Scale and tempo of brain expansion in the course of human evolution implies that this process was driven by a positive feedback. The ‘cultural drive’ hypothesis suggests a possible mechanism for the runaway brain-culture coevolution wherein high-fidelity social learning results in accumulation of cultural traditions which, in turn, promote selection for still more efficient social learning. Here we explore this evolutionary mechanism by means of computer modeling. Simulations confirm its plausibility in a social species in a socio-ecological situation that makes the sporadic invention of new beneficial and cognitively demanding behaviours possible. The chances for the runaway brain-culture coevolution increase when some of the culturally transmitted behaviours are individually beneficial while the others are group-beneficial. In this case, ‘cultural drive’ is possible under varying levels of between-group competition and migration. Modeling implies that brain expansion can receive additional boost if the evolving mechanisms of social learning are costly in terms of brain expansion (e.g., rely on complex neuronal curcuits) and tolerant to the complexity of information transferred, that is, make it possible to transfer complex skills and concepts easily. Human language presumably fits this description. Modeling also confirms that the runaway brain-culture coevolution can be accelerated by additional positive feedback loops via population growth and lifespan extension, and that between-group competition and cultural group selection can facilitate the propagation of group-beneficial behaviours and remove maladaptive cultural traditions from the population’s culture, which individual selection is unable to do.

Technological advances in DNA sequencing over the last decade now permit the production and curation of large genomic datasets in an increasing number of non-model species. Additionally, this new data provides the opportunity for combining datasets, resulting in larger studies with a broader taxonomic range. Whilst the benefits of new sequencing platforms are obvious, shifts in sequencing technology can also pose challenges for those wishing to combine new sequencing data with data sequenced on older platforms. Here, we outline the types of studies where the use of curated data might be beneficial, and highlight potential biases that might be introduced by combining data from different sequencing platforms. As an example of the challenges associated with combining data across sequencing platforms, we focus on the impact of the shift in Illumina's base calling technology from a four-channel to a two-channel system. We caution that when data is combined from these two systems, erroneous guanine base calls that result from the two-channel chemistry can make their way through a bioinformatic pipeline, eventually leading to inaccurate and potentially misleading conclusions. We also suggest solutions for dealing with such potential artifacts, which make samples sequenced on different sequencing platforms appear more differentiated from one another than they really are. Finally, we stress the importance of archiving tissue samples and the associated sequences for the continued reproducibility and reusability of sequencing data in the face of ever-changing sequencing platform technology.

Background: Clinical trial simulations and pharmacometric modeling of biomarker profiles for under-represented groups are challenging because the underlying studies frequently do not have sufficient participants from these groups. Objectives: To investigate generative adversarial networks (GANs), an artificial intelligence (AI) technology that enables realistic simulations of complex patterns, for modeling clinical biomarker profiles of under-represented groups. Methods: GANs consist of generator and discriminator neural networks that operate in tandem. GAN architectures were developed for modeling univariate and joint distributions of a panel of 16 diabetes-relevant biomarkers from the National Health and Nutrition Examination Survey (NHANES), which contains laboratory and clinical biomarker data from a population-based sample of individuals of all ages, racial groups, and ethnicities. Conditional GANs were used to model biomarker profiles for race/ethnicity categories. GAN performance was assessed by comparing GAN outputs to test data. Results: The biomarkers exhibited non-normal distributions and varied in their bivariate correlation patterns. Univariate distributions were modeled with generator and discriminator neural networks consisting of two dense layers with rectified linear unit-activation. The distributions of GAN-generated biomarkers were similar to the test data distributions. The joint distributions of the biomarker panel in the GAN-generated data were dispersed and overlapped with the joint distribution of the test data as assessed by three multi-dimensional projection methods. Conditional GANs satisfactorily modeled the joint distribution of the biomarker panel in the Black, Hispanic, White, and “Other” race/ethnicity categories. Conclusions: GAN are a promising AI approach for generating virtual patient data with realistic biomarker distributions for under-represented race/ethnicity groups.

What is Different About Pulsed Field Ablation … Everything?David E. Haines, MDBeaumont Health System, Oakland University William Beaumont School of Medicine, Royal Oak, Michigan, USAFunding: NoneDisclosures: Dr. Haines is a consultant for Ablacon, Inc., Affera, Inc., Biosense Webster, Inc., Boston Scientific Corporation, Inc., Medtronic, Inc., and Philips Healthcare, Inc. He has equity interest in Ablacon, Inc. and Affera, Inc.Corresponding author:David E. Haines, MD Director, Heart Rhythm Center Professor, Cardiovascular Medicine Oakland University William Beaumont School of Medicine 3601 West 13 Mile Road Royal Oak, MI 48073 248-898-4176 [email protected] the time of early preclinical reports of the efficacy, speed and safety of pulsed field ablation (PFA), the interventional electrophysiology community has been waiting in anxious anticipation for its clinical approval and release. As most people actively engaged in interventional electrophysiology know, PFA is the technology that creates myocardial lesions with trains of very high voltage pulses that are nanoseconds or microseconds in duration.1 This form of ablation is nonthermal, and cell injury/death is created by electroporation of the organelles and sarcolemmal membrane, with cell death occurring via apoptosis as well as other mechanisms.2 Because myocardial ablation is the result of an electrical field effect, electrode-tissue proximity is important but contact force is not. The physiological effect of acute PFA is striking in that there is immediate loss of electrical signal so that acute pulmonary vein isolation is achieved from a single shot catheter in under one second (figure 1). Preclinical animal studies have demonstrated effective chronic lesions that have been reliably transmural for atrial ablations.3 But the most compelling aspect of PFA is the apparent tissue selectivity of this energy form. At doses sufficient to create reliable transmural lesions in animals, there is little or no discernable injury to the esophagus, phrenic nerves, coronary arteries or distal pulmonary veins, in contrast to ablation with thermal techniques such as radiofrequency or cryoballoon ablation, where thermal collateral injury to contiguous structures can lead to substantial morbidity and death.4,5So, what is the catch? Is there any downside to PFA compared to other ablation technologies? The answer is that we do not know. Despite a substantial body of preclinical experience published to date, clinical outcomes with PFA are just starting to be reported. In this issue of theJournal , Neven et al describe the acute pathological effects of PFA in a swine model over the first 60 minutes and compare them to findings from chronic animals at 3 weeks and 3 months.6 For their study, they mostly employed a suction electrode for epicardial delivery (some lesions created with a circular catheter under blood) and delivered a single unipolar cathodal pulse of mostly 200 J (some dose ranging performed with chronic lesions between 30 – 200 J) at various sites on the right and left ventricles. Pathology on acute specimens was examined 0 to 60 minutes post ablation, and chronic specimens were examined after 3 weeks and 3 months. They reported that acute lesions showed contraction band necrosis and interstitial edema, and at >/= 3 weeks, there was sharply demarcated connective tissue that evolved into scar.What new insights have we gained from the present study that we can now apply to the burgeoning field of clinical PFA? Unfortunately, despite considerable effort put forth by these investigators, their results are not generalizable to the wider field of PFA. No study reporting outcomes using one proprietary PFA system will be necessarily applicable to results from a competing proprietary system. The field of catheter ablation has become accustomed to interchangeability of one RF generator or catheter for another. That is because the thermodynamics of electrical resistive heating of tissue is predictable, and there are limited operator parameters (power, time, contact force) and design parameters (electrode size, convective cooling) that affect tissue heating. The biological effects of hyperthermia are straightforward and reproducible; thus, it is possible for scientists and clinicians to compare experiences from one proprietary RFA system to another and draw some generalizable conclusions. 7 Not so with PFA. To paraphrase an old saying, “When you’ve seen one PFA system, you’ve seenone PFA system.” The operator-controlled parameters are familiar (energy level, catheter-tissue position), but the design parameter variations are dizzying and most importantly unknown to us . A precedent was set early in the development of this field that the PFA waveform was proprietary, and that the commercialized product was a “black box”. A few of the parameters that can be modulated by the manufacturer include pulse amplitude, pulse duration, unipolar/bipolar, monophasic/biphasic, interpulse delay, interphase delay, pulse train number, pulse train duration and more. For example, the waveform used by Neven et al. was a milliseconds duration, monophasic damped sine wave generated by an external defibrillator (Lifepak 9, Physio-Control, Inc; Redmond, WA) and delivered in a unipolar cathodal fashion to an indifferent dispersive skin electrode. In contrast, most PFA systems deliver pulses are nanoseconds to microseconds in duration with a range of variation of the other parameters listed above (figure 2). Thus, the outcomes from ablation with a proprietary PFA system cannot and should not be extrapolated to different proprietary systems that may have dramatically different waveforms that result in different procedural outcomes.One of the major unanswered questions in the field of PFA is what is the time course of clinical effect after energy delivery? The hope and anticipation has been that lesions created by PFA will be more durable than those created with thermal ablation techniques (RFA or cryoablation). A dramatic features of catheter ablation with PFA is that disappearance of the local electrograms is seen immediately after pulse delivery (figure 1). Unfortunately, this does not necessarily indicate that a permanent lesion has been created. Beyond the border of irreversible electroporation there is a penumbra of reversible electroporation manifested by loss of the electrical signal but maintenance of viability. In the heart, this has been described pathologically as a rim of tissue with enhanced with hematoxylin and eosin staining, and maintenance of mitochondrial activity as delineated by cytochrome C oxidase staining.8 Thus, the acute end point of conduction block and loss of local electrogram signal employed in RF ablation does not indicate that a permanent lesion has been made with PFA. With myocardial ablation, the extent of reversible electroporation beyond the border of permanent injury has not been fully characterized, nor has the time course of recovery of normal function. There are many anecdotal reports of pulmonary vein reconnection after acute PVI with PFA in patients with atrial fibrillation. Unfortunately, the present study did not report mapping data and compare the extent of acute physiological effect to the acute pathological lesions.Therefore, a challenge for operators performing PFA is that acute electrogram voltage mapping cannot be used as a metric to assess therapeutic effect. The strategy adopted for PVI with PFA is to deliver a very large ablation dose, since injury to collateral structures is rare.9 The larger the energy delivery, the more likely it will be that permanent block is achieved. One experienced operator concluded “Go big or go home”. Once again, the pulse wave morphology, pulse width and pulse train number are proprietary features of the system that are preselected. The operator can choose different pulse amplitudes, but in almost all cases the maximum setting is selected. Is there such a thing as too much energy delivery with PFA? In preclinical studies, very high energy delivery has been associated with large volume microbubble production and evidence of thermal effects (charring) at the electrode-tissue interface. Creating a large uncontrolled lesion may be appropriate for a narrowly defined anatomical target like the pulmonary vein antrum but may not be appropriate for targeting other arrhythmogenic substrates because of concern about excessive injury to the surrounding myocardium. The consequences of very high PFA energy delivery in the clinical setting are unknown but most experts believe that there should be an upper safe limit established for each unique PFA system. So, the manufacturers will decide the dosing that the clinician will use. Will the recommended dose be safe and effective for all patients going forward? Time will tell. Ideally, we should have a method to assess myocardial viability after PFA prior to removing catheters from the heart, so that touch up ablations with improved catheter-tissue proximity can be performed. With RFA, promising technologies like real time magnetic resonance imaging,10 near field ultrasound imaging11 and NADH fluorescence12 have been explored, but their utility in assessing acute PFA lesions is unknown.The era of PFA is exciting and full of promise, but there are many unanswered questions that remain. As we gain more clinical experience with PFA, the benefits and limitations of the various commercial systems will become more obvious. Because of its speed and safety, PFA is likely to become the dominant mode of ablation for PVI, but we need to move forward in this field cautiously with recognition that all of the consequences of this ablation mode are still unknown.References:Verma A, Asivatham SJ, Deneke T, Castellvi Q, Neal RE. Primer on pulsed electrical field ablation: understanding the benefits and limitations. Circulation Arrhythm Electrophysiol. 2021; 14: e010086. doi.org/10.1161/CIRCEP.121.010086.Napotnik TB, Polajzer T, Miklavcic D. Cell death due to electroporation – A review. Bioielectrochemistry. 2021; 141:107871.Stewart MT, Haines DE, Verma A, Kirchhof N, Barka N, Grassl E, Howard B. Intracardiac pulsed field ablation: Proof of feasibility in a chronic porcine model. Heart Rhythm. 2019; 16:754-764. doi: 10.1016/j.hrthm.2018.10.030.Bradley CJ, Haines DE. Pulsed field ablation for pulmonary vein isolation in the treatment of atrial fibrillation. J Cardiovasc Electrophysiol. 2020 Aug;31(8):2136-2147. doi: 10.1111/jce.14414.Koruth J.S., Kuroki K., Kawamura I., et. al.: Pulsed field ablation vs radiofrequency ablation: esophageal injury in a novel porcine model. Circ Arrhythm Electrophysiol 2020; 13:Neven K, van Driel VJHM, Vink A, du Pre BC, van Wessel H, Futing A, Doevendans PA, Wittkampf FHM, van Es R. Characteristics and time course of acute and chronic myocardial lesion formation after electroporation ablation in the porcine model. J Cardiovasc Electrophysiol. 2022 (in press).Haines DE. Biophysics and Pathophysiology of Radiofrequency Lesion Formation. In: Catheter Ablation of Cardiac Arrhythmias, 4th Edition. Huang SKS, Miller JM, editors. Philadelphia, PA: Elsevier Saunders Publishing, 2020.Nakagawa H, Castellvi, Neal R, Girouard S, Kuroda S, Hussein AA, Saliba WI, Wazni OM. Histological characterization of reversible and irreversible ventricular lesion boundaries produced by pulsed field ablation. Heart Rhythm 2021; 18: S151-S152. doi: 0.1016/j.hrthm.2021.06.386Reddy VY, Neuzil P, Koruth JS, Petru J, Funosako M, Cochet H, Sediva L, Chovanec M, Dukkipati SR, Jais P. Pulsed field ablation for pulmonary vein isolation in atrial fibrillation. J Am Coll Cardiol 2019; 74: pp. 315-326. doi: 10.1016/j.jacc.2019.04.021.Mukherjee RK, Roujol S, Chubb H, Harrison J, Williams S, Whitaker J, O’Neill L, Silberbauer J, Neji R, Schneider R, Pohl T, Lloyd T, O’Neill M, Razavi R. Epicardial electroanatomical mapping, radiofrequency ablation, and lesion imaging in the porcine left ventricle under real-time magnetic resonance imaging guidance-an in vivo feasibility study. Europace. 2018 Sep 1;20(FI2):f254-f262. doi: 10.1093/europace/eux341.Haines DE, Wright M, Harks E, Deladi S, Fokkenrood S, Brink R, Belt H, Kolen AF, Mihajlovic N, Zuo F, Rankin D, Stoffregen W, Cockayne D, Cefalu J. Near-Field Ultrasound Imaging During Radiofrequency Catheter Ablation: Tissue Thickness and Epicardial Wall Visualization and Assessment of Radiofrequency Ablation Lesion Formation and Depth. Circ Arrhythm Electrophysiol. 2017 Dec;10(12):e005295. doi: 10.1161/CIRCEP.117.005295.Swift L, Gil DA, Jaimes R 3rd, Kay M, Mercader M, Sarvazyan N. Visualization of epicardial cryoablation lesions using endogenous tissue fluorescence. Circ Arrhythm Electrophysiol. 2014 Oct;7(5):929-37. doi: 10.1161/CIRCEP.114.001750.Figures:Figure 1 – A circular ablation catheter is positioned in the right superior pulmonary vein antrum (PV 1 thorugh 9) and high frequency near field pulmonary vein potentials were recorded. Immediately after delivery of a PFA pulse, the pulmonary vein potentials are eliminated.Figure 2 – A. Irreversible electroporation waveform similar to that employed by Neven et al. from a Lifepak 9 defibrillator (Physio-control Service Manual No. 803763-06, Physio-control, Redmond, WA). B. Representative waveform from a pulsed field ablation generator using a train of biphasic microsecond duration pulses.

Saline-alkali soils are widely distributed in China, affecting plant growth and sustainable development of ecosystems. This study characterized the effects of planting Melia azedarach L. on chemical properties and microbial communities in saline-alkali soils [bare (CK), bulk (BS) and rhizosphere soil (RS)]. Compared with the bare soil, planting Melia azedarach L. lowered salt content and concentrations of extractable Na, K, Ca, Mg and Cl-, but significantly increased organic matter, total nitrogen, total phosphorus, available phosphorus, soil urease activity and alkaline phosphatase activity in the rhizosphere soil. High-throughput sequencing results indicated that bacterial richness and diversity decreased in the order RS>BS>CK. The richness of fungi was ranked RS>CK>BS, and their diversity decreased in the order CK>RS>BS. The three dominant bacterial phyla were Proteobacteria, Actinobacteria and Bacteroidetes, and the three dominant fungal phyla were Ascomycota, Basidiomycota and Glomeromycota. Redundancy analysis indicated that total phosphorus concentration and alkaline phosphatase activity significantly influenced bacterial diversity, whereas soil Ca and Mg concentrations were closely related to the fungal community diversity. In conclusion, planting Melia azedarach L. improved soil properties, increased the diversity and richness of soil microbial communities, and thus ameliorated the saline-alkali soil.

Denitrification plays a central role in the global nitrogen cycle, reducing and removing nitrogen from marine and terrestrial ecosystems. The flux of nitrogen species through this pathway has a widespread impact, affecting ecological carrying capacity, agriculture, and climate. Nitrite reductase (Nir) and nitric oxide reductase (NOR) are the two central enzymes in this pathway. Here we present a previously unreported Nir domain architecture in members of Phylum Chloroflexi. Phylogenetic analyses of protein domains within Nir indicate that an ancestral horizontal transfer and fusion event produced this chimeric domain architecture. We also identify an expanded genomic diversity of a rarely reported nitric oxide reductase subtype, eNOR. Together, these results suggest a greater diversity of denitrification enzyme arrangements exist than have been previously reported.

Background: This study investigates the use of modern machine learning (ML) techniques to improve prediction of survival after orthotopic heart transplantation (OHT). Methods: Retrospective study of adult patients undergoing primary, isolated OHT between 2000-2019 as identified in the United Network for Organ Sharing (UNOS) registry. The primary outcome was one-year post-transplant survival. Patients were randomly divided into training (80%) and validation (20%) sets. Dimensionality reduction and data re-sampling were employed during training. Multiple machine learning algorithms were combined into a final ensemble ML model. Discriminatory capability was assessed using area under receiver-operating-characteristic curve (AUROC), net reclassification index (NRI), and decision curve analysis (DCA). Results: A total of 33,657 OHT patients were evaluated. One-year mortality was 11% (n=3,738). In the validation cohort, the AUROC of singular logistic regression was 0.649 (95% CI 0.628-0.670) compared to 0.691 (95% CI 0.671-0.711) with random forest, 0.691 (95% CI 0.671-0.712) with deep neural network, and 0.653 (95% CI 0.632-0.674) with Adaboost. A final ensemble ML model was created that demonstrated the greatest improvement in AUROC: 0.764 (95% CI 0.745-0.782) (p<0.001). The ensemble ML model improved predictive performance by 72.9% ±3.8% (p<0.001) as assessed by NRI compared to logistic regression. DCA showed the final ensemble method improved risk prediction across the entire spectrum of predicted risk as compared to all other models (p<0.001). Conclusions: Modern ML techniques can improve risk prediction in OHT compared to traditional approaches. This may have important implications in patient selection, programmatic evaluation, allocation policy, and patient counseling and prognostication.

The study of mutations that impact fertility has a catch-22. Fertility mutants are often lost since they cannot simply be propagated and maintained. This has hindered progress in understanding the genetics of fertility. In mice, several molecules are found to be required for the interactions between the sperm and egg, with JUNO and IZUMO1 being the only known receptor pair on the egg and sperm surface, respectively. In C. elegans, a total of 12 proteins on the sperm or oocyte have been identified to mediate their interactions. Majority of these genes were identified through mutants isolated from genetic screens. In this review, we summarize the several key screening strategies that led to the identification of fertility mutants in C. elegans and provide a perspective about future research using genetic approaches. Recently, advancements in new technologies such as high-throughput sequencing and Crispr-based genome editing tools have accelerated the molecular, cell biological, and mechanistic analysis of fertility genes. We review how these valuable tools advance our understanding of the molecular underpinnings of C. elegans fertilization and complement fertility research in humans and other species.

Background and Purpose: Improvement of cognitive deficits in schizophrenia remains an unmet need due to the lack of new therapies and drugs. Recent studies have reported that fingolimod, an immunomodulatory drug for treating multiple sclerosis, demonstrates anti-inflammatory and neuroprotective effects in several neurological disease models. This suggests its usefulness for ameliorating cognitive dysfunction in schizophrenia. Herein, we assessed the efficacy profile and mechanism of fingolimod in a rat model of phencyclidine (PCP)-induced schizophrenia. Experimental Approach: Sprague-Dawley rats were treated with PCP for 14 days. The therapeutic effect of fingolimod on cognitive function was assessed using the Morris water maze and fear conditioning tests. Hippocampal neurogenesis and the expression of astrocytes and microglia were evaluated by immunostaining. Cytokine expression was quantified using multiplexed flow cytometry. Brain-derived neurotrophic factor expression and phosphorylation of extracellular signal-regulated kinase were determined using western blot analysis. Key Results: Fingolimod attenuated cognitive deficits and restored hippocampal neurogenesis in a dose-dependent manner in PCP-treated rats. Fingolimod treatment exerted anti-inflammatory effects by inhibiting microglial activation and IL-6 and IL-1β pro-inflammatory cytokine expression. The underlying mechanism involves the upregulation of brain-derived neurotrophic factor protein expression and activation of the extracellular signal-regulated kinase signalling pathway. Conclusion and Implications: To the best of our knowledge, this is the first preclinical study to assess the effects of fingolimod on cognitive function in schizophrenia models. Our results support the role of the immune system in cognitive alterations in schizophrenia and highlight the potential of immunomodulatory strategies to improve cognitive deficits in schizophrenia.

Studies of populations oscillating through time have a long history in ecology as these dynamics can help provide insights into the causes of population regulation. A particularly difficult challenge is determining the relative role of deterministic versus stochastic forces in producing this oscillatory behavior. Another classic ecological study area is the study of spatial synchrony which also has helped unravel underlying population dynamic principles. One possible approach to understanding the causes of population cycles is based on the idea that a focus on spatiotemporal behavior, oscillations in coupled populations, can provide much further insight into the relative role of deterministic versus stochastic forces. Using ideas based on concepts from statistical physics, we develop results showing that in a system with coupling between adjacent populations, a study of spatial synchrony provides much information about the underlying causes of oscillations. Novel, to ecology, measures of spatial synchrony are a key step.

Changing climatic conditions and unsustainable land use are perceived as major threats to savannas worldwide. In the past, land use in African savannas was dominated by livestock-farming as one of the major economic products, which led to degraded, shrub encroached pastures in many regions. One response to this widespread degradation is a shift from land use dominated by cattle to strategies characterized by animal compositions with more mixed feeding regimes and higher browser proportions. However, the consequences for ecosystem properties and processes remain so far largely unclear. We used the ecohydrological, spatially explicit savanna model EcoHyD to assess the impacts of two contrasting, herbivore-related land use strategies on a Namibian savannah: grazing versus browsing herbivores. We varied the densities of grazers and browsers and determined the resulting composition and diversity of the plant community, total vegetation cover, soil moisture and water use by plants. Our results show that properties making plants less attractive to herbivores were best adapted to different densities of grazing (cattle) or browsing (pure browsing wildlife) animals. Also, properties leading to a competitive advantage under limited water availability were among the dominant ones. Overall, the results are in line with our expectations: we found heavy shrub encroachment with a loss of the perennial grass matrix under high stocking rates of cattle. A novel and unexpected result was that regardless of the density of browsers, grass cover and plant functional diversity were significantly higher in wildlife scenarios. This increased grass cover, but also the higher total cover improved water uptake by plants. We conclude that in contrast to grazers, browsers even in high densities do not lead to ecosystem degradation, but rather sustain a diverse vegetation with high cover of perennial grasses over a long time, implying also a lower erosion risk and higher provision of ecosystem services.

Myeloid cell leukemia-1 (MCL1), an anti-apoptotic BCL-2 family protein plays a major role in the control of apoptosis as the regulator of mitochondrial permeability which is deregulated in various solid and hematological malignancies. Interaction of the executioner proteins Bak/Bax with anti-apoptotic MCL1 and its cellular composition determines the apoptotic or survival pathway. This study highlighted the deleterious MCL1-Bax stabilizing effect of the mutation V220F on MCL1 structure through computational protein-protein interaction predictions and molecular dynamics simulations. The single point mutation at V220F was selected as it is residing at the hydrophobic core region of BH3 conserved domain, the site of Bax binding. The molecular dynamics simulation studies showed increase in stability of the mutated MCL1 before and after Bax binding comparable with the native MCL1. The clusters from free energy landscape found out structural variation in folding pattern with additional helix near the BH3 domain in the mutated structure. This loop to helix structural change in the mutated complex favored stable interaction of the complex and also induced Bax conformational change. Moreover, molecular mechanics based binding free energy calculations confirmed increased affinity of Bax towards mutated MCL1. Residue-wise interaction network analysis showed the individual residues in Bax binding responsible for the change in stability and interaction due to the protein mutation. In conclusion, the overall findings from the study reveal that the presence of V220F mutation on MCL1 is responsible for the structural confirmational change leading to disruption of its biological functions which might be responsible for tumorigenesis. The mutation could possibly be used as future diagnostic markers in treating cancers.

This is the first report of a case of COVID-19 after allogeneic stem cell transplantation. Our case suggests that COVID-19 may exist without characteristic CT images, especially in immunocompromised hosts, such as patients after transplantation.

BACKGROUND: Workplace burnout can result in negative consequences for clinicians and patients. We assessed burnout prevalence and sources among pediatric hematology/oncology inpatient nurses, ambulatory nurses, physicians (MDs), and advanced practice providers (APPs) by evaluating effects of job demands and involvement in patient safety events (PSEs). METHODS: A cross-sectional survey (Maslach Burnout Inventory) measured emotional exhaustion, depersonalization, and reduced personal accomplishment. The NASA Task Load Index measured mental demand, physical demand, temporal demand, effort, and frustration. Relative weights analyses estimated the unique contributions of tasks and PSEs on burnout. Post-hoc analyses evaluated open-response comments for burnout factors. RESULTS: Burnout prevalence was 33%, 20%, 34% and 33% in inpatient nurses, ambulatory nurses, and MD, and APPs respectively (N=481, response rate 69%). Reduced personal accomplishment was significantly higher in inpatient nurses than MDs & APPs. Job frustration was the most significant predictor of burnout across all four cohorts. Other significant predictors of burnout included temporal demand (nursing groups & MDs) effort (inpatient nurses & MDs) and PSE involvement (ambulatory nurses). Open-response comments identified time constraints, lack of administrator support, insufficient institutional support for self-care, and inadequate staffing and/or turnover as sources of frustration. CONCLUSIONS: All four clinician groups reported substantial levels of burnout, and job demands predicted burnout. The body of knowledge on job stress and workplace burnout supports targeting organizational-level sources, versus individual-level factors, as the most effective prevention and reduction strategy. This study elaborates on this evidence by identifying structural drivers of burnout within a multidisciplinary context of pediatric hematology/oncology clinicians.

Compounds with (NHC)→E coordination bond are being generated and their chemistry is being explored over the past 15 years (NHC= N-heterocyclic carbenes, E = main group elements). Many examples of species with N-heterocyclic olefins (NHOs) are known, which exhibit umpolung chemistry. Increasing number of chemical species, which carry NHC as a functional unit, are being reported. There is a need to understand their electronic structure. Alkylated imidazole oximes (cationic, found useful in medicinal chemistry) ((NHC)-C(H)=N-OH(+)) carry NHC unit as a functional group. Similarly, the corresponding nitroso-N-heterocyclic olefins ((NHC)=C(R)-N=O) also carry NHC as a functional unit. It is important to establish the interaction between the NHC unit and the rest part of the molecule in these species. Density functional (DFT) study has been carried out to explore the electronic structure details of a few oximes and nitroso NHOs. The results indicate that a structure with NHC→C coordination interaction can be considered as one of the resonance structures of these species.

Purpose: We designed a multicenter, retrospective study to investigate the current trends in initial management of reflux with respect to EAU guidelines in Urology clinics of our country. Materials and Methods: The study group consisted of 1988 renal units (RU) of 1345 patients treated surgically due to VUR between years 2003-2017 in 9 different institutions. Patients were divided into 2 groups according to time of initial treatment and also grouped according to risk factors by “EAU guidelines on VUR”. Results: 1426 RUs were treated initially conservatively and 562 RUs were initially treated with surgery. In initially surgically treated group, success rates of surgery decreased significantly in low and moderate risk groups after 2013 (p=0.046, p=0.0001, respectively), while success rates were not significantly different in high risk group (p=0.46). While 26.6% of patients in low risk group were initially surgically treated before 2013, this rate has increased to 34.6% after 2013, but the difference was not statistically significant (p=0.096). However, performing surgery as the initial treatment approach increased significantly in both moderate and high risk groups (p=0.000 and p=0.0001, respectively) after 2013. Overall success rates of endoscopic and UNC operations were 65% and 92.9% before 2013, 60% and 78.5% after 2013, respectively. Thus the overall success rate for surgery was 72.6%. There was significant difference between success rates of UNC operations before and after 2013(p=0.000), while the difference was not significant in the STING group (p=0.076). Conclusion: Current trends in management of reflux in our country do not yet follow the EAU guidelines on VUR in low and moderate risk groups.

Long isolation period for suspected child cases was proposed based in one case. New evidence suggests that children are not as dangerous as they seemed, as a vehicle for this infection. We must be cautious when making recommendations for a disease that affects millions of people, based on just one case.

Fangzhu, which has been lost for thousands of years, is an ancient device for water collection from air, its mechanism is unknown yet. Here we elucidate its possible surface-geometric and related physical properties by the oldest the Yin-Yang contradiction. In view of modern nanotechnology, we reveal that Fangzhu’s water-harvesting ability is obtained through a hydrophilic-hydrophobic hierarchy of the surface, mimicking spider web’s water collection, lotus or desert beetle’s water intake. The convex-concave hierarchy of Fangzhu’s textured surface enables it to have low wettability(high geometric potential) to attract water molecules from air through the nano-scale convex surface and transfer the attracted water along the concave surface to the collector. A mathematical model is established to reveal three main factors affecting its effectiveness, i.e., the air velocity, the surface temperature and surface structure. The lost technology can play an extremely important role in modern architecture, ocean engineering, transportation and others to catch water from air for everyday use.