in various human tissues, and involved in numerous physiological and pathological processes remains. It facilitates the transport of organic cations, zwitterions, with selectivity for positively charged solutes. Ergothioneine, an antioxidant compound, and acetylcholine (Ach) are among its substrates. Given the lack of experimentally solved structures of this protein, this study aimed at generating a reliable 3D model of OCTN1 to shed light on its substrate-binding preferences and the role of sodium in substrate recognition and transport. A chimeric model was built by grafting the large extracellular loop 1 (EL1) from an AlphaFold-generated model onto a homology model. Molecular dynamics simulations revealed domain-specific mobility, with EL1 exhibiting the highest impact on overall stability. Molecular docking simulations identified cytarabine and verapamil as highest affinity ligands, consistent with their known inhibitory effects on OCTN1. Furthermore, MM/GBSA analysis allowed the categorization of substrates into weak, good, and strong binders, with molecular weight strongly correlating with binding affinity to the recognition site. Key recognition residues, including Tyr211, Glu381, and Arg469, were identified through interaction analysis. Ach demonstrated a low interaction energy, supporting the hypothesis of its one-directional transport towards to outside of the membrane. Regarding the role of sodium, our model suggested the involvement of Glu381 in sodium binding. Molecular dynamics simulations of systems at increasing levels of Na+ concentrations revealed increased sodium occupancy around Glu381, supporting experimental data associating Na+ concentration to molecule transport. In conclusion, this study provides valuable insights into the 3D structure of OCTN1, its substrate-binding preferences, and the role of sodium in the recognition. These findings contribute to the understanding of OCTN1 involvement in various physiological and pathological processes and may have implications for drug development and disease management.

Care of The Older Fighter: Position Statement of the Association of Ringside Physicians.

Older Fighters are defined as combat sports athletes older than 35 years, based on heightened medical risks and historical classification. Age-related changes to the neurological, cardiopulmonary, endocrinological, thermoregulatory, osmoregulatory, and musculoskeletal systems increase these athletes' risks for injury and may prolong their recovery. These age-related risks warrant special considerations for competition, licensure, prefight medical clearance, in-fight supervision, post-fight examination, and counseling regarding training practices and retirement from combat sports. Neurological considerations include increased risk of intracranial lesions, intracranial hemorrhage, and sequelae from traumatic brain injury (TBI), warranting more comprehensive neurological evaluation and neuroimaging. Increased risk of myocardial ischemia and infarction warrant careful assessment of cardiac risk factors and scrutiny of cardiovascular fitness. Older fighters may take longer time to recover from musculoskeletal injury; post-injury clearance should be individualized.

Alpine Viticulture and Climate Change: Environmental Resources and Limitations for Grapevine Ripening in Valtellina, Italy.

The effects of the spatial and temporal variability of environmental factors on viticulture are particularly important in mountainous wine regions due to their complex geomorphology. A typical example is Valtellina, an Italian valley in the middle of the Alpine chain known for its wine production. The aim of this work was to assess the effects of the current climatic conditions on Alpine viticultural production by evaluating the relationship between sugar accumulation, acid degradation, and environmental factors. To achieve this objective, a 21-year time series of ripening curves from 15 vineyards (cv Nebbiolo) along the Valtellina wine-growing belt was collected. The ripening curves were then analysed in conjunction with meteorological data to assess the influence of geographical and climatic characteristics, as well as other limiting environmental factors, on grape ripening. Valtellina is currently characterised by a stable warm phase, with yearly precipitation slightly higher than in the past. In this context, the timing of ripening and the level of total acidity are correlated with altitude, temperature, and summer thermal excess. Precipitation shows good correlations with all the maturity indices, so higher precipitation leads to late ripening and higher total acidity. Considering the oenological goal of local wineries, the results suggest that the Alpine area of Valtellina is currently facing favourable environmental conditions, with early development and increased levels of sugar while maintaining good levels of acidity.

The Role of Gender in Patients with Borderline Personality Disorder: Differences Related to Hopelessness, Alexithymia, Coping Strategies, and Sensory Profile.

Background and Objectives: Gender differences are poorly investigated in patients with borderline personality disorder (BPD), although they could be useful in determining the most appropriate pharmacological and non-pharmacological treatment. The aim of the present study was to compare sociodemographic and clinical characteristics and the emotional and behavioral dimensions (such as coping, alexithymia, and sensory profile) between males and females with BPD. Material and Methods: Two hundred seven participants were recruited. Sociodemographic and clinical variables were collected through a self-administered questionnaire. The Adolescent/Adult Sensory Profile (AASP), Beck Hopelessness Scale (BHS), Coping Orientation to Problems Experienced (COPE), and Toronto Alexithymia Scale (TAS-20) were administered. Results: Male patients with BPD showed more involuntary hospitalizations and greater use of alcohol and illicit substances compared to females. Conversely, females with BPD reported more frequent medication abuse than males. Furthermore, females had high levels of alexithymia and hopelessness. Regarding coping strategies, females with BPD reported higher levels of "restraint coping" and "use of instrumental social support" at COPE. Finally, females with BPD had higher scores in the Sensory Sensitivity and Sensation Avoiding categories at the AASP. Conclusions: Our study highlights gender differences in substance use, emotion expression, future vision, sensory perception, and coping strategies in patients with BPD. Further gender studies may clarify these differences and guide the development of specific and differential treatments in males and females with BPD.

Physiological and Transcriptomic Evaluation of Drought Effect on Own-Rooted and Grafted Grapevine Rootstock (1103P and 101-14MGt).

Grapevines worldwide are grafted onto Vitis spp. rootstocks in order to improve their tolerance to biotic and abiotic stresses. Thus, the response of vines to drought is the result of the interaction between the scion variety and the rootstock genotype. In this work, the responses of genotypes to drought were evaluated on 1103P and 101-14MGt plants, own-rooted and grafted with Cabernet Sauvignon, in three different water deficit conditions (80, 50, and 20% soil water content, SWC). Gas exchange parameters, stem water potential, root and leaf ABA content, and root and leaf transcriptomic response were investigated. Under well-watered conditions, gas exchange and stem water potential were mainly affected by the grafting condition, whereas under sever water deficit they were affected by the rootstock genotype. Under severe stress conditions (20% SWC), 1103P showed an "avoidance" behavior. It reduced stomatal conductance, inhibited photosynthesis, increased ABA content in the roots, and closed the stomata. The 101-14MGt maintained a high photosynthetic rate, limiting the reduction of soil water potential. This behavior results in a "tolerance" strategy. An analysis of the transcriptome showed that most of the differentially expressed genes were detected at 20% SWC, and more significantly in roots than in leaves. A core set of genes has been highlighted on the roots as being related to the root response to drought that are not affected by genotype nor grafting. Genes specifically regulated by grafting and genes specifically regulated by genotype under drought conditions have been identified as well. The 1103P, more than the 101-14MGt, regulated a high number of genes in both own-rooted and grafted conditions. This different regulation revealed that 1103P rootstock readily perceived the water scarcity and rapidly faced the stress, in agreement with its avoidance strategy.

Large screening of DNA-compatible reaction conditions for Suzuki and Sonogashira cross-coupling reactions and for reverse amide bond formation.

Progress in DNA-encoded chemical library synthesis and screening crucially relies on the availability of DNA-compatible reactions, which proceed with high yields and excellent purity for a large number of possible building blocks. In the past, experimental conditions have been presented for the execution of Suzuki and Sonogashira cross-coupling reactions on-DNA. In this article, our aim was to optimize Suzuki and Sonogashira reactions, comparing our results to previously published procedures. We have tested the performance of improved conditions using 606 building blocks (including boronic acids, pinacol boranes and terminal alkynes), achieving >70% conversion for 84% of the tested molecules. Moreover, we describe efficient experimental conditions for the on-DNA synthesis of amide bonds, starting from DNA derivatives carrying a carboxylic acid moiety and 300 primary, secondary and aromatic amines, as amide bonds are frequently found in DNA-encoded chemical libraries thanks to their excellent DNA compatibility.

Effects of repetitive transcranial magnetic stimulation on suicidal behavior: A systematic review.

The efficacy and tolerability of repetitive transcranial magnetic stimulation (rTMS) in major depression is well-known and documented by existing studies. However, whether rTMS may be effective on suicidal behavior is unclear and needs to be further investigated. This systematic review is aimed to investigate the available literature about the effects of rTMS on suicidal behavior and provide a comprehensive overview of the available evidence. A systematic search regarding the association between rTMS and suicidal behavior was carried out. All relevant articles concerning this association were comprehensively searched on PubMed, Scopus, Science Direct, and PsycInfo databases. After a careful search, 16 articles (7 sham-controlled studies, 5 uncontrolled studies, 4 case-series) met inclusion criteria and were selected in this systematic review. Overall, the left dorsolateral prefrontal cortex (DLPFC) was identified as the most frequent stimulation target by most studies. Unfortunately, actually it is not clear whether suicidal behavior reduction may be mediated, at least in some cases, by depression attenuation. While some methodological heterogeneity was found in terms of stimulation parameters (e.g., frequency, number of sessions, intensity of stimulation), most of the analyzed articles showed that rTMS is a safe, applicable, well tolerated and reproducible method in treating suicidal behavior. The most effective treatment seems to be the bilateral rTMS as well as the combination with antidepressants. Further longitudinal studies are required in order to replicate the mentioned study results.

Gender Differences in COVID-19 Lockdown Impact on Mental Health of Undergraduate Students.

Background: Prolonged university closures and social distancing-imposed measures due to the COVID-19 pandemic obliged students to at-home learning with online lectures and educational programs promoting potential social isolation, loneliness, hopelessness, and episodes of clinical decompensation. Methods: A web-based cross-sectional survey was carried out in a university institute in Milan, Northern Italy, to assess the COVID-19 lockdown impact on the mental health of the undergraduate students. We estimated the odds ratios (OR) and the corresponding 95% confidence intervals (CI) using adjusted logistic regression models. Results: Of the 8,177 students, 12.8% reported depressive symptoms, 25.6% anxiety, 8.7% insomnia, and 10.6% reported impulsive tracts, with higher proportions among females than males. Mental health symptoms were positively associated with caring for a person at home, a poor housing quality, and a worsening in working performance. Among males compared with females, a poor housing quality showed a stronger positive association with depressive symptoms and impulsivity, and a worsening in the working performance was positively associated with depressive and anxiety symptoms. In addition, the absence of private space was positively associated with depression and anxiety, stronger among males than females. Conclusions: To our knowledge, this is the first multidisciplinary consortium study, involving public mental health, environmental health, and architectural design. Further studies are needed to confirm or refute our findings and consequent recommendations to implement well-being interventions in pandemic conditions.

Results and Clinical Interpretation of Germline RET Analysis in a Series of Patients with Medullary Thyroid Carcinoma: The Challenge of the Variants of Uncertain Significance.

Germline RET variants are responsible for approximately 25% of medullary thyroid carcinoma (MTC) cases. Identification of RET variant carriers allows for the adoption of preventative measures which are dependent on the risk associated with the specific alteration. From 2002 to 2020, at our cancer genetics clinic, RET genetic testing was performed in 163 subjects (102 complete gene analyses and 61 targeted analyses), 72 of whom presented with MTC. A germline RET variant was identified in 31.9% of patients affected by MTC (93.8% of those having positive family history and 14.3% of clinically sporadic cases). Subsequent target testing in relatives allowed us to identify 22 asymptomatic carriers, who could undertake appropriate screening. Overall, patients with germline RET variants differed significantly from those who tested negative by family history (p < 0.001) and mean age at MTC diagnosis (44.45 vs. 56.42 years; p = 0.010), but the difference was not significant when only carriers of moderate risk variants were considered (51.78 vs. 56.42 years; p = 0.281). Out of 12 different variants detected in 49 patients, five (41.7%) were of uncertain significance (VUS). For two of these, p.Ser904Phe and p.Asp631_Leu633delinsGlu, co-segregation and genotype/phenotype analysis, matched with data from the literature, provided evidence supporting their classification in the moderate and the highest/high risk class (with a MEN2B phenotype), respectively.

How Do Novel M-Rootstock (Vitis Spp.) Genotypes Cope with Drought?

Most of the vineyards around the world are in areas characterized by seasonal drought, where water deficits and high temperatures represent severe constraints on the regular grapevine growth cycle. Although grapevines are well adapted to arid and semi-arid environments, water stress can cause physiological changes, from mild to irreversible. Screening of available Vitis spp. genetic diversity for new rootstock breeding programs has been proposed as a way for which new viticulture challenges may be faced. In 2014, novel genotypes (M-rootstocks) were released from the University of Milan. In this work, the behavior of M1, M3 and M4 in response to decreasing water availabilities (80%, 50% and 20% soil water content, SWC) was investigated at the physiological and gene expression levels, evaluating gas exchange, stem water potential and transcript abundances of key genes related to ABA (abscisic acid) biosynthesis (VvZEP, VvNCED1 and VvNCED2) and signaling (VvPP2C4, VvSnRK2.6 and VvABF2), and comparing them to those of cuttings of nine commercial rootstocks widely used in viticulture. M-rootstocks showed a change at physiological levels in severe water-stressed conditions (20% soil water content, SWC), reducing the stomatal conductance and stem water potential, but maintaining high photosynthetic activity. Water use efficiency was high in water-limiting conditions. The transcriptional changes were observed at 50% SWC, with an increment of transcripts of VvNCED1 and VvNCED2 genes. M-rootstocks showed similar behavior to 1103P and 110R rootstocks, two highly tolerant commercial genotypes. These rootstocks adopted a tolerant strategy to face water-stressed conditions.

Cardiovascular risk in patients with severe mental illness in Italy.

BACKGROUND: Patients with severe mental illness (SMI), such as schizophrenia or bipolar disorders, are more frequently affected by metabolic syndrome and cardiovascular (CV) diseases than the general population, with a significant reduction in life expectancy. Beyond metabolic syndrome, quantifying the risk of CV morbidity in the long-term may help clinicians to put in place preventive strategies. In this study, we assessed 10-year CV risk in patients with SMI and healthy individuals using an algorithm validated on the Italian general population. METHODS: Patients aged 35-69 years diagnosed with SMI were consecutively recruited from psychiatric acute care units. Single CV risk factors were assessed, and 10-year CV risk calculated by means of the CUORE Project 10-year CV risk algorithm, based on the combination of the following risk factors: age, systolic blood pressure, total and high-density lipoprotein cholesterol, diabetes, smoking habit, and hypertensive treatment. Patients' data were compared with those from the general population. The 10-year CV risk was log-transformed, and multivariable linear regression was used to estimate mean ratios, adjusting for age, and education. RESULTS: Three hundred patients and 3,052 controls were included in the analysis. Among men, the 10-year CV risk score was very similar between patients with SMI and the general population (mean ratio [MR]: 1.02; 95%CI 0.77-1.37), whereas a 39% increase in 10-year CV risk was observed in women with SMI compared to the general population (MR: 1.39; 95%CI 1.16-1.66). CONCLUSIONS: In our study, women with SMI were consistently more at risk than the general population counterpart, even at younger age.

COVID-19 Lockdown: Housing Built Environment's Effects on Mental Health.

Since the World Health Organization (WHO) declared the coronavirus infectious disease 2019 (COVID-19) outbreak a pandemic on 11 March, severe lockdown measures have been adopted by the Italian Government. For over two months of stay-at-home orders, houses became the only place where people slept, ate, worked, practiced sports, and socialized. As consolidated evidence exists on housing as a determinant of health, it is of great interest to explore the impact that COVID-19 response-related lockdown measures have had on mental health and well-being. We conducted a large web-based survey on 8177 students from a university institute in Milan, Northern Italy, one of the regions most heavily hit by the pandemic in Europe. As emerged from our analysis, poor housing is associated with increased risk of depressive symptoms during lockdown. In particular, living in apartments <60 m2 with poor views and scarce indoor quality is associated with, respectively, 1.31 (95% CI: 1046-1637), 1.368 (95% CI: 1166-1605), and 2.253 (95% CI: 1918-2647) times the risk of moderate-severe and severe depressive symptoms. Subjects reporting worsened working performance from home were over four times more likely to also report depression (OR = 4.28, 95% CI: 3713-4924). Housing design strategies should focus on larger and more livable living spaces facing green areas. We argue that a strengthened multi-interdisciplinary approach, involving urban planning, public mental health, environmental health, epidemiology, and sociology, is needed to investigate the effects of the built environment on mental health, so as to inform welfare and housing policies centered on population well-being.

Covid-19 pandemic impact on mental health: a web-based cross-sectional survey on a sample of Italian general practitioners.

BACKGROUND: Since the World Health Organization declared the new 2019 coronavirus disease (Covid-19) outbreak first a Public Health Emergency of International Concern and then a pandemic, Italy held more than 195.350 cases and 26.380 deaths. Working in the frontline with suspected Covid-19 infection patients, general practitioners (GPs) are daily under both physical and psychological pressure.  Methods: A web-based cross-sectional survey was carried out on italian GPs working in Genoa (Italy), to assess the impact of Covid-19 pandemic on mental health. The survey was anonymous and a free Google Forms® software was used. RESULTS: One hundred thirty-one GPs completed the survey. Compared to GPs with absent or mild depressive symptoms (PHQ-9 < 10), GPs reporting moderate to severe depressive symptoms (N=30, 22.9%; PHQ-9 ≥ 10) reported more helplessness (96.7% vs. 79.2%, p=.025), spent more than three hours searching for COVID-19 information (43.3% vs. 19.8%, p=.024), perceived less adequate personal protective equipment (PPE) (6.7% vs. 23.8%, p=.049) and visited more COVID-19 infected patients (16.63 ± 27.30 vs. 9.52 ± 11.75, p=.041). Moreover, PHQ-9 ≥ 10 GPs reported a significant higher severity for both anxiety and insomnia (13.43 ± 4.96 vs. 4.88 ± 3.53 and 11.60 ± 5.53 vs. 4.84 ± 3.81, respectively; p<.001), and a worse quality of life in both mental (34.60 ± 7.45 vs. 46.01 ± 7.83, p<.001) and physical (43.50 ± 9.37 vs. 52.94 ± 4.78, p<.001) component summary. CONCLUSIONS: Our results give early insight into the urgent need to provide continuity of care for patients at the community-level, adequate PPE to GPs and a clear guidance from public health institutions. A precarious healthcare system both at a national and regional level might have triggered negative mental health outcomes in Italian GPs.

Application of an HPLC-MS/MS method for Teicoplanin drug substance and related impurities, part 2: Identity assignment of related impurities.

A liquid chromatographic MS-compatible method was applied to the structural elucidation of Teicoplanin for identification CRS components. The method, previously developed by our group, involves the use of LiChrospher 100 RP-18 column with a mobile phase composed of ammonium formate 25 mM at pH 6.00 and acetonitrile (ACN). All the peaks with a 0.10% UV area, largely above the disregard limit of 0.15% as fixed by EMA, were considered and submitted to MS/MS fragmentation experiments. The study of MS/MS spectrum collected for Teicoplanin complex major component (namely A2-2) allowed to elucidate the fragmentation pathway and enabled the successful identity assignment of all the 42 detected species. Elution order was also rationalized. An in house batch sample of Teicoplanin was analyzed and, while the 86% of the detected species were structurally identical to those in Teicoplanin for identification CRS, five new derivatives were revealed and structurally characterized. In both the Teicoplanin samples, all the considered species were found to have a Teicoplanin-like structure that allows their classification as closely related impurities, with a significant implication in their qualification threshold.

A new MS compatible HPLC-UV method for Teicoplanin drug substance and related impurities, part 1: Development and validation studies.

Teicoplanin is a glycopeptide antibiotic prepared by fermentation from cultures of Actinoplanes teichomyceticus, used as drug of last resort for the treatment of bacterial infections in humans. This study, which is the first in a series of two parts, describes the development of a LC method for the separation of Teicoplanin drug substance and its related impurities compatible with MS detection. The separation conditions for Teicoplanin were set on a LiChrospher 100 RP-18 column under gradient elution with a mobile phase composed of ammonium formate 25 mM at pH 6.00 and ACN. The new method was shown equivalent in terms of selectivity to the one reported in the European Pharmacopoeia Teicoplanin monograph, and was validated according to ICH Q2 R1 guidelines for the drug substance assay. The new method offers similar performance to the compendial one but has the advantage of being fully compatible with MS and it can be proposed as a useful tool also for controlling the quality of Teicoplanin fermentation batches and the occurrence of potential impurities.

Oral Bioavailability and Pharmacokinetics of Nonanimal Chondroitin Sulfate and Its Constituents in Healthy Male Volunteers.

The pharmacokinetic profile of a new 800-mg tablet of nonanimal chondroitin sulfate (CS) (Mythocondro®, 800-mg tablets, Gnosis S.p.A., Italy) was investigated vs an animal CS in healthy volunteers for a total period of 48 hours. After a single 2400-mg dose of the test and the reference formulation, total CS, the compositional disaccharides (ΔDi6S, ΔDi4S and ΔDi0S), and the overall charge density were quantified in plasma. The safety and tolerability profile after a single dose of this new nonanimal CS tablets was excellent. After baseline-corrected concentrations, an overall greater plasma concentration was observed after 24 hours of ∼44% and after 48 hours of ∼45% from administration of nonanimal when compared to animal-derived CS. Moreover, nonanimal CS increases the specific sulfation in the 6-position of N-acetyl-galactosamine in human plasma CS and, as a consequence, the overall charge density, reaching double values (0.91), after 48 hours compared to bovine CS and to endogenous CS. In conclusion, nonanimal CS, possessing a lower molecular weight than an animal-derived sample, produces a greater CS concentration for a more prolonged period of time in plasma and an increase in charge density and specific 6-sulfation of endogenous plasma CS.

Multi-parameter characterization of water stress tolerance in Vitis hybrids for new rootstock selection.

Drought in grapevine could be faced using tolerant rootstocks. The present work aims at the evaluation of 25 new genotypes potentially tolerant to drought by using recent methods of phenotypical screening (thermography and on-solid reaction spectroscopy). Plants were grown in well-watered and stressed field conditions. Proxi for transpiration, wood hydrophobicity and starch content were used to characterize and classify the genotypes. The predominant role of the environment was highlighted, nevertheless genotype and genotype × environment interaction showed significant variations as well. Hybrids were classified based on their steady, susceptible or adaptable behavior. The 14 most promising genotypes were identified, 5 of them showing two tolerance mechanisms. In the future, results from this experiment will support viticulture in water limited areas releasing new drought-tolerant interspecific hybrids to be tested after grafting with different scions.

Brain imaging before primary lung cancer resection: a controversial topic.

OBJECTIVE: International and national recommendations for brain imaging in patients planned to undergo potentially curative resection of non-small-cell lung cancer (NSCLC) are variably implemented throughout the United Kingdom [Hudson BJ, Crawford MB, and Curtin J et al (2015) Brain imaging in lung cancer patients without symptoms of brain metastases: a national survey of current practice in EnglandClin Radiol https://doi.org/10.1016/j.crad.2015.02.007]. However, the recommendations are not based on high-quality evidence and do not take into account cost implications and local resources. Our aim was to determine local practice based on historic outcomes in this patient cohort. METHODS: This retrospective study took place in a regional thoracic surgical centre in the United Kingdom. Pathology records for all patients who had undergone lung resection with curative intent during the time period January 2012-December 2014 were analysed in October 2015. Electronic pathology and radiology reports were accessed for each patient and data collected about their histological findings, TNM stage, resection margins, and the presence of brain metastases on either pre-operative or post-operative imaging. From the dates given on imaging, we calculated the number of days post-resection that the brain metastases were detected. RESULTS: 585 patients were identified who had undergone resection of their lung cancer. Of these, 471 had accessible electronic radiology records to assess for the radiological evidence of brain metastases. When their electronic records were evaluated, 25/471 (5.3%) patients had radiological evidence of brain metastasis. Of these, five patients had been diagnosed with a brain metastasis at initial presentation and had undergone primary resection of the brain metastasis followed by resection of the lung primary. One patient had been diagnosed with both a primary lung and a primary bowel adenocarcinoma; on review of the case, it was felt that the brain metastasis was more likely to have originated from the bowel cancer. One had been clinically diagnosed with a cerebral abscess while the radiology had been reported as showing a metastatic deposit. Of the remaining 18/471 (3.8%) patients who presented with brain metastases after their surgical resection, 12 patients had adenocarcinoma, four patients had squamous cell carcinoma, one had basaloid, and one had large-cell neuroendocrine. The mean number of days post-resection that the brain metastases were identified was 371 days, range 14-1032 days, median 295 days (date of metastases not available for two patients). CONCLUSION: The rate of brain metastases identified in this study was similar to previous studies. This would suggest that preoperative staging of the central nervous system may change the management pathway in a small group of patients. However, for this group of patients, the change would be significant either sparing them non-curative surgery or allowing aggressive management of oligometastatic disease. Therefore, we would recommend pre-operative brain imaging with MRI for all patients undergoing potentially curative lung resection.

Thermostat Influence on the Structural Development and Material Removal during Abrasion of Nanocrystalline Ferrite.

We consider a nanomachining process of hard, abrasive particles grinding on the rough surface of a polycrystalline ferritic work piece. Using extensive large-scale molecular dynamics (MD) simulations, we show that the mode of thermostating, i.e., the way that the heat generated through deformation and friction is removed from the system, has crucial impact on tribological and materials related phenomena. By adopting an electron-phonon coupling approach to parametrize the thermostat of the system, thus including the electronic contribution to the thermal conductivity of iron, we can reproduce the experimentally measured values that yield realistic temperature gradients in the work piece. We compare these results to those obtained by assuming the two extreme cases of only phononic heat conduction and instantaneous removal of the heat generated in the machining interface. Our discussion of the differences between these three cases reveals that although the average shear stress is virtually temperature independent up to a normal pressure of approximately 1 GPa, the grain and chip morphology as well as most relevant quantities depend heavily on the mode of thermostating beyond a normal pressure of 0.4 GPa. These pronounced differences can be explained by the thermally activated processes that guide the reaction of the Fe lattice to the external mechanical and thermal loads caused by nanomachining.