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This work describes the application of a pressure-enhanced liquid chromatography (PE-LC) setup to tune the separation of various large molecules comprised of nucleic acids (oligonucleotides, messenger ribonucleic acid [mRNA], and deoxyribonucleic acid [DNA]). When adding pressure as a method development parameter, it indeed becomes possible to modify retention, selectivity, and peak width. As an example, the separation of oligonucleotides having sizes comprised between 40 and 100-mer in ion-pairing reversed-phase liquid chromatography (IP-RPLC) was drastically improved by using a stepwise pressure gradient to selectively shift the retention of a peak or group of peaks. Resolution was increased from 1.5 to 11.8 when setting a rapid high pressure step (twofold increased pressure) during the run. On the other hand, it was also possible to improve the separation of erythropoietin (EPO) mRNA and related impurities under ion-exchange chromatography (IEX). However, with this biomolecule, the best separation was achieved by reducing the pressure in the system. Finally, for another sample (DNA ladder) under IEX conditions, the pressure was found to have a limited impact on the overall selectivity. As highlighted in this work, pressure is an additional parameter that can be successfully used to develop LC methods of large biomolecules.

25.08.2022 відбулася робота Біологічної секції щорічної Міжнародної Гамовської конференції у режимі он-лайн на платформі Zoom. Традиційно Біологічна секція проходить під назвою “The Importance of G. Gamow's Ideas for Biology of the 21st Century”. У роботі секції брали участь відомі науковці, що ведуть дослідження в області молекулярної біології та генетики з провідних наукових установ України, Канади, США, Великої Британії і Німеччини, також брали участь аспіранти та студенти (загалом 52 учасника). Було представлено 13 усних доповідей, серед них доповіді – «Генетичні ресурси рослин для підвищення стресостійкості – на прикладі зернових культур» - проф., д.б.н. Бьорнер А. (Інститут генетики рослин і досліджень сільськогосподарських рослин імені Лейбніца, Гатерслебен, Німеччина); «Дослідження загальногеномних асоціації для виявлення локусів та генів-кандидатів, що впливають на вміст білка в зерні пшениці м’якої» – проф., д.б.н. Мішева С. (Інститут фізіології рослин і генетики Болгарської академії наук, Софія, Болгарія); «Дослідження молекулярної еволюції та таксономічне застосування 5S рДНК при аналізі роду Aconitum» – проф., д.б.н. Волков Р.А. (Чернівецький національний університет імені Юрія Федьковича, Чернівці, Україна); «Подолання селекційних бар'єрів для пшениці» - проф. Гріффітс С. і доктор Вінген Л.У. (Центр Джона Іннеса, Норвіч, Велика Британія); «Оцінка сучасного стану популяцій Gentiana lutea L. Українських Карпат: Еколого-генетичні підходи» – доц., к.б.н. Прокоп'як М.З. (Тернопільський національний педагогічний університет імені Володимира Гнатюка, Тернопіль, Україна); «Часова динаміка спектрів фонового світіння Photobacterium phosphoreum» – проф., д.б.н. Мартинюк В.С. (Київський національний університет імені Тараса Шевченка, Київ, Україна.); «Нові мутації STARD8 і STARD9 виявлені в 46 гонадах XY пацієнтів з дисгенезією, що підтримують ці гени як кандидатів на DSD» – Сіроха Д. і проф., д.б.н. Лівшиц Л.А. (Інститут молекулярної біології і генетики НАН України, Київ, Україна); «MYD88 і CXCR4, два гени, які відіграють вирішальну роль у макроглобулінемії Вальденстрема» – д.б.н. Мончак Ю. (Завідувач відділу молекулярної генетики, Центр охорони здоров'я університету Макгілла, Університет Макгілла та Монреальський університет, Канада); «Джордж Гамов і генетичний код ДНК» – проф., д.ф.н. Сегре Г. (Університет Пенсільванії, США). Серед підготовлених доповідей вважаємо необхідним відмітити високу якість та актуальність виконаних на сучасному рівні досліджень молодих та починаючих науковців: «Біоінформаційний аналіз нуклеотидних послідовностей локусів Gli-1 Triticum aestivum L.» – аспірант Попович Ю.А., проф., д.б.н. Чеботар С.В. (ОНУ імені І.І. Мечникова, Одеса, Україна); «Скринінг продуцентів тіопептидних антибіотиків за допомогою репортерної системи на основі промотору гена tipA» – аспірант Тістечок С.І. (Львівський національний університет імені Івана Франка, Україна); «Довгі та короткі варіанти 5S рДНК у геномах видів Apis» – аспірант Рошка Н.М. (Чернівецький національний університет імені Юрія Федьковича, Чернівці, Україна). Як позитивну рису роботи біологічної секції було відмічено багатоплановість охопленої тематики, що має генетичне підґрунтя, та перспективність досліджень, що виконуються на стику наук. Учасники Біологічної секції звернули увагу, що Г.А. Гамов зробив внесок у розвиток саме молекулярної біології, поставивши питання про розшифрування генетичного коду, тому необхідно у назву конференції додати – «molecular biology», щоб назва конференції виглядала наступним чином: «Аstronomy and Beyond: Astrophysics, Cosmology and Gravitation, Astroparticle physics, Rradioastronomy, Astrobiology and Molecular biology».

Background Sugar-sweetened beverage (SSB) taxes have emerged as an effective and increasingly popular tool to reduce added sugar intake, an important contributor to obesity and non-communicable diseases. A common barrier to the implementation of well-designed SSB taxes is the opposition of commercial actors. Focusing on the WHO European Region, this study seeks to map if and how key stakeholders have experienced industry efforts to influence SSB taxes. Methods We identified 11 countries in the WHO European Region which have implemented SSB taxes or attempted to do so. Using an online survey informed by the global literature on industry interference with SSB taxation, we approached 70 in-country policymakers, advocates and academics. The data were analysed using an existing framework of corporate political activity. Results Twenty-three experts from nine countries responded to the survey. Transnational SSB producers and their business associations were identified as the most active opponents of SSB taxation. Industry claims that the policy would have negative economic effects were identified as the most common and powerful arguments. Direct lobbying was reported in all study countries. Shifts in political activity were recognisable across stages of the policy process, moving from outright opposition to attempts to delay or weaken the policy after its announcement. Conclusion Those seeking to introduce effective SSB taxation can use our findings to pre-empt and counter industry opposition. We identify several measures for preventing and mitigating industry interference with SSB tax policy.

Treatment with sotorasib has shown intracranial complete responses and continued intracranial stabilization in KRAS G12C-mutated non-small-cell lung carcinoma (NSCLC) patients with previously treated, stable brain metastases in a post hoc analysis of the ongoing CodeBreaK 100 trial. We present the case of a patient with KRAS G12C-mutant adenocarcinoma of the lung with active untreated brain metastases with a nearly complete intracranial response only 6 weeks after start of sotorasib illustrating the benefit of sotorasib in patients with active, previously untreated brain metastases in KRAS G12C-mutated NSCLC.

Many chromatographers have observed that the operating pressure can dramatically change the chromatographic retention of solutes. Small molecules show observables changes, yet even more sizable effects are encountered with large biomolecules. With this work, we have explored the use of pressure as a method development parameter to alter the reversed-phase selectivity of peptide and protein separations. An apparatus for the facile manipulation of column pressure was assembled through a two-pump system and postcolumn flow restriction. The primary pump provided an eluent flow through the column, while the secondary pump provided a pressure-modulating flow at a tee junction after the column but ahead of a flow restrictor. Using this setup, we were able to quickly program various constant pressure changes and even pressure gradients. It was reconfirmed that pressure changes impact the retention of large molecules to a much greater degree than small molecules, making it especially interesting to consider the use of pressure to selectively separate solutes of different sizes. The addition of pressure to bring the column operating pressure beyond 500 bar was enough to change the elution order of insulin (a peptide hormone) and cytochrome C (a small serum protein). Moreover, with the proposed setup, it was possible to combine eluent and pressure gradients in the same analytical run. This advanced technique was applied to improve the separation of insulin from one of its forced degradation impurities. We have referred to this method as pressure-enhanced liquid chromatography and believe that it can offer unseen selectivity, starting with peptide and protein reversed-phase separations.

Accurate modelling of the performance of a yacht in varying environmental conditions can significantly improve a yachts performance. However, a racing yacht is a highly complex multi-physics system meaning that real-time performance prediction tools are always semi-empirical, leaving significant room for improvement. In this paper we first use unsupervised machine learning to analyse full-scale yacht performance data. The widely documented ORC VPP (ORC, 2015) and the commercial Windesign VPP are compared to the data across a range of wind conditions. The data is then used to train machine learning models. A number of machine learning regression algorithms are explored including Neural Networks, Random Forests and Support Vector Machines and improvements of 82% are obtained compared to the commercial tools. The use of physics- based learning models (Weymouth and Yue, 2013) is explored in order to reduce the amount of data required to achieve accurate predictions. It is found that machine learning models can outperform empirical models even when predicting performance in environmental conditions that have not been supplied to the model as part of the training dataset.

The development of stable materials, processable on alarge area,is a prerequisite for perovskite industrialization. Beyond the perovskiteabsorber itself, this should also guide the development of all otherlayers in the solar cell. In this regard, the use of NiO x as a hole transport material (HTM) offers severaladvantages, as it can be deposited with high throughput on large areasand on flat or textured surfaces via sputtering, a well-establishedindustrial method. However, NiO x may triggerthe degradation of perovskite solar cells (PSCs) when exposed to environmentalstressors. Already after 100 h of damp heat stressing, a strong fillfactor (FF) loss appears in conjunction with a characteristic S-shaped J-V curve. By performing a wide range of analysison cells and materials, completed by device simulation, the causeof the degradation is pinpointed and mitigation strategies are proposed.When NiO x is heated in an air-tight environment,its free charge carrier density drops, resulting in a band misalignmentat the NiO x /perovskite interface and inthe formation of a barrier impeding hole extraction. Adding an organiclayer between the NiO x and the perovskiteenables higher performances but not long-term thermal stability, forwhich reducing the NiO x thickness is necessary.

Shear Alfvén wave (SAW)/drift Alfvén wave (DAW) fluctuations can be destabilized by energetic particles (EPs) as well as thermal plasma components, which play a key role in the EP energy and momentum transport processes in burning fusion plasmas. The drift Alfvén energetic particle stability (`DAEPS`) code, which is an eigenvalue code using the finite element method (FEM), was developed to analyze Alfvén instabilities excited by EPs. The model equations, consisting of quasi-neutrality condition and Schrödinger-like form of vorticity equation, are derived within the general fishbone-like dispersion relation (GFLDR) theoretical framework, which is widely used to analyze SAW/DAW physics. The mode structure decomposition (MSD) approach and asymptotic matching between the inertial/singular layer and ideal regions are adopted. Therefore, the `DAEPS` code can provide not only frequency and growth/damping rate, but also the parallel mode structure as well as the asymptotic behavior corresponding to the singular layer contribution. Thus, it fully describes fluid and kinetic continuous spectra as well as unstable and damped modes. The model equations have been extended to include general axisymmetric geometry, and to solve for the response of circulating and trapped particles by means of the action angle approach. In this work, we discuss linear dispersion relation and parallel mode structure of drift Alfvén instabilities excited by EPs, computed by the `DAEPS` code with realistic experimental plasma profile and magnetic configuration. Based on this information, we adopt the Dyson-Schrödinger Model (DSM) to further analyze EP energy and momentum flux. We will also briefly discuss how the parallel mode structure of the drift Alfvén instabilities can be used in the DSM to calculate the nonlinear radial envelope evolution and the EP transport.

The Antarctic Slope Front and the associated Antarctic Slope Current shield the continental shelves in East Antarctica from offshore warm water that holds the potential for considerable ice shelf melting and, consequently, sea level rise. Here, we present two-year-long records of temperature, salinity, and velocity (2019-2020), obtained from two oceanographic moorings located within the slope front/current over bathymetries of around 1000m and 2000m slightly east of the prime meridian. The two-year data record reveals clear differences in the seasonality of the thermocline depth and the baroclinicity of the current between the deep and shallow mooring locations. In combination with climatologies of hydrography and satellite-derived surface geostrophic currents, we use the new data to refine the baroclinic seasonality of the ASF. The results highlight the role of surface buoyancy fluxes via seasonal sea ice melt and freeze. Finally, the slope current is shown to control flow into and out of the cavity of the close-by Fimbulisen Ice Shelf on seasonal time scales depending on the orientation of the entrances of the cavity. Our findings contribute to a better understanding of the processes controlling the slope front/current seasonality and resulting inflow into the East-Antarctic ice shelf cavities.

Ambiviruses are hybrid infectious elements encoding the hallmark gene of RNA viruses, the RNA-dependent RNA polymerase, and self-cleaving RNA ribozymes found in many viroids. Ambiviruses are thought to be pathogens of fungi, although the majority of reported genomes have been identified in metatranscriptomes. Here, we present a comprehensive screen for ambiviruses in more than 46,500 fungal transcriptomes from the Sequence Read Archive (SRA). Our data-driven virus discovery approach identified more than 2,500 ambiviral sequences across the kingdom Fungi with a striking expansion in members of the phylum Basidiomycota representing the most complex fungal organisms. Our study unveils a large diversity of unknown ambiviruses with as little as 27% protein sequence identity to known members and sheds new light on the evolution of this distinct class of infectious agents with RNA genomes. No evidence for the presence of ambiviruses in human microbiomes was obtained from a comprehensive screen of respective metatranscriptomes available in the SRA.

Alarge superconducting machine, JT-60SA has been constructed to provide major contributions to the ITER program and DEMO design. For the success of the ITER project and fusion reactor, understanding and development of plasma controllability in ITER and DEMO relevant higher beta regimes are essential. JT-60SA has focused the program on the plasma controllability for scenario development and risk mitigation in ITER as well as on investigating DEMO relevant regimes. This paper summarizes the high research priorities and strategy for the JT-60SA project. Recent works on simulation studies to prepare the plasma physics and control experiments are presented, such as plasma breakdown and equilibrium controls, hybrid and steady-state scenario development, and risk mitigation techniques. Contributions of JT-60SA to ITER and DEMOhave been clarified through those studies. Peer Reviewed Article escrit per 127 autors/autores: M Yoshida, G Giruzzi, N Aiba, J F Artaud, J Ayllon-Guerola, L Balbinot, OBeeke, E Belonohy, P Bettini, W Bin, A Bierwage, T Bolzonella, M Bonotto, CBoulbe, J Buermans, M Chernyshova, S Coda, R Coelho, S Davis, C Day, GDeTommasi, M Dibon, A Ejiri, G Falchetto, A Fassina, B Faugeras, L Figini, M Fukumoto, S Futatani, K Galazka, J Garcia, M Garcia-Muñoz, L Garzotti, L Giacomelli, L Giudicotti, S Hall, N Hayashi, C Hoa, M Honda, K Hoshino, M Iafrati, A Iantchenko, S Ide, S Iio, R Imazawa, S Inoue, A Isayama, E Joffrin, K Kamiya, Y Ko, M Kobayashi, T Kobayashi, G Kocsis, A Kovacsik, T Kurki-Suonio, B Lacroix, P Lang, Ph Lauber, A Louzguiti, E de la Luna, G Marchiori, M Mattei, A Matsuyama, S Mazzi, A Mele, F Michel, Y Miyata, J Morales, P Moreau, A Moro, T Nakano, M Nakata, E Narita, R Neu, S Nicollet, M Nocente, S Nowak, F P Orsitto, V Ostuni, Y Ohtani, N Oyama, R Pasqualotto, B Pégourié, E Perelli, L Pigatto, C Piccinni, A Pironti, P Platania, B Ploeckl, D Ricci, P Roussel, G Rubino, R Sano, K Särkimäki, K Shinohara, S Soare, C Sozzi, S Sumida, T Suzuki, Y Suzuki, T Szabolics, T Szepesi, Y Takase, M Takech, N Tamura, K Tanaka, H Tanaka, M Tardocchi, A Terakado, H Tojo, T Tokuzawa, A Torre, N Tsujii, H Tsutsui, Y Ueda, H Urano, M Valisa, M Vallar, J Vega, F Villone, T Wakatsuki, T Wauters, M Wischmeier, S Yamoto, L Zani

Certain biomolecules have proven to be difficult to analyze by liquid chromatography (LC), especially under certain chromatographic conditions. The separation of proteins in aqueous mobile phases is one such example because there is the potential for both hydrophobic and ionic secondary interactions to occur with chromatographic hardware to the detriment of peak recovery, peak shape, and the overall sensitivity of the LC analysis. To decrease non-specific adsorption and undesired secondary interactions between column hardware and biomolecules, we have developed and applied a new hydrophilically modified hybrid surface (h-HST) for size exclusion chromatography (SEC) and anion exchange (AEX) separations of proteins and nucleic acids. This surface incorporates additional oxygen and carbon atoms onto an ethylene bridge hybrid siloxane polymer. As a result, it exhibits reduced electrostatic properties and hydrophilicity that facilitates challenging aqueous separations. Flow injection tests with a phosphate buffer showed superior protein recovery from an h-HST frit when compared to unmodified ethylene-bridged hybrid HST, titanium, stainless steel, and PEEK frits. When applied to SEC of rituximab, ramucirumab, and trastuzumab emtansine with a 50 mM ammonium acetate buffer, this new hydrophilic chromatographic hardware yielded improved monomer and aggregate recovery, higher plate numbers, and more symmetrical peaks. AEX columns also benefited from h-HST hardware. An acidic mAb (eculizumab) showed improved recovery, more stable retention, and a sharper peak when eluted from an h-HST versus SS column. Moreover, AEX separations of intact mRNA samples (Cas9 and EPO mRNA) were improved, where it was seen that h-HST column hardware provided higher sensitivity and more repeatable peak areas from injection to injection. As such, there is significant potential in the use of h-HST chromatographic hardware to facilitate more robust and more sensitive analyses for a multitude of challenging separations and analytes.

Epilepsie kann sich auf verschiedene Arten äußern. Oft ist es schwierig, sie zu diagnostizieren. Für eine bestmögliche Hilfe der betroffenen Kinder und ihrer Familien nehmen Pflegende eine Schlüsselrolle ein – von der Beobachtung der Anfälle über ihre Dokumentation und Begleitung bis hin zum Umgang mit den Auswirkungen.

BACKGROUND: Collateral effects and consequences of the coronavirus disease 19 (COVID-19) pandemic on kidney transplant recipients remain widely unknown. METHODS: This retrospective cohort study examined changes in admission rates, incidences of diseases leading to hospitalization, in-patient procedures, and maintenance medication in long-term kidney transplant recipients with functioning graft during the early COVID-19 pandemic in Germany. Data were derived from a nationwide health insurance database. Analysis was performed from March 15 to September 30 and compared the years 2019 and 2020. Effects on mortality and adverse allograft events were compared with COVID-19-attributed effects. RESULTS: A total of 7725 patients were included in the final analysis. Admissions declined in 2020 by 17%, with the main dip during a 3-month lockdown (–31%) but without a subsequent rebound. Incidences for hospitalization did not increase for any investigated disease entities, whereas decreasing trends were noted for non-COVID-19 pulmonary and urogenital infections (incidence rate ratio 0.8, 95% CI, 0.62 to 1.03, and 0.82, 95% CI, 0.65 to 1.04, respectively). Non-COVID-19 hospital stays were 0.6 days shorter (P=0.03) and not complicated by increased dialysis, ventilation, or intensive care treatment rates. In-hospital and 90-day mortality remained stable. Incidences of severe COVID-19 requiring hospitalization was 0.09 per 1000 patient-days, and in-hospital mortality was 9%. A third (31%) of patients with calcineurin-inhibitor medication and without being hospitalized for COVID-19 reduced doses by at least 25%, which was associated with an increased allograft rejection risk (adjusted hazard ratio 1.29, 95% CI, 1.02 to 1.63). COVID-19 caused 17% of all deaths but had no significant association with allograft rejections. All-cause mortality remained stable (incidence rate ratio 1.15, 95% CI, 0.91 to 1.46), also when restricting analysis to patients with no or outpatient-treated COVID-19 (0.97, 95% CI, 0.76 to 1.25). CONCLUSION: Despite significant collateral effects, mortality remained unchanged during the early COVID-19 pandemic. Considerable temporary reductions in admissions are safe, whereas reducing immunosuppression results in increased allograft rejection risk.

Aims Long-term sequelae may occur after SARS-CoV-2 infection. We comprehensively assessed organ-specific functions in individuals after mild to moderate SARS-CoV-2 infection compared with controls from the general population. Methods and results Four hundred and forty-three mainly non-hospitalized individuals were examined in median 9.6 months after the first positive SARS-CoV-2 test and matched for age, sex, and education with 1328 controls from a population-based German cohort. We assessed pulmonary, cardiac, vascular, renal, and neurological status, as well as patient-related outcomes. Bodyplethysmography documented mildly lower total lung volume (regression coefficient −3.24, adjusted P = 0.014) and higher specific airway resistance (regression coefficient 8.11, adjusted P = 0.001) after SARS-CoV-2 infection. Cardiac assessment revealed slightly lower measures of left (regression coefficient for left ventricular ejection fraction on transthoracic echocardiography −0.93, adjusted P = 0.015) and right ventricular function and higher concentrations of cardiac biomarkers (factor 1.14 for high-sensitivity troponin, 1.41 for N-terminal pro-B-type natriuretic peptide, adjusted P ≤ 0.01) in post-SARS-CoV-2 patients compared with matched controls, but no significant differences in cardiac magnetic resonance imaging findings. Sonographically non-compressible femoral veins, suggesting deep vein thrombosis, were substantially more frequent after SARS-CoV-2 infection (odds ratio 2.68, adjusted P Conclusion Subjects who apparently recovered from mild to moderate SARS-CoV-2 infection show signs of subclinical multi-organ affection related to pulmonary, cardiac, thrombotic, and renal function without signs of structural brain damage, neurocognitive, or quality-of-life impairment. Respective screening may guide further patient management.

Sex development is an intricate and crucial process in all vertebrates that ensures the continued propagation of genetic diversity within a species, and ultimately their survival. Perturbations in this process can manifest as disorders/differences of sex development (DSD). Various transcriptional networks have been linked to development of the gonad into either male or female, which is actively driven by a set of genes that function in a juxtaposed manner and is maintained through the developmental stages to preserve the final sexual identity. One such identified gene is Chromobox homolog 2 (CBX2), an important ortholog of the Polycomb group (PcG) proteins, that functions as both chromatin modifier and highly dynamic transactivator. CBX2 was shown to be an essential factor for gonadal development in mammals, as genetic variants or loss-of-function of CBX2 can cause sex reversal in mice and humans. Here we will provide an overview of CBX2, its biological functions at molecular level, and the CBX2-dependent transcriptional landscape in gonadal development and DSD.

Demand for dynamic random access memory (DRAM) bandwidth has outpaced DRAM transistor performance. Given the options of major process investment to scale beyond sixth-generation graphics double-data-rate (GDDR6) or replace GDDR6 with costly high bandwidth memory (HBM), this article presents a solution that simultaneously increases pin and energy efficiency through the integration of four-level pulse amplitude modulation (PAM-4) into the single-ended memory interface. Building upon the existing GDDR6 architecture, evolutionary modifications to input, output, clocking, and data path, along with the component package design, enable a per-pin data rate of more than 22 Gb/s.

Long-pulse operation of a self-sustained fusion reactor using toroidal magnetic containment requires control over the content of alpha particles produced by D-T fusion reactions. On the one hand, MeV-class alpha particles must stay confined to heat the plasma. On the other hand, decelerated helium ash must be expelled before diluting the fusion fuel. Our kinetic-magnetohydrodynamic hybrid simulations of a large tokamak plasma confirm the existence of a parameter window where such energy-selective confinement can be accomplished by exploiting internal relaxation events known as `sawtooth crashes'. The physical picture -- consisting of a synergy between magnetic geometry, optimal crash duration and rapid particle motion -- is completed by clarifying the role played by magnetic drifts. Besides causing asymmetry between co- and counter-going particle populations, magnetic drifts determine the size of the confinement window by dictating where and how much `reconnection' occurs in particle orbit topology., Comment: Main article: 9 pages, 7 figures. Supplementary material: 9 pages, 15 figures. References: 3 pages. 2021 IAEA TCM EPPI Conference

Supplementary Data from Therapy-Related Transcriptional Subtypes in Matched Primary and Recurrent Head and Neck Cancer

Supplementary Table from Therapy-Related Transcriptional Subtypes in Matched Primary and Recurrent Head and Neck Cancer

Purpose:The genetic relatedness between primary and recurrent head and neck squamous cell carcinomas (HNSCC) reflects the extent of heterogeneity and therapy-driven selection of tumor subpopulations. Yet, current treatment of recurrent HNSCC ignores the molecular characteristics of therapy-resistant tumor populations.Experimental Design:From 150 tumors, 74 primary HNSCCs were RNA sequenced and 38 matched primary/recurrent tumor pairs were both whole-exome and RNA sequenced. Transcriptome analysis determined the predominant classical (CL), basal (BA), and inflamed-mesenchymal (IMS) transcriptional subtypes according to an established classification. Genomic alterations and clonal compositions of tumors were evaluated from whole-exome data.Results:Although CL and IMS subtypes were more common in primary HNSCC with low recurrence rates, the BA subtype was more prevalent and stable in recurrent tumors. The BA subtype was associated with a transcriptional signature of partial epithelial-to-mesenchymal transition (p-EMT) and early recurrence. In 44% of matched cases, the dominant subtype changed from primary to recurrent tumors, preferably from IMS to BA or CL. Expression analysis of prognostic gene sets identified upregulation of hypoxia, p-emt, and radiotherapy resistance signatures and downregulation of tumor inflammation in recurrences compared with index tumors. A relevant subset of primary/recurrent tumor pairs presented no evidence for a common clonal origin.Conclusions:Our study showed a high degree of genetic and transcriptional heterogeneity between primary/recurrent tumors, suggesting therapy-related selection of a transcriptional subtype with characteristics unfavorable for therapy. We conclude that therapy decisions should be based on genetic and transcriptional characteristics of recurrences rather than primary tumors to enable optimally tailored treatment strategies.

Supplementary Figure from Therapy-Related Transcriptional Subtypes in Matched Primary and Recurrent Head and Neck Cancer

During movements, neural signals are translated into muscle fibre shortening, lengthening or they remain isometric. This study investigated cortical excitatory and inhibitory processes in relation to muscle fascicle dynamics during fixed-end rapid contractions. Fourteen adults performed submaximal and maximal ankle dorsiflexions. Single and paired pulse transcranial magnetic stimulation over the cortical representation projecting to the tibialis anterior (TA) was applied during rest, the activation and deactivation phase of contractions to test for short- (SICI) and long-interval intracortical inhibition (LICI) and intracortical facilitation (ICF). Ultrasound images were taken to measure muscle fascicle dynamics of the superficial (TASF) and deep (TADP) TA compartments. The results show significantly greater maximal shortening velocities (p = 0.003, d = 0.26, CI [4.89, 18.52]) and greater maximal fascicle shortening (p = 0.003, d = 0.86, CI [0.29, 3.13]) in TASF than TADP during submaximal dorsiflexions. Significantly lower SICI levels during activation compared to deactivation (p = 0.019, d = 1.12, CI [19.82, 1.76]) and at rest (p SF but not TADP shortening velocity correlated with SICI levels at activation (p = 0.06) and with the rate of torque development (p = 0.02). The results suggest that SICI might be related to muscle fascicle behavior and that intracortical inhibition and excitation are phase-dependently modulated.

Despite intensive basic scientific, translational, and clinical efforts in the last decades, glioblastoma remains a devastating disease with a highly dismal prognosis. Apart from the implementation of temozolomide into the clinical routine, novel treatment approaches have largely failed, emphasizing the need for systematic examination of glioblastoma therapy resistance in order to identify major drivers and thus, potential vulnerabilities for therapeutic intervention. Recently, we provided proof-of-concept for the systematic identification of combined modality radiochemotherapy treatment vulnerabilities via integration of clonogenic survival data upon radio(chemo)therapy with low-density transcriptomic profiling data in a panel of established human glioblastoma cell lines. Here, we expand this approach to multiple molecular levels, including genomic copy number, spectral karyotyping, DNA methylation, and transcriptome data. Correlation of transcriptome data with inherent therapy resistance on the single gene level yielded several candidates that were so far underappreciated in this context and for which clinically approved drugs are readily available, such as the androgen receptor (AR). Gene set enrichment analyses confirmed these results, and identified additional gene sets, including reactive oxygen species detoxification, mammalian target of rapamycin complex 1 (MTORC1) signaling, and ferroptosis/autophagy-related regulatory circuits to be associated with inherent therapy resistance in glioblastoma cells. To identify pharmacologically accessible genes within those gene sets, leading edge analyses were performed yielding candidates with functions in thioredoxin/peroxiredoxin metabolism, glutathione synthesis, chaperoning of proteins, prolyl hydroxylation, proteasome function, and DNA synthesis/repair. Our study thus confirms previously nominated targets for mechanism-based multi-modal glioblastoma therapy, provides proof-of-concept for this workflow of multi-level data integration, and identifies novel candidates for which pharmacological inhibitors are readily available and whose targeting in combination with radio(chemo)therapy deserves further examination. In addition, our study also reveals that the presented workflow requires mRNA expression data, rather than genomic copy number or DNA methylation data, since no stringent correlation between these data levels could be observed. Finally, the data sets generated in the present study, including functional and multi-level molecular data of commonly used glioblastoma cell lines, represent a valuable toolbox for other researchers in the field of glioblastoma therapy resistance.

The editorial of Thermal Engineering of this issue continues the discussion on scientific research needs in vital areas in which thermal engineering has important participation. The main goal is to motivate the readers, within their specialties, to identify possible subjects for their future research. Our modern life would not be possible without electricity and the fuels used in transportation and equipment that bring the so appreciated comfort to the sociedy. Energy is crucial for the development and progress of nations to the point where the level of development of a country is estimated qualitatively by its energy consumption. In these contexts, along with the threat of lack of fossil fuel for the future and the worldwide debate about environemntal impacts, humanity is presented the hard question about how to generate clean energy in a sustainable way facing the estimation that by 2050 the demand of energy will double the demand of the beginning of the century. Oil is the most used fuel nowadays. Its excessive use, however, can birng consequences as for example, its complete depletion and the negative environmental impacts due to the gases generated by its combustion. The International Panel on Climate Change (IPCC) established the goal of stabilizing the level of CO2 concentration below 500 ppm and to limit the increase of the global temperature to 2oC above the pre-industial levels. Taking into consideration the increase need of energy and the relevany of environamental impact matters, renewable energy has been considered an attractive option. It replaces fossil fuels and the tehcnology used for its generation has been substantilly improved in years. Among the most viable sources of renewable energy (solar, wind, thermal, nuclear), bionergy is the one that has the possibility to use the big spetrum of organic substacts (including toxic waste) while at the same time fixes the carbon. Algae is one of those examples. A large range of biofuels as for example, biogas, biohydrogen, biomehtane, biodiesel, bioethanol and biocoal, can be obtained from algae biomass. The mission of Thermal Engineering is to document the scientific progress in areas related to thermal engineering (e.g., energy, oil and renewable fuels). We are confident that we will continue to receive articles’ submissions that contribute to the progress of science.

In this work, we revisit the linear gyro-kinetic theory of geodesic acoustic modes (GAMs) and derive a general dispersion relation for an arbitrary equilibrium distribution function of ions. A bi-Maxwellian distribution of ions is then used to study the effects of ion temperature anisotropy on GAM frequency and growth rate. We find that ion temperature anisotropy yields sensible modifications to both the GAM frequency and growth rate as both tend to increase with anisotropy and these results are strongly affected by the electron to ion temperature ratio.

Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has a remarkable kidney tropism. While kidney effects are common in severe coronavirus disease 2019 (COVID-19), data on non-severe courses are limited. Here we provide a multilevel analysis of kidney outcomes after non-severe COVID-19 to test for eventual kidney sequela. Methods This cross-sectional study investigates individuals after COVID-19 and matched controls recruited from the Hamburg City Health Study (HCHS) and its COVID-19 program. The HCHS is a prospective population-based cohort study within the city of Hamburg, Germany. During the COVID-19 pandemic the study additionally recruited subjects after polymerase chain reaction–confirmed SARS-CoV-2 infections. Matching was performed by age, sex and education. Main outcomes were estimated glomerular filtration rate (eGFR), albuminuria, Dickkopf3, haematuria and pyuria. Results A total of 443 subjects in a median of 9 months after non-severe COVID-19 were compared with 1328 non-COVID-19 subjects. The mean eGFR was mildly lower in post-COVID-19 than non-COVID-19 subjects, even after adjusting for known risk factors {β = −1.84 [95% confidence interval (CI) −3.16 to −0.52]}. However, chronic kidney disease [odds ratio (OR) 0.90 (95% CI 0.48–1.66)] or severely increased albuminuria [OR 0.76 (95% CI 0.49–1.09)] equally occurred in post-COVID-19 and non-COVID-19 subjects. Haematuria, pyuria and proteinuria were also similar between the two cohorts, suggesting no ongoing kidney injury after non-severe COVID-19. Further, Dickkopf3 was not increased in the post-COVID-19 cohort, indicating no systematic risk for ongoing GFR decline [β = −72.19 (95% CI −130.0 to −14.4)]. Conclusion While mean eGFR was slightly lower in subjects after non-severe COVID-19, there was no evidence for ongoing or progressive kidney sequela.

The sizes and shapes of ice crystals influence the radiative properties of clouds, as well as precipitation initiation and aerosol scavenging. However, ice crystal growth mechanisms remain only partially characterized. We present the growth processes of two complex ice crystal habits observed in Arctic mixed-phase clouds during the Ny-Ålesund AeroSol Cloud ExperimeNT campaign. First, are capped-columns with multiple columns growing out of the plates' corners that we define as columns on capped-columns. These ice crystals originated from cycling through the columnar and plate temperature growth regimes, during their vertical transport by in-cloud circulation. Second, is aged rime on the surface of ice crystals having grown into faceted columns or plates depending on the environmental conditions. Despite their complexity, the shapes of these ice crystals allow to infer their growth history and provide information about the in-cloud conditions. Additionally, these ice crystals exhibit complex shapes and could enhance aggregation and secondary ice production., Geophysical Research Letters, 50 (1), ISSN:0094-8276, ISSN:1944-8007

Atmospheric muon neutrinos are produced by meson decays in cosmic-ray-induced air showers. The flux depends on meteorological quantities such as the air temperature, which affects the density of air. Competition between decay and re-interaction of those mesons in the first particle production generations gives rise to a higher neutrino flux when the air density in the stratosphere is lower, corresponding to a higher temperature. A measurement of a temperature dependence of the atmospheric $\nu_{\mu}$ flux provides a novel method for constraining hadro\-nic interaction models of air showers. It is particularly sensitive to the production of kaons. Studying this temperature dependence for the first time requires a large sample of high-energy neutrinos as well as a detailed understanding of atmospheric properties. We report the significant ($> 10 \sigma$) observation of a correlation between the rate of more than 260,000 neutrinos, detected by IceCube between 2012 and 2018, and atmospheric temperatures of the stratosphere, measured by the Atmospheric Infrared Sounder (AIRS) instrument aboard NASA's AQUA satellite. For the observed 10$\%$ seasonal change of effective atmospheric temperature we measure a 3.5(3)$\%$ change in the muon neutrino flux. This observed correlation deviates by about 2-3 standard deviations from the expected correlation of 4.3$\%$ as obtained from theoretical predictions under the assumption of various hadronic interaction models, Comment: Preprint submitted to EPJC

Immune checkpoint inhibition has emerged as an integral part of the standard-of-care for head and neck squamous cell carcinoma (HNSCC) in recurrent and/or metastatic stages. Clinical responses are impressive but remain limited to a minority of patients. Primary resistance of never-responders is considered to derive from host- and tumor-specific characteristics, the latter comprising tumor immune checkpoint activity, immune contexture, tumor mutational burden, neo-antigen load, and others. Secondary resistance of initially responding patients in addition, appears to be driven predominantly by irreversible T-cell exhaustion and therapy-induced selection of tumor cell clones with mutations in critical genes involved in the response to immune checkpoint inhibition. With particular focus on primary resistance against immune checkpoint inhibition, scientific interest of preclinical and clinical researchers currently aims at the development and evaluation of combined modality treatment approaches. Radiotherapy is a highly promising partner in this regard and represents a crucial treatment modality for patients with locally advanced HNSCC. Historically established as cytotoxic anti-cancer treatment, a growing body of evidence has shown additional locoregional and systemic immunomodulatory effects of radiotherapy. These are largely attributed to reprogramming of the tumor microenvironment driven by dying and senescent irradiated tumor and normal tissue cells and the concomitant cascade of danger signals, chemokines, and cytokines which stimulate immune cell recruitment and activation. Moreover, the irradiated state of tumor cells bears interesting analogy to the anti-viral state, since fragments of nuclear and mitochondrial DNA that are released into the cytosol can stimulate cytosolic nucleic acid sensors to produce intra-tumoral type I interferons which are essential to (re-)activate the cancer immunity cycle and (re-)invigorate systemic anti-tumor T-cell responses. Apart from these tumor adjuvanticity enhancing effects, several reports have also described increased tumor antigenicity upon radiotherapy originating from radiation-induced exposure of neo-antigens. Collectively, radiotherapy thus may serve as a means of personalized in situ vaccination which can synergize with immune checkpoint inhibition and may help to undermine primary resistance. First clinical experiences have shown that scheduling and dosing of such combined modality treatment regimens are challenging. Moreover, recent preclinical evidence suggests that particularly the role of radiation-induced cytokines and interferons appears to be complex in such combined modality settings due to their ambiguous effects on tumor and immune cells in the tumor microenvironment. The signaling cascades that orchestrate immune cell (re-)activation and cell fate decisions in irradiated tumor cells, including tumor cell survival, proliferation, and/or metastasis formation, are intimately interconnected and require further in-depth investigation.

Search processes in the natural world are often punctuated by home returns that reset the position of foraging animals, birds, and insects. Many theoretical, numerical, and experimental studies have now demonstrated that this strategy can drastically facilitate search, which could explain its prevalence. To further facilitate search, foragers also work as a group: modifying their surroundings in highly sophisticated ways e.g., by leaving chemical scent trails that imprint the memory of previous excursions. Here, we design a controlled experiment to show that the benefit coming from such ``environmental memory'' is significant even for a single, non-intelligent, searcher that is limited to simple physical interactions with its surroundings. To this end, we employ a self-propelled bristle robot that moves randomly within an arena filled with obstacles that the robot can push around. To mimic home returns, we reset the bristle robot's position at constant time intervals. We show that trails created by the robot give rise to a form of environmental memory that facilitates search by increasing the effective diffusion coefficient. Numerical simulations, and theoretical estimates, designed to capture the essential physics of the experiment support our conclusions and indicate that these are not limited to the particular system studied herein., Comment: 16 pages 11 figures

For magnetic confinement fusion in tokamak plasmas, some of the limitations to the particle and energy confinement times are caused by turbulence and collisions between particles in toroidal geometry, which determine the "anomalous" and the neoclassical transport, respectively. In this work, we focus on the implementation of neoclassical physics in the gyrokinetic code TRIMEG, which is a TRIangular MEsh-based Gyrokinetic code that can handle both the closed and open field line geometries of a divertor tokamak. We report on the implementation of a simplified Lorentz collision operator in TRIMEG. Since the code uses an unstructured mesh, a procedure for calculating the flux surface averages of particle and energy fluxes and the bootstrap current is derived without relying on the poloidal coordinate, which is useful also for other simulations in unstructured meshes. With the newly implemented collision operator, we study electron transport and bootstrap current generation for various simplified and realistic geometries. In comparison to neoclassical theory, good agreement is obtained for the large aspect ratio case regarding the particle and energy fluxes as well as the bootstrap current. However, some discrepancies are observed at moderate aspect ratio and for a case with the realistic geometry of the ASDEX Upgrade tokamak. These deviations can be explained by different treatments and approximations in theory and simulation. In this paper, we demonstrate the capability to calculate the electron transport and bootstrap current generation in TRIMEG, which will allow for the self-consistent inclusion of neoclassical effects in gyrokinetic simulations in the future.

The LIGO/Virgo collaboration published the catalogs GWTC-1, GWTC-2.1 and GWTC-3 containing candidate gravitational-wave (GW) events detected during its runs O1, O2 and O3. These GW events can be possible sites of neutrino emission. In this paper, we present a search for neutrino counterparts of 90 GW candidates using IceCube DeepCore, the low-energy infill array of the IceCube Neutrino Observatory. The search is conducted using an unbinned maximum likelihood method, within a time window of 1000 s and uses the spatial and timing information from the GW events. The neutrinos used for the search have energies ranging from a few GeV to several tens of TeV. We do not find any significant emission of neutrinos, and place upper limits on the flux and the isotropic-equivalent energy emitted in low-energy neutrinos. We also conduct a binomial test to search for source populations potentially contributing to neutrino emission. We report a non-detection of a significant neutrino-source population with this test., Comment: Submitted to ApJ