bluuebunny/crossref_metadata_2025 huggingface dataset:
Histone-Net: a multi-paradigm computational framework for histone occupancy and modification prediction
Authors: Asim Muhammad Nabeel , Ibrahim Muhammad Ali , Malik Muhammad Imran , Razzak Imran , Dengel Andreas , Ahmed Sheraz
Published: July 2022

Deep exploration of histone occupancy and covalent post-translational modifications (e.g., acetylation, methylation) is essential to decode gene expression regulation, chromosome packaging, DNA damage, and transcriptional activation. Existing computational approaches are unable to precisely predict histone occupancy and modifications mainly due to the use of sub-optimal statistical representation of histone sequences. For the establishment of an improved histone occupancy and modification landscape for multiple histone markers, the paper in hand presents an end-to-end computational multi-paradigm framework “Histone-Net”. To learn local and global residue context aware sequence representation, Histone-Net generates unsupervised higher order residue embeddings (DNA2Vec) and presents a different application of language modelling, where it encapsulates histone occupancy and modification information while generating higher order residue embeddings (SuperDNA2Vec) in a supervised manner. We perform an intrinsic and extrinsic evaluation of both presented distributed representation learning schemes. A comprehensive empirical evaluation of Histone-Net over ten benchmark histone markers data sets for three different histone sequence analysis tasks indicates that SuperDNA2Vec sequence representation and softmax classifier-based approach outperforms state-of-the-art approach by an average accuracy of 7%. To eliminate the overhead of training separate binary classifiers for all ten histone markers, Histone-Net is evaluated in multi-label classification paradigm, where it produces decent performance for simultaneous prediction of histone occupancy, acetylation, and methylation.
A hybrid adjacency and time-based data structure for analysis of temporal networks
Authors: Hilsabeck Tanner , Arastuie Makan , Xu Kevin S.
Published: July 2022

Dynamic or temporal networks enable representation of time-varying edges between nodes. Conventional adjacency-based data structures used for storing networks such as adjacency lists were designed without incorporating time and can thus quickly retrieve all edges between two sets of nodes (anode-based slice) but cannot quickly retrieve all edges that occur within a given time interval (atime-based slice). We propose a hybrid data structure for storing temporal networks that stores edges in both an adjacency dictionary, enabling rapid node-based slices, and an interval tree, enabling rapid time-based slices. Our hybrid structure also enablescompound slices, where one needs to slice both over nodes and time, either by slicing first over nodes or slicing first over time. We further propose an approach for predictive compound slicing, which attempts to predict whether a node-based or time-based compound slice is more efficient. We evaluate our hybrid data structure on many real temporal network data sets and find that they achieve much faster slice times than existing data structures with only a modest increase in creation time and memory usage.
Establishing an Ehlers-Danlos Syndrome Clinic: Lessons Learned
Authors: Knight Dacre R. T. , Confiado Sunnie M. , Bruno Katelyn A. , Fairweather DeLisa , Seymour-Sonnier Andrea M. , Jain Angita , Gehin Jessica M. , Whelan Emily R. , Culberson Joshua H. , Munipalli Bala , Dawson Nancy L. , Rozen Todd D. , Wick Joseph J. , Kotha Archana
Published: July 2022

In a large academic medical center, patient requests from the community and internal referrals for evaluation of suspected hypermobility conditions were being denied consultation because services specific to this condition were not available. We identified this gap and developed a comprehensive evaluation for this unique patient population. The objective of this paper is to demonstrate a solution for improving outcomes in a neglected patient population by establishing an innovative outpatient clinic specifically tailored for patients with EDS.

We describe the lessons learned on establishing a specialty clinic for treating patients with hypermobility syndromes including hypermobile Ehlers-Danlos syndrome (hEDS) and hypermobile syndrome disorder (HSD). Findings were collected from a patient focus group that was instrumental in understanding common care gaps. We document the firsthand perspective of three patients presenting with hypermobility accompanied by joint pain and denote the complicated state of healthcare in recognizing and treating this condition. A summary of patient demographics and characteristics was collected from patients seen in the clinic from November 14, 2019 to April 13, 2021.

The firsthand accounts illustrate the challenges faced in treating this condition and the need for, and success of, this clinic using a coordinated care model. Demographics reveal a primarily white female population under the age of 50 with many comorbidities. Genetic testing was largely negative, with more patients diagnosed with HSD than hEDS.

Our shared experience of launching a successful EDS clinic may assist other clinicians in establishing similar care models.
Learning to See: Using Mixed OR Methods to Model Radiology Staff Workload and Support Decision Making in CT
Authors: Conlon Mary , Molloy Owen
Published: July 2022

Demand for Computer Tomography (CT) is growing year on year and the population of Ireland is increasingly aging and ailing. Anecdotally, radiology staff reported increasing levels of workload associated with the patient profile. In this paper, we propose a framework combining discrete event simulation (DES) modeling and soft systems methodologies (SSM) for use in healthcare which captures the staff experience and metrics to evidence workload. The framework was applied in a single-scanner CT department, which completes circa 6000 examinations per year. The scanner case load consists of unscheduled work [inpatient (IP) and emergency department (ED)] and scheduled work [outpatient (OP) and general practitioner (GP)]. The three stage framework is supported by qualitative and quantitative methods and uses DES as a decision support tool. Firstly, workflow mapping and system dynamics are used to conceptualize the problem situation and instigate a preliminary data analysis. Secondly, SSM tools are used to identify components for a DES model and service improvement scenarios. Lastly, the DES model results are used to inform decision-making and identify a satisficing solution. Data from the DES model provided evidence of the differing workload (captured in staff time) for the IP and OP cohorts. For non-contrast examinations, inpatient workload is 2.5 times greater than outpatient. Average IP process delays of 11.9 min were demonstrated compared to less than 1 min for OP. The findings recommend that OP and IP diagnostic imaging be provided separately, for efficiency, workload management and infection control reasons.
An appropriate treatment interval does not affect the prognosis of patients with breast Cancer
Authors: Gao Wei , Wang Jiaxing , Yin Sifei , Geng Cuizhi , Xu Binghe
Published: July 2022

Purpose

Major public health emergencies may lead to delays or alterations in the treatment of patients with breast cancer at each stage of diagnosis and treatment. How much do these delays and treatment changes affect treatment outcomes in patients with breast cancer?

Methods

This review summarized relevant research in the past three decades and identified the effect of delayed treatment on the prognosis of patients with breast cancer in terms of seeking medical treatment, neoadjuvant treatment, surgery, postoperative chemotherapy, radiotherapy, and targeted therapies.

Results

Delay in seeking medical help for ≥12 weeks affected the prognosis. Surgical treatment within 4 weeks of diagnosis did not affect patient prognosis. Starting neoadjuvant chemotherapy within 8 weeks after diagnosis, receiving surgical treatment at 8 weeks or less after the completion of neoadjuvant chemotherapy, and receiving radiotherapy 8 weeks after surgery did not affect patient prognosis. Delayed chemotherapy did not increase the risk of relapse in patients with luminal A breast cancer. Every 4 weeks of delay in the start of postoperative chemotherapy in patients with luminal B, triple-negative, or HER2-positive breast cancer treated with trastuzumab will adversely affect the prognosis. Targeted treatment delays in patients with HER2-positive breast cancer should not exceed 60 days after surgery or 4 months after diagnosis. Radiotherapy within 8 weeks after surgery did not increase the risk of recurrence in patients with early breast cancer who were not undergoing adjuvant chemotherapy.

Conclusion

Different treatments have different time sensitivities, and the careful evaluation and management of these delays will be helpful in minimizing the negative effects on patients.
Legal Realism and ‘Working’ Rules
Authors: Frydrych David
Published: July 2022

The American Legal Realists offered several hypotheses about alternative drivers of official decision-making (i.e., considerations other than the rules on the books). This article identifies a tension between two of those hypotheses: the ‘extra-legal’ factors and ‘working’ rules. This tension gets exacerbated in Frederick Schauer’s account of Legal Realism, one which places his Dislocated Determinacy thesis—about working rules constituting an additional ground for the existence of ‘easy’ cases and determinacy across a legal system—into doubt.
Iterating on multiple collections in synchrony
Authors: PERNA STEFANO , TANNEN VAL , WONG LIMSOON
Published: July 2022

Modern programming languages typically provide some form of comprehension syntax which renders programs manipulating collection types more readable and understandable. However, comprehension syntax corresponds to nested loops in general. There is no simple way of using it to express efficient general synchronized iterations on multiple ordered collections, such as linear-time algorithms for low-selectivity database joins. Synchrony fold is proposed here as a novel characterization of synchronized iteration. Central to this characterization is a monotonicisBeforepredicate for relating the orderings on the two collections being iterated on and an antimonotoniccanSeepredicate for identifying matching pairs in the two collections to synchronize and act on. A restriction is then placed on Synchrony fold, cutting its extensional expressive power to match that of comprehension syntax, giving us Synchrony generator. Synchrony generator retains sufficient intensional expressive power for expressing efficient synchronized iteration on ordered collections. In particular, it is proved to be a natural generalization of the database merge join algorithm, extending the latter to more general database joins. Finally, Synchrony iterator is derived from Synchrony generator as a novel form of iterator. While Synchrony iterator has the same extensional and intensional expressive power as Synchrony generator, the former is better dovetailed with comprehension syntax. Thereby, algorithms requiring synchronized iterations on multiple ordered collections, including those for efficient general database joins, become expressible naturally in comprehension syntax.
Clustered colouring of graph classes with bounded treedepth or pathwidth
Authors: Norin Sergey , Scott Alex , Wood David R.
Published: July 2022

The clustered chromatic number of a class of graphs is the minimum integer
$k$
such that for some integer
$c$
every graph in the class is
$k$
-colourable with monochromatic components of size at most
$c$
. We determine the clustered chromatic number of any minor-closed class with bounded treedepth, and prove a best possible upper bound on the clustered chromatic number of any minor-closed class with bounded pathwidth. As a consequence, we determine the fractional clustered chromatic number of every minor-closed class.
Pattern diversity and isolation enhancement of UWB MIMO antenna based on characteristic modes for mobile terminals
Authors: Jayant Shailesh , Srivastava Garima , Kumar Sachin
Published: July 2022

A printed ultra-wideband (UWB) multiple input multiple output antenna with isolation enhancement and pattern diversity is presented, which is based on characteristic modes (CM) for upcoming wireless mobile platforms. The presented antenna is composed of dual UWB antenna elements (AEs) – an antipodal Vivaldi and a circular-shaped monopole positioned on the two opposite edges of the antenna's rectangular-shaped ground surface. The two AEs are capable to stimulate distinct modes in the ground surface and therefore obtaining the required distinct radiation (far-field) patterns and highly isolated AEs without introducing any decoupling structure (DS). The measured results demonstrate that both AEs are UWB with an operating frequency from 2.6 to 11 GHz. The measured isolation is more than 30.1 dB with a maximum value of 55 dB in UWB. The peak realized gain is over 0.83 dBi. The radiation efficiency is greater than 75%. The Envelope Correlation Coefficient is <0.08.
Intelligenzsteigerung durch Neuroenhancement?
Authors: Neubauer Aljoscha C. , Wood Guilherme
Published: July 2022

Zusammenfassung. Die menschliche Intelligenz gehört zu den bestuntersuchten psychologischen Merkmalen, in denen interindividuelle Differenzen bestehen. Die mehr als 100jährige Forschungsgeschichte hat einen hoch belastbaren Wissensstand hervorgebracht; dieser umfasst die Definition, die Psychometrie, die (ontogenetische) Entwicklung, die Struktur, die Vorhersagekraft für real-life-Variablen, das Wissen über elementar-kognitive, verhaltensgenetische und neurobiologische Grundlagen der Intelligenz, u.v.m. Jüngst steht zudem die Frage des ‚enhancements‘ der Intelligenz im Fokus, eine Frage, die nicht zuletzt durch die aktuelle philosophische Strömung des Transhumanismus stark an Bedeutung gewinnt. Der Transhumanismus nimmt eine substanzielle Erhöhung (enhancement) von Fähigkeiten und anderen (auch) psychologischen Eigenschaften des Menschen ins Zentrum und postuliert, dass ein soziokultureller Fortschritt – und letztlich das Überlegen des Homo Sapiens und unseres Planeten – erst durch technologischen Fortschritt ermöglicht werde. Viele Transhumanisten stellen eine substanzielle Steigerung der Intelligenz in den Vordergrund, die primär durch (neuro–)‌technologische und pharmakologische Maßnahmen zu bewerkstelligen seien. Diese Debatten sind jedoch oft gekennzeichnet durch übertrieben optimistische Annahmen der Möglichkeiten moderner neurowissenschaftlicher Methoden bei gleichzeitiger Vernachlässigung der potenziellen negativen Folgen für das Individuum, für die Gesellschaften und insgesamt für unsere Spezies. Im gegenständlichen Überblicksbeitrag werden behaviorale, neuroelektrische und pharmakologische Methoden im Hinblick auf ihr aktuelles Potenzial einer Steigerung der individuellen Intelligenz analysiert. Die zwischenzeitlich zu diesen Fragen vorliegenden experimentellen Studien, sowie verfügbare Metaanalysen lassen allerdings den Schluss zu, dass bislang keine der gegenwärtig verfügbaren Methoden das Potenzial haben, die individuelle Intelligenz substanziell zu steigern. Und selbst falls solche möglicherweise in absehbarer Zeit zur Verfügung stünden, müssen zuvor sowohl individuelle als auch gesellschaftliche (negative) Konsequenzen einer kritischen Analyse unterzogen werden. Diese sind Gegenstand einer abschließenden Diskussion.
Understanding Mechanisms of Media Use for the Social Sharing of	Emotion
Authors: Choi Mina , Toma Catalina L.
Published: July 2022

Abstract. The social sharing of emotion is the process of communicating with others about one’s significant emotional experiences. Recent research has shown that interpersonal media such as texting, voice calling, and social network site posts are widely used for social sharing, yet it has not investigated how and why people use these media. This article takes on the task of investigating the mechanism responsible for media selection for the first instance of social sharing. A survey of undergraduates ( N = 227) shows that respondents’ media use for sharing positive and negative events was driven by their perceptions of media affordances and by their habitual media use with the target of their disclosure. For positive events, respondents articulated preferences for accessibility, while for negative events, they preferred bandwidth and privacy affordances. Habitual media use was the strongest predictor of media use for social sharing, but the perceived importance of these affordances predicted media use above and beyond media habits. These findings extend the social-sharing framework and the literature on media selection in social contexts.
The HDO Cycle on Mars: Comparison of ACS Observations With GCM Simulations
Authors: Rossi Loïc , Vals Margaux , Alday Juan , Montmessin Franck , Fedorova Anna , Trokhimovskiy Alexander , Korablev Oleg , Lefèvre Franck , Gonzalez‐Galindo Francisco , Luginin Mikhail , Bierjon Antoine , Forget François , Millour Ehouarn
Published: July 2022

The D/H ratio and its implications on the atmospheric escape, make it an essential observable to study the current and past inventory of water on Mars. With the arrival of the Trace Gas Orbiter around Mars, new measurements of the D/H ratio are now available and require tools to interpret the observations and understand the HDO cycle. We here present simulations of an updated version of the Laboratoire de Météorologie Dynamique Mars Global Climate Model which includes HDO and in particular the fractionation processes it undergoes. We compare our model simulations with the HDO observations in solar occultation from the Atmospheric Chemistry Suite mid‐infrared channel on board the Trace Gas Orbiter (Alday et al., 2021; https://doi.org/10.5281/ZENODO.5100448). The model successfully reproduces the general trends of the D/H ratio, indicating that the main physical processes are captured by theory. A consistent simulation of condensation processes is found to be key in the representation of the D/H ratio. Improvements in the representation of clouds and on the water cycle will help improving the representation of the HDO cycle and better help extrapolate back in times the conditions of water escape on Mars.
Gene-based polygenic risk scores analysis of alcohol use disorder in African Americans
Authors: Lai Dongbing , Schwantes-An Tae-Hwi , Abreu Marco , Chan Grace , Hesselbrock Victor , Kamarajan Chella , Liu Yunlong , Meyers Jacquelyn L. , Nurnberger John I. , Plawecki Martin H. , Wetherill Leah , Schuckit Marc , Zhang Pengyue , Edenberg Howard J. , Porjesz Bernice , Agrawal Arpana , Foroud Tatiana
Published: July 2022

Genome-wide association studies (GWAS) in admixed populations such as African Americans (AA) have limited sample sizes, resulting in poor performance of polygenic risk scores (PRS). Based on the observations that many disease-causing genes are shared between AA and European ancestry (EA) populations, and some disease-causing variants are located within the boundaries of these genes, we proposed a novel gene-based PRS framework (PRSgene) by using variants located within disease-associated genes. Using the AA GWAS of alcohol use disorder (AUD) from the Million Veteran Program and the EA GWAS of problematic alcohol use as the discovery GWAS, we identified 858 variants from 410 genes that were AUD-related in both AA and EA. PRSgene calculated using these variants were significantly associated with AUD in three AA target datasets (P-values ranged from 7.61E−05 to 6.27E−03; Betas ranged from 0.15 to 0.21) and outperformed PRS calculated using all variants (P-values ranged from 7.28E−03 to 0.16; Betas ranged from 0.06 to 0.18). PRSgene were also associated with AUD in an EA target dataset (P-value = 0.02, Beta = 0.11). In AA, individuals in the highest PRSgene decile had an odds ratio of 1.76 (95% CI: 1.32–2.34) to develop AUD compared to those in the lowest decile. The 410 genes were enriched in 54 Gene Ontology biological processes, including ethanol oxidation and processes involving the synaptic system, which are known to be AUD-related. In addition, 26 genes were targets of drugs used to treat AUD or other diseases that might be considered for repurposing to treat AUD. Our study demonstrated that the gene-based PRS had improved performance in evaluating AUD risk in AA and provided new insight into AUD genetics.
The epidemiology of endodontic complexity in general dental practice: a prevalence study
Authors: Essam Obyda , Kasperek Dariusz , Boyle Edward L. , Jarad Fadi
Published: July 2022

Aim To determine the prevalence and the epidemiology of the factors influencing endodontic complexities in general dental practice.

Method Eligible cases where endodontic treatment was indicated as a treatment option were collected by a total of 30 general dental practitioners based in the UK. Online-based Endodontic Complexity Assessment Tool (E-CAT) was used to determine the perceived complexity of each case. In total, 22 categories, including patient- and tooth-related factors, were recorded.

Results Collectively, 435 non-surgical root canal treatment cases were assessed. Overall, 72% of the root canal treatments encountered in general dental practice were found to be either uncomplicated (Class I) or moderately complicated (Class II) and can be considered within the remit of general dental practitioners. Despite the relatively equal distribution of the assessed teeth, the proportion of extraction as a proposed treatment for posterior teeth was more than double that of anterior teeth.

Conclusion The results obtained in this study provide a good resource and databank for researchers, educators, public health commissioners and academic institutions to access a wide range of information concerning the prevalence and distribution of endodontic complexity.
Stanniocalcin 2 drives malignant transformation of human glioblastoma cells by targeting SNAI2 and Matrix Metalloproteinases
Authors: Yun Eun-Jin , Kim Donghwi , Hsieh Jer-Tsong , Baek Seung Tae
Published: July 2022

Glioblastoma multiforme (GBM) is the most malignant brain tumor and is refractory to conventional therapies. Although previous studies have proposed that the interaction between gene mutations and the external environment leads to the occurrence of GBM, the pathogenesis of GBM is still unclear and much remains to be studied. Herein, we show an association between human glycoprotein stanniocalcin-2 (STC2) and aggressive GBM progression, and demonstrate the underlying mechanism. Elevated STC2 expression and secretion greatly increase GBM cell growth and invasive phenotypes. Mechanistically, both, conditioned media (CM) containing STC2 and recombinant STC2, can induce the transformation of GBM cells into more malignant phenotypes by upregulating the expression of the epithelial-mesenchymal transition transcription factor, snail family transcription repressor 2 (SNAI2) as well as matrix metalloproteinases (MMPs). Moreover, we further demonstrate that the oncogenic function of STC2 in GBM is mediated through the MAPK signaling pathway. Collectively, these results identify the mechanism of STC2 targeting SNAI2 and MMPs through the MAPK pathway in GBM, and provide insights into a potential therapeutic strategy for GBM.
Oncogenic TRIB2 interacts with and regulates PKM2 to promote aerobic glycolysis and lung cancer cell procession
Authors: Liu Yuan-Rong , Song Dan-Dan , Liang Dong-Min , Li You-Jie , Yan Yun-Fei , Sun Hong-Fang , Zhang Mei-Ling , Hu Jin-Xia , Zhao Yu-Long , Liang Yan , Li Yan-Mei , Yang Zhen , Wang Ran-Ran , Zheng Hou-Feng , Wang Pingyu , Xie Shu-Yang
Published: July 2022

PKM2 is an important regulator of the aerobic glycolysis that plays a vital role in cancer cell metabolic reprogramming. In general, Trib2 is considered as a “pseudokinase”, contributing to different kinds of cancer. However, the detailed roles of TRIB2 in regulating cancer metabolism by PKM2 remain unclear. This study demonstrated that TRIB2, not a “pseudokinase”, has the kinase activity to directly phosphorylate PKM2 at serine 37 in cancer cells. The elevated pSer37-PKM2 would subsequently promote the PKM2 dimers to enter into nucleus and increase the expression of LDHA, GLUT1, and PTBP1. The aerobic glycolysis is then elevated to promote cancer cell proliferation and migration in TRIB2- or PKM2-overexpressed cultures. The glucose uptake and lactate production increased, but the ATP content decreased in TRIB2- or PKM2-treated cultures. Experiments of TRIB2−/− mice further supported that TRIB2 could regulate aerobic glycolysis by PKM2. Thus, these results reveal the new kinase activity of TRIB2 and its mechanism in cancer metabolism may be related to regulating PKM2 to promote lung cancer cell proliferation in vitro and in vivo, suggesting promising therapeutic targets for cancer therapy by controlling cancer metabolism.
Selective activation and expansion of regulatory T cells using lipid encapsulated mRNA encoding a long-acting IL-2 mutein
Authors: de Picciotto Seymour , DeVita Nicholas , Hsiao Chiaowen Joyce , Honan Christopher , Tse Sze-Wah , Nguyen Mychael , Ferrari Joseph D. , Zheng Wei , Wipke Brian T. , Huang Eric
Published: July 2022

Interleukin-2 (IL-2) is critical for regulatory T cell (Treg) function and homeostasis. At low doses, IL-2 can suppress immune pathologies by expanding Tregs that constitutively express the high affinity IL-2Rα subunit. However, even low dose IL-2, signaling through the IL2-Rβ/γ complex, may lead to the activation of proinflammatory, non-Treg T cells, so improving specificity toward Tregs may be desirable. Here we use messenger RNAs (mRNA) to encode a half-life-extended human IL-2 mutein (HSA-IL2m) with mutations promoting reliance on IL-2Rα. Our data show that IL-2 mutein subcutaneous delivery as lipid-encapsulated mRNA nanoparticles selectively activates and expands Tregs in mice and non-human primates, and also reduces disease severity in mouse models of acute graft versus host disease and experimental autoimmune encephalomyelitis. Single cell RNA-sequencing of mouse splenic CD4+T cells identifies multiple Treg states with distinct response dynamics following IL-2 mutein treatment. Our results thus demonstrate the potential of mRNA-encoded HSA-IL2m immunotherapy to treat autoimmune diseases.
Healthy cloned offspring derived from freeze-dried somatic cells
Authors: Wakayama Sayaka , Ito Daiyu , Hayashi Erika , Ishiuchi Takashi , Wakayama Teruhiko
Published: July 2022

Maintaining biodiversity is an essential task, but storing germ cells as genetic resources using liquid nitrogen is difficult, expensive, and easily disrupted during disasters. Our aim is to generate cloned mice from freeze-dried somatic cell nuclei, preserved at −30 °C for up to 9 months after freeze drying treatment. All somatic cells died after freeze drying, and nucleic DNA damage significantly increased. However, after nuclear transfer, we produced cloned blastocysts from freeze-dried somatic cells, and established nuclear transfer embryonic stem cell lines. Using these cells as nuclear donors for re-cloning, we obtained healthy cloned female and male mice with a success rate of 0.2–5.4%. Here, we show that freeze-dried somatic cells can produce healthy, fertile clones, suggesting that this technique may be important for the establishment of alternative, cheaper, and safer liquid nitrogen-free bio-banking solutions.
A versatile active learning workflow for optimization of genetic and metabolic networks
Authors: Pandi Amir , Diehl Christoph , Yazdizadeh Kharrazi Ali , Scholz Scott A. , Bobkova Elizaveta , Faure Léon , Nattermann Maren , Adam David , Chapin Nils , Foroughijabbari Yeganeh , Moritz Charles , Paczia Nicole , Cortina Niña Socorro , Faulon Jean-Loup , Erb Tobias J.
Published: July 2022

Optimization of biological networks is often limited by wet lab labor and cost, and the lack of convenient computational tools. Here, we describe METIS, a versatile active machine learning workflow with a simple online interface for the data-driven optimization of biological targets with minimal experiments. We demonstrate our workflow for various applications, including cell-free transcription and translation, genetic circuits, and a 27-variable synthetic CO2-fixation cycle (CETCH cycle), improving these systems between one and two orders of magnitude. For the CETCH cycle, we explore 1025 conditions with only 1,000 experiments to yield the most efficient CO2-fixation cascade described to date. Beyond optimization, our workflow also quantifies the relative importance of individual factors to the performance of a system identifying unknown interactions and bottlenecks. Overall, our workflow opens the way for convenient optimization and prototyping of genetic and metabolic networks with customizable adjustments according to user experience, experimental setup, and laboratory facilities.
Atypical sideways recognition of CD1a by autoreactive γδ T cell receptors
Authors: Wegrecki Marcin , Ocampo Tonatiuh A. , Gunasinghe Sachith D. , von Borstel Anouk , Tin Shin Yi , Reijneveld Josephine F. , Cao Thinh-Phat , Gully Benjamin S. , Le Nours Jérôme , Moody D. Branch , Van Rhijn Ildiko , Rossjohn Jamie
Published: July 2022

CD1a is a monomorphic antigen-presenting molecule on dendritic cells that presents lipids to αβ T cells. Whether CD1a represents a ligand for other immune receptors remains unknown. Here we use CD1a tetramers to show that CD1a is a ligand for Vδ1+γδ T cells. Functional studies suggest that two γδ T cell receptors (TCRs) bound CD1a in a lipid-independent manner. The crystal structures of three Vγ4Vδ1 TCR-CD1a-lipid complexes reveal that the γδ TCR binds at the extreme far side and parallel to the long axis of the β-sheet floor of CD1a’s antigen-binding cleft. Here, the γδ TCR co-recognises the CD1a heavy chain and β2 microglobulin in a manner that is distinct from all other previously observed γδ TCR docking modalities. The ‘sideways’ and lipid antigen independent mode of autoreactive CD1a recognition induces TCR clustering on the cell surface and proximal T cell signalling as measured by CD3ζ phosphorylation. In contrast with the ‘end to end’ binding of αβ TCRs that typically contact carried antigens, autoreactive γδ TCRs support geometrically diverse approaches to CD1a, as well as antigen independent recognition.
Engineering consortia by polymeric microbial swarmbots
Authors: Wang Lin , Zhang Xi , Tang Chenwang , Li Pengcheng , Zhu Runtao , Sun Jing , Zhang Yunfeng , Cui Hua , Ma Jiajia , Song Xinyu , Zhang Weiwen , Gao Xiang , Luo Xiaozhou , You Lingchong , Chen Ye , Dai Zhuojun
Published: July 2022

Synthetic microbial consortia represent a new frontier for synthetic biology given that they can solve more complex problems than monocultures. However, most attempts to co-cultivate these artificial communities fail because of the winner-takes-all in nutrients competition. In soil, multiple species can coexist with a spatial organization. Inspired by nature, here we show that an engineered spatial segregation method can assemble stable consortia with both flexibility and precision. We create microbial swarmbot consortia (MSBC) by encapsulating subpopulations with polymeric microcapsules. The crosslinked structure of microcapsules fences microbes, but allows the transport of small molecules and proteins. MSBC method enables the assembly of various synthetic communities and the precise control over the subpopulations. These capabilities can readily modulate the division of labor and communication. Our work integrates the synthetic biology and material science to offer insights into consortia assembly and serve as foundation to diverse applications from biomanufacturing to engineered photosynthesis.
An expanded reference map of the human gut microbiome reveals hundreds of previously unknown species
Authors: Leviatan Sigal , Shoer Saar , Rothschild Daphna , Gorodetski Maria , Segal Eran
Published: July 2022

The gut is the richest ecosystem of microbes in the human body and has great influence on our health. Despite many efforts, the set of microbes inhabiting this environment is not fully known, limiting our ability to identify microbial content and to research it. In this work, we combine new microbial metagenomic assembled genomes from 51,052 samples, with previously published genomes to produce a curated set of 241,118 genomes. Based on this set, we procure a new and improved human gut microbiome reference set of 3594 high quality species genomes, which successfully matches 83.65% validation samples’ reads. This improved reference set contains 310 novel species, including one that exists in 19% of validation samples. Overall, this study provides a gut microbial genome reference set that can serve as a valuable resource for further research.
Wavelength-multiplexed hook nanoantennas for machine learning enabled mid-infrared spectroscopy
Authors: Ren Zhihao , Zhang Zixuan , Wei Jingxuan , Dong Bowei , Lee Chengkuo
Published: July 2022

Infrared (IR) plasmonic nanoantennas (PNAs) are powerful tools to identify molecules by the IR fingerprint absorption from plasmon-molecules interaction. However, the sensitivity and bandwidth of PNAs are limited by the small overlap between molecules and sensing hotspots and the sharp plasmonic resonance peaks. In addition to intuitive methods like enhancement of electric field of PNAs and enrichment of molecules on PNAs surfaces, we propose a loss engineering method to optimize damping rate by reducing radiative loss using hook nanoantennas (HNAs). Furthermore, with the spectral multiplexing of the HNAs from gradient dimension, the wavelength-multiplexed HNAs (WMHNAs) serve as ultrasensitive vibrational probes in a continuous ultra-broadband region (wavelengths from 6 μm to 9 μm). Leveraging the multi-dimensional features captured by WMHNA, we develop a machine learning method to extract complementary physical and chemical information from molecules. The proof-of-concept demonstration of molecular recognition from mixed alcohols (methanol, ethanol, and isopropanol) shows 100% identification accuracy from the microfluidic integrated WMHNAs. Our work brings another degree of freedom to optimize PNAs towards small-volume, real-time, label-free molecular recognition from various species in low concentrations for chemical and biological diagnostics.
Bixbyite-type Ln2O3 as promoters of metallic Ni for alkaline electrocatalytic hydrogen evolution
Authors: Sun Hongming , Yan Zhenhua , Tian Caiying , Li Cha , Feng Xin , Huang Rong , Lan Yinghui , Chen Jing , Li Cheng-Peng , Zhang Zhihong , Du Miao
Published: July 2022

The active-site density, intrinsic activity, and durability of Ni-based catalysts are critical to their application in industrial alkaline water electrolysis. This work develops a kind of promoters, the bixbyite-type lanthanide metal sesquioxides (Ln2O3), which can be implanted into metallic Ni by selective high-temperature reduction to achieve highly efficient Ni/Ln2O3hybrid electrocatalysts toward hydrogen evolution reaction. The screened Ni/Yb2O3catalyst shows the low overpotential (20.0 mV at 10 mA cm−2), low Tafel slope (44.6 mV dec−1), and excellent long-term durability (360 h at 500 mA cm−2), significantly outperforming the metallic Ni and benchmark Pt/C catalysts. The remarkable hydrogen evolution activity and stability of Ni/Yb2O3are attributed to that the Yb2O3promoter with high oxophilicity and thermodynamic stability can greatly enlarge the active-site density, reduce the energy barrier of water dissociation, optimize the free energy of hydrogen adsorption, and avoid the oxidation corrosion of Ni.
Structures of LIG1 that engage with mutagenic mismatches inserted by polβ in base excision repair
Authors: Tang Qun , Gulkis Mitchell , McKenna Robert , Çağlayan Melike
Published: July 2022

DNA ligase I (LIG1) catalyzes the ligation of the nick repair intermediate after gap filling by DNA polymerase (pol) β during downstream steps of the base excision repair (BER) pathway. However, how LIG1 discriminates against the mutagenic 3′-mismatches incorporated by polβ at atomic resolution remains undefined. Here, we determine the X-ray structures of LIG1/nick DNA complexes with G:T and A:C mismatches and uncover the ligase strategies that favor or deter the ligation of base substitution errors. Our structures reveal that the LIG1 active site can accommodate a G:T mismatch in the wobble conformation, where an adenylate (AMP) is transferred to the 5′-phosphate of a nick (DNA-AMP), while it stays in the LIG1-AMP intermediate during the initial step of the ligation reaction in the presence of an A:C mismatch at the 3′-strand. Moreover, we show mutagenic ligation and aberrant nick sealing of dG:T and dA:C mismatches, respectively. Finally, we demonstrate that AP-endonuclease 1 (APE1), as a compensatory proofreading enzyme, removes the mismatched bases and interacts with LIG1 at the final BER steps. Our overall findings provide the features of accurate versus mutagenic outcomes coordinated by a multiprotein complex including polβ, LIG1, and APE1 to maintain efficient repair.
Monomethyl auristatin antibody and peptide drug conjugates for trimodal cancer chemo-radio-immunotherapy
Authors: Hingorani Dina V. , Allevato Michael M. , Camargo Maria F. , Lesperance Jacqueline , Quraishi Maryam A. , Aguilera Joseph , Franiak-Pietryga Ida , Scanderbeg Daniel J. , Wang Zhiyong , Molinolo Alfredo A. , Alvarado Diego , Sharabi Andrew B. , Bui Jack D. , Cohen Ezra E. W. , Adams Stephen R. , Gutkind J. Silvio , Advani Sunil J.
Published: July 2022

Locally advanced cancers remain therapeutically challenging to eradicate. The most successful treatments continue to combine decades old non-targeted chemotherapies with radiotherapy that unfortunately increase normal tissue damage in the irradiated field and have systemic toxicities precluding further treatment intensification. Therefore, alternative molecularly guided systemic therapies are needed to improve patient outcomes when applied with radiotherapy. In this work, we report a trimodal precision cytotoxic chemo-radio-immunotherapy paradigm using spatially targeted auristatin warheads. Tumor-directed antibodies and peptides conjugated to radiosensitizing monomethyl auristatin E (MMAE) specifically produce CD8 T cell dependent durable tumor control of irradiated tumors and immunologic memory. In combination with ionizing radiation, MMAE sculpts the tumor immune infiltrate to potentiate immune checkpoint inhibition. Here, we report therapeutic synergies of targeted cytotoxic auristatin radiosensitization to stimulate anti-tumor immune responses providing a rationale for clinical translational of auristatin antibody drug conjugates with radio-immunotherapy combinations to improve tumor control.
Mechanistic basis for maintenance of CHG DNA methylation in plants
Authors: Fang Jian , Jiang Jianjun , Leichter Sarah M. , Liu Jie , Biswal Mahamaya , Khudaverdyan Nelli , Zhong Xuehua , Song Jikui
Published: July 2022

DNA methylation is an evolutionarily conserved epigenetic mechanism essential for transposon silencing and heterochromatin assembly. In plants, DNA methylation widely occurs in the CG, CHG, and CHH (H = A, C, or T) contexts, with the maintenance of CHG methylation mediated by CMT3 chromomethylase. However, how CMT3 interacts with the chromatin environment for faithful maintenance of CHG methylation is unclear. Here we report structure-function characterization of the H3K9me2-directed maintenance of CHG methylation by CMT3 and its Zea mays ortholog ZMET2. Base-specific interactions and DNA deformation coordinately underpin the substrate specificity of CMT3 and ZMET2, while a bivalent readout of H3K9me2 and H3K18 allosterically stimulates substrate binding. Disruption of the interaction with DNA or H3K9me2/H3K18 led to loss of CMT3/ZMET2 activity in vitro and impairment of genome-wide CHG methylation in vivo. Together, our study uncovers how the intricate interplay of CMT3, repressive histone marks, and DNA sequence mediates heterochromatic CHG methylation.
Removal and recovery of ammonia from simulated wastewater using Ti3C2Tx MXene in flow electrode capacitive deionization
Authors: Mansoor Naqsh E. , Diaz Luis A. , Shuck Christopher E. , Gogotsi Yury , Lister Tedd E. , Estrada David
Published: July 2022

Flowing electrode capacitive deionization systems (FE-CDI) have recently garnered attention because of their ability to prevent cross contamination and operate in uninterrupted cycles ad infinitum. Typically, FE-CDI electrodes suffer from low conductivity, reducing deionization performance. Utilization of higher mass loadings to combat this leads to poor rheological properties. Herein, Ti3C2Tx MXene was introduced as 1 mg mL−1 slurry electrodes in an FE-CDI system for the removal and recovery of ammonia from simulated agricultural wastewater. The electrode performance was evaluated by operating the FE-CDI system with a feed solution of 500 mg L−1 NH4Cl running in batch mode at a constant voltage of 1.20 and −1.20 V in charging and discharging modes, respectively. Despite the low loading, Ti3C2Tx flowing electrodes showed markedly improved performance, achieving 60% ion removal efficiency in a saturation time of 115 min with an adsorption capacity of 460 mg g−1. To understand the high adsorption performance of the electrodes, physiochemical and structural analysis was done via a variety of characterization techniques such as SEM, TEM, XRD, DLS, and Raman spectroscopy. Cyclic voltammetry and galvanostatic charge/discharge profiles were obtained to evaluate the electrochemical properties of the electrodes. The system proved to be an energy-saving technology by exhibiting a charge efficiency of 58–70% while operating at an energy consumption of 0.45 kWh kg−1. A 92% regeneration efficiency showed that the electrodes were stable and suitable for long term and scalable usage. The results demonstrate that MXenes have the potential to improve the FE-CDI process for energy-efficient removal and recovery of ammonia.
Antibody evasion by SARS-CoV-2 Omicron subvariants BA.2.12.1, BA.4 and BA.5
Authors: Wang Qian , Guo Yicheng , Iketani Sho , Nair Manoj S. , Li Zhiteng , Mohri Hiroshi , Wang Maple , Yu Jian , Bowen Anthony D. , Chang Jennifer Y. , Shah Jayesh G. , Nguyen Nadia , Chen Zhiwei , Meyers Kathrine , Yin Michael T. , Sobieszczyk Magdalena E. , Sheng Zizhang , Huang Yaoxing , Liu Lihong , Ho David D.
Published: July 2022

SARS-CoV-2 Omicron subvariants BA.2.12.1 and BA.4/5 have surged notably to become dominant in the United States and South Africa, respectively1,2. These new subvariants carrying further mutations in their spike proteins raise concerns that they may further evade neutralizing antibodies, thereby further compromising the efficacy of COVID-19 vaccines and therapeutic monoclonals. We now report findings from a systematic antigenic analysis of these surging Omicron subvariants. BA.2.12.1 is only modestly (1.8-fold) more resistant to sera from vaccinated and boosted individuals than BA.2. However, BA.4/5 is substantially (4.2-fold) more resistant and thus more likely to lead to vaccine breakthrough infections. Mutation at spike residue L452 found in both BA.2.12.1 and BA.4/5 facilitates escape from some antibodies directed to the so-called class 2 and 3 regions of the receptor-binding domain3. The F486V mutation found in BA.4/5 facilitates escape from certain class 1 and 2 antibodies but compromises the spike affinity for the viral receptor. The R493Q reversion mutation, however, restores receptor affinity and consequently the fitness of BA.4/5. Among therapeutic antibodies authorized for clinical use, only bebtelovimab retains full potency against both BA.2.12.1 and BA.4/5. The Omicron lineage of SARS-CoV-2 continues to evolve, successively yielding subvariants that are not only more transmissible but also more evasive to antibodies.
Cysteine mitigates the effect of NaCl salt toxicity in flax (Linum usitatissimum L) plants by modulating antioxidant systems
Authors: Hussein Hebat-Allah A. , Alshammari Shifaa O.
Published: July 2022

Agriculture, the main water-consuming factor, faces a global water scarcity crisis. Saline water is an alternative water source, while excess NaCl decreases plant growth and productivity of crops. L-cysteine (Cys) is a promising thiol amino acid in plant growth and development. Flax; Linum usitatissimum L. is an economical plant with low salt tolerance. NaCl salt stress at 50 and 100 mM inhibited the growth parameters, the photosynthetic pigments, total soluble sugars, total phenols, and amino nitrogen in flax plants. Salt stress led to a marked rise in proline and lipid peroxidation and altered the protein profile. Foliar application of cysteine at 0.8 and 1.6 mM mitigates the unfriendly effects of NaCl stress on flax plants. Cysteine enhanced the growth traits, photosynthetic pigments, amino nitrogen, total phenols, and new polypeptides in NaCl-stressed plants. However, cysteine declined the total sugars, proline, the activity of peroxidase, and ascorbate peroxidase. The results confirmed that cysteine had reductant properties. Furthermore, it decreased the NaCl oxidative stress and maintained the stability of membranes by lowering lipid peroxidation. Overall, the redox capacity of L-cysteine is the cause behind its potential counteracting of the adverse effects of NaCl toxicity on the growth of flax plants.
Hydrophilic ZnO thin films doped with ytterbium and europium oxide
Authors: Tański Tomasz , Zaborowska Marta , Jarka Paweł , Woźniak Anna
Published: July 2022

Hydrophilic photocatalytically active ZnO and ZnO thin films doped with Yb2O3 and Eu2O3 (rare earth metal oxide, REM) with optical transmittance exceeding 76% in the visible light range (λ = 550 nm) were prepared by a combination of sol–gel technique, spin-coating and high temperature thermal treatment at 500 and 600 °C. The thin films were tested using advanced research methods, i.e.: morphology and topography and fractures along with approximate thickness values were investigated on scanning electron microscope (SEM), chemical composition was determined using X-ray Energy Dispersive Spectroscopy (X-ray Energy Spectroscopy), topography and roughness were measured on atomic force microscope (AFM), water contact angle values were determined by sitting water droplet method, optical properties of the fabricated materials were investigated using UV/Vis spectrophotometer. The decolorization efficiency of rhodamine B in aqueous solution was analyzed over a period of 190 min, obtaining degradation rates of: 54.7% and 43.1%, for ZnO and ZnO coatings doped with ytterbium oxide and europium oxide, respectively. The roughness of thin hybrid coatings did not exceed 50 nm, ensuring effective absorption of electromagnetic radiation by the layers. The methodology presented by the authors for the fabrication of thin hybrid films characterized by the key properties of self-cleaning coatings can be successfully applied to coatings of photovoltaic panels and architectural glass structures.