bluuebunny/crossref_metadata_2025 huggingface dataset:
Hares from the Late Pleistocene of Ukraine: a phylogenetic analysis and the status of Lepus tanaiticus (Mammalia, Lagomorpha)
Authors: Rabiniak Emilia , Rekovets Leonid , Kovalchuk Oleksandr , Baca Mateusz , Popović Danijela , Strzała Tomasz , Barkaszi Zoltán
Published: August 2023

Hares (genus Lepus) are widely distributed in Europe, and they are adapted to various types of habitats. Many species are known to hybridise, and previous molecular genetic studies have revealed recurrent introgressions between species at all stages of the genus’s radiation. The Don hare (Lepus tanaiticus) was described from the Late Pleistocene of the Southern Urals and subsequently reported from coeval deposits of various regions of northern Eurasia. It is morphologically close to the mountain hare (Lepus timidus) and recent studies of mitochondrial DNA questioned its status as an independent species. Here we compare cytochrome b and control-region sequences of mtDNA of arctic Lepus, including, for the first time, eight specimens from Late Pleistocene localities of Ukraine, in order to analyse the phylogenetic relationships between representatives of different taxa. The phylogenetic tree and haplotype network analyses do not support the taxonomic distinctness of the Don hare, and only specimens of Lepus arcticus and Lepus othus form monophyletic groups based on the control-region sequences. Instead, L. tanaiticus are scattered among specimens of L. timidus. The obtained results support the hypothesis that the Don hare is an ancient morphotype of L. timidus, and its distinctive morphological traits are the result of increased geographical variation of the latter due to range expansion and adaptation to the specific conditions of the periglacial biome, similarly to other Late Pleistocene small-mammal species.
Haematopoietic Stem Cell Transplantation for the Treatment of Multiple Sclerosis: Recent Advances
Authors: Mariottini Alice , De Matteis Eleonora , Cencioni Maria Teresa , Muraro Paolo A.
Published: August 2023

Purpose of Review

Autologous haematopoietic stem cell transplantation (AHSCT) is increasingly considered a treatment option for patients with multiple sclerosis (MS), an autoimmune demyelinating and degenerative disease of the central nervous system (CNS). AHSCT persistently suppresses inflammation and improves the disease course in large proportions of patients with relapsing–remitting (RR) MS. Aim of this article is to review the relevant new knowledge published during the last 3 years.

Recent Findings

Laboratory studies reported confirmatory and new insights into the immunological and biomarker effects of AHSCT. Retrospective clinical studies confirmed excellent outcomes in RRMS, showing possible superior effectiveness over standard therapies and suggesting a possible benefit in early secondary progressive (SP) MS with inflammatory features. New data on risks of infertility and secondary autoimmunity were also reported.

Further evidence on the high effectiveness and acceptable safety of AHSCT strengthens its position as a clinical option for aggressive RRMS. Further research is needed to better define its role in treatment-naïve and progressive forms of MS, ideally within randomised clinical trials (RCTs).
2-Methoxyestradiol and Hydrogen Peroxide as Promising Biomarkers in Parkinson’s Disease
Authors: Bastian Paulina , Konieczna Lucyna , Dulski Jarosław , Daca Agnieszka , Jacewicz Dagmara , Płoska Agata , Knap Narcyz , Sławek Jarosław , Bączek Tomasz , Kalinowski Leszek , Drzeżdżon Joanna , Roszmann Anna , Belka Mariusz , Górska-Ponikowska Magdalena
Published: August 2023

Estrogens function in numerous physiological processes including controlling brain cell growth and differentiation. 2-Methoxestradiol (2-ME2), a 17β-estradiol (E2) metabolite, is known for its anticancer effects as observed both in vivo and in vitro. 2-ME2 affects all actively dividing cells, including neurons. The study aimed to determine whether 2-ME2 is a potentially cancer-protective or rather neurodegenerative agent in a specific tissue culture model as well as a clinical setup. In this study, 2-ME2 activity was determined in a Parkinson’s disease (PD) in vitro model based on the neuroblastoma SH-SY5Y cell line. The obtained results suggest that 2-ME2 generates nitro-oxidative stress and controls heat shock proteins (HSP), resulting in DNA strand breakage and apoptosis. On the one hand, it may affect intensely dividing cells preventing cancer development; however, on the other hand, this kind of activity within the central nervous system may promote neurodegenerative diseases like PD. Thus, the translational value of 2-ME2’s neurotoxic activity in a PD in vitro model was also investigated. LC–MS/MS technique was used to evaluate estrogens and their derivatives, namely, hydroxy and methoxyestrogens, in PD patients’ blood, whereas the stopped-flow method was used to assess hydrogen peroxide (H2O2) levels. Methoxyestrogens and H2O2 levels were increased in patients’ blood as compared to control subjects, but hydoxyestrogens were simultaneously decreased. From the above, we suggest that the determination of plasma levels of methoxyestrogens and H2O2 may be a novel PD biomarker. The presented research is the subject of the pending patent application “The use of hydrogen peroxide and 17β-estradiol and its metabolites as biomarkers in the diagnosis of neurodegenerative diseases,” no. P.441360.
Pediatric Heterotopic Ossification: A Comprehensive Review
Authors: Markes Alexander R. , Venishetty Nikit , Gatto Andrew , Swarup Ishaan
Published: August 2023

Purpose of Review

The purpose of this review is to provide a comprehensive analysis of heterotopic ossification (HO) in pediatric patients, including an in-depth examination of the risk factors associated with this condition, current prophylactic measures, and available management strategies.

Recent Findings

HO is a medical disorder in which bone tissue inexplicably develops in soft tissues such as muscles and tendons. It involves the formation of mature, lamellar bone in extra-skeletal soft tissue, and its formation is influenced by oxygen tension, pH, the availability of micronutrients, and mechanical stimulation. HO has many cellular origins, with the most common theory being multipotent cells in local tissue. The diagnosis of HO is typically made based on exam, radiographs, and CT. Management includes both prophylactic nonsurgical options and surgical resection for severe or recalcitrant cases.

The review highlights the incidence, risk factors, and management strategies associated with HO in pediatric patients. HO is a rare condition in children, with severe neurologic injury being the most common cause. Pediatric patients most commonly develop HO following severe neurologic injury, followed by trauma and surgery. Current prophylactic measures, include nonsteroidal anti-inflammatory drugs and radiation therapy though limited literature on their use in the pediatric population exists. For recalcitrant symptomatic cases, wide surgical resection can be considered but has a higher risk profile and associated morbidity. This review highlights the need for further pediatric specific research to inform guidelines and management strategies for this debilitating condition.
A Yolo-Based Model for Breast Cancer Detection in Mammograms
Authors: Prinzi Francesco , Insalaco Marco , Orlando Alessia , Gaglio Salvatore , Vitabile Salvatore
Published: August 2023

This work aims to implement an automated data-driven model for breast cancer detection in mammograms to support physicians’ decision process within a breast cancer screening or detection program. The public available CBIS-DDSM and the INbreast datasets were used as sources to implement the transfer learning technique on full-field digital mammography proprietary dataset. The proprietary dataset reflects a real heterogeneous case study, consisting of 190 masses, 46 asymmetries, and 71 distortions. Several Yolo architectures were compared, including YoloV3, YoloV5, and YoloV5-Transformer. In addition, Eigen-CAM was implemented for model introspection and outputs explanation by highlighting all the suspicious regions of interest within the mammogram. The small YoloV5 model resulted in the best developed solution obtaining an mAP of 0.621 on proprietary dataset. The saliency maps computed via Eigen-CAM have proven capable solution reporting all regions of interest also on incorrect prediction scenarios. In particular, Eigen-CAM produces a substantial reduction in the incidence of false negatives, although accompanied by an increase in false positives. Despite the presence of hard-to-recognize anomalies such as asymmetries and distortions on the proprietary dataset, the trained model showed encouraging detection capabilities. The combination of Yolo predictions and the generated saliency maps represent two complementary outputs for the reduction of false negatives. Nevertheless, it is imperative to regard these outputs as qualitative tools that invariably necessitate clinical radiologic evaluation. In this view, the model represents a trusted predictive system to support cognitive and decision-making, encouraging its integration into real clinical practice.
Assessing the Strength and Deformation Properties of Serpentinite Rocks in Dry and Saturated Conditions
Authors: Diamantis Konstantinos , Fereidooni Davood
Published: August 2023

It is clear that the engineering properties of various rocks in dry and wet conditions are different. In general, the properties decrease with the presence of water. The present research investigates the effect of rock saturation on the strength and deformation properties of serpentinites collected from central Greece. A comprehensive laboratory test program was planned to evaluate unit weight, effective porosity, uniaxial compressive strength, elasticity modulus, and Brazilian tensile strength in saturated states. All the results of the above-mentioned saturated properties were compared with the respective properties measured in dry conditions taken from previous studies. Simple regression analyses were used to correlate the physical and mechanical properties of the two referred states. The obtained results revealed that the values of the considered physical and mechanical properties of the studied serpentinite rocks are deceased with the presence of water. There are good relations between different rock properties in dry and saturated states. Generally, the relations are better in dry state. All correlations between the same rock properties in dry and saturated states are as direct linear relations, whereas relationships between the mechanical and physical properties are mainly exponential. Some of them are logarithmic or power equations.
Navigating Uncertainty in Weapon System-of-Systems Planning: A Hybrid Multiobjective Network-Based Optimization and Fuzzy Set Approach
Authors: Hu Chongshuang , Wang Xingliang , Li Minghao , Jiang Jiang
Published: August 2023

The evaluation of the capability of network-based systems of systems has replaced the simple method that considers return on investment, becoming a new paradigm for planning national defence capabilities. However, the dual uncertainty of the key system attributes of scenes and weapons has brought great challenges for decision-making. Based on this, we developed a multiobjective optimization model with multiple stages and scenarios under uncertainty to determine plans. In this study, we consider planning risk and planning cost as the two objectives. To solve this problem, we propose a hybrid solution for a network-based optimization method integrated with fuzzy set theory. The network-based optimization method combines the NSGA-II-DE and complex network theory. We use the characteristics of the network to evaluate the capabilities of the WSoS, and the NSGA-II-DE is used to generate a development plan and finally output a set of Pareto optimal solutions. We use fuzzy sets to determine the fuzzy membership of each plan on the Pareto front and determine a satisfactory solution. Finally, we conduct simulation experiments to verify the rationality of the methods proposed in this article. The results can provide a set of efficient solutions for military planners, helping generate a variety of planning solutions and trade-offs according to their preferences.

Graphical Abstract
Effects of carbon-sequestering coral aggregate on pore structures and compressive strength of concrete
Authors: Mi Renjie , Wang Yifei , Yu Tao , Li Wengui
Published: August 2023

CO2 sequestration/storage shows considerable impacts on the pore structures and compressive strength of concrete. This paper presents a study in which coral aggregates were presoaked in Ca(OH)2 slurries with different solid-to-liquid ratios (i.e. 0.2, 0.4, and 0.6 g/mL) followed by accelerated carbonation. The effects of CO2 sequestration on the particle size distribution, cylinder compressive strength, water absorption, and apparent density of coral aggregate were investigated. The evolution of pore structures in coral aggregate concrete after CO2 sequestration was also studied. Additionally, the effect of CO2 sequestration on the development of compressive strength of coral aggregate concrete was explored. The results showed that CO2 sequestration affected the properties of coral aggregate. Moreover, the porosity of CaCO3 formed by CO2 sequestration was the highest in the concrete. With the increase of solid-to-liquid ratio, the porosity of cement pastes and the CaCO3 increased, and more big pores existed in the cement pastes and CaCO3. Furthermore, the compressive strength of coral aggregate concrete when the solid-to-liquid ratio was 0.2 g/mL increased compared with that before CO2 sequestration, but the compressive strength reduced when the ratio increased to 0.6 g/mL.
Applied Regression Models in the Social Sciences
Authors: Poston, Jr Dudley L. , Conde Eugenia , Field Layton M.
Published: August 2023

This accessible and practical textbook gives students the perfect guide to the use of regression models in testing and evaluating hypotheses dealing with social relationships. A range of statistical methods suited to a wide variety of dependent variables is explained, which will allow students to read, understand, and interpret complex statistical analyses of social data. Each chapter contains example applications using relevant statistical methods in both Stata and R, giving students direct experience of applying their knowledge. A full suite of online resources - including statistical command files, datasets and results files, homework assignments, class discussion topics, PowerPoint slides, and exam questions - supports the student to work independently with the data, and the instructor to deliver the most effective possible course. This is the ideal textbook for advanced undergraduate and beginning graduate students taking courses in applied social statistics.
Aligning values to labels: A best-worst analysis of food labels
Authors: McLeod Alexandria , Yang Wei , Fang Di , Nayga Rodolfo M.
Published: August 2023

Consumer misperception and misinterpretation of food labels can lead to consumers not buying a product or purchasing products that do not align with their environmental or sustainability interests. Consumer purchasing behavior can be explained by looking at consumer food values or food quality attributes. This study aimed to (a) determine the effect label information has on consumer preference shares for selected sustainability-related food labels and (b) if correlations exist between food labels and food values. To the best of our knowledge, this is the first study to examine the comprehension of 12 different labels and identify how food labels relate to food value preferences. Responses from the best-worst scaling experiment of food value and environmental food label choice sets were analyzed using the random parameter logit model. Results reveal preference shares changed for each label as more information was provided to the respondents about the various labels included in the study. These findings should support food policy efforts requiring strict, clear label standards. Food labels should represent the food’s core food values to increase consumer preference for the product. These findings also further support the need for efforts to increase consumer knowledge and understanding of the labels on food packaging.
Illusions of Sovereignty: Understanding Populist Crowds with Hannah Arendt
Authors: Rensmann Lars
Published: August 2023

This article reconstructs Hannah Arendt's theoretical arguments in relation to current authoritarian-populist crowds, which can be understood as organized mobs of the twenty-first century. Drawn from all classes and originating in societal and political disenfranchisement, in Arendt's understanding they are rebellious nihilists who falsely believe they represent the people as a whole while they exclude any citizens who do not share their tribal nationalism and leader worshiping. Illuminating conditions of their emergence, Arendt also helps to elucidate what drives the populist crowds’ illusions about an uncompromising “sovereign will” they and their leaders claim to embody. Such illusions benefit from broader modern trends eroding differences between facts, opinion, truth, and lies. In public environments suffering from destabilized factual truths, organized lies can easily fill a political vacuum generated by crises of political modernity. Unpacking interrelated theoretical trajectories, it is argued that an Arendtian framework can significantly contribute to the study of present-day authoritarian populism.
Like a Meteorite: The Life of Mike Davis
Authors: Reifer Tom
Published: August 2023

This article surveys the lifetime work of scholar-activist Mike Davis, and his attentiveness to the wide-ranging synthesis of the global political economy and ecology of capitalism and militarism, focusing on labor and social history, and to inequalities of race, class, gender, and nation, and struggles for diversity and inclusion, marking his distinctive style. Covering themes ranging from American exceptionalism, working-class formation, struggles for the eight-hour workday, the political economy and ecology of the Third World, and the growth of today's informal proletariat, the article underlines the author's deepest commitments to a lifetime of scholarship. These include democratic control over the means of production, and the remaking of the global system on new and enlarged, more peaceful and just socioecological foundations, now essential if humanity and other sentient beings are to survive and thrive.
Beyond “Death Do Us Part”: Spousal Intestate Succession in Nineteenth-Century Hispanic America
Authors: Deere Carmen Diana
Published: August 2023

In colonial Hispanic America, widows and widowers were in an unfavorable position if their spouse died without a will, only inheriting from them if the deceased left no blood relatives to the 10th degree of kinship. This article examines the extent to which the intestate position of the surviving spouse improved in the new civil codes of the sixteen republics, and how their approaches were influenced by the circulation of ideas. It finds that in all except one the spouse came to be favored over the extended family. If the deceased left children, two approaches developed with respect to the inclusion of spouses: where they obtained an unconditional right to an inheritance share equal to a child, and where their inheriting depended on their relative poverty or need. These reforms took place in concert with the rise of the centrality of the conjugal unit as the focus of affection, loyalty, and responsibilities, and prior to such reforms in Europe. The countries that went furthest in elevating the position of spouses, Venezuela and Argentina, were those most deeply influenced by the ideas and changes fostered by liberalism.
Production as Criticism: Staging Wartime Rape in the Opera Canon
Authors: Cormier Margaret
Published: August 2023

This article explores contemporary representations of wartime sexual violence on the operatic stage. Rape and the threat of rape loom over many operas in the canon, but even those operas that do not thematise rape may have sexual violence introduced to them in performance. Through analysis of four twenty-first century productions, I consider how the idea of sexual violence works in these wartime stories. Staging the implicit or explicit sexual violence in canonic operas can, in the best cases, allow for nuanced commentary on the subject in our cultural moment. But putting sexual violence on stage is controversial and can pose real risks to audience members. Instead of dismissing the proliferation of depictions of rape in wartime opera productions as mere scandalmongering, I explore specific representations through a feminist ethical framework, and ask: What do we risk and what might we gain by putting rape on stage in these operas?
Why we need to look at decolonisation in the law library
Authors: Clarke Marilyn
Published: August 2023

Decolonisation remains as a topical debate in academic libraries. Goldsmiths, University of London Library, led a decolonisation initiative which inspired many other academic libraries to engage in social justice. Here IALS librarian Marilyn Clarke, who was previously Director of Library Services at Goldsmiths, examines what's happening in law libraries when it comes to this matter, and asks whether legal knowledge and the law school can be decolonised.
Ground Surface‐Soil Thermal Inversion From In Situ Measurement
Authors: Yang Qian , Zhang Man , Zhou Jianjun
Published: August 2023

Soil heat flux at the ground surface (G) is an essential component of energy for the recirculation of water and other masses on the land surface. However, direct measurement is difficult and inaccurate, and available data are inadequate owing to the inconvenience of installing the heat sensor plate immediately beneath the true surface. Additionally, thermal properties such as the diffusivity, conductivity, and volumetric heat capacity are intricately influenced by water, vegetation, labile weather, and environmental conditions. Errors of estimation for them from indirect measurement of water content can be substantial and almost impossible without adequately and accurately determination of the soil parameters in situ. In this study, a more general parabolic heat equation is analytically solved for thermal diffusion of gradually varying state properties, and an inverse method is used to determine the parameters so that the properties and G can be simultaneously obtained at a site of measurement. Comparison and validation against data from a numerical model and experimental‐site measurements indicate well agreement and consistency. The retrieved G reveals relatively larger in scale that indicates a non‐negligible disparity from the under‐surface plate measured and the estimations by previous heat‐correction methods, suggesting that G should be regarded more significant in roles for the studies of near‐surface processes, particularly in rather dry conditions and in sub‐diurnal time scale. The present inversion provides some insights into the soil thermal physics of the land surface. Finally, a formula is suggested for the completion of the plate‐based heat flux measurements.
Revealing Their True Stripes: Mg/Ca Banding in the Paleogene Planktonic Foraminifera GenusMorozovellaand Implications for Paleothermometry
Authors: John Eleanor H. , Staudigel Philip T. , Buse Benjamin , Lear Caroline H. , Pearson Paul N. , Slater Sophie M.
Published: August 2023

The Mg/Ca ratio of foraminiferal calcite is a widely used empirical proxy for ocean temperature. Foraminiferal Mg/Ca‐temperature relationships are based on extant species and are species‐specific, introducing uncertainty when applying them to the fossil tests of extinct groups. Many modern species show remarkable heterogeneity in their intra‐test Mg distributions, typically due to the presence of high Mg bands, which have a biological origin. Importantly, banding patterns differ between species, which could affect Mg/Ca‐temperature relationships. Few studies have looked at intra‐test variability in Mg/Ca ratios in extinct species of foraminifera, despite the obvious implications for paleothermometry. We used electron probe microanalysis (EPMA) to investigate intra‐test Mg distributions in the fossil tests of two species of planktonic foraminifera from the extinct muricate mixed‐layer‐dwelling genusMorozovella, commonly used in Paleogene sea surface temperature reconstructions. BothM.aragonensisandM.cratershow striking Mg banding patterns with multiple high and low Mg/Ca band pairs throughout the test wall in all chambers. The intra‐test Mg variability inM.aragonensisandM.crateris similar to that in modern species widely used in paleoclimate reconstructions and banding patterns are consistent with published growth models for modern forms, albeit with subtle differences. The presence of Mg bands supports the application of Mg/Ca‐palaeothermometry in extinctMorozovellaspecies as well as the utility of EPMA for examining preservation of foraminifera tests in paleoclimatological studies. However, we emphasize the importance of rigorous assessments of inter‐ and intra‐test Mg variability when using microanalytical techniques for foraminiferal Mg/Ca paleothermometry.
Motility mediates satellite formation in confined biofilms
Authors: Cordero Mireia , Mitarai Namiko , Jauffred Liselotte
Published: August 2023

Bacteria have spectacular survival capabilities and can spread in many, vastly different environments. For instance, when pathogenic bacteria infect a host, they expand by proliferation and squeezing through narrow pores and elastic matrices. However, the exact role of surface structures—important for biofilm formation and motility—and matrix density in colony expansion and morphogenesis is still largely unknown. Using confocal laser-scanning microscopy, we show how satellite colonies emerge around Escherichia coli colonies embedded in semi-dense hydrogel in controlled in vitro assays. Using knock-out mutants, we tested how extra-cellular structures, (e.g., exo-polysaccharides, flagella, and fimbria) control this morphology. Moreover, we identify the extra-cellular matrix’ density, where this morphology is possible. When paralleled with mathematical modelling, our results suggest that satellite formation allows bacterial communities to spread faster. We anticipate that this strategy is important to speed up expansion in various environments, while retaining the close interactions and protection provided by the community.
Extensive breaking of genetic code degeneracy with non-canonical amino acids
Authors: McFeely Clinton A. L. , Shakya Bipasana , Makovsky Chelsea A. , Haney Aidan K. , Ashton Cropp T. , Hartman Matthew C. T.
Published: August 2023

Genetic code expansion (GCE) offers many exciting opportunities for the creation of synthetic organisms and for drug discovery methods that utilize in vitro translation. One type of GCE, sense codon reassignment (SCR), focuses on breaking the degeneracy of the 61 sense codons which encode for only 20 amino acids. SCR has great potential for genetic code expansion, but extensive SCR is limited by the post-transcriptional modifications on tRNAs and wobble reading of these tRNAs by the ribosome. To better understand codon-tRNA pairing, here we develop an assay to evaluate the ability of aminoacyl-tRNAs to compete with each other for a given codon. We then show that hyperaccurate ribosome mutants demonstrate reduced wobble reading, and when paired with unmodified tRNAs lead to extensive and predictable SCR. Together, we encode seven distinct amino acids across nine codons spanning just two codon boxes, thereby demonstrating that the genetic code hosts far more re-assignable space than previously expected, opening the door to extensive genetic code engineering.
Endothelial ERα promotes glucose tolerance by enhancing endothelial insulin transport to skeletal muscle
Authors: Sacharidou Anastasia , Chambliss Ken , Peng Jun , Barrera Jose , Tanigaki Keiji , Luby-Phelps Katherine , Özdemir İpek , Khan Sohaib , Sirsi Shashank R. , Kim Sung Hoon , Katzenellenbogen Benita S. , Katzenellenbogen John A. , Kanchwala Mohammed , Sathe Adwait A. , Lemoff Andrew , Xing Chao , Hoyt Kenneth , Mineo Chieko , Shaul Philip W.
Published: August 2023

The estrogen receptor (ER) designated ERα has actions in many cell and tissue types that impact glucose homeostasis. It is unknown if these include mechanisms in endothelial cells, which have the potential to influence relative obesity, and processes in adipose tissue and skeletal muscle that impact glucose control. Here we show that independent of impact on events in adipose tissue, endothelial ERα promotes glucose tolerance by enhancing endothelial insulin transport to skeletal muscle. Endothelial ERα-deficient male mice are glucose intolerant and insulin resistant, and in females the antidiabetogenic actions of estradiol (E2) are absent. The glucose dysregulation is due to impaired skeletal muscle glucose disposal that results from attenuated muscle insulin delivery. Endothelial ERα activation stimulates insulin transcytosis by skeletal muscle microvascular endothelial cells. Mechanistically this involves nuclear ERα-dependent upregulation of vesicular trafficking regulator sorting nexin 5 (SNX5) expression, and PI3 kinase activation that drives plasma membrane recruitment of SNX5. Thus, coupled nuclear and non-nuclear actions of ERα promote endothelial insulin transport to skeletal muscle to foster normal glucose homeostasis.
Resolving the spatial architecture of myeloma and its microenvironment at the single-cell level
Authors: John Lukas , Poos Alexandra M. , Brobeil Alexander , Schinke Carolina , Huhn Stefanie , Prokoph Nina , Lutz Raphael , Wagner Barbara , Zangari Maurizio , Tirier Stephan M. , Mallm Jan-Philipp , Schumacher Sabrina , Vonficht Dominik , Solé-Boldo Llorenç , Quick Sabine , Steiger Simon , Przybilla Moritz J. , Bauer Katharina , Baumann Anja , Hemmer Stefan , Rehnitz Christoph , Lückerath Christian , Sachpekidis Christos , Mechtersheimer Gunhild , Haberkorn Uwe , Dimitrakopoulou-Strauss Antonia , Reichert Philipp , Barlogie Bart , Müller-Tidow Carsten , Goldschmidt Hartmut , Hillengass Jens , Rasche Leo , Haas Simon F. , van Rhee Frits , Rippe Karsten , Raab Marc S. , Sauer Sandra , Weinhold Niels
Published: August 2023

In multiple myeloma spatial differences in the subclonal architecture, molecular signatures and composition of the microenvironment remain poorly characterized. To address this shortcoming, we perform multi-region sequencing on paired random bone marrow and focal lesion samples from 17 newly diagnosed patients. Using single-cell RNA- and ATAC-seq we find a median of 6 tumor subclones per patient and unique subclones in focal lesions. Genetically identical subclones display different levels of spatial transcriptional plasticity, including nearly identical profiles and pronounced heterogeneity at different sites, which can include differential expression of immunotherapy targets, such as CD20 and CD38. Macrophages are significantly depleted in the microenvironment of focal lesions. We observe proportional changes in the T-cell repertoire but no site-specific expansion of T-cell clones in intramedullary lesions. In conclusion, our results demonstrate the relevance of considering spatial heterogeneity in multiple myeloma with potential implications for models of cell-cell interactions and disease progression.
RORγt-Raftlin1 complex regulates the pathogenicity of Th17 cells and colonic inflammation
Authors: Singh Amir Kumar , Kumar Ritesh , Yin Jianyi , Brooks II John F. , Kathania Mahesh , Mukherjee Sandip , Kumar Jitendra , Conlon Kevin P. , Basrur Venkatesha , Chen Zhe , Han Xianlin , Hooper Lora V. , Burstein Ezra , Venuprasad K.
Published: August 2023

Th17 cells that produce Interleukin IL-17 are pathogenic in many human diseases, including inflammatory bowel disease, but are, paradoxically, essential for maintaining the integrity of the intestinal barrier in a non-inflammatory state. However, the intracellular mechanisms that regulate distinct transcriptional profiles and functional diversity of Th17 cells remain unclear. Here we show Raftlin1, a lipid raft protein, specifically upregulates and forms a complex with RORγt in pathogenic Th17 cells. Disruption of the RORγt-Raftlin1 complex results in the reduction of pathogenic Th17 cells in response to Citrobacter rodentium; however, there is no effect on nonpathogenic Th17 cells in response to commensal segmented filamentous bacteria. Mechanistically, we show that Raftlin1 recruits distinct phospholipids to RORγt and promotes the pathogenicity of Th17 cells. Thus, we have identified a mechanism that drives the pathogenic function of Th17 cells, which could provide a platform for advanced therapeutic strategies to dampen Th17-mediated inflammatory diseases.
The RIX domain defines a class of polymorphic T6SS effectors and secreted adaptors
Authors: Kanarek Katarzyna , Fridman Chaya Mushka , Bosis Eran , Salomon Dor
Published: August 2023

Bacteria use the type VI secretion system (T6SS) to deliver toxic effectors into bacterial or eukaryotic cells during interbacterial competition, host colonization, or when resisting predation. Identifying effectors is a challenging task, as they lack canonical secretion signals or universally conserved domains. Here, we identify a protein domain, RIX, that defines a class of polymorphic T6SS cargo effectors. RIX is widespread in the Vibrionaceae family and is located at N-termini of proteins containing diverse antibacterial and anti-eukaryotic toxic domains. We demonstrate that RIX-containing proteins are delivered via T6SS into neighboring cells and that RIX is necessary and sufficient for T6SS-mediated secretion. In addition, RIX-containing proteins can enable the T6SS-mediated delivery of other cargo effectors by a previously undescribed mechanism. The identification of RIX-containing proteins significantly enlarges the repertoire of known T6SS effectors, especially those with anti-eukaryotic activities. Furthermore, our findings also suggest that T6SSs may play an underappreciated role in the interactions between vibrios and eukaryotes.
Charge-state lifetimes of single molecules on few monolayers of NaCl
Authors: Kaiser Katharina , Lieske Leonard-Alexander , Repp Jascha , Gross Leo
Published: August 2023

In molecular tunnel junctions, where the molecule is decoupled from the electrodes by few-monolayers-thin insulating layers, resonant charge transport takes place by sequential charge transfer to and from the molecule which implies transient charging of the molecule. The corresponding charge state transitions, which involve tunneling through the insulating decoupling layers, are crucial for understanding electrically driven processes such as electroluminescence or photocurrent generation in such a geometry. Here, we use scanning tunneling microscopy to investigate the decharging of single ZnPc and H2Pc molecules through NaCl films of 3 to 5 monolayers thickness on Cu(111) and Au(111). To this end, we approach the tip to the molecule at resonant tunnel conditions up to a regime where charge transport is limited by tunneling through the NaCl film. The resulting saturation of the tunnel current is a direct measure of the lifetimes of the anionic and cationic states, i.e., the molecule’s charge-state lifetime, and thus provides a means to study charge dynamics and, thereby, exciton dynamics. Comparison of anion and cation lifetimes on different substrates reveals the critical role of the level alignment with the insulator’s conduction and valence band, and the metal-insulator interface state.
Sustainable production of dopamine hydrochloride from softwood lignin
Authors: Dong Lin , Wang Yanqin , Dong Yuguo , Zhang Yin , Pan Mingzhu , Liu Xiaohui , Gu Xiaoli , Antonietti Markus , Chen Zupeng
Published: August 2023

Dopamine is not only a widely used commodity pharmaceutical for treating neurological diseases but also a highly attractive base for advanced carbon materials. Lignin, the waste from the lignocellulosic biomass industry, is the richest source of renewable aromatics on earth. Efficient production of dopamine direct from lignin is a highly desirable target but extremely challenging. Here, we report an innovative strategy for the sustainable production of dopamine hydrochloride from softwood lignin with a mass yield of 6.4 wt.%. Significantly, the solid dopamine hydrochloride is obtained by a simple filtration process in purity of 98.0%, which avoids the tedious separation and purification steps. The approach begins with the acid-catalyzed depolymerization, followed by deprotection, hydrogen-borrowing amination, and hydrolysis of methoxy group, transforming lignin into dopamine hydrochloride. The technical economic analysis predicts that this process is an economically competitive production process. This study fulfills the unexplored potential of dopamine hydrochloride synthesis from lignin.
Multiple antiferromagnetic phases and magnetic anisotropy in exfoliated CrBr3 multilayers
Authors: Yao Fengrui , Multian Volodymyr , Wang Zhe , Ubrig Nicolas , Teyssier Jérémie , Wu Fan , Giannini Enrico , Gibertini Marco , Gutiérrez-Lezama Ignacio , Morpurgo Alberto F.
Published: August 2023

In twisted two-dimensional (2D) magnets, the stacking dependence of the magnetic exchange interaction can lead to regions of ferromagnetic and antiferromagnetic interlayer order, separated by non-collinear, skyrmion-like spin textures. Recent experimental searches for these textures have focused on CrI3, known to exhibit either ferromagnetic or antiferromagnetic interlayer order, depending on layer stacking. However, the very strong uniaxial anisotropy of CrI3 disfavors smooth non-collinear phases in twisted bilayers. Here, we report the experimental observation of three distinct magnetic phases—one ferromagnetic and two antiferromagnetic—in exfoliated CrBr3 multilayers, and reveal that the uniaxial anisotropy is significantly smaller than in CrI3. These results are obtained by magnetoconductance measurements on CrBr3 tunnel barriers and Raman spectroscopy, in conjunction with density functional theory calculations, which enable us to identify the stackings responsible for the different interlayer magnetic couplings. The detection of all locally stable magnetic states predicted to exist in CrBr3 and the excellent agreement found between theory and experiments, provide complete information on the stacking-dependent interlayer exchange energy and establish twisted bilayer CrBr3 as an ideal system to deterministically create non-collinear magnetic phases.
Genome mining shows that retroviruses are pervasively invading vertebrate genomes
Authors: Wang Jianhua , Han Guan-Zhu
Published: August 2023

Endogenous retroviruses (ERVs) record past retroviral infections, providing molecular archives for interrogating the evolution of retroviruses and retrovirus-host interaction. However, the vast majority of ERVs are not active anymore due to various disruptive mutations, and ongoing retroviral invasion of vertebrate genomes has been rarely documented. Here we analyze genomics data from 2004 vertebrates for mining invading ERVs (ERVi). We find that at least 412 ERVi elements representing 217 viral operational taxonomic units are invading the genomes of 123 vertebrates, 18 of which have been assessed to be threatened species. Our results reveal an unexpected prevalence of ongoing retroviral invasion in vertebrates and expand the diversity of retroviruses recently circulating in the wild. We characterize the pattern and nature of ERVi in the historical and biogeographical context of their hosts, for instance, the generation of model organisms, sympatric speciation, and domestication. We suspect that these ERVi are relevant to conservation of threatened species, zoonoses in the wild, and emerging infectious diseases in humans.
LINE-1 regulates cortical development by acting as long non-coding RNAs
Authors: Mangoni Damiano , Simi Alessandro , Lau Pierre , Armaos Alexandros , Ansaloni Federico , Codino Azzurra , Damiani Devid , Floreani Lavinia , Di Carlo Valerio , Vozzi Diego , Persichetti Francesca , Santoro Claudio , Pandolfini Luca , Tartaglia Gian Gaetano , Sanges Remo , Gustincich Stefano
Published: August 2023

Long Interspersed Nuclear Elements-1s (L1s) are transposable elements that constitute most of the genome’s transcriptional output yet have still largely unknown functions. Here we show that L1s are required for proper mouse brain corticogenesis operating as regulatory long non-coding RNAs. They contribute to the regulation of the balance between neuronal progenitors and differentiation, the migration of post-mitotic neurons and the proportions of different cell types. In cortical cultured neurons, L1 RNAs are mainly associated to chromatin and interact with the Polycomb Repressive Complex 2 (PRC2) protein subunits enhancer of Zeste homolog 2 (Ezh2) and suppressor of zeste 12 (Suz12). L1 RNA silencing influences PRC2’s ability to bind a portion of its targets and the deposition of tri-methylated histone H3 (H3K27me3) marks. Our results position L1 RNAs as crucial signalling hubs for genome-wide chromatin remodelling, enabling the fine-tuning of gene expression during brain development and evolution.
Surprising stability of recent global carbon cycling enables improved fossil fuel emission verification
Authors: Birner Benjamin , Rödenbeck Christian , Dohner Julia L. , Schwartzman Armin , Keeling Ralph F.
Published: August 2023

The interannual to decadal variability in natural carbon sinks limits the explanation of recent changes in atmospheric CO2 concentration. Here we account for interannual and decadal variability using a simple quasi-mechanistic model of the net land carbon exchange with terms scaling with atmospheric CO2 and a weighted spatial average of temperature anomalies. This approach reduces the unexplained residual in Earth’s carbon cycle budget from ±0.76 GtC per year obtained using process models to ±0.50 GtC per year, with the largest improvements on decadal timescales despite assuming constant dynamics. Our findings reveal remarkable stability of the carbon cycle and allow verification of reported global emissions to within 4.4% (95% confidence level) over the five-year stocktake cycle of the Paris Agreement—half the uncertainty reported previously.
Developmental changes in exploration resemble stochastic optimization
Authors: Giron Anna P. , Ciranka Simon , Schulz Eric , van den Bos Wouter , Ruggeri Azzurra , Meder Björn , Wu Charley M.
Published: August 2023

Human development is often described as a ‘cooling off’ process, analogous to stochastic optimization algorithms that implement a gradual reduction in randomness over time. Yet there is ambiguity in how to interpret this analogy, due to a lack of concrete empirical comparisons. Using data from n = 281 participants ages 5 to 55, we show that cooling off does not only apply to the single dimension of randomness. Rather, human development resembles an optimization process of multiple learning parameters, for example, reward generalization, uncertainty-directed exploration and random temperature. Rapid changes in parameters occur during childhood, but these changes plateau and converge to efficient values in adulthood. We show that while the developmental trajectory of human parameters is strikingly similar to several stochastic optimization algorithms, there are important differences in convergence. None of the optimization algorithms tested were able to discover reliably better regions of the strategy space than adult participants on this task.
Single-nucleotide variant calling in single-cell sequencing data with Monopogen
Authors: Dou Jinzhuang , Tan Yukun , Kock Kian Hong , Wang Jun , Cheng Xuesen , Tan Le Min , Han Kyung Yeon , Hon Chung-Chau , Park Woong-Yang , Shin Jay W. , Jin Haijing , Wang Yujia , Chen Han , Ding Li , Prabhakar Shyam , Navin Nicholas , Chen Rui , Chen Ken
Published: August 2023

Single-cell omics technologies enable molecular characterization of diverse cell types and states, but how the resulting transcriptional and epigenetic profiles depend on the cell’s genetic background remains understudied. We describe Monopogen, a computational tool to detect single-nucleotide variants (SNVs) from single-cell sequencing data. Monopogen leverages linkage disequilibrium from external reference panels to identify germline SNVs and detects putative somatic SNVs using allele cosegregating patterns at the cell population level. It can identify 100 K to 3 M germline SNVs achieving a genotyping accuracy of 95%, together with hundreds of putative somatic SNVs. Monopogen-derived genotypes enable global and local ancestry inference and identification of admixed samples. It identifies variants associated with cardiomyocyte metabolic levels and epigenomic programs. It also improves putative somatic SNV detection that enables clonal lineage tracing in primary human clonal hematopoiesis. Monopogen brings together population genetics, cell lineage tracing and single-cell omics to uncover genetic determinants of cellular processes.
PCNA recruits cohesin loader Scc2 to ensure sister chromatid cohesion
Authors: Psakhye Ivan , Kawasumi Ryotaro , Abe Takuya , Hirota Kouji , Branzei Dana
Published: August 2023

Sister chromatid cohesion, established during replication by the ring-shaped multiprotein complex cohesin, is essential for faithful chromosome segregation. Replisome-associated proteins are required to generate cohesion by two independent pathways. One mediates conversion of cohesins bound to unreplicated DNA ahead of replication forks into cohesive entities behind them, while the second promotes cohesin de novo loading onto newly replicated DNA. The latter process depends on the cohesin loader Scc2 (NIPBL in vertebrates) and the alternative PCNA loader CTF18-RFC. However, the mechanism of de novo cohesin loading during replication is unknown. Here we show that PCNA physically recruits the yeast cohesin loader Scc2 via its C-terminal PCNA-interacting protein motif. Binding to PCNA is crucial, as the scc2-pip mutant deficient in Scc2–PCNA interaction is defective in cohesion when combined with replisome mutants of the cohesin conversion pathway. Importantly, the role of NIPBL recruitment to PCNA for cohesion generation is conserved in vertebrate cells.