bluuebunny/crossref_metadata_2025 huggingface dataset:
Propagation Mechanism of Branched Downward Positive Leader Resulting in a Negative Cloud‐To‐Ground Flash
Authors: Ding Z. , Rakov V. A. , Zhu Y. , Kereszy I. , Chen S. , Tran M. D.
Published: January 2024

Our basic knowledge of downward positive lightning leaders is incomplete due to their rarity and limited ability of VHF mapping systems to image positive streamers. Here, using high‐speed optical records and wideband electric field and magnetic field derivative signatures, we examine in detail the development of a descending positive leader, which extended intermittently via alternating branching at altitudes of 4.2 to 1.9 km and involved luminosity transients separated by millisecond‐scale quiet intervals. We show that the transients (a) are mostly initiated in previously created but already decayed branches, at a distance of the order of 100 m above the branch lower extremity, (b) extend bidirectionally with negative charge moving up, (c) establish a temporary (1 ms or so) steady‐current connection to the negative part of the overall bidirectional leader tree, and (d) exhibit brightening accompanied by new breakdowns at the positive leader end. One of the transients unexpectedly resulted in a negative cloud‐to‐ground discharge. Both positive and negative ends of the transients extended at speeds of 106–107 m/s, while the overall positive leader extension speed was as low as 103–104 m/s. Wideband electric field signatures of the transients were similar to K‐changes, with their millisecond‐ and microsecond‐scale features being associated with the steady current and new breakdowns, respectively. For transients with both ends visible in our optical records, charge transfers and average currents were estimated to be typically a few hundreds of millicoulombs and some hundreds of amperes, respectively.
Amplified Production and Export of Dissolved Inorganic Carbon During Hot and Wet Subtropical Monsoon
Authors: Wen Hang , Li Si‐Liang , Chen Xi , Qin Caiqing , Li Li
Published: January 2024

Understanding the origins and processes of riverine dissolved inorganic carbon (DIC) is crucial for predicting the global carbon cycle with projected, more frequent climate extremes yet our knowledge has remained fragmented. Here we ask: How and how much do DIC production and export vary across space (shallow vs. deep, uphill vs. depression) and time (daily, seasonal, and annual)? How do the relative contributions of biogenic (soil respiration) and geogenic (carbonate weathering) sources differ under different temperature and hydrological conditions? We answer these questions using a catchment‐scale reactive transport model constrained by stream flow, stable water isotopes, stream DIC, and carbon isotope data from a headwater karstic catchment in southwest China in a subtropical monsoon climate. Results show climate seasonality regulates the timing of DIC production and export. In hot‐wet seasons, high temperature accelerates soil respiration and carbonate weathering (up to a factor of three) via elevating soil CO2 and carbonate solubility, whereas high discharge enhances export by two orders of magnitude compared to cold‐dry seasons. Carbonate weathering is driven more by soil CO2 than water flow. At the annual scale, 92.9% and 7.1% of DIC was produced in shallow and deep zone, respectively, whereas 64.5% and 35.5% of DIC was exported from shallow and deep zone, respectively. These results highlight the uniqueness of subtropical karst areas as synchronous reactors and transporters of DIC during the hot‐wet monsoon, contrasting the asynchronous production and export in other climate regions. A future hotter and wetter climate with more intensive storms in the region may further intensify DIC production and export, accentuating the potential of subtropical karst regions as global hot spots for carbon cycling.
Cellular zinc metabolism and zinc signaling: from biological functions to diseases and therapeutic targets
Authors: Chen Bonan , Yu Peiyao , Chan Wai Nok , Xie Fuda , Zhang Yigan , Liang Li , Leung Kam Tong , Lo Kwok Wai , Yu Jun , Tse Gary M. K. , Kang Wei , To Ka Fai
Published: January 2024

Zinc metabolism at the cellular level is critical for many biological processes in the body. A key observation is the disruption of cellular homeostasis, often coinciding with disease progression. As an essential factor in maintaining cellular equilibrium, cellular zinc has been increasingly spotlighted in the context of disease development. Extensive research suggests zinc’s involvement in promoting malignancy and invasion in cancer cells, despite its low tissue concentration. This has led to a growing body of literature investigating zinc’s cellular metabolism, particularly the functions of zinc transporters and storage mechanisms during cancer progression. Zinc transportation is under the control of two major transporter families: SLC30 (ZnT) for the excretion of zinc and SLC39 (ZIP) for the zinc intake. Additionally, the storage of this essential element is predominantly mediated by metallothioneins (MTs). This review consolidates knowledge on the critical functions of cellular zinc signaling and underscores potential molecular pathways linking zinc metabolism to disease progression, with a special focus on cancer. We also compile a summary of clinical trials involving zinc ions. Given the main localization of zinc transporters at the cell membrane, the potential for targeted therapies, including small molecules and monoclonal antibodies, offers promising avenues for future exploration.
Aberrant resting-state co-activation network dynamics in major depressive disorder
Authors: An Ziqi , Tang Kai , Xie Yuanyao , Tong Chuanjun , Liu Jiaming , Tao Quan ,   DIRECT Consortium, Yan Chao-Gan , Chen Xiao , Cao Li-Ping , Chen Wei , Cheng Yu-Qi , Fang Yi-Ru , Gong Qi-Yong , Guo Wen-Bin , Kuang Li , Li Bao-Juan , Li Tao , Liu Yan-Song , Liu Zhe-Ning , Lu Jian-Ping , Luo Qing-Hua , Meng Hua-Qing , Peng Dai-Hui , Qiu Jiang , Shen Yue-Di , Si Tian-Mei , Tang Yan-Qing , Wang Chuan-Yue , Wang Fei , Wang Hua-Ning , Wang Kai , Wang Xiang , Wang Ying , Wu Xiao-Ping , Xie Chun-Ming , Xie Guang-Rong , Xie Peng , Xu Xiu-Feng , Yang Hong , Yang Jian , Yao Shu-Qiao , Yu Yong-Qiang , Yuan Yong-Gui , Zhang Ke-Rang , Zhang Wei , Zhang Zhi-Jun , Zhu Jun-Juan , Zuo Xi-Nian , Zhao Jing-Ping , Zang Yu-Feng , Feng Yanqiu
Published: January 2024

Major depressive disorder (MDD) is a globally prevalent and highly disabling disease characterized by dysfunction of large-scale brain networks. Previous studies have found that static functional connectivity is not sufficient to reflect the complicated and time-varying properties of the brain. The underlying dynamic interactions between brain functional networks of MDD remain largely unknown, and it is also unclear whether neuroimaging-based dynamic properties are sufficiently robust to discriminate individuals with MDD from healthy controls since the diagnosis of MDD mainly depends on symptom-based criteria evaluated by clinical observation. Resting-state functional magnetic resonance imaging (fMRI) data of 221 MDD patients and 215 healthy controls were shared by REST-meta-MDD consortium. We investigated the spatial-temporal dynamics of MDD using co-activation pattern analysis and made individual diagnoses using support vector machine (SVM). We found that MDD patients exhibited aberrant dynamic properties (such as dwell time, occurrence rate, transition probability, and entropy of Markov trajectories) in some transient networks including subcortical network (SCN), activated default mode network (DMN), de-activated SCN-cerebellum network, a joint network, activated attention network (ATN), and de-activated DMN-ATN, where some dynamic properties were indicative of depressive symptoms. The trajectories of other networks to deactivated DMN-ATN were more accessible in MDD patients. Subgroup analyses also showed subtle dynamic changes in first-episode drug-naïve (FEDN) MDD patients. Finally, SVM achieved preferable accuracies of 84.69%, 76.77%, and 88.10% in discriminating patients with MDD, FEDN MDD, and recurrent MDD from healthy controls with their dynamic metrics. Our findings reveal that MDD is characterized by aberrant dynamic fluctuations of brain network and the feasibility of discriminating MDD patients using dynamic properties, which provide novel insights into the neural mechanism of MDD.
BCL-XL regulates the timing of mitotic apoptosis independently of BCL2 and MCL1 compensation
Authors: Yu Chun Yin , Yeung Tsz Kwan , Fu Wai Kuen , Poon Randy Y. C.
Published: January 2024

Mitotic catastrophe induced by prolonged mitotic arrest is a major anticancer strategy. Although antiapoptotic BCL2-like proteins, including BCL-XL, are known to regulate apoptosis during mitotic arrest, adaptive changes in their expression can complicate loss-of-function studies. Our studies revealed compensatory alterations in the expression of BCL2 and MCL1 when BCL-XL is either downregulated or overexpressed. To circumvent their reciprocal regulation, we utilized a degron-mediated system to acutely silence BCL-XL just before mitosis. Our results show that in epithelial cell lines including HeLa and RPE1, BCL-XL and BCL2 acted collaboratively to suppress apoptosis during both unperturbed cell cycle and mitotic arrest. By tagging BCL-XL and BCL2 with a common epitope, we estimated that BCL-XL was less abundant than BCL2 in the cell. Nonetheless, BCL-XL played a more prominent antiapoptotic function than BCL2 during interphase and mitotic arrest. Loss of BCL-XL led to mitotic cell death primarily through a BAX-dependent process. Furthermore, silencing of BCL-XL led to the stabilization of MCL1, which played a significant role in buffering apoptosis during mitotic arrest. Nevertheless, even in a MCL1-deficient background, depletion of BCL-XL accelerated mitotic apoptosis. These findings underscore the pivotal involvement of BCL-XL in controlling timely apoptosis during mitotic arrest, despite adaptive changes in the expression of other BCL2-like proteins.
Mapping of individual sensory nerve axons from digits to spinal cord with the transparent embedding solvent system
Authors: Yi Yating , Li Youqi , Zhang Shiwen , Men Yi , Wang Yuhong , Jing Dian , Ding Jiayi , Zhu Qingjie , Chen Zexi , Chen Xingjun , Li Jun-Liszt , Wang Yilong , Wang Jun , Peng Hanchuan , Zhang Li , Luo Wenjing , Feng Jian Q. , He Yongwen , Ge Woo-Ping , Zhao Hu
Published: January 2024

Achieving uniform optical resolution for a large tissue sample is a major challenge for deep imaging. For conventional tissue clearing methods, loss of resolution and quality in deep regions is inevitable due to limited transparency. Here we describe the Transparent Embedding Solvent System (TESOS) method, which combines tissue clearing, transparent embedding, sectioning and block-face imaging. We used TESOS to acquire volumetric images of uniform resolution for an adult mouse whole-body sample. The TESOS method is highly versatile and can be combined with different microscopy systems to achieve uniformly high resolution. With a light sheet microscope, we imaged the whole body of an adult mouse, including skin, at a uniform 0.8 × 0.8 × 3.5 μm3 voxel resolution within 120 h. With a confocal microscope and a 40×/1.3 numerical aperture objective, we achieved a uniform sub-micron resolution in the whole sample to reveal a complete projection of individual nerve axons within the central or peripheral nervous system. Furthermore, TESOS allowed the first mesoscale connectome mapping of individual sensory neuron axons spanning 5 cm from adult mouse digits to the spinal cord at a uniform sub-micron resolution.
Learning low-rank latent mesoscale structures in networks
Authors: Lyu Hanbaek , Kureh Yacoub H. , Vendrow Joshua , Porter Mason A.
Published: January 2024

Researchers in many fields use networks to represent interactions between entities in complex systems. To study the large-scale behavior of complex systems, it is useful to examine mesoscale structures in networks as building blocks that influence such behavior. In this paper, we present an approach to describe low-rank mesoscale structures in networks. We find that many real-world networks possess a small set of latent motifs that effectively approximate most subgraphs at a fixed mesoscale. Such low-rank mesoscale structures allow one to reconstruct networks by approximating subgraphs of a network using combinations of latent motifs. Employing subgraph sampling and nonnegative matrix factorization enables the discovery of these latent motifs. The ability to encode and reconstruct networks using a small set of latent motifs has many applications in network analysis, including network comparison, network denoising, and edge inference.
African bushpigs exhibit porous species boundaries and appeared in Madagascar concurrently with human arrival
Authors: Balboa Renzo F. , Bertola Laura D. , Brüniche-Olsen Anna , Rasmussen Malthe Sebro , Liu Xiaodong , Besnard Guillaume , Salmona Jordi , Santander Cindy G. , He Shixu , Zinner Dietmar , Pedrono Miguel , Muwanika Vincent , Masembe Charles , Schubert Mikkel , Kuja Josiah , Quinn Liam , Garcia-Erill Genís , Stæger Frederik Filip , Rakotoarivony Rianja , Henrique Margarida , Lin Long , Wang Xi , Heaton Michael P. , Smith Timothy P. L. , Hanghøj Kristian , Sinding Mikkel-Holger S. , Atickem Anagaw , Chikhi Lounès , Roos Christian , Gaubert Philippe , Siegismund Hans R. , Moltke Ida , Albrechtsen Anders , Heller Rasmus
Published: January 2024

Several African mammals exhibit a phylogeographic pattern where closely related taxa are split between West/Central and East/Southern Africa, but their evolutionary relationships and histories remain controversial. Bushpigs (Potamochoerus larvatus) and red river hogs (P. porcus) are recognised as separate species due to morphological distinctions, a perceived lack of interbreeding at contact, and putatively old divergence times, but historically, they were considered conspecific. Moreover, the presence of Malagasy bushpigs as the sole large terrestrial mammal shared with the African mainland raises intriguing questions about its origin and arrival in Madagascar. Analyses of 67 whole genomes revealed a genetic continuum between the two species, with putative signatures of historical gene flow, variable FST values, and a recent divergence time (<500,000 years). Thus, our study challenges key arguments for splitting Potamochoerus into two species and suggests their speciation might be incomplete. Our findings also indicate that Malagasy bushpigs diverged from southern African populations and underwent a limited bottleneck 1000-5000 years ago, concurrent with human arrival in Madagascar. These results shed light on the evolutionary history of an iconic and widespread African mammal and provide insight into the longstanding biogeographic puzzle surrounding the bushpig’s presence in Madagascar.
Quasi-2D Fermi surface in the anomalous superconductor UTe2
Authors: Eaton A. G. , Weinberger T. I. , Popiel N. J. M. , Wu Z. , Hickey A. J. , Cabala A. , Pospíšil J. , Prokleška J. , Haidamak T. , Bastien G. , Opletal P. , Sakai H. , Haga Y. , Nowell R. , Benjamin S. M. , Sechovský V. , Lonzarich G. G. , Grosche F. M. , Vališka M.
Published: January 2024

The heavy fermion paramagnet UTe2exhibits numerous characteristics of spin-triplet superconductivity. Efforts to understand the microscopic details of this exotic superconductivity have been impeded by uncertainty regarding the underlying electronic structure. Here we directly probe the Fermi surface of UTe2by measuring magnetic quantum oscillations in pristine quality crystals. We find an angular profile of quantum oscillatory frequency and amplitude that is characteristic of a quasi-2D Fermi surface, which we find is well described by two cylindrical Fermi sheets of electron- and hole-type respectively. Additionally, we find that both cylindrical Fermi sheets possess considerable undulation but negligible small-scale corrugation, which may allow for their near-nesting and therefore promote magnetic fluctuations that enhance the triplet pairing mechanism. Importantly, we find no evidence for the presence of any 3D Fermi surface sections. Our results place strong constraints on the possible symmetry of the superconducting order parameter in UTe2.
Nlrc3 signaling is indispensable for hematopoietic stem cell emergence via Notch signaling in vertebrates
Authors: Cai Shuyang , Li Honghu , Tie Ruxiu , Shan Wei , Luo Qian , Wang Shufen , Feng Cong , Chen Huiqiao , Zhang Meng , Xu Yulin , Li Xia , Chen Ming , Lu Jiahui , Qian Pengxu , Huang He
Published: January 2024

Hematopoietic stem and progenitor cells generate all the lineages of blood cells throughout the lifespan of vertebrates. The emergence of hematopoietic stem and progenitor cells is finely tuned by a variety of signaling pathways. Previous studies have revealed the roles of pattern-recognition receptors such as Toll-like receptors and RIG-I-like receptors in hematopoiesis. In this study, we find that Nlrc3, a nucleotide-binding domain leucine-rich repeat containing family gene, is highly expressed in hematopoietic differentiation stages in vivo and vitro and is required in hematopoiesis in zebrafish. Mechanistically, nlrc3 activates the Notch pathway and the downstream gene of Notch hey1. Furthermore, NF-kB signaling acts upstream of nlrc3 to enhance its transcriptional activity. Finally, we find that Nlrc3 signaling is conserved in the regulation of murine embryonic hematopoiesis. Taken together, our findings uncover an indispensable role of Nlrc3 signaling in hematopoietic stem and progenitor cell emergence and provide insights into inflammation-related hematopoietic ontogeny and the in vitro expansion of hematopoietic stem and progenitor cells.
Diverse array of neutralizing antibodies elicited upon Spike Ferritin Nanoparticle vaccination in rhesus macaques
Authors: Sankhala Rajeshwer S. , Lal Kerri G. , Jensen Jaime L. , Dussupt Vincent , Mendez-Rivera Letzibeth , Bai Hongjun , Wieczorek Lindsay , Mayer Sandra V. , Zemil Michelle , Wagner Danielle A. , Townsley Samantha M. , Hajduczki Agnes , Chang William C. , Chen Wei-Hung , Donofrio Gina C. , Jian Ningbo , King Hannah A. D. , Lorang Cynthia G. , Martinez Elizabeth J. , Rees Phyllis A. , Peterson Caroline E. , Schmidt Fabian , Hart Tricia J. , Duso Debra K. , Kummer Lawrence W. , Casey Sean P. , Williams Jazmean K. , Kannan Shruthi , Slike Bonnie M. , Smith Lauren , Swafford Isabella , Thomas Paul V. , Tran Ursula , Currier Jeffrey R. , Bolton Diane L. , Davidson Edgar , Doranz Benjamin J. , Hatziioannou Theodora , Bieniasz Paul D. , Paquin-Proulx Dominic , Reiley William W. , Rolland Morgane , Sullivan Nancy J. , Vasan Sandhya , Collins Natalie D. , Modjarrad Kayvon , Gromowski Gregory D. , Polonis Victoria R. , Michael Nelson L. , Krebs Shelly J. , Joyce M. Gordon
Published: January 2024

The repeat emergence of SARS-CoV-2 variants of concern (VoC) with decreased susceptibility to vaccine-elicited antibodies highlights the need to develop next-generation vaccine candidates that confer broad protection. Here we describe the antibody response induced by the SARS-CoV-2 Spike Ferritin Nanoparticle (SpFN) vaccine candidate adjuvanted with the Army Liposomal Formulation including QS21 (ALFQ) in non-human primates. By isolating and characterizing several monoclonal antibodies directed against the Spike Receptor Binding Domain (RBD), N-Terminal Domain (NTD), or the S2 Domain, we define the molecular recognition of vaccine-elicited cross-reactive monoclonal antibodies (mAbs) elicited by SpFN. We identify six neutralizing antibodies with broad sarbecovirus cross-reactivity that recapitulate serum polyclonal antibody responses. In particular, RBD mAb WRAIR-5001 binds to the conserved cryptic region with high affinity to sarbecovirus clades 1 and 2, including Omicron variants, while mAb WRAIR-5021 offers complete protection from B.1.617.2 (Delta) in a murine challenge study. Our data further highlight the ability of SpFN vaccination to stimulate cross-reactive B cells targeting conserved regions of the Spike with activity against SARS CoV-1 and SARS-CoV-2 variants.
Targeting IL-17A enhances imatinib efficacy in Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia
Authors: Wang Feng , Li Yunxuan , Yang Zhaona , Cao Wenbin , Liu Ying , Zhao Luyao , Zhang Tingting , Zhao Chenxi , Yu Jinmei , Yu Jiaojiao , Zhou Jichao , Zhang Xiaowei , Li Ping-Ping , Han Mingzhe , Feng Sizhou , Ng Billy Wai-Lung , Hu Zhuo-Wei , Jiang Erlie , Li Ke , Cui Bing
Published: January 2024

Dysregulated hematopoietic niches remodeled by leukemia cells lead to imbalances in immunological mediators that support leukemogenesis and drug resistance. Targeting immune niches may ameliorate disease progression and tyrosine kinase inhibitor (TKI) resistance in Philadelphia chromosome-positive B-ALL (Ph+ B-ALL). Here, we show that T helper type 17 (Th17) cells and IL-17A expression are distinctively elevated in Ph+ B-ALL patients. IL-17A promotes the progression of Ph+ B-ALL. Mechanistically, IL-17A activates BCR-ABL, IL6/JAK/STAT3, and NF-kB signalling pathways in Ph+ B-ALL cells, resulting in robust cell proliferation and survival. In addition, IL-17A-activated Ph+ B-ALL cells secrete the chemokine CXCL16, which in turn promotes Th17 differentiation, attracts Th17 cells and forms a positive feedback loop supporting leukemia progression. These data demonstrate an involvement of Th17 cells in Ph+ B-ALL progression and suggest potential therapeutic options for Ph+ B-ALL with Th17-enriched niches.
Efficacy of Bifidobacterium animalis subsp. lactis BL-99 in the treatment of functional dyspepsia: a randomized placebo-controlled clinical trial
Authors: Zhang Qi , Li Guang , Zhao Wen , Wang Xifan , He Jingjing , Zhou Limian , Zhang Xiaoxu , An Peng , Liu Yinghua , Zhang Chengying , Zhang Yong , Liu Simin , Zhao Liang , Liu Rong , Li Yixuan , Jiang Wenjian , Wang Xiaoyu , Wang Qingyu , Fang Bing , Zhao Yuyang , Ren Yimei , Niu Xiaokang , Li Dongjie , Shi Shaoqi , Hung Wei-Lian , Wang Ran , Liu Xinjuan , Ren Fazheng
Published: January 2024

Current treatment for functional dyspepsia (FD) has limited and unsustainable efficacy. Probiotics have the sustainable potential to alleviate FD. This randomized controlled clinical trial (Chinese Clinical Trial Registry, ChiCTR2000041430) assigned 200 FD patients to receive placebo, positive-drug (rabeprazole), or Bifidobacterium animalis subsp. lactis BL-99 (BL-99; low, high doses) for 8-week. The primary outcome was the clinical response rate (CRR) of FD score after 8-week treatment. The secondary outcomes were CRR of FD score at other periods, and PDS, EPS, serum indicators, fecal microbiota and metabolites. The CRR in FD score for the BL-99_high group [45 (90.0%)] was significantly higher than that for placebo [29 (58.0%), p = 0.001], BL-99_low [37 (74.0%), p = 0.044] and positive_control [35 (70.0%), p = 0.017] groups after 8-week treatment. This effect was sustained until 2-week after treatment but disappeared 8-week after treatment. Further metagenomic and metabolomics revealed that BL-99 promoted the accumulation of SCFA-producing microbiota and the increase of SCFA levels in stool and serum, which may account for the increase of serum gastrin level. This study supports the potential use of BL-99 for the treatment of FD.
A mode-locked random laser generating transform-limited optical pulses
Authors: von der Weid Jean Pierre , Correia Marlon M. , Tovar Pedro , Gomes Anderson S. L. , Margulis Walter
Published: January 2024

Ever since the mid-1960’s, locking the phases of modes enabled the generation of laser pulses of duration limited only by the uncertainty principle, opening the field of ultrafast science. In contrast to conventional lasers, mode spacing in random lasers is ill-defined because optical feedback comes from scattering centres at random positions, making it hard to use mode locking in transform limited pulse generation. Here the generation of sub-nanosecond transform-limited pulses from a mode-locked random fibre laser is reported. Rayleigh backscattering from decimetre-long sections of telecom fibre serves as laser feedback, providing narrow spectral selectivity to the Fourier limit. The laser is adjustable in pulse duration (0.34–20 ns), repetition rate (0.714–1.22 MHz) and can be temperature tuned. The high spectral-efficiency pulses are applied in distributed temperature sensing with 9.0 cm and 3.3 × 10−3 K resolution, exemplifying how the results can drive advances in the fields of spectroscopy, telecommunications, and sensing.
Elevated CSF GAP-43 is associated with accelerated tau accumulation and spread in Alzheimer’s disease
Authors: Franzmeier Nicolai , Dehsarvi Amir , Steward Anna , Biel Davina , Dewenter Anna , Roemer Sebastian Niclas , Wagner Fabian , Groß Mattes , Brendel Matthias , Moscoso Alexis , Arunachalam Prithvi , Blennow Kaj , Zetterberg Henrik , Ewers Michael , Schöll Michael
Published: January 2024

In Alzheimer’s disease, amyloid-beta (Aβ) triggers the trans-synaptic spread of tau pathology, and aberrant synaptic activity has been shown to promote tau spreading. Aβ induces aberrant synaptic activity, manifesting in increases in the presynaptic growth-associated protein 43 (GAP-43), which is closely involved in synaptic activity and plasticity. We therefore tested whether Aβ-related GAP-43 increases, as a marker of synaptic changes, drive tau spreading in 93 patients across the aging and Alzheimer’s spectrum with available CSF GAP-43, amyloid-PET and longitudinal tau-PET assessments. We found that (1) higher GAP-43 was associated with faster Aβ-related tau accumulation, specifically in brain regions connected closest to subject-specific tau epicenters and (2) that higher GAP-43 strengthened the association between Aβ and connectivity-associated tau spread. This suggests that GAP-43-related synaptic changes are linked to faster Aβ-related tau spread across connected regions and that synapses could be key targets for preventing tau spreading in Alzheimer’s disease.
A genome-wide association meta-analysis implicates Hedgehog and Notch signaling in Dupuytren’s disease
Authors: Riesmeijer Sophie A. , Kamali Zoha , Ng Michael , Drichel Dmitriy , Piersma Bram , Becker Kerstin , Layton Thomas B. , Nanchahal Jagdeep , Nothnagel Michael , Vaez Ahmad , Hennies Hans Christian , Werker Paul M. N. , Furniss Dominic , Nolte Ilja M.
Published: January 2024

Dupuytren’s disease (DD) is a highly heritable fibrotic disorder of the hand with incompletely understood etiology. A number of genetic loci, including Wnt signaling members, have been previously identified. Our overall aim was to identify novel genetic loci, to prioritize genes within the loci for functional studies, and to assess genetic correlation with associated disorders. We performed a meta-analysis of six DD genome-wide association studies from three European countries and extensive bioinformatic follow-up analyses. Leveraging 11,320 cases and 47,023 controls, we identified 85 genome-wide significant single nucleotide polymorphisms in 56 loci, of which 11 were novel, explaining 13.3–38.1% of disease variance. Gene prioritization implicated the Hedgehog and Notch signaling pathways. We also identified a significant genetic correlation with frozen shoulder. The pathways identified highlight the potential for new therapeutic targets and provide a basis for additional mechanistic studies for a common disorder that can severely impact hand function.
Direct laser-written optomechanical membranes in fiber Fabry-Perot cavities
Authors: Tenbrake Lukas , Faßbender Alexander , Hofferberth Sebastian , Linden Stefan , Pfeifer Hannes
Published: January 2024

Integrated micro- and nanophotonic optomechanical experiments enable the manipulation of mechanical resonators on the single phonon level. Interfacing these structures requires elaborate techniques limited in tunability, flexibility, and scaling towards multi-mode systems. Here, we demonstrate a cavity optomechanical experiment using 3D-laser-written polymer membranes inside fiber Fabry-Perot cavities. Vacuum coupling rates of g0/2π ≈ 30 kHz to the fundamental megahertz mechanical mode are reached. We observe optomechanical spring tuning of the mechanical resonator frequency by tens of kilohertz exceeding its linewidth at cryogenic temperatures. The direct fiber coupling, its scaling capabilities to coupled resonator systems, and the potential implementation of dissipation dilution structures and integration of electrodes make it a promising platform for fiber-tip integrated accelerometers, optomechanically tunable multi-mode mechanical systems, and directly fiber-coupled systems for microwave to optics conversion.
Orbital-flop transition of superfluid 3He in anisotropic silica aerogel
Authors: Nguyen M. D. , Simon Joshua , Scott J. W. , Zimmerman A. M. , Tsai Y. C. Cincia , Halperin W. P.
Published: January 2024

Superfluid 3He is a paradigm for odd-parity Cooper pairing, ranging from neutron stars to uranium-based superconducting compounds. Recently it has been shown that 3He, imbibed in anisotropic silica aerogel with either positive or negative strain, preferentially selects either the chiral A-phase or the time-reversal-symmetric B-phase. This control over basic order parameter symmetry provides a useful model for understanding imperfect unconventional superconductors. For both phases, the orbital quantization axis is fixed by the direction of strain. Unexpectedly, at a specific temperature Tx, the orbital axis flops by 90∘, but in reverse order for A and B-phases. Aided by diffusion limited cluster aggregation simulations of anisotropic aerogel and small angle X-ray measurements, we are able to classify these aerogels as either “planar" and “nematic" concluding that the orbital-flop is caused by competition between short and long range structures in these aerogels.
Surface hydrophobization of hydrogels via interface dynamics-induced network reconfiguration
Authors: Yi Bo , Li Tianjie , Yang Boguang , Chen Sirong , Zhao Jianyang , Zhao Pengchao , Zhang Kunyu , Wang Yi , Wang Zuankai , Bian Liming
Published: January 2024

Effective and easy regulation of hydrogel surface properties without changing the overall chemical composition is important for their diverse applications but remains challenging to achieve. We report a generalizable strategy to reconfigure hydrogel surface networks based on hydrogel–substrate interface dynamics for manipulation of hydrogel surface wettability and bioadhesion. We show that the grafting of hydrophobic yet flexible polymeric chains on mold substrates can significantly elevate the content of hydrophobic polymer backbones and reduce the presence of polar groups in hydrogel surface networks, thereby transforming the otherwise hydrophilic hydrogel surface into a hydrophobic surface. Experimental results show that the grafted highly dynamic hydrophobic chains achieved with optimal grafting density, chain length, and chain structure are critical for such substantial hydrogel surface network reconfiguration. Molecular dynamics simulations further reveal the atomistic details of the hydrogel network reconfiguration induced by the dynamic interface interactions. The hydrogels prepared using our strategy show substantially enhanced bioadhesion and transdermal delivery compared with the hydrogels of the same chemical composition but fabricated via the conventional method. Our findings provide important insights into the dynamic hydrogel–substrate interactions and are instrumental to the preparation of hydrogels with custom surface properties.
Resting-state EEG measures cognitive impairment in Parkinson’s disease
Authors: Anjum Md Fahim , Espinoza Arturo I. , Cole Rachel C. , Singh Arun , May Patrick , Uc Ergun Y. , Dasgupta Soura , Narayanan Nandakumar S.
Published: January 2024

Cognitive dysfunction is common in Parkinson’s disease (PD). We developed and evaluated an EEG-based biomarker to index cognitive functions in PD from a few minutes of resting-state EEG. We hypothesized that synchronous changes in EEG across the power spectrum can measure cognition. We optimized a data-driven algorithm to efficiently capture these changes and index cognitive function in 100 PD and 49 control participants. We compared our EEG-based cognitive index with the Montreal cognitive assessment (MoCA) and cognitive tests across different domains from National Institutes of Health (NIH) Toolbox using cross-validations, regression models, and randomization tests. Finally, we externally validated our approach on 32 PD participants. We observed cognition-related changes in EEG over multiple spectral rhythms. Utilizing only 8 best-performing electrodes, our proposed index strongly correlated with cognition (MoCA: rho = 0.68, p value < 0.001; NIH-Toolbox cognitive tests: rho ≥ 0.56, p value < 0.001) outperforming traditional spectral markers (rho = −0.30–0.37). The index showed a strong fit in regression models (R2 = 0.46) with MoCA, yielded 80% accuracy in detecting cognitive impairment, and was effective in both PD and control participants. Notably, our approach was equally effective (rho = 0.68, p value < 0.001; MoCA) in out-of-sample testing. In summary, we introduced a computationally efficient data-driven approach for cross-domain cognition indexing using fewer than 10 EEG electrodes, potentially compatible with dynamic therapies like closed-loop neurostimulation. These results will inform next-generation neurophysiological biomarkers for monitoring cognition in PD and other neurological diseases.
Multiflavor Mott insulators in quantum materials and ultracold atoms
Authors: Chen Gang V. , Wu Congjun
Published: January 2024

Mott insulators with large and active (or multiflavor) local Hilbert spaces widely occur in quantum materials and ultracold atomic systems, and are dubbed “multiflavor Mott insulators”. For these multiflavor Mott insulators, the spin-only description with the quadratic spin interactions is often insufficient to capture the major physical processes. In the situation with active orbitals, the Kugel-Khomskii superexchange model was then proposed. We briefly review this historical model and discuss the modern developments beyond the original spin-orbital context. These include and are not restricted to the 4d/5d transition metal compounds with the spin-orbit-entangled J = 3/2 quadruplets, the rare-earth magnets with two weakly-separated crystal field doublets, breathing magnets and/or the cluster and molecular magnets, et al. We explain the microscopic origin of the emergent Kugel-Khomskii physics in each realization with some emphasis on the J = 3/2 quadruplets, and refer the candidate multiflavor Mott insulators as “J = 3/2 Mott insulators”. For the ultracold atoms, we review the multiflavor Mott insulator realization with the ultracold alkaline and alkaline-earth atoms on the optical lattices. Despite a large local Hilbert space from the atomic hyperfine spin states, the system could naturally realize a large symmetry group such as the Sp(N) and SU(N) symmetries. These ultracold atomic systems lie in the large-N regime of these symmetry groups and are characterized by strong quantum fluctuations. The Kugel-Khomskii physics and the exotic quantum ground states with the “baryon-like” physics can appear in various limits. We conclude with our vision and outlook on this subject.
Positive and negative aspects of bacteriophages and their immense role in the food chain
Authors: Ranveer Soniya Ashok , Dasriya Vaishali , Ahmad Md Faruque , Dhillon Harmeet Singh , Samtiya Mrinal , Shama Eman , Anand Taruna , Dhewa Tejpal , Chaudhary Vishu , Chaudhary Priya , Behare Pradip , Ram Chand , Puniya Dharun Vijay , Khedkar Gulab D. , Raposo António , Han Heesup , Puniya Anil Kumar
Published: January 2024

Bacteriophages infect and replicate inside a bacterial host as well as serve as natural bio-control agents. Phages were once viewed as nuisances that caused fermentation failures with cheese-making and other industrial processes, which lead to economic losses, but phages are now increasingly being observed as being promising antimicrobials that can fight against spoilage and pathogenic bacteria. Pathogen-free meals that fulfil industry requirements without synthetic additives are always in demand in the food sector. This study introduces the readers to the history, sources, and biology of bacteriophages, which include their host ranges, absorption mechanisms, lytic profiles, lysogenic profiles, and the influence of external factors on the growth of phages. Phages and their derivatives have emerged as antimicrobial agents, biodetectors, and biofilm controllers, which have been comprehensively discussed in addition to their potential applications in the food and gastrointestinal tract, and they are a feasible and safe option for preventing, treating, and/or eradicating contaminants in various foods and food processing environments. Furthermore, phages and phage-derived lytic proteins can be considered potential antimicrobials in the traditional farm-to-fork context, which include phage-based mixtures and commercially available phage products. This paper concludes with some potential safety concerns that need to be addressed to enable bacteriophage use efficiently.
Cytosolic sorting platform complexes shuttle type III secretion system effectors to the injectisome in Yersinia enterocolitica
Authors: Wimmi Stephan , Balinovic Alexander , Brianceau Corentin , Pintor Katherine , Vielhauer Jan , Turkowyd Bartosz , Helbig Carlos , Fleck Moritz , Langenfeld Katja , Kahnt Jörg , Glatter Timo , Endesfelder Ulrike , Diepold Andreas
Published: January 2024

Bacteria use type III secretion injectisomes to inject effector proteins into eukaryotic target cells. Recruitment of effectors to the machinery and the resulting export hierarchy involve the sorting platform. These conserved proteins form pod structures at the cytosolic interface of the injectisome but are also mobile in the cytosol. Photoactivated localization microscopy in Yersinia enterocolitica revealed a direct interaction of the sorting platform proteins SctQ and SctL with effectors in the cytosol of live bacteria. These proteins form larger cytosolic protein complexes involving the ATPase SctN and the membrane connector SctK. The mobility and composition of these mobile pod structures are modulated in the presence of effectors and their chaperones, and upon initiation of secretion, which also increases the number of injectisomes from ~5 to ~18 per bacterium. Our quantitative data support an effector shuttling mechanism, in which sorting platform proteins bind to effectors in the cytosol and deliver the cargo to the export gate at the membrane-bound injectisome.
BilR is a gut microbial enzyme that reduces bilirubin to urobilinogen
Authors: Hall Brantley , Levy Sophia , Dufault-Thompson Keith , Arp Gabriela , Zhong Aoshu , Ndjite Glory Minabou , Weiss Ashley , Braccia Domenick , Jenkins Conor , Grant Maggie R. , Abeysinghe Stephenie , Yang Yiyan , Jermain Madison D. , Wu Chih Hao , Ma Bing , Jiang Xiaofang
Published: January 2024

Metabolism of haem by-products such as bilirubin by humans and their gut microbiota is essential to human health, as excess serum bilirubin can cause jaundice and even neurological damage. The bacterial enzymes that reduce bilirubin to urobilinogen, a key step in this pathway, have remained unidentified. Here we used biochemical analyses and comparative genomics to identify BilR as a gut-microbiota-derived bilirubin reductase that reduces bilirubin to urobilinogen. We delineated the BilR sequences from similar reductases through the identification of key residues critical for bilirubin reduction and found that BilR is predominantly encoded by Firmicutes species. Analysis of human gut metagenomes revealed that BilR is nearly ubiquitous in healthy adults, but prevalence is decreased in neonates and individuals with inflammatory bowel disease. This discovery sheds light on the role of the gut microbiome in bilirubin metabolism and highlights the significance of the gut–liver axis in maintaining bilirubin homeostasis.
Heating and cooling are fundamentally asymmetric and evolve along distinct pathways
Authors: Ibáñez M. , Dieball C. , Lasanta A. , Godec A. , Rica R. A.
Published: January 2024

According to conventional wisdom, a system placed in an environment with a different temperature tends to relax to the temperature of the latter, mediated by the flows of heat or matter that are set solely by the temperature difference. It is becoming clear, however, that thermal relaxation is much more intricate when temperature changes push the system far from thermodynamic equilibrium. Here, by using an optically trapped colloidal particle, we show that microscale systems under such conditions heat up faster than they cool down. We find that between any pair of temperatures, heating is not only faster than cooling but the respective processes, in fact, evolve along fundamentally distinct pathways, which we explain with a new theoretical framework that we call thermal kinematics. Our results change the view of thermalization at the microscale and will have a strong impact on energy-conversion applications and thermal management of microscopic devices, particularly in the operation of Brownian heat engines.
Disordered enthalpy–entropy descriptor for high-entropy ceramics discovery
Authors: Divilov Simon , Eckert Hagen , Hicks David , Oses Corey , Toher Cormac , Friedrich Rico , Esters Marco , Mehl Michael J. , Zettel Adam C. , Lederer Yoav , Zurek Eva , Maria Jon-Paul , Brenner Donald W. , Campilongo Xiomara , Filipović Suzana , Fahrenholtz William G. , Ryan Caillin J. , DeSalle Christopher M. , Crealese Ryan J. , Wolfe Douglas E. , Calzolari Arrigo , Curtarolo Stefano
Published: January 2024

The need for improved functionalities in extreme environments is fuelling interest in high-entropy ceramics1–3. Except for the computational discovery of high-entropy carbides, performed with the entropy-forming-ability descriptor4, most innovation has been slowly driven by experimental means1–3. Hence, advancement in the field needs more theoretical contributions. Here we introduce disordered enthalpy–entropy descriptor (DEED), a descriptor that captures the balance between entropy gains and enthalpy costs, allowing the correct classification of functional synthesizability of multicomponent ceramics, regardless of chemistry and structure. To make our calculations possible, we have developed a convolutional algorithm that drastically reduces computational resources. Moreover, DEED guides the experimental discovery of new single-phase high-entropy carbonitrides and borides. This work, integrated into the AFLOW computational ecosystem, provides an array of potential new candidates, ripe for experimental discoveries.
Nav1.7 as a chondrocyte regulator and therapeutic target for osteoarthritis
Authors: Fu Wenyu , Vasylyev Dmytro , Bi Yufei , Zhang Mingshuang , Sun Guodong , Khleborodova Asya , Huang Guiwu , Zhao Libo , Zhou Renpeng , Li Yonggang , Liu Shujun , Cai Xianyi , He Wenjun , Cui Min , Zhao Xiangli , Hettinghouse Aubryanna , Good Julia , Kim Ellen , Strauss Eric , Leucht Philipp , Schwarzkopf Ran , Guo Edward X. , Samuels Jonathan , Hu Wenhuo , Attur Mukundan , Waxman Stephen G. , Liu Chuan-ju
Published: January 2024

Osteoarthritis (OA) is the most common joint disease. Currently there are no effective methods that simultaneously prevent joint degeneration and reduce pain1. Although limited evidence suggests the existence of voltage-gated sodium channels (VGSCs) in chondrocytes2, their expression and function in chondrocytes and in OA remain essentially unknown. Here we identify Nav1.7 as an OA-associated VGSC and demonstrate that human OA chondrocytes express functional Nav1.7 channels, with a density of 0.1 to 0.15 channels per µm2 and 350 to 525 channels per cell. Serial genetic ablation of Nav1.7 in multiple mouse models demonstrates that Nav1.7 expressed in dorsal root ganglia neurons is involved in pain, whereas Nav1.7 in chondrocytes regulates OA progression. Pharmacological blockade of Nav1.7 with selective or clinically used pan-Nav channel blockers significantly ameliorates the progression of structural joint damage, and reduces OA pain behaviour. Mechanistically, Nav1.7 blockers regulate intracellular Ca2+ signalling and the chondrocyte secretome, which in turn affects chondrocyte biology and OA progression. Identification of Nav1.7 as a novel chondrocyte-expressed, OA-associated channel uncovers a dual target for the development of disease-modifying and non-opioid pain relief treatment for OA.
The logic of recurrent circuits in the primary visual cortex
Authors: Oldenburg Ian Antón , Hendricks William D. , Handy Gregory , Shamardani Kiarash , Bounds Hayley A. , Doiron Brent , Adesnik Hillel
Published: January 2024

Recurrent cortical activity sculpts visual perception by refining, amplifying or suppressing visual input. However, the rules that govern the influence of recurrent activity remain enigmatic. We used ensemble-specific two-photon optogenetics in the mouse visual cortex to isolate the impact of recurrent activity from external visual input. We found that the spatial arrangement and the visual feature preference of the stimulated ensemble and the neighboring neurons jointly determine the net effect of recurrent activity. Photoactivation of these ensembles drives suppression in all cells beyond 30 µm but uniformly drives activation in closer similarly tuned cells. In nonsimilarly tuned cells, compact, cotuned ensembles drive net suppression, while diffuse, cotuned ensembles drive activation. Computational modeling suggests that highly local recurrent excitatory connectivity and selective convergence onto inhibitory neurons explain these effects. Our findings reveal a straightforward logic in which space and feature preference of cortical ensembles determine their impact on local recurrent activity.
Differences in the nutritional quality of improved finger millet genotypes in Ethiopia
Authors: Teklu Demeke , Gashu Dawd , Joy Edward J. M. , Bailey Elizabeth H. , Wilson Lolita , Amede Tilahun , Broadley Martin R.
Published: January 2024

Improved crop genotypes are constantly introduced. However, information on their nutritional quality is generally limited. The present study reports the proximate composition and the concentration and relative bioavailability of minerals of improved finger millets of different genotypes. Grains of finger millet genotypes (n = 15) grown in research station during 2019 and 2020 in Ethiopia, and replicated three times in a randomized complete block design, were analysed for proximate composition, mineral concentration (iron, zinc, calcium, selenium), and antinutritional factors (phytate, tannin and oxalate). Moreover, the antinutritional factors to mineral molar ratio method was used to estimate mineral bioavailability. The result shows a significant genotypic variation in protein, fat and fibre level, ranging from 10% to 14.6%, 1.0 to 3.8%, and 1.4 to 4.6%, respectively. Similarly, different finger millets genotypes had significantly different mineral concentrations ranging from 3762 ± 332 to 5893 ± 353 mg kg−1 for Ca, 19.9 ± 1.6 to 26.2 ± 2.7 mg kg−1 for Zn, 36.3 ± 4.6 to 52.9 ± 9.1 mg kg−1 for Fe and 36.6 ± 11 to 60.9 ± 22 µg kg−1 for Se. Phytate (308–360 µg g−1), tannin (0.15–0.51 mg g−1) and oxalate (1.26–4.41 mg g−1) concentrations were also influenced by genotype. Antinutritional factors to minerals molar ratio were also significantly different by genotypes but were below the threshold for low mineral bioavailability. Genotype significantly influenced mineral and antinutritional concentrations of finger millet grains. In addition, all finger millet genotypes possess good mineral bioavailability. Especially, the high Ca concentration in finger millet, compared to in other cereals, could play a vital role to combating Ca deficiency. The result suggests the different finger millet genotypes possess good nutrient content and may contribute to the nutrition security of the local people.