bluuebunny/crossref_metadata_2025 huggingface dataset:
A decomposition of light’s spin angular momentum density
Authors: Vernon Alex J. , Golat Sebastian , Rigouzzo Claire , Lim Eugene A. , Rodríguez-Fortuño Francisco J.
Published: July 2024

Light carries intrinsic spin angular momentum (SAM) when the electric or magnetic field vector rotates over time. A familiar vector equation calculates the direction of light’s SAM density using the right-hand rule with reference to the electric and magnetic polarisation ellipses. Using Maxwell’s equations, this vector equation can be decomposed into a sum of two distinct terms, akin to the well-known Poynting vector decomposition into orbital and spin currents. We present the first general study of this spin decomposition, showing that the two terms, which we call canonical and Poynting spin, are chiral analogies to the canonical and spin momenta of light in its interaction with matter. Like canonical momentum, canonical spin is directly measurable. Both canonical and Poynting spin incorporate spatial variation of the electric and magnetic fields and are influenced by optical vortices. The decomposition allows us to show that a linearly polarised vortex beam, which has no total SAM, can nevertheless exert longitudinal chiral pressure due to equal and opposite canonical and Poynting spins.
Super-resolution diffractive neural network for all-optical direction of arrival estimation beyond diffraction limits
Authors: Gao Sheng , Chen Hang , Wang Yichen , Duan Zhengyang , Zhang Haiou , Sun Zhi , Shen Yuan , Lin Xing
Published: July 2024

Wireless sensing of the wave propagation direction from radio sources lays the foundation for communication, radar, navigation, etc. However, the existing signal processing paradigm for the direction of arrival estimation requires the radio frequency electronic circuit to demodulate and sample the multichannel baseband signals followed by a complicated computing process, which places the fundamental limit on its sensing speed and energy efficiency. Here, we propose the super-resolution diffractive neural networks (S-DNN) to process electromagnetic (EM) waves directly for the DOA estimation at the speed of light. The multilayer meta-structures of S-DNN generate super-oscillatory angular responses in local angular regions that can perform the all-optical DOA estimation with angular resolutions beyond the diffraction limit. The spatial-temporal multiplexing of passive and reconfigurable S-DNNs is utilized to achieve high-resolution DOA estimation over a wide field of view. The S-DNN is validated for the DOA estimation of multiple radio sources over 5 GHz frequency bandwidth with estimation latency over two to four orders of magnitude lower than the state-of-the-art commercial devices in principle. The results achieve the angular resolution over an order of magnitude, experimentally demonstrated with four times, higher than diffraction-limited resolution. We also apply S-DNN’s edge computing capability, assisted by reconfigurable intelligent surfaces, for extremely low-latency integrated sensing and communication with low power consumption. Our work is a significant step towards utilizing photonic computing processors to facilitate various wireless sensing and communication tasks with advantages in both computing paradigms and performance over electronic computing.
Protein Condensate Atlas from predictive models of heteromolecular condensate composition
Authors: Saar Kadi L. , Scrutton Rob M. , Bloznelyte Kotryna , Morgunov Alexey S. , Good Lydia L. , Lee Alpha A. , Teichmann Sarah A. , Knowles Tuomas P. J.
Published: July 2024

Biomolecular condensates help cells organise their content in space and time. Cells harbour a variety of condensate types with diverse composition and many are likely yet to be discovered. Here, we develop a methodology to predict the composition of biomolecular condensates. We first analyse available proteomics data of cellular condensates and find that the biophysical features that determine protein localisation into condensates differ from known drivers of homotypic phase separation processes, with charge mediated protein-RNA and hydrophobicity mediated protein-protein interactions playing a key role in the former process. We then develop a machine learning model that links protein sequence to its propensity to localise into heteromolecular condensates. We apply the model across the proteome and find many of the top-ranked targets outside the original training data to localise into condensates as confirmed by orthogonal immunohistochemical staining imaging. Finally, we segment the condensation-prone proteome into condensate types based on an overlap with biomolecular interaction profiles to generate a Protein Condensate Atlas. Several condensate clusters within the Atlas closely match the composition of experimentally characterised condensates or regions within them, suggesting that the Atlas can be valuable for identifying additional components within known condensate systems and discovering previously uncharacterised condensates.
Toddlers strategically adapt their information search
Authors: Poli Francesco , Li Yi-Lin , Naidu Pravallika , Mars Rogier B. , Hunnius Sabine , Ruggeri Azzurra
Published: July 2024

Adaptive information seeking is essential for humans to effectively navigate complex and dynamic environments. Here, we developed a gaze-contingent eye-tracking paradigm to examine the early emergence of adaptive information-seeking. Toddlers (N = 60, 18-36 months) and adults (N = 42) either learnt that an animal was equally likely to be found in any of four available locations, or that it was most likely to be found in one particular location. Afterwards, they were given control of a torchlight, which they could move with their eyes to explore the otherwise pitch-black task environment. Eye-movement data and Markov models show that, from 24 months of age, toddlers become more exploratory than adults, and start adapting their exploratory strategies to the information structure of the task. These results show that toddlers’ search strategies are more sophisticated than previously thought, and identify the unique features that distinguish their information search from adults’.
Realization of higher-order topological lattices on a quantum computer
Authors: Koh Jin Ming , Tai Tommy , Lee Ching Hua
Published: July 2024

Programmable quantum simulators may one day outperform classical computers at certain tasks. But at present, the range of viable applications with noisy intermediate-scale quantum (NISQ) devices remains limited by gate errors and the number of high-quality qubits. Here, we develop an approach that places digital NISQ hardware as a versatile platform for simulating multi-dimensional condensed matter systems. Our method encodes a high-dimensional lattice in terms of many-body interactions on a reduced-dimension model, thereby taking full advantage of the exponentially large Hilbert space of the host quantum system. With circuit optimization and error mitigation techniques, we measured on IBM superconducting quantum processors the topological state dynamics and protected mid-gap spectra of higher-order topological lattices, in up to four dimensions, with high accuracy. Our projected resource requirements scale favorably with system size and lattice dimensionality compared to classical computation, suggesting a possible route to useful quantum advantage in the longer term.
Single cell transcriptomes and multiscale networks from persons with and without Alzheimer’s disease
Authors: Wang Qi , Antone Jerry , Alsop Eric , Reiman Rebecca , Funk Cory , Bendl Jaroslav , Dudley Joel T. , Liang Winnie S. , Karr Timothy L. , Roussos Panos , Bennett David A. , De Jager Philip L. , Serrano Geidy E. , Beach Thomas G. , Van Keuren-Jensen Kendall , Mastroeni Diego , Reiman Eric M. , Readhead Benjamin P.
Published: July 2024

The emergence of single nucleus RNA sequencing (snRNA-seq) offers to revolutionize the study of Alzheimer’s disease (AD). Integration with complementary multiomics data such as genetics, proteomics and clinical data provides powerful opportunities to link cell subpopulations and molecular networks with a broader disease-relevant context. We report snRNA-seq profiles from superior frontal gyrus samples from 101 well characterized subjects from the Banner Brain and Body Donation Program in combination with whole genome sequences. We report findings that link common AD risk variants with CR1 expression in oligodendrocytes as well as alterations in hematological parameters. We observed an AD-associated CD83(+) microglial subtype with unique molecular networks and which is associated with immunoglobulin IgG4 production in the transverse colon. Our major observations were replicated in two additional, independent snRNA-seq data sets. These findings illustrate the power of multi-tissue molecular profiling to contextualize snRNA-seq brain transcriptomics and reveal disease biology.
Correlative single-molecule and structured illumination microscopy of fast dynamics at the plasma membrane
Authors: Winkelmann Hauke , Richter Christian P. , Eising Jasper , Piehler Jacob , Kurre Rainer
Published: July 2024

Total internal reflection fluorescence (TIRF) microscopy offers powerful means to uncover the functional organization of proteins in the plasma membrane with very high spatial and temporal resolution. Traditional TIRF illumination, however, shows a Gaussian intensity profile, which is typically deteriorated by overlaying interference fringes hampering precise quantification of intensities—an important requisite for quantitative analyses in single-molecule localization microscopy (SMLM). Here, we combine flat-field illumination by using a standard πShaper with multi-angular TIR illumination by incorporating a spatial light modulator compatible with fast super-resolution structured illumination microscopy (SIM). This distinct combination enables quantitative multi-color SMLM with a highly homogenous illumination. By using a dual camera setup with optimized image splitting optics, we achieve a versatile combination of SMLM and SIM with up to three channels. We deploy this setup for establishing robust detection of receptor stoichiometries based on single-molecule intensity analysis and single-molecule Förster resonance energy transfer (smFRET). Homogeneous illumination furthermore enables long-term tracking and localization microscopy (TALM) of cell surface receptors identifying spatial heterogeneity of mobility and accessibility in the plasma membrane. By combination of TALM and SIM, spatially and molecularly heterogenous diffusion properties can be correlated with nanoscale cytoskeletal organization and dynamics.
The Hippo pathway transcription factors YAP and TAZ play HPV-type dependent roles in cervical cancer
Authors: Patterson Molly R. , Cogan Joseph A. , Cassidy Rosa , Theobald Daisy A. , Wang Miao , Scarth James A. , Anene Chinedu A. , Whitehouse Adrian , Morgan Ethan L. , Macdonald Andrew
Published: July 2024

Human papillomaviruses (HPVs) cause most cervical cancers and an increasing number of anogenital and oral carcinomas, with most cases caused by HPV16 or HPV18. HPV hijacks host signalling pathways to promote carcinogenesis. Understanding these interactions could permit identification of much-needed therapeutics for HPV-driven malignancies. The Hippo signalling pathway is important in HPV+ cancers, with the downstream effector YAP playing a pro-oncogenic role. In contrast, the significance of its paralogue TAZ remains largely uncharacterised in these cancers. We demonstrate that TAZ is dysregulated in a HPV-type dependent manner by a distinct mechanism to that of YAP and controls proliferation via alternative cellular targets. Analysis of cervical cancer cell lines and patient biopsies revealed that TAZ expression was only significantly increased in HPV18+ and HPV18-like cells and TAZ knockdown reduced proliferation, migration and invasion only in HPV18+ cells. RNA-sequencing of HPV18+ cervical cells revealed that YAP and TAZ have distinct targets, suggesting they promote carcinogenesis by different mechanisms. Thus, in HPV18+ cancers, YAP and TAZ play non-redundant roles. This analysis identified TOGARAM2 as a previously uncharacterised TAZ target and demonstrates its role as a key effector of TAZ-mediated proliferation, migration and invasion in HPV18+ cancers.
Isotopologues of potassium 2,2,2-trifluoroethoxide for applications in positron emission tomography and beyond
Authors: Zhao Qunchao , Telu Sanjay , Jana Susovan , Morse Cheryl L. , Pike Victor W.
Published: July 2024

The 2,2,2-trifluoroethoxy group increasingly features in drugs and potential tracers for biomedical imaging with positron emission tomography (PET). Herein, we describe a rapid and transition metal-free conversion of fluoroform with paraformaldehyde into highly reactive potassium 2,2,2-trifluoroethoxide (CF3CH2OK) and demonstrate robust applications of this synthon in one-pot, two-stage 2,2,2-trifluoroethoxylations of both aromatic and aliphatic precursors. Moreover, we show that these transformations translate easily to fluoroform that has been labeled with either carbon-11 (t1/2 = 20.4 min) or fluorine-18 (t1/2 = 109.8 min), so allowing the appendage of complex molecules with a no-carrier-added 11C- or 18F- 2,2,2-trifluoroethoxy group. This provides scope to create candidate PET tracers with radioactive and metabolically stable 2,2,2-trifluoroethoxy moieties. We also exemplify syntheses of isotopologues of potassium 2,2,2-trifluoroethoxide and show their utility for stable isotopic labeling which can be of further benefit for drug discovery and development.
Germ granule compartments coordinate specialized small RNA production
Authors: Chen Xiangyang , Wang Ke , Mufti Farees Ud Din , Xu Demin , Zhu Chengming , Huang Xinya , Zeng Chenming , Jin Qile , Huang Xiaona , Yan Yong-hong , Dong Meng-qiu , Feng Xuezhu , Shi Yunyu , Kennedy Scott , Guang Shouhong
Published: July 2024

Germ granules are biomolecular condensates present in most animal germ cells. One function of germ granules is to help maintain germ cell totipotency by organizing mRNA regulatory machinery, including small RNA-based gene regulatory pathways. The C. elegans germ granule is compartmentalized into multiple subcompartments whose biological functions are largely unknown. Here, we identify an uncharted subcompartment of the C. elegans germ granule, which we term the E granule. The E granule is nonrandomly positioned within the germ granule. We identify five proteins that localize to the E granule, including the RNA-dependent RNA polymerase (RdRP) EGO-1, the Dicer-related helicase DRH-3, the Tudor domain-containing protein EKL-1, and two intrinsically disordered proteins, EGC-1 and ELLI-1. Localization of EGO-1 to the E granule enables synthesis of a specialized class of 22G RNAs, which derive exclusively from 5’ regions of a subset of germline-expressed mRNAs. Defects in E granule assembly elicit disordered production of endogenous siRNAs, which disturbs fertility and the RNAi response. Our results define a distinct subcompartment of the C. elegans germ granule and suggest that one function of germ granule compartmentalization is to facilitate the localized production of specialized classes of small regulatory RNAs.
Ragopathies and the rising influence of RagGTPases on human diseases
Authors: Sambri Irene , Ferniani Marco , Ballabio Andrea
Published: July 2024

RagGTPases (Rags) play an essential role in the regulation of cell metabolism by controlling the activities of both mechanistic target of rapamycin complex 1 (mTORC1) and Transcription factor EB (TFEB). Several diseases, herein named ragopathies, are associated to Rags dysfunction. These diseases may be caused by mutations either in genes encoding the Rags, or in their upstream regulators. The resulting phenotypes may encompass a variety of clinical features such as cataract, kidney tubulopathy, dilated cardiomyopathy and several types of cancer. In this review, we focus on the key clinical, molecular and physio-pathological features of ragopathies, aiming to shed light on their underlying mechanisms.
Long-range inhibition from prelimbic to cingulate areas of the medial prefrontal cortex enhances network activity and response execution
Authors: Utashiro Nao , MacLaren Duncan Archibald Allan , Liu Yu-Chao , Yaqubi Kaneschka , Wojak Birgit , Monyer Hannah
Published: July 2024

It is well established that the medial prefrontal cortex (mPFC) exerts top-down control of many behaviors, but little is known regarding how cross-talk between distinct areas of the mPFC influences top-down signaling. We performed virus-mediated tracing and functional studies in male mice, homing in on GABAergic projections whose axons are located mainly in layer 1 and that connect two areas of the mPFC, namely the prelimbic area (PrL) with the cingulate area 1 and 2 (Cg1/2). We revealed the identity of the targeted neurons that comprise two distinct types of layer 1 GABAergic interneurons, namely single-bouquet cells (SBCs) and neurogliaform cells (NGFs), and propose that this connectivity links GABAergic projection neurons with cortical canonical circuits. In vitro electrophysiological and in vivo calcium imaging studies support the notion that the GABAergic projection neurons from the PrL to the Cg1/2 exert a crucial role in regulating the activity in the target area by disinhibiting layer 5 output neurons. Finally, we demonstrated that recruitment of these projections affects impulsivity and mechanical responsiveness, behaviors which are known to be modulated by Cg1/2 activity.
Enhancing cross-protection against influenza by heterologous sequential immunization with mRNA LNP and protein nanoparticle vaccines
Authors: Dong Chunhong , Zhu Wandi , Wei Lai , Kim Joo Kyung , Ma Yao , Kang Sang-Moo , Wang Bao-Zhong
Published: July 2024

Enhancing influenza vaccine cross-protection is imperative to alleviate the significant public health burden of influenza. Heterologous sequential immunization may synergize diverse vaccine formulations and routes to improve vaccine potency and breadth. Here we investigate the effects of immunization strategies on the generation of cross-protective immune responses in female Balb/c mice, utilizing mRNA lipid nanoparticle (LNP) and protein-based PHC nanoparticle vaccines targeting influenza hemagglutinin. Our findings emphasize the crucial role of priming vaccination in shaping Th bias and immunodominance hierarchies. mRNA LNP prime favors Th1-leaning responses, while PHC prime elicits Th2-skewing responses. We demonstrate that cellular and mucosal immune responses are pivotal correlates of cross-protection against influenza. Notably, intranasal PHC immunization outperforms its intramuscular counterpart in inducing mucosal immunity and conferring cross-protection. Sequential mRNA LNP prime and intranasal PHC boost demonstrate optimal cross-protection against antigenically drifted and shifted influenza strains. Our study offers valuable insights into tailoring immunization strategies to optimize influenza vaccine effectiveness.
The reactive pyruvate metabolite dimethylglyoxal mediates neurological consequences of diabetes
Authors: Rhein Sina , Costalunga Riccardo , Inderhees Julica , Gürtzgen Tammo , Faupel Teresa Christina , Shaheryar Zaib , Arrulo Pereira Adriana , Othman Alaa , Begemann Kimberly , Binder Sonja , Stölting Ines , Dorta Valentina , Nawroth Peter P. , Fleming Thomas , Oexle Konrad , Prevot Vincent , Nogueiras Ruben , Meyhöfer Svenja , Meyhöfer Sebastian M. , Schwaninger Markus
Published: July 2024

Complications of diabetes are often attributed to glucose and reactive dicarbonyl metabolites derived from glycolysis or gluconeogenesis, such as methylglyoxal. However, in the CNS, neurons and endothelial cells use lactate as energy source in addition to glucose, which does not lead to the formation of methylglyoxal and has previously been considered a safer route of energy consumption than glycolysis. Nevertheless, neurons and endothelial cells are hotspots for the cellular pathology underlying neurological complications in diabetes, suggesting a cause that is distinct from other diabetes complications and independent of methylglyoxal. Here, we show that in clinical and experimental diabetes plasma concentrations of dimethylglyoxal are increased. In a mouse model of diabetes, ilvb acetolactate-synthase-like (ILVBL, HACL2) is the enzyme involved in formation of increased amounts of dimethylglyoxal from lactate-derived pyruvate. Dimethylglyoxal reacts with lysine residues, forms Nε−3-hydroxy-2-butanonelysine (HBL) as an adduct, induces oxidative stress more strongly than other dicarbonyls, causes blood-brain barrier disruption, and can mimic mild cognitive impairment in experimental diabetes. These data suggest dimethylglyoxal formation as a pathway leading to neurological complications in diabetes that is distinct from other complications. Importantly, dimethylglyoxal formation can be reduced using genetic, pharmacological and dietary interventions, offering new strategies for preventing CNS dysfunction in diabetes.
Geological evidence for extensive basin ejecta as plains terrains in the Moon’s South Polar Region
Authors: Qiao Le , Xu Luyuan , Head James W. , Chen Jian , Zhang Yuzheng , Li Bo , Ling Zongcheng
Published: July 2024

Water ice and other volatiles that accumulated in the Moon’s polar regions are among the top priority targets for lunar exploration, due to their significances in both lunar geology and extraterrestrial resource utilization. Locating suitable landing sites and determining the provenance of sampled/measured surface materials are critical for future landed missions. Here, we map over 800 sites of plains terrains in the Moon’s south polar region, with a total surface area of ~46,000 km2. Orbital measurements and analog studies show that most of these plains have apparently higher albedo and lower iron content than volcanic mare plains, suggesting an origin of ejecta-induced debris flows from distant impact craters, especially from the Schrödinger basin. Our findings suggest that the entire lunar south polar region probably have experienced contributions from distant basin materials. We recommend these plains as priority landing sites for future exploration of lunar polar volatiles and early bombardment history.
m3C32 tRNA modification controls serine codon-biased mRNA translation, cell cycle, and DNA-damage response
Authors: Cui Jia , Sendinc Erdem , Liu Qi , Kim Sujin , Fang Jaden Y. , Gregory Richard I.
Published: July 2024

The epitranscriptome includes a diversity of RNA modifications that influence gene expression. N3-methylcytidine (m3C) mainly occurs in the anticodon loop (position C32) of certain tRNAs yet its role is poorly understood. Here, using HAC-Seq, we report comprehensive METTL2A/2B-, METTL6-, and METTL2A/2B/6-dependent m3C profiles in human cells. METTL2A/2B modifies tRNA-arginine and tRNA-threonine members, whereas METTL6 modifies the tRNA-serine family. However, decreased m3C32 on tRNA-Ser-GCT isodecoders is only observed with combined METTL2A/2B/6 deletion. Ribo-Seq reveals altered translation of genes related to cell cycle and DNA repair pathways in METTL2A/2B/6-deficient cells, and these mRNAs are enriched in AGU codons that require tRNA-Ser-GCT for translation. These results, supported by reporter assays, help explain the observed altered cell cycle, slowed proliferation, and increased cisplatin sensitivity phenotypes of METTL2A/2B/6-deficient cells. Thus, we define METTL2A/2B/6-dependent methylomes and uncover a particular requirement of m3C32 tRNA modification for serine codon-biased mRNA translation of cell cycle, and DNA repair genes.
Ion diffusion retarded by diverging chemical susceptibility
Authors: Cai Yuhang , Wang Zhaowu , Wan Jiawei , Li Jiachen , Guo Ruihan , Ager Joel W. , Javey Ali , Zheng Haimei , Jiang Jun , Wu Junqiao
Published: July 2024

For first-order phase transitions, the second derivatives of Gibbs free energy (specific heat and compressibility) diverge at the transition point, resulting in an effect known as super-elasticity along the pressure axis, or super-thermicity along the temperature axis. Here we report a chemical analogy of these singularity effects along the atomic doping axis, where the second derivative of Gibbs free energy (chemical susceptibility) diverges at the transition point, leading to an anomalously high energy barrier for dopant diffusion in co-existing phases, an effect we coin as super-susceptibility. The effect is realized in hydrogen diffusion in vanadium dioxide (VO2) with a metal-insulator transition (MIT). We show that hydrogen faces three times higher energy barrier and over one order of magnitude lower diffusivity when it diffuses across a metal-insulator domain wall in VO2. The additional energy barrier is attributed to a volumetric energy penalty that the diffusers need to pay for the reduction of latent heat. The super-susceptibility and resultant retarded atomic diffusion are expected to exist universally in all phase transformations where the transformation temperature is coupled to chemical composition, and inspires new ways to engineer dopant diffusion in phase-coexisting material systems.
Lipid-mediated intracellular delivery of recombinant bioPROTACs for the rapid degradation of undruggable proteins
Authors: Chan Alexander , Haley Rebecca M. , Najar Mohd Altaf , Gonzalez-Martinez David , Bugaj Lukasz J. , Burslem George M. , Mitchell Michael J. , Tsourkas Andrew
Published: July 2024

Recently, targeted degradation has emerged as a powerful therapeutic modality. Relying on “event-driven” pharmacology, proteolysis targeting chimeras (PROTACs) can degrade targets and are superior to conventional inhibitors against undruggable proteins. Unfortunately, PROTAC discovery is limited by warhead scarcity and laborious optimization campaigns. To address these shortcomings, analogous protein-based heterobifunctional degraders, known as bioPROTACs, have been developed. Compared to small-molecule PROTACs, bioPROTACs have higher success rates and are subject to fewer design constraints. However, the membrane impermeability of proteins severely restricts bioPROTAC deployment as a generalized therapeutic modality. Here, we present an engineered bioPROTAC template able to complex with cationic and ionizable lipids via electrostatic interactions for cytosolic delivery. When delivered by biocompatible lipid nanoparticles, these modified bioPROTACs can rapidly degrade intracellular proteins, exhibiting near-complete elimination (up to 95% clearance) of targets within hours of treatment. Our bioPROTAC format can degrade proteins localized to various subcellular compartments including the mitochondria, nucleus, cytosol, and membrane. Moreover, substrate specificity can be easily reprogrammed, allowing modular design and targeting of clinically-relevant proteins such as Ras, Jnk, and Erk. In summary, this work introduces an inexpensive, flexible, and scalable platform for efficient intracellular degradation of proteins that may elude chemical inhibition.
Strategies for modeling aging and age-related diseases
Authors: Jothi D. , Kulka Linda Anna Michelle
Published: July 2024

The ability to reprogram patient-derived-somatic cells to IPSCs (Induced Pluripotent Stem Cells) has led to a better understanding of aging and age-related diseases like Parkinson’s, and Alzheimer’s. The established patient-derived disease models mimic disease pathology and can be used to design drugs for aging and age-related diseases. However, the age and genetic mutations of the donor cells, the employed reprogramming, and the differentiation protocol might often pose challenges in establishing an appropriate disease model. In this review, we will focus on the various strategies for the successful reprogramming and differentiation of patient-derived cells to disease models for aging and age-related diseases, emphasizing the accuracy in the recapitulation of disease pathology and ways to overcome the limitations of its potential application in cell replacement therapy and drug development.
Single-cell atlas of the human brain vasculature across development, adulthood and disease
Authors: Wälchli Thomas , Ghobrial Moheb , Schwab Marc , Takada Shigeki , Zhong Hang , Suntharalingham Samuel , Vetiska Sandra , Gonzalez Daymé Rodrigues , Wu Ruilin , Rehrauer Hubert , Dinesh Anuroopa , Yu Kai , Chen Edward L. Y. , Bisschop Jeroen , Farnhammer Fiona , Mansur Ann , Kalucka Joanna , Tirosh Itay , Regli Luca , Schaller Karl , Frei Karl , Ketela Troy , Bernstein Mark , Kongkham Paul , Carmeliet Peter , Valiante Taufik , Dirks Peter B. , Suva Mario L. , Zadeh Gelareh , Tabar Viviane , Schlapbach Ralph , Jackson Hartland W. , De Bock Katrien , Fish Jason E. , Monnier Philippe P. , Bader Gary D. , Radovanovic Ivan
Published: July 2024

A broad range of brain pathologies critically relies on the vasculature, and cerebrovascular disease is a leading cause of death worldwide. However, the cellular and molecular architecture of the human brain vasculature remains incompletely understood1. Here we performed single-cell RNA sequencing analysis of 606,380 freshly isolated endothelial cells, perivascular cells and other tissue-derived cells from 117 samples, from 68 human fetuses and adult patients to construct a molecular atlas of the developing fetal, adult control and diseased human brain vasculature. We identify extensive molecular heterogeneity of the vasculature of healthy fetal and adult human brains and across five vascular-dependent central nervous system (CNS) pathologies, including brain tumours and brain vascular malformations. We identify alteration of arteriovenous differentiation and reactivated fetal as well as conserved dysregulated genes and pathways in the diseased vasculature. Pathological endothelial cells display a loss of CNS-specific properties and reveal an upregulation of MHC class II molecules, indicating atypical features of CNS endothelial cells. Cell–cell interaction analyses predict substantial endothelial-to-perivascular cell ligand–receptor cross-talk, including immune-related and angiogenic pathways, thereby revealing a central role for the endothelium within brain neurovascular unit signalling networks. Our single-cell brain atlas provides insights into the molecular architecture and heterogeneity of the developing, adult/control and diseased human brain vasculature and serves as a powerful reference for future studies.
A maternal brain hormone that builds bone
Authors: Babey Muriel E. , Krause William C. , Chen Kun , Herber Candice B. , Torok Zsofia , Nikkanen Joni , Rodriguez Ruben , Zhang Xiao , Castro-Navarro Fernanda , Wang Yuting , Wheeler Erika E. , Villeda Saul , Leach J. Kent , Lane Nancy E. , Scheller Erica L. , Chan Charles K. F. , Ambrosi Thomas H. , Ingraham Holly A.
Published: July 2024

In lactating mothers, the high calcium (Ca2+) demand for milk production triggers significant bone loss1. Although oestrogen normally counteracts excessive bone resorption by promoting bone formation, this sex steroid drops precipitously during this postpartum period. Here we report that brain-derived cellular communication network factor 3 (CCN3) secreted from KISS1 neurons of the arcuate nucleus (ARCKISS1) fills this void and functions as a potent osteoanabolic factor to build bone in lactating females. We began by showing that our previously reported female-specific, dense bone phenotype2 originates from a humoral factor that promotes bone mass and acts on skeletal stem cells to increase their frequency and osteochondrogenic potential. This circulatory factor was then identified as CCN3, a brain-derived hormone from ARCKISS1 neurons that is able to stimulate mouse and human skeletal stem cell activity, increase bone remodelling and accelerate fracture repair in young and old mice of both sexes. The role of CCN3 in normal female physiology was revealed after detecting a burst of CCN3 expression in ARCKISS1 neurons coincident with lactation. After reducing CCN3 in ARCKISS1 neurons, lactating mothers lost bone and failed to sustain their progeny when challenged with a low-calcium diet. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone for both sexes and define a new maternal brain hormone for ensuring species survival in mammals.
Repeated plague infections across six generations of Neolithic Farmers
Authors: Seersholm Frederik Valeur , Sjögren Karl-Göran , Koelman Julia , Blank Malou , Svensson Emma M. , Staring Jacqueline , Fraser Magdalena , Pinotti Thomaz , McColl Hugh , Gaunitz Charleen , Ruiz-Bedoya Tatiana , Granehäll Lena , Villegas-Ramirez Berenice , Fischer Anders , Price T. Douglas , Allentoft Morten E. , Iversen Astrid K. N. , Axelsson Tony , Ahlström Torbjörn , Götherström Anders , Storå Jan , Kristiansen Kristian , Willerslev Eske , Jakobsson Mattias , Malmström Helena , Sikora Martin
Published: July 2024

In the period between 5,300 and 4,900 calibrated years before present (cal.bp), populations across large parts of Europe underwent a period of demographic decline1,2. However, the cause of this so-called Neolithic decline is still debated. Some argue for an agricultural crisis resulting in the decline3, others for the spread of an early form of plague4. Here we use population-scale ancient genomics to infer ancestry, social structure and pathogen infection in 108 Scandinavian Neolithic individuals from eight megalithic graves and a stone cist. We find that the Neolithic plague was widespread, detected in at least 17% of the sampled population and across large geographical distances. We demonstrate that the disease spread within the Neolithic community in three distinct infection events within a period of around 120 years. Variant graph-based pan-genomics shows that the Neolithic plague genomes retained ancestral genomic variation present inYersinia pseudotuberculosis, including virulence factors associated with disease outcomes. In addition, we reconstruct four multigeneration pedigrees, the largest of which consists of 38 individuals spanning six generations, showing a patrilineal social organization. Lastly, we document direct genomic evidence for Neolithic female exogamy in a woman buried in a different megalithic tomb than her brothers. Taken together, our findings provide a detailed reconstruction of plague spread within a large patrilineal kinship group and identify multiple plague infections in a population dated to the beginning of the Neolithic decline.
CryoET of β-amyloid and tau within postmortem Alzheimer’s disease brain
Authors: Gilbert Madeleine A. G. , Fatima Nayab , Jenkins Joshua , O’Sullivan Thomas J. , Schertel Andreas , Halfon Yehuda , Wilkinson Martin , Morrema Tjado H. J. , Geibel Mirjam , Read Randy J. , Ranson Neil A. , Radford Sheena E. , Hoozemans Jeroen J. M. , Frank René A. W.
Published: July 2024

A defining pathological feature of most neurodegenerative diseases is the assembly of proteins into amyloid that form disease-specific structures1. In Alzheimer’s disease, this is characterized by the deposition of β-amyloid and tau with disease-specific conformations. The in situ structure of amyloid in the human brain is unknown. Here, using cryo-fluorescence microscopy-targeted cryo-sectioning, cryo-focused ion beam-scanning electron microscopy lift-out and cryo-electron tomography, we determined in-tissue architectures of β-amyloid and tau pathology in a postmortem Alzheimer’s disease donor brain. β-amyloid plaques contained a mixture of fibrils, some of which were branched, and protofilaments, arranged in parallel arrays and lattice-like structures. Extracellular vesicles and cuboidal particles defined the non-amyloid constituents of β-amyloid plaques. By contrast, tau inclusions formed parallel clusters of unbranched filaments. Subtomogram averaging a cluster of 136 tau filaments in a single tomogram revealed the polypeptide backbone conformation and filament polarity orientation of paired helical filaments within tissue. Filaments within most clusters were similar to each other, but were different between clusters, showing amyloid heterogeneity that is spatially organized by subcellular location. The in situ structural approaches outlined here for human donor tissues have applications to a broad range of neurodegenerative diseases.
Resolving chaperone-assisted protein folding on the ribosome at the peptide level
Authors: Wales Thomas E. , Pajak Aleksandra , Roeselová Alžběta , Shivakumaraswamy Santosh , Howell Steven , Kjær Svend , Hartl F. Ulrich , Engen John R. , Balchin David
Published: July 2024

Protein folding in vivo begins during synthesis on the ribosome and is modulated by molecular chaperones that engage the nascent polypeptide. How these features of protein biogenesis influence the maturation pathway of nascent proteins is incompletely understood. Here, we use hydrogen–deuterium exchange mass spectrometry to define, at peptide resolution, the cotranslational chaperone-assisted folding pathway of Escherichia coli dihydrofolate reductase. The nascent polypeptide folds along an unanticipated pathway through structured intermediates not populated during refolding from denaturant. Association with the ribosome allows these intermediates to form, as otherwise destabilizing carboxy-terminal sequences remain confined in the ribosome exit tunnel. Trigger factor binds partially folded states without disrupting their structure, and the nascent chain is poised to complete folding immediately upon emergence of the C terminus from the exit tunnel. By mapping interactions between the nascent chain and ribosomal proteins, we trace the path of the emerging polypeptide during synthesis. Our work reveals new mechanisms by which cellular factors shape the conformational search for the native state.
Explaining Conformational Diversity in Protein Families through Molecular Motions
Authors: Lombard Valentin , Grudinin Sergei , Laine Elodie
Published: July 2024

Proteins play a central role in biological processes, and understanding their conformational variability is crucial for unraveling their functional mechanisms. Recent advancements in high-throughput technologies have enhanced our knowledge of protein structures, yet predicting their multiple conformational states and motions remains challenging. This study introduces Dimensionality Analysis for protein Conformational Exploration (DANCE) for a systematic and comprehensive description of protein families conformational variability. DANCE accommodates both experimental and predicted structures. It is suitable for analysing anything from single proteins to superfamilies. Employing it, we clustered all experimentally resolved protein structures available in the Protein Data Bank into conformational collections and characterized them as sets of linear motions. The resource facilitates access and exploitation of the multiple states adopted by a protein and its homologs. Beyond descriptive analysis, we assessed classical dimensionality reduction techniques for sampling unseen states on a representative benchmark. This work improves our understanding of how proteins deform to perform their functions and opens ways to a standardised evaluation of methods designed to sample and generate protein conformations.
Improving data archiving practices in ancient genomics
Authors: Bergström Anders
Published: July 2024

Ancient DNA is producing a rich record of past genetic diversity in humans and other species. However, unless the primary data is appropriately archived, its long-term value will not be fully realised. I surveyed publicly archived data from 42 recent ancient genomics studies. Half of the studies archived incomplete datasets, preventing accurate replication and representing a loss of data of potential future use. No studies met all criteria that could be considered best practice. Based on these results, I make six recommendations for data producers: (1) archive all sequencing reads, not just those that aligned to a reference genome, (2) archive read alignments too, but as secondary analysis files, (3) provide correct experiment metadata on samples, libraries and sequencing runs, (4) provide informative sample metadata, (5) archive data from low-coverage and negative experiments, and (6) document archiving choices in papers, and peer review these. Given the reliance on destructive sampling of finite material, ancient genomics studies have a particularly strong responsibility to ensure the longevity and reusability of generated data.
Dataset of the rumen microbiota and epithelial transcriptomics and proteomics in goat affected by solid diets
Authors: Chai Jianmin , Lv Xiaokang , Zhuang Yimin , Diao Qiyu , Cui Kai , Deng Feilong , Li Ying , Zhang Naifeng
Published: July 2024

Although early solid diet supplementation is a common practice to improve the growth and development in goat kids, its biological mechanism how solid diet induces rumen microbiota and epithelial development is still unknow. In this study, rumen fermentation parameters, 16S rRNA sequencing for rumen content and epithelial microbiota, transcriptomics and proteomics of epithelium were determined to classify the effects of solid diet supplementation. Here, we classified the changes of goat phenotypes (i.e., growth performance, rumen fermentation and development) and linked them to the changes of rumen microbiota, transcriptome and expressed proteins. The mechanism of solid diet improving rumen development was elucidated preliminarily. Moreover, different roles between the rumen content and epithelial microbiota were identified. Thess datasets expands our understanding of the association between the early diet intervention and rumen development, providing the useful information how nutrient strategy affects rumen function and subsequently improves the host growth. The generated data provides insights in the importance of rumen niche microbiota and microbe-host interactions, which benefits future studies.
Spatial variations and health risk assessment of heavy metal levels in groundwater of Qatar
Authors: Manawi Yehia , Subeh Mosab , Al-Marri Jaber , Al-Sulaiti Huda
Published: July 2024

The present work’s objective is to give a comprehensive overview of the quality of groundwater in Qatar in terms of heavy metals content as well as investigating the cause and effect of the elevation in their levels above the WHO/US-EPA standards. The scope of the study included (1) physical and chemical analysis of 82 groundwater samples collected from various locations around Qatar, (2) development of ArcGIS maps depicting the variations in the levels, (3) assessment of the human health risks associated with the existing levels using three of the most used models which are: Hazard index (HI), Nemerow comprehensive pollution index (NCPI) and Incremental Lifetime Cancer Risk (ILCR). There is no extensive study ever reported to assess the health risks linked with the consumption of groundwater characterized with such heavy metals levels in Qatar. The chronic daily intake (CDI) of the investigated heavy metals (Ag, Mn, Cr, V, Mo and Sr) through ingestion and dermal pathways had a range of 1.4 × 10–5–6.7 × 10–1 mg/kg/day while the NCPI’s range was reported at 0–4.39. Moreover, the HI and ILCR were found to have a range of 0–3.2 and 5.6 × 10–4–5.5 × 10–2, respectively. The assessment of health risks, conducted in the present work, could be beneficial in building the baseline of heavy metals levels in groundwater in Qatar. This will also help in the determination of any future contamination of groundwater.
Estimation of apparent thermal inertia of roofing materials from aerial thermal imagery
Authors: Mandanici Emanuele , Lo Grasso Gabriele , Tini Maria A. , Zanutta Antonio
Published: July 2024

The rapid expansion of urban areas and soil sealing is enhancing the Urban Heat Island (UHI) phenomenon, especially during heat waves. The different thermal inertia of the building materials compared to natural surfaces is one of the major driving factors of UHI. The present contribution aims to test a methodology for mapping the Apparent Thermal Inertia (ATI)—a proxy that can be derived from remote sensing data—of roofing surfaces at the scale of an entire city and with a high spatial resolution. Day and night aerial thermal images with the resolution of 0.5 m were acquired over two test areas in Bologna (Italy), together with satellite multispectral data. Statistics on the buildings in the test areas are computed considering different classes of roofing materials (e.g. bituminous sheath, clay tiles, metal sheet, gravel tiles). Observed median ATI values for each class range from 0.03 to 0.09 K

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with interquartile ranges between 0.02 and 0.14 K

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, so the intra-class variability in some cases appears higher than the variability among different material classes, proving the importance of ATI mapping for UHI investigations.
The factors of quality of life among patients after myocardial infarction in Poland: a cross-sectional study. The quality of life among patients after myocardial infarction
Authors: Kolarczyk Ewelina , Kohanová Dominika , Witkowska Agnieszka , Szymiczek Marek , Młynarska Agnieszka
Published: July 2024

The quality of life (QoL) is now recognised as a central indicator of the effectiveness of interventions especially in patients after myocardial infarction (MI). The QoL may be important predict poor outcomes in cardiac patients.The present work aims to increase knowledge of the level of QoL in patients after MI. Moreover, the paper analyses the QoL in relation to sociodemographic factors and the degree of functioning in chronic disease. The study was conducted among 231 patients who were hospitalized due to MI within the period of June 2021 to June 2022 in the Hospital in Racibórz in Poland. The WHO Quality of Life Questionnaire and the Chronic Disease Functioning Scale were used. The analysis showed a statistically significant correlation (coefficient value 0.5 <|r/rho|≤ 0.7) between general functioning in chronic disease and the average QoL (rho = 0.56; p < 0.001)and somatic QoL levels(rho = 0.52; p < 0.001), as well as a moderately strong positive correlation with the QoL level on the psychological domain (rho = 0.50; p < 0.001), social domain(rho = 0.48; p < 0.001) and environmental domain (rho = 0.43; p < 0.001). The results of this study suggested that healthcare workers adopts appropriate policies for the implementation of quality of life, which can reduce the number of repetitive referrals to the hospital and costs imposed on the health system.
Utilizing combusted PET plastic waste and biogenic oils as efficient pour point depressants for crude oil
Authors: Ghobashy Mohamed Mohamady , Rashad A. M. , Attia S. K. , Elsayed A. E. , Osman D. I.
Published: July 2024

The deposition of paraffin on pipelines during crude oil transit and low-temperature restart processes poses a significant challenge for the oil industry. Addressing this issue necessitates the exploration of innovative materials and methods. Pour point depressants (PPDs) emerge as crucial processing aids to modify paraffin crystallization and enhance crude oil flow. This study focuses on the combustion of polyethylene terephthalate (PET) waste, a prevalent plastic, in two distinct oils (castor and jatropha). The resulting black waxy substances (PET/Castor and PET/Jatropha) were introduced in varying weights (1000, 2000, and 3000 ppm) to crude oil. The PET/castor oil combination demonstrated a remarkable reduction in pour point from 18 to −21 °C at 3000 ppm concentration, significantly more effective than PET/jatropha blends. Substantial decreases in viscosity (up to 75%) and shear stress (up to 72%) were also observed for both blends, most prominently at lower temperatures near the pour point. The synergistic effect of PET and oils as nucleating agents that alter crystallization patterns and restrict crystal growth contributes to this enhanced low-temperature flow. This highlights the potential of PET plastic waste as an economical, abundant, and eco-friendly additive to develop high-performance PPDs for crude oil.