bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interventions to support patients with sharing genetic test results with at-risk relatives: a synthesis without meta-analysis (SWiM)
Authors: Ballard Lisa Marie , Band Rebecca , Lucassen Anneke M. 
Published: June 2023

AbstractWhilst the finding of heritable susceptibility to disease was once relatively rare, mainstreaming of genetic testing has resulted in a steady increase. Patients are often encouraged to share their genetic test results with relevant relatives, but relatives may not receive this information, leaving them without knowledge of their own risk. Therefore, strategies to help communicate such information are important. This review aimed to explore the efficacy of existing interventions to improve the sharing of genetic test results. A synthesis without meta-analysis design was used. A systematic search of Medline, CINAHL, PsychINFO, and AMED was conducted, and five studies were identified worldwide. Data were extracted for each study regarding study aim, participant characteristics, condition, intervention details, comparison, study duration, outcome measures, theory and behaviour change techniques used. Limited efficacy and application of theory was found. Knowledge, motivation and self-efficacy were not increased in any intervention. No gender differences in communication behaviour were encountered in interventions that recruited men and women. Two studies reported an evaluation of acceptability, which showed that the interventions were well received by patients and health professionals. No study reported the involvement of the target population in any phase of intervention development. Given the lack of health psychology-informed interventions in this area of clinical genetics, we recommend genetic health professionals, health psychologists and patients collaborate on all stages of future interventions that involve the cascading of genetic health information within families. We also provide guidance regarding use of theory and intervention elements for future intervention development.
A fluorinated cation introduces new interphasial chemistries to enable high-voltage lithium metal batteries
Authors: Liu Qian , Jiang Wei , Xu Jiayi , Xu Yaobin , Yang Zhenzhen , Yoo Dong-Joo , Pupek Krzysztof Z. , Wang Chongmin , Liu Cong , Xu Kang , Zhang Zhengcheng 
Published: June 2023

AbstractFluorides have been identified as a key ingredient in interphases supporting aggressive battery chemistries. While the precursor for these fluorides must be pre-stored in electrolyte components and only delivered at extreme potentials, the chemical source of fluorine so far has been confined to either negatively-charge anions or fluorinated molecules, whose presence in the inner-Helmholtz layer of electrodes, and consequently their contribution to the interphasial chemistry, is restricted. To pre-store fluorine source on positive-charged species, here we show a cation that carries fluorine in its structure is synthesized and its contribution to interphasial chemistry is explored for the very first time. An electrolyte carrying fluorine in both cation and anion brings unprecedented interphasial chemistries that translate into superior battery performance of a lithium-metal battery, including high Coulombic efficiency of up to 99.98%, and Li0-dendrite prevention for 900 hours. The significance of this fluorinated cation undoubtedly extends to other advanced battery systems beyond lithium, all of which universally require kinetic protection of highly fluorinated interphases.
Cyclic di-AMP traps proton-coupled K+ transporters of the KUP family in an inward-occluded conformation
Authors: Fuss Michael F. , Wieferig Jan-Philip , Corey Robin A. , Hellmich Yvonne , Tascón Igor , Sousa Joana S. , Stansfeld Phillip J. , Vonck Janet , Hänelt Inga 
Published: June 2023

AbstractCyclic di-AMP is the only known essential second messenger in bacteria and archaea, regulating different proteins indispensable for numerous physiological processes. In particular, it controls various potassium and osmolyte transporters involved in osmoregulation. In Bacillus subtilis, the K+/H+ symporter KimA of the KUP family is inactivated by c-di-AMP. KimA sustains survival at potassium limitation at low external pH by mediating potassium ion uptake. However, at elevated intracellular K+ concentrations, further K+ accumulation would be toxic. In this study, we reveal the molecular basis of how c-di-AMP binding inhibits KimA. We report cryo-EM structures of KimA with bound c-di-AMP in detergent solution and reconstituted in amphipols. By combining structural data with functional assays and molecular dynamics simulations we reveal how c-di-AMP modulates transport. We show that an intracellular loop in the transmembrane domain interacts with c-di-AMP bound to the adjacent cytosolic domain. This reduces the mobility of transmembrane helices at the cytosolic side of the K+ binding site and therefore traps KimA in an inward-occluded conformation.
How soluble misfolded proteins bypass chaperones at the molecular level
Authors: Halder Ritaban , Nissley Daniel A. , Sitarik Ian , Jiang Yang , Rao Yiyun , Vu Quyen V. , Li Mai Suan , Pritchard Justin , O’Brien Edward P. 
Published: June 2023

AbstractSubpopulations of soluble, misfolded proteins can bypass chaperones within cells. The extent of this phenomenon and how it happens at the molecular level are unknown. Through a meta-analysis of the experimental literature we find that in all quantitative protein refolding studies there is always a subpopulation of soluble but misfolded protein that does not fold in the presence of one or more chaperones, and can take days or longer to do so. Thus, some misfolded subpopulations commonly bypass chaperones. Using multi-scale simulation models we observe that the misfolded structures that bypass various chaperones can do so because their structures are highly native like, leading to a situation where chaperones do not distinguish between the folded and near-native-misfolded states. More broadly, these results provide a mechanism by which long-time scale changes in protein structure and function can persist in cells because some misfolded states can bypass components of the proteostasis machinery.
Acentrosomal spindles assemble from branching microtubule nucleation near chromosomes in Xenopus laevis egg extract
Authors: Gouveia Bernardo , Setru Sagar U. , King Matthew R. , Hamlin Aaron , Stone Howard A. , Shaevitz Joshua W. , Petry Sabine 
Published: June 2023

AbstractMicrotubules are generated at centrosomes, chromosomes, and within spindles during cell division. Whereas microtubule nucleation at the centrosome is well characterized, much remains unknown about where, when, and how microtubules are nucleated at chromosomes. To address these questions, we reconstitute microtubule nucleation from purified chromosomes in meiotic Xenopus egg extract and find that chromosomes alone can form spindles. We visualize microtubule nucleation near chromosomes using total internal reflection fluorescence microscopy to find that this occurs through branching microtubule nucleation. By inhibiting molecular motors, we find that the organization of the resultant polar branched networks is consistent with a theoretical model where the effectors for branching nucleation are released by chromosomes, forming a concentration gradient that spatially biases branching microtbule nucleation. In the presence of motors, these branched networks are ultimately organized into functional spindles, where the number of emergent spindle poles scales with the number of chromosomes and total chromatin area.
CAJAL enables analysis and integration of single-cell morphological data using metric geometry
Authors: Govek Kiya W. , Nicodemus Patrick , Lin Yuxuan , Crawford Jake , Saturnino Artur B. , Cui Hannah , Zoga Kristi , Hart Michael P. , Camara Pablo G. 
Published: June 2023

AbstractHigh-resolution imaging has revolutionized the study of single cells in their spatial context. However, summarizing the great diversity of complex cell shapes found in tissues and inferring associations with other single-cell data remains a challenge. Here, we present CAJAL, a general computational framework for the analysis and integration of single-cell morphological data. By building upon metric geometry, CAJAL infers cell morphology latent spaces where distances between points indicate the amount of physical deformation required to change the morphology of one cell into that of another. We show that cell morphology spaces facilitate the integration of single-cell morphological data across technologies and the inference of relations with other data, such as single-cell transcriptomic data. We demonstrate the utility of CAJAL with several morphological datasets of neurons and glia and identify genes associated with neuronal plasticity inC. elegans. Our approach provides an effective strategy for integrating cell morphology data into single-cell omics analyses.
Molecular choreography of primer synthesis by the eukaryotic Pol α-primase
Authors: Yuan Zuanning , Georgescu Roxana , Li Huilin , O’Donnell Michael E. 
Published: June 2023

AbstractThe eukaryotic polymerase α (Pol α) synthesizes an RNA-DNA hybrid primer of 20–30 nucleotides. Pol α is composed of Pol1, Pol12, Primase 1 (Pri1), and Pri2. Pol1 and Pri1 contain the DNA polymerase and RNA primase activities, respectively. It has been unclear how Pol α hands over an RNA primer from Pri1 to Pol1 for DNA primer extension, and how the primer length is defined. Here we report the cryo-EM analysis of yeast Pol α in the apo, primer initiation, primer elongation, RNA primer hand-off from Pri1 to Pol1, and DNA extension states, revealing a series of very large movements. We reveal a critical point at which Pol1-core moves to take over the 3’-end of the RNA from Pri1. DNA extension is limited by a spiral motion of Pol1-core. Since both Pri1 and Pol1-core are flexibly attached to a stable platform, primer growth produces stress that limits the primer length.
A phase Ib trial of pembrolizumab plus paclitaxel or flat-dose capecitabine in 1st/2nd line metastatic triple-negative breast cancer
Authors: Page David B. , Pucilowska Joanna , Chun Brie , Kim Isaac , Sanchez Katherine , Moxon Nicole , Mellinger Staci , Wu Yaping , Koguchi Yoshinobu , Conrad Valerie , Redmond William L. , Martel Maritza , Sun Zhaoyu , Campbell Mary B. , Conlin Alison , Acheson Anupama , Basho Reva , McAndrew Philomena , El-Masry Mary , Park Dorothy , Bennetts Laura , Seitz Robert S. , Nielsen Tyler J. , McGregor Kimberly , Rajamanickam Venkatesh , Bernard Brady , Urba Walter J. , McArthur Heather L. 
Published: June 2023

AbstractChemoimmunotherapy with anti-programmed cell death 1/ligand 1 and cytotoxic chemotherapy is a promising therapeutic modality for women with triple-negative breast cancer, but questions remain regarding optimal chemotherapy backbone and biomarkers for patient selection. We report final outcomes from a phase Ib trial evaluating pembrolizumab (200 mg IV every 3 weeks) with either weekly paclitaxel (80 mg/m2 weekly) or flat-dose capecitabine (2000 mg orally twice daily for 7 days of every 14-day cycle) in the 1st/2nd line setting. The primary endpoint is safety (receipt of 2 cycles without grade III/IV toxicities requiring discontinuation or ≥21-day delays). The secondary endpoint is efficacy (week 12 objective response). Exploratory aims are to characterize immunologic effects of treatment over time, and to evaluate novel biomarkers. The trial demonstrates that both regimens meet the pre-specified safety endpoint (paclitaxel: 87%; capecitabine: 100%). Objective response rate is 29% for pembrolizumab/paclitaxel (n = 4/13, 95% CI: 10–61%) and 43% for pembrolizumab/capecitabine (n = 6/14, 95% CI: 18–71%). Partial responses are observed in two subjects with chemo-refractory metaplastic carcinoma (both in capecitabine arm). Both regimens are associated with significant peripheral leukocyte contraction over time. Response is associated with clinical PD-L1 score, non-receipt of prior chemotherapy, and the H&E stromal tumor-infiltrating lymphocyte score, but also by a novel 27 gene IO score and spatial biomarkers (lymphocyte spatial skewness). In conclusion, pembrolizumab with paclitaxel or capecitabine is safe and clinically active. Both regimens are lymphodepleting, highlighting the competing immunostimulatory versus lymphotoxic effects of cytotoxic chemotherapy. Further exploration of the IO score and spatial TIL biomarkers is warranted. The clinical trial registration is NCT02734290.
Photoexcitation induced magnetic phase transition and spin dynamics in antiferromagnetic MnPS3 monolayer
Authors: Gao Yinlu , Jiang Xue , Qiu Zhiyong , Zhao Jijun 
Published: June 2023

AbstractAntiferromagnetic spin dynamics is the key issue to develop spintronic devices. We adopt ab initio nonadiabatic molecular dynamics with spin–orbit-coupling (SOC) to investigate photoinduced spin dynamics in an antiferromagnetic semiconductor MnPS3 monolayer. Optical doping triggers MnPS3 from Néel antiferromagnetic to ferromagnetic phase at an experimentally achievable electron–hole pair density of 1.11 × 1014 cm−2. This phase transition can be ascribed to the light-induced mid-gap states of S-p orbitals, which lower the electron excitation energy and strengthen the SOC effect between S-p and Mn-d orbitals. The excited S-p electrons first decay to the mid-gap states due to p–p electron–phonon-coupling and then relax to the spin-down Mn-d orbitals via SOC. Such a dramatic relaxation process prolongs the photogenerated carrier lifetime up to 648 fs, providing an explanation for the unusual optoelectronic performance of MnPS3. The reversible switching of magnetic order via optical means gives an important clue for information storage and highly efficient photocatalysts utilizing antiferromagnetic semiconductors.
Effect of gravity on the spreading of a droplet deposited by liquid needle deposition technique
Authors: Baldygin Aleksey , Ahmed Abrar , Baily Ryan , Ismail Md Farhad , Khan Muhammed , Rodrigues Nigel , Salehi Ali-Reza , Ramesh Megnath , Bhattacharya Sanjay , Willers Thomas , Gowanlock Derek , Waghmare Prashant R. 
Published: June 2023

AbstractThis study represents an experimental investigation, complemented with a mathematical model, to decipher the effect of gravity on the spreading dynamics of a water droplet. For the theoretical discussion, an overall energy balance approach is adopted to explain the droplet spreading under both microgravity (μg) and terrestrial gravity condition. Besides explaining the mechanism of the droplet spreading under microgravity condition achieved during the parabolic flight, a technique with a detailed experimental set-up has also been developed for the successful deposition of droplet. A rational understanding is formulated through experimental investigation and theoretical analysis, which allows us to distinguish the transient variation of the spreading of a droplet, between microgravity and terrestrial gravity condition. The spreading of the droplet is predicted by the non-linear overall energy balance equation, which accounts for the operating parameters in the form of non-dimensional groups like Reynolds number ($${{{\rm{Re}}}}$$
Re
), Weber number (We) and Bond number (Bo). To distinctly identify the difference in the drop spreading at terrestrial and microgravity conditions, the Bo with transient gravitational field obtained through the on-board accelerometer is considered. The obtained theoretical results are further corroborated by experimental results which are obtained from the parabolic flight.
Understanding biofouling and contaminant accretion on submerged marine structures
Authors: Vuong Paton , McKinley Allan , Kaur Parwinder 
Published: June 2023

AbstractFouling of maritime infrastructure is pervasive due to abundant biological and chemical activity within the oceanic environment. Marine biofilms and their successional growths are prevalent issues in biofouling, but current industrial and research-based analyses often do not provide a holistic view of the fouling biodiversity. Cathodic protection is a longstanding system safeguarding infrastructure from the corrosive marine environment, but limited studies on interactions between biological growth and cathodic activity have been conducted in the context of marine fouling. This review identifies knowledge gaps in the understanding of marine fouling and highlights approaches to better direct development of effective anti-fouling measures.
Entropic repulsion of cholesterol-containing layers counteracts bioadhesion
Authors: Friedrichs Jens , Helbig Ralf , Hilsenbeck Julia , Pandey Prithvi Raj , Sommer Jens-Uwe , Renner Lars David , Pompe Tilo , Werner Carsten 
Published: June 2023

AbstractControl of adhesion is a striking feature of living matter that is of particular interest regarding technological translation1–3. We discovered that entropic repulsion caused by interfacial orientational fluctuations of cholesterol layers restricts protein adsorption and bacterial adhesion. Moreover, we found that intrinsically adhesive wax ester layers become similarly antibioadhesive when containing small quantities (under 10 wt%) of cholesterol. Wetting, adsorption and adhesion experiments, as well as atomistic simulations, showed that repulsive characteristics depend on the specific molecular structure of cholesterol that encodes a finely balanced fluctuating reorientation at the interface of unconstrained supramolecular assemblies: layers of cholesterol analogues differing only in minute molecular variations showed markedly different interfacial mobility and no antiadhesive effects. Also, orientationally fixed cholesterol layers did not resist bioadhesion. Our insights provide a conceptually new physicochemical perspective on biointerfaces and may guide future material design in regulation of adhesion.
Signalling by senescent melanocytes hyperactivates hair growth
Authors: Wang Xiaojie , Ramos Raul , Phan Anne Q. , Yamaga Kosuke , Flesher Jessica L. , Jiang Shan , Oh Ji Won , Jin Suoqin , Jahid Sohail , Kuan Chen-Hsiang , Nguyen Truman Kt , Liang Heidi Y. , Shettigar Nitish Udupi , Hou Renzhi , Tran Kevin H. , Nguyen Andrew , Vu Kimberly N. , Phung Jennie L. , Ingal Jonard P. , Levitt Katelyn M. , Cao Xiaoling , Liu Yingzi , Deng Zhili , Taguchi Nobuhiko , Scarfone Vanessa M. , Wang Guangfang , Paolilli Kara Nicole , Wang Xiaoyang , Guerrero-Juarez Christian F. , Davis Ryan T. , Greenberg Elyse Noelani , Ruiz-Vega Rolando , Vasudeva Priya , Murad Rabi , Widyastuti Lily Halida Putri , Lee Hye-Lim , McElwee Kevin J. , Gadeau Alain-Pierre , Lawson Devon A. , Andersen Bogi , Mortazavi Ali , Yu Zhengquan , Nie Qing , Kunisada Takahiro , Karin Michael , Tuckermann Jan , Esko Jeffrey D. , Ganesan Anand K. , Li Ji , Plikus Maksim V. 
Published: June 2023

AbstractNiche signals maintain stem cells in a prolonged quiescence or transiently activate them for proper regeneration1. Altering balanced niche signalling can lead to regenerative disorders. Melanocytic skin nevi in human often display excessive hair growth, suggesting hair stem cell hyperactivity. Here, using genetic mouse models of nevi2,3, we show that dermal clusters of senescent melanocytes drive epithelial hair stem cells to exit quiescence and change their transcriptome and composition, potently enhancing hair renewal. Nevus melanocytes activate a distinct secretome, enriched for signalling factors. Osteopontin, the leading nevus signalling factor, is both necessary and sufficient to induce hair growth. Injection of osteopontin or its genetic overexpression is sufficient to induce robust hair growth in mice, whereas germline and conditional deletions of either osteopontin or CD44, its cognate receptor on epithelial hair cells, rescue enhanced hair growth induced by dermal nevus melanocytes. Osteopontin is overexpressed in human hairy nevi, and it stimulates new growth of human hair follicles. Although broad accumulation of senescent cells, such as upon ageing or genotoxic stress, is detrimental for the regenerative capacity of tissue4, we show that signalling by senescent cell clusters can potently enhance the activity of adjacent intact stem cells and stimulate tissue renewal. This finding identifies senescent cells and their secretome as an attractive therapeutic target in regenerative disorders.
Injury prevents Ras mutant cell expansion in mosaic skin
Authors: Gallini Sara , Annusver Karl , Rahman Nur-Taz , Gonzalez David G. , Yun Sangwon , Matte-Martone Catherine , Xin Tianchi , Lathrop Elizabeth , Suozzi Kathleen C. , Kasper Maria , Greco Valentina 
Published: June 2023

AbstractHealthy skin is a mosaic of wild-type and mutant clones1,2. Although injury can cooperate with mutated Ras family proteins to promote tumorigenesis3–12, the consequences in genetically mosaic skin are unknown. Here we show that after injury, wild-type cells suppress aberrant growth induced by oncogenic Ras. HrasG12V/+ and KrasG12D/+ cells outcompete wild-type cells in uninjured, mosaic tissue but their expansion is prevented after injury owing to an increase in the fraction of proliferating wild-type cells. Mechanistically, we show that, unlike HrasG12V/+ cells, wild-type cells respond to autocrine and paracrine secretion of EGFR ligands, and this differential activation of the EGFR pathway explains the competitive switch during injury repair. Inhibition of EGFR signalling via drug or genetic approaches diminishes the proportion of dividing wild-type cells after injury, leading to the expansion of HrasG12V/+ cells. Increased proliferation of wild-type cells via constitutive loss of the cell cycle inhibitor p21 counteracts the expansion of HrasG12V/+ cells even in the absence of injury. Thus, injury has a role in switching the competitive balance between oncogenic and wild-type cells in genetically mosaic skin.
Origin and evolutionary malleability of T cell receptor α diversity
Authors: Giorgetti Orlando B. , O’Meara Connor P. , Schorpp Michael , Boehm Thomas 
Published: June 2023

AbstractLymphocytes of vertebrate adaptive immune systems acquired the capability to assemble, from split genes in the germline, billions of functional antigen receptors1–3. These receptors show specificity; unlike the broadly tuned receptors of the innate system, antibodies (Ig) expressed by B cells, for instance, can accurately distinguish between the two enantiomers of organic acids4, whereas T cell receptors (TCRs) reliably recognize single amino acid replacements in their peptide antigens5. In developing lymphocytes, antigen receptor genes are assembled from a comparatively small set of germline-encoded genetic elements in a process referred to as V(D)J recombination6,7. Potential self-reactivity of some antigen receptors arising from the quasi-random somatic diversification is suppressed by several robust control mechanisms8–12. For decades, scientists have puzzled over the evolutionary origin of somatically diversifying antigen receptors13–16. It has remained unclear how, at the inception of this mechanism, immunologically beneficial expanded receptor diversity was traded against the emerging risk of destructive self-recognition. Here we explore the hypothesis that in early vertebrates, sequence microhomologies marking the ends of recombining elements became the crucial targets of selection determining the outcome of non-homologous end joining-based repair of DNA double-strand breaks generated during RAG-mediated recombination. We find that, across the main clades of jawed vertebrates, TCRα repertoire diversity is best explained by species-specific extents of such sequence microhomologies. Thus, selection of germline sequence composition of rearranging elements emerges as a major factor determining the degree of diversity of somatically generated antigen receptors.