bluuebunny/crossref_metadata_2025 huggingface dataset:
Radically Legal
Authors: Kusiak Joanna
Published: June 2024

Right in the middle of the German constitution, a group of ordinary citizens discovers a forgotten clause that allows them to take 240,000 homes back from multi-billion corporations. In this work of creative non-fiction, scholar-activist and Nine Dots Prize winner Joanna Kusiak tells the story of a grassroots movement that convinced a million Berliners to pop the speculative housing bubble. She offers a vision of urban housing as democratically held commons, legally managed by a radically new institutional model that works through democratic conflicts. Moving between interdisciplinary analysis and her own personal story, Kusiak connects the dots between the past and the present, the local and the global, and shows the potential of radically legal politics as a means of strengthening our democracies and reviving the rule of law. This title is also available as Open Access on Cambridge Core.
Far‐Field Groundwater Response to the Lamb Waves From the 2022 Hunga‐Tonga Volcano Eruption
Authors: Zhang Xin , Chen Mingyu , Zhong Tianren , De Santis Angelo , Han Peng
Published: June 2024

On 15 January 2022, the largest eruption of the Hunga‐Tonga volcano in recorded history produced a plume registered by multi‐parametric instruments around the world. However, the far‐field hydrogeological responses to Lamb waves from this eruption remain underexplored. We studied the responses of groundwater to the volcanic eruption in the far‐field over 8,700 km, including 274 wells. Results show that the Lamb waves with a speed of 316 m/s affects the groundwater system, leading to similar fluctuations in well water level (WL) and opposite phase fluctuation in borehole strain. Different wells exhibit diverse responses in WL amplitudes, possibly for heterogeneities in local aquifer systems. Gain values of 5 wells that simultaneously measure atmospheric pressure, borehole air pressure, borehole strain and WL are consistent with results obtained through cross‐power spectrum estimation. This work demonstrates a novel response in far‐field groundwater systems induced by Lamb waves and expects application for aquifer parameter estimation.
Optimizing In‐Situ Measurement of Representative BVOC Emission Factors Considering Intraspecific Variability
Authors: Zeng Jianqiang , Zhang Yanli , Pang Weihua , Ran Haofan , Guo Hao , Song Wei , Wang Xinming
Published: June 2024

Accurately measuring emission factors (Es) of biogenic volatile organic compounds (BVOCs) with consideration of intraspecific variability is vital but often overlooked. This study presents in‐situ measurements of BVOC emissions from 114 Eucalyptus urophylla individuals using the LI‐6800 portable photosynthesis system. We observed intraspecific variability exceeding an order of magnitude in BVOC Es. Despite this variability, our approach yielded statistically representative Es for E. urophylla, yet challenging the feasibility of extensive field measurements. By quickly screening net photosynthesis rate (Pn) across a broad set of individuals and selecting those within a specific Pn range, such as mean ± 0.1 × SD (standard deviation) of Pn for all screened individuals, for detailed BVOC emission measurements, we achieved comparable mean Es with approximately 10% of the original sampling effort. This offers a practical solution for efficient and accurate field measurement of representative BVOC Es, significantly reducing required sample size while effectively addressing intraspecific variability.
Silicon-photonics-enabled chip-based 3D printer
Authors: Corsetti Sabrina , Notaros Milica , Sneh Tal , Stafford Alex , Page Zachariah A. , Notaros Jelena
Published: June 2024

Imagine if it were possible to create 3D objects in the palm of your hand within seconds using only a single photonic chip. Although 3D printing has revolutionized the way we create in nearly every aspect of modern society, current 3D printers rely on large and complex mechanical systems to enable layer-by-layer addition of material. This limits print speed, resolution, portability, form factor, and material complexity. Although there have been recent efforts in developing novel photocuring-based 3D printers that utilize light to transform matter from liquid resins to solid objects using advanced methods, they remain reliant on bulky and complex mechanical systems. To address these limitations, we combine the fields of silicon photonics and photochemistry to propose the first chip-based 3D printer. The proposed system consists of only a single millimeter-scale photonic chip without any moving parts that emits reconfigurable visible-light holograms up into a simple stationary resin well to enable non-mechanical 3D printing. Furthermore, we experimentally demonstrate a stereolithography-inspired proof-of-concept version of the chip-based 3D printer using a visible-light beam-steering integrated optical phased array and visible-light-curable resin, showing 3D printing using a chip-based system for the first time. This work demonstrates the first steps towards a highly-compact, portable, and low-cost solution for the next generation of 3D printers.
The association of triglyceride–glucose index with major adverse cardiovascular and cerebrovascular events after acute myocardial infarction: a meta-analysis of cohort studies
Authors: Liu Huiruo , Wang Liangshan , Wang Hong , Hao Xing , Du Zhongtao , Li Chenglong , Hou Xiaotong
Published: June 2024

Background

Insulin resistance (IR) is indicated to be linked with adverse outcomes of acute myocardial infarction (AMI), for its pro-inflammatory and pro-thromboplastic function. The triglyceride-glucose (TyG) index is a newly developed substitute marker for IR. The aim of this pooled analysis was to provide a summary of the relationship of TyG index with occurrences of major adverse cardiovascular and cerebrovascular events (MACCEs) among populations suffering from AMI.

Methods

Cohorts reporting multivariate-adjusted hazard ratios of TyG index with MACCEs or its independent events were identified through systematically searching PubMed, MEDLINE, Web of science, Embase and Cochrane databases. Results were combined using a random-effects model.

Results

21 cohorts comprising 20403 individuals were included. Compared to individuals in the lowest TyG category, patients in the highest TyG category exhibited elevated risks of both MACCEs (P < 0.00001) and all-cause death (P < 0.00001). These findings were in line with the results as TyG analyzed as continuous variables (MACCEs: P = 0.006; all-cause death: P < 0.00001). Subgroup analysis demonstrated that diabetic status, type of AMI, nor the reperfusion therapy did not destruct this correlation (for subgroups, all P < 0.05).

Conclusion

All these indicated that higher TyG index could potentially predict MACCEs and all-cause death in patients with AMI as an independent indicator.
BCAAs acutely drive glucose dysregulation and insulin resistance: role of AgRP neurons
Authors: Shah Harsh , Gannaban Ritchel B. , Haque Zobayda Farzana , Dehghani Fereshteh , Kramer Alyssa , Bowers Frances , Ta Matthew , Huynh Thy , Ramezan Marjan , Maniates Ashley , Shin Andrew C.
Published: June 2024

Background

High-protein diets are often enriched with branched-chain amino acids (BCAAs) known to enhance protein synthesis and provide numerous physiological benefits, but recent studies reveal their association with obesity and diabetes. In support of this, protein or BCAA supplementation is shown to disrupt glucose metabolism while restriction improves it. However, it is not clear if these are primary, direct effects of BCAAs or secondary to other physiological changes during chronic manipulation of dietary BCAAs.

Methods

Three-month-old C57Bl/6 mice were acutely treated with either vehicle/BCAAs or BT2, a BCAA-lowering compound, and detailed in vivo metabolic phenotyping, including frequent sampling and pancreatic clamps, were conducted.

Results

Using a catheter-guided frequent sampling method in mice, here we show that a single infusion of BCAAs was sufficient to acutely elevate blood glucose and plasma insulin. While pre-treatment with BCAAs did not affect glucose tolerance, a constant infusion of BCAAs during hyperinsulinemic–euglycemic clamps impaired whole-body insulin sensitivity. Similarly, a single injection of BT2 was sufficient to prevent BCAA rise during fasting and markedly improve glucose tolerance in high-fat-fed mice, suggesting that abnormal glycemic control in obesity may be causally linked to high circulating BCAAs. We further show that chemogenetic over-activation of AgRP neurons in the hypothalamus, as present in obesity, significantly impairs glucose tolerance that is completely normalized by acute BCAA reduction. Interestingly, most of these effects were demonstrated only in male, but not in female mice.

Conclusion

These findings suggest that BCAAs per se can acutely impair glucose homeostasis and insulin sensitivity, thus offering an explanation for how they may disrupt glucose metabolism in the long-term as observed in obesity and diabetes. Our findings also reveal that AgRP neuronal regulation of blood glucose is mediated through BCAAs, further elucidating a novel mechanism by which brain controls glucose homeostasis.
HOXD10 attenuates renal fibrosis by inhibiting NOX4-induced ferroptosis
Authors: Li Xin , Ma Tian-Kui , Wang Pu , Shi Hang , Hai Sang , Qin Yu , Zou Yun , Zhu Wan-Ting , Li Hui-Min , Li Yan-Nong , Yin Li , Xu Yan-Yan , Yang Qi , Zhang Shuang , Ding Hong
Published: June 2024

In chronic kidney disease (CKD), renal fibrosis is an unavoidable result of various manifestations. However, its pathogenesis is not yet fully understood. Here, we revealed the novel role of Homeobox D10 (HOXD10) in CKD-related fibrosis. HOXD10 expression was downregulated in CKD-related in vitro and in vivo fibrosis models. UUO model mice were administered adeno-associated virus (AAV) containing HOXD10, and HOXD10 overexpression plasmids were introduced into human proximal tubular epithelial cells induced by TGF-β1. The levels of iron, reactive oxygen species (ROS), lipid ROS, the oxidized glutathione/total glutathione (GSSG/GSH) ratio, malonaldehyde (MDA), and superoxide dismutase (SOD) were determined using respective assay kits. Treatment with AAV–HOXD10 significantly attenuated fibrosis and renal dysfunction in UUO model mice by inhibiting NOX4 transcription, ferroptosis pathway activation, and oxidative stress. High levels of NOX4 transcription, ferroptosis pathway activation and profibrotic gene expression induced by TGF-β1/erastin (a ferroptosis agonist) were abrogated by HOXD10 overexpression in HK-2 cells. Moreover, bisulfite sequencing PCR result determined that HOXD10 showed a hypermethylated level in TGF-β1-treated HK-2 cells. The binding of HOXD10 to the NOX4 promoter was confirmed by chromatin immunoprecipitation (ChIP) analysis and dual-luciferase reporter assays. Targeting HOXD10 may represent an innovative therapeutic strategy for fibrosis treatment in CKD.
Single-cell transcriptomic atlas reveals increased regeneration in diseased human inner ear balance organs
Authors: Wang Tian , Ling Angela H. , Billings Sara E. , Hosseini Davood K. , Vaisbuch Yona , Kim Grace S. , Atkinson Patrick J. , Sayyid Zahra N. , Aaron Ksenia A. , Wagh Dhananjay , Pham Nicole , Scheibinger Mirko , Zhou Ruiqi , Ishiyama Akira , Moore Lindsay S. , Maria Peter Santa , Blevins Nikolas H. , Jackler Robert K. , Alyono Jennifer C. , Kveton John , Navaratnam Dhasakumar , Heller Stefan , Lopez Ivan A. , Grillet Nicolas , Jan Taha A. , Cheng Alan G.
Published: June 2024

Mammalian inner ear hair cell loss leads to permanent hearing and balance dysfunction. In contrast to the cochlea, vestibular hair cells of the murine utricle have some regenerative capacity. Whether human utricular hair cells regenerate in vivo remains unknown. Here we procured live, mature utricles from organ donors and vestibular schwannoma patients, and present a validated single-cell transcriptomic atlas at unprecedented resolution. We describe markers of 13 sensory and non-sensory cell types, with partial overlap and correlation between transcriptomes of human and mouse hair cells and supporting cells. We further uncover transcriptomes unique to hair cell precursors, which are unexpectedly 14-fold more abundant in vestibular schwannoma utricles, demonstrating the existence of ongoing regeneration in humans. Lastly, supporting cell-to-hair cell trajectory analysis revealed 5 distinct patterns of dynamic gene expression and associated pathways, including Wnt and IGF-1 signaling. Our dataset constitutes a foundational resource, accessible via a web-based interface, serving to advance knowledge of the normal and diseased human inner ear.
Vortex entropy and superconducting fluctuations in ultrathin underdoped Bi2Sr2CaCu2O8+x superconductor
Authors: Hu Shuxu , Qiao Jiabin , Gu Genda , Xue Qi-Kun , Zhang Ding
Published: June 2024

Vortices in superconductors can help identify emergent phenomena but certain fundamental aspects of vortices, such as their entropy, remain poorly understood. Here, we study the vortex entropy in underdoped Bi2Sr2CaCu2O8+x by measuring both magneto-resistivity and Nernst effect on ultrathin flakes (≤2 unit-cell). We extract the London penetration depth from the magneto-transport measurements on samples with different doping levels. It reveals that the superfluid phase stiffness ρs scales linearly with the superconducting transition temperature Tc, down to the extremely underdoped case. On the same batch of ultrathin flakes, we measure the Nernst effect via on-chip thermometry. Together, we obtain the vortex entropy and find that it decays exponentially with Tc or ρs. We further analyze the Nernst signal above Tc in the framework of Gaussian superconducting fluctuations. The combination of electrical and thermoelectric measurements in the two-dimensional limit provides fresh insight into high temperature superconductivity.
Spectro-temporal acoustical markers differentiate speech from song across cultures
Authors: Albouy Philippe , Mehr Samuel A. , Hoyer Roxane S. , Ginzburg Jérémie , Du Yi , Zatorre Robert J.
Published: June 2024

Humans produce two forms of cognitively complex vocalizations: speech and song. It is debated whether these differ based primarily on culturally specific, learned features, or if acoustical features can reliably distinguish them. We study the spectro-temporal modulation patterns of vocalizations produced by 369 people living in 21 urban, rural, and small-scale societies across six continents. Specific ranges of spectral and temporal modulations, overlapping within categories and across societies, significantly differentiate speech from song. Machine-learning classification shows that this effect is cross-culturally robust, vocalizations being reliably classified solely from their spectro-temporal features across all 21 societies. Listeners unfamiliar with the cultures classify these vocalizations using similar spectro-temporal cues as the machine learning algorithm. Finally, spectro-temporal features are better able to discriminate song from speech than a broad range of other acoustical variables, suggesting that spectro-temporal modulation—a key feature of auditory neuronal tuning—accounts for a fundamental difference between these categories.
Superconducting spintronic heat engine
Authors: Araujo Clodoaldo Irineu Levartoski de , Virtanen Pauli , Spies Maria , González-Orellana Carmen , Kerschbaumer Samuel , Ilyn Maxim , Rogero Celia , Heikkilä Tero Tapio , Giazotto Francesco , Strambini Elia
Published: June 2024

Heat engines are key devices that convert thermal energy into usable energy. Strong thermoelectricity, at the basis of electrical heat engines, is present in superconducting spin tunnel barriers at cryogenic temperatures where conventional semiconducting or metallic technologies cease to work. Here we realize a superconducting spintronic heat engine consisting of a ferromagnetic insulator/superconductor/insulator/ferromagnet tunnel junction (EuS/Al/AlOx/Co). The efficiency of the engine is quantified for bath temperatures ranging from 25 mK up to 800 mK, and at different load resistances. Moreover, we show that the sign of the generated thermoelectric voltage can be inverted according to the parallel or anti-parallel orientation of the two ferromagnetic layers, EuS and Co. This realizes a thermoelectric spin valve controlling the sign and strength of the Seebeck coefficient, thereby implementing a thermoelectric memory cell. We propose a theoretical model that allows describing the experimental data and predicts the engine efficiency for different device parameters.
Months-long tracking of neuronal ensembles spanning multiple brain areas with Ultra-Flexible Tentacle Electrodes
Authors: Yasar Tansel Baran , Gombkoto Peter , Vyssotski Alexei L. , Vavladeli Angeliki D. , Lewis Christopher M. , Wu Bifeng , Meienberg Linus , Lundegardh Valter , Helmchen Fritjof , von der Behrens Wolfger , Yanik Mehmet Fatih
Published: June 2024

We introduce Ultra-Flexible Tentacle Electrodes (UFTEs), packing many independent fibers with the smallest possible footprint without limitation in recording depth using a combination of mechanical and chemical tethering for insertion. We demonstrate a scheme to implant UFTEs simultaneously into many brain areas at arbitrary locations without angle-of-insertion limitations, and a 512-channel wireless logger. Immunostaining reveals no detectable chronic tissue damage even after several months. Mean spike signal-to-noise ratios are 1.5-3x compared to the state-of-the-art, while the highest signal-to-noise ratios reach 89, and average cortical unit yields are ~1.75/channel. UFTEs can track the same neurons across sessions for at least 10 months (longest duration tested). We tracked inter- and intra-areal neuronal ensembles (neurons repeatedly co-activated within 25 ms) simultaneously from hippocampus, retrosplenial cortex, and medial prefrontal cortex in freely moving rodents. Average ensemble lifetimes were shorter than the durations over which we can track individual neurons. We identify two distinct classes of ensembles. Those tuned to sharp-wave ripples display the shortest lifetimes, and the ensemble members are mostly hippocampal. Yet, inter-areal ensembles with members from both hippocampus and cortex have weak tuning to sharp wave ripples, and some have unusual months-long lifetimes. Such inter-areal ensembles occasionally remain inactive for weeks before re-emerging.
Structural basis of promoter recognition by Staphylococcus aureus RNA polymerase
Authors: Yuan Linggang , Liu Qingyang , Xu Liqiao , Wu Bing , Feng Yu
Published: June 2024

Bacterial RNAP needs to form holoenzyme with σ factors to initiate transcription. While Staphylococcus aureus σA controls housekeeping functions, S. aureus σB regulates virulence, biofilm formation, persistence, cell internalization, membrane transport, and antimicrobial resistance. Besides the sequence difference, the spacers between the −35 element and −10 element of σB regulated promoters are shorter than those of σA regulated promoters. Therefore, how σB recognizes and initiates transcription from target promoters can not be inferred from that of the well studied σ. Here, we report the cryo-EM structures of S. aureus RNAP-promoter open complexes comprising σA and σB, respectively. Structural analyses, in combination with biochemical experiments, reveal the structural basis for the promoter specificity of S. aureus transcription. Although the −10 element of σA regulated promoters is recognized by domain σA2 as single-stranded DNA, the −10 element of σB regulated promoters is co-recognized by domains σB2 and σB3 as double-stranded DNA, accounting for the short spacers of σB regulated promoters. S. aureus RNAP is a validated target of antibiotics, and our structures pave the way for rational drug design targeting S. aureus RNAP.
Machine-learning structural reconstructions for accelerated point defect calculations
Authors: Mosquera-Lois Irea , Kavanagh Seán R. , Ganose Alex M. , Walsh Aron
Published: June 2024

Defects dictate the properties of many functional materials. To understand the behaviour of defects and their impact on physical properties, it is necessary to identify the most stable defect geometries. However, global structure searching is computationally challenging for high-throughput defect studies or materials with complex defect landscapes, like alloys or disordered solids. Here, we tackle this limitation by harnessing a machine-learning surrogate model to qualitatively explore the structural landscape of neutral point defects. By learning defect motifs in a family of related metal chalcogenide and mixed anion crystals, the model successfully predicts favourable reconstructions for unseen defects in unseen compositions for 90% of cases, thereby reducing the number of first-principles calculations by 73%. Using CdSexTe1−x alloys as an exemplar, we train a model on the end member compositions and apply it to find the stable geometries of all inequivalent vacancies for a range of mixing concentrations, thus enabling more accurate and faster defect studies for configurationally complex systems.
Cubic double perovskites host noncoplanar spin textures
Authors: Paddison Joseph A. M. , Zhang Hao , Yan Jiaqiang , Cliffe Matthew J. , McGuire Michael A. , Do Seung-Hwan , Gao Shang , Stone Matthew B. , Dahlbom David , Barros Kipton , Batista Cristian D. , Christianson Andrew D.
Published: June 2024

Magnetic materials with noncoplanar magnetic structures can show unusual physical properties driven by nontrivial topology. Topologically-active states are often multi-q structures, which are challenging to stabilize in models and to identify in materials. Here, we use inelastic neutron-scattering experiments to show that the insulating double perovskites Ba2YRuO6 and Ba2LuRuO6 host a noncoplanar 3-q structure on the face-centered cubic lattice. Quantitative analysis of our neutron-scattering data reveals that these 3-q states are stabilized by biquadratic interactions. Our study identifies double perovskites as a highly promising class of materials to realize topological magnetism, elucidates the stabilization mechanism of the 3-q state in these materials, and establishes neutron spectroscopy on powder samples as a valuable technique to distinguish multi-q from single-q states, facilitating the discovery of topologically-nontrivial magnetic materials.
A cost-effectiveness analysis of early detection and bundled treatment of postpartum hemorrhage alongside the E-MOTIVE trial
Authors: Williams Eleanor V. , Goranitis Ilias , Oppong Raymond , Perry Samuel J. , Devall Adam J. , Martin James T. , Mammoliti Kristie-Marie , Beeson Leanne E. , Sindhu Kulandaipalayam N. , Galadanci Hadiza , Alwy Al‑beity Fadhlun , Qureshi Zahida , Hofmeyr G. Justus , Moran Neil , Fawcus Sue , Mandondo Sibongile , Middleton Lee , Hemming Karla , Oladapo Olufemi T. , Gallos Ioannis D. , Coomarasamy Arri , Roberts Tracy E.
Published: June 2024

Timely detection and treatment of postpartum hemorrhage (PPH) are crucial to prevent complications or death. A calibrated blood-collection drape can help provide objective, accurate and early diagnosis of PPH, and a treatment bundle can address delays or inconsistencies in the use of effective interventions. Here we conducted an economic evaluation alongside the E-MOTIVE trial, an international, parallel cluster-randomized trial with a baseline control phase involving 210,132 women undergoing vaginal delivery across 78 secondary-level hospitals in Kenya, Nigeria, South Africa and Tanzania. We aimed to assess the cost-effectiveness of the E-MOTIVE intervention, which included a calibrated blood-collection drape for early detection of PPH and a bundle of first-response treatments (uterine massage, oxytocic drugs, tranexamic acid, intravenous fluids, examination and escalation), compared with usual care. We used multilevel modeling to estimate incremental cost-effectiveness ratios from the perspective of the public healthcare system for outcomes of cost per severe PPH (blood loss ≥1,000 ml) avoided and cost per disability-adjusted life-year averted. Our findings suggest that the use of a calibrated blood-collection drape for early detection of PPH and bundled first-response treatment is cost-effective and should be perceived by decision-makers as a worthwhile use of healthcare budgets. ClinicalTrials.gov identifier: NCT04341662.
Sustained aviremia despite anti-retroviral therapy non-adherence in male children after in utero HIV transmission
Authors: Bengu Nomonde , Cromhout Gabriela , Adland Emily , Govender Katya , Herbert Nicholas , Lim Nicholas , Fillis Rowena , Sprenger Kenneth , Vieira Vinicius , Kannie Samantha , van Lobenstein Jeroen , Chinniah Kogielambal , Kapongo Constant , Bhoola Roopesh , Krishna Malini , Mchunu Noxolo , Pascucci Giuseppe Rubens , Cotugno Nicola , Palma Paolo , Tagarro Alfredo , Rojo Pablo , Roider Julia , Garcia-Guerrero Maria C. , Ochsenbauer Christina , Groll Andreas , Reddy Kavidha , Giaquinto Carlo , Rossi Paolo , Hong Seohyun , Dong Krista , Ansari M. Azim , Puertas Maria C. , Ndung’u Thumbi , Capparelli Edmund , Lichterfeld Mathias , Martinez-Picado Javier , Kappes John C. , Archary Moherndran , Goulder Philip
Published: June 2024

After sporadic reports of post-treatment control of HIV in children who initiated combination anti-retroviral therapy (cART) early, we prospectively studied 284 very-early-cART-treated children from KwaZulu-Natal, South Africa, after vertical HIV transmission to assess control of viremia. Eighty-four percent of the children achieved aviremia on cART, but aviremia persisting to 36 or more months was observed in only 32%. We observed that male infants have lower baseline plasma viral loads (P = 0.01). Unexpectedly, a subset (n = 5) of males maintained aviremia despite unscheduled complete discontinuation of cART lasting 3–10 months (n = 4) or intermittent cART adherence during 17-month loss to follow-up (n = 1). We further observed, in vertically transmitted viruses, a negative correlation between type I interferon (IFN-I) resistance and viral replication capacity (VRC) (P < 0.0001) that was markedly stronger for males than for females (r = −0.51 versus r = −0.07 for IFN-α). Although viruses transmitted to male fetuses were more IFN-I sensitive and of higher VRC than those transmitted to females in the full cohort (P < 0.0001 and P = 0.0003, respectively), the viruses transmitted to the five males maintaining cART-free aviremia had significantly lower replication capacity (P < 0.0001). These data suggest that viremic control can occur in some infants with in utero–acquired HIV infection after early cART initiation and may be associated with innate immune sex differences.
Deconwolf enables high-performance deconvolution of widefield fluorescence microscopy images
Authors: Wernersson Erik , Gelali Eleni , Girelli Gabriele , Wang Su , Castillo David , Mattsson Langseth Christoffer , Verron Quentin , Nguyen Huy Q. , Chattoraj Shyamtanu , Martinez Casals Anna , Blom Hans , Lundberg Emma , Nilsson Mats , Marti-Renom Marc A. , Wu Chao-ting , Crosetto Nicola , Bienko Magda
Published: June 2024

Microscopy-based spatially resolved omic methods are transforming the life sciences. However, these methods rely on high numerical aperture objectives and cannot resolve crowded molecular targets, limiting the amount of extractable biological information. To overcome these limitations, here we develop Deconwolf, an open-source, user-friendly software for high-performance deconvolution of widefield fluorescence microscopy images, which efficiently runs on laptop computers. Deconwolf enables accurate quantification of crowded diffraction limited fluorescence dots in DNA and RNA fluorescence in situ hybridization images and allows robust detection of individual transcripts in tissue sections imaged with ×20 air objectives. Deconvolution of in situ spatial transcriptomics images with Deconwolf increased the number of transcripts identified more than threefold, while the application of Deconwolf to images obtained by fluorescence in situ sequencing of barcoded Oligopaint probes drastically improved chromosome tracing. Deconwolf greatly facilitates the use of deconvolution in many bioimaging applications.
Profiling expression strategies for a type III polyketide synthase in a lysate-based, cell-free system
Authors: Sword Tien T. , Dinglasan Jaime Lorenzo N. , Abbas Ghaeath S. K. , Barker J. William , Spradley Madeline E. , Greene Elijah R. , Gooden Damian S. , Emrich Scott J. , Gilchrist Michael A. , Doktycz Mitchel J. , Bailey Constance B.
Published: June 2024

Some of the most metabolically diverse species of bacteria (e.g., Actinobacteria) have higher GC content in their DNA, differ substantially in codon usage, and have distinct protein folding environments compared to tractable expression hosts like Escherichia coli. Consequentially, expressing biosynthetic gene clusters (BGCs) from these bacteria in E. coli often results in a myriad of unpredictable issues with regard to protein expression and folding, delaying the biochemical characterization of new natural products. Current strategies to achieve soluble, active expression of these enzymes in tractable hosts can be a lengthy trial-and-error process. Cell-free expression (CFE) has emerged as a valuable expression platform as a testbed for rapid prototyping expression parameters. Here, we use a type III polyketide synthase from Streptomyces griseus, RppA, which catalyzes the formation of the red pigment flaviolin, as a reporter to investigate BGC refactoring techniques. We applied a library of constructs with different combinations of promoters and rppA coding sequences to investigate the synergies between promoter and codon usage. Subsequently, we assess the utility of cell-free systems for prototyping these refactoring tactics prior to their implementation in cells. Overall, codon harmonization improves natural product synthesis more than traditional codon optimization across cell-free and cellular environments. More importantly, the choice of coding sequences and promoters impact protein expression synergistically, which should be considered for future efforts to use CFE for high-yield protein expression. The promoter strategy when applied to RppA was not completely correlated with that observed with GFP, indicating that different promoter strategies should be applied for different proteins. In vivo experiments suggest that there is correlation, but not complete alignment between expressing in cell free and in vivo. Refactoring promoters and/or coding sequences via CFE can be a valuable strategy to rapidly screen for catalytically functional production of enzymes from BCGs, which advances CFE as a tool for natural product research.
Impact of vitamin D deficiency on iron status in children with type I diabetes
Authors: Moslhy Eman A. M. , Tadros May M. M. , Thabet Rasha A. , Hemida Eman H. A. , Noureldeen Amani F. H.
Published: June 2024

Vitamin D deficiency (VDD) and anemia are both public health nutrition concerns. An association between VDD and anemia has been suggested in various healthy and diseased populations. The current study aimed to elucidate the effect of VDD on iron status in children with type I diabetes mellitus (T1DM). The study recruited two groups of children with T1DM: control group comprised of 38 T1DM children with sufficient vitamin D (> 30 ng/ml) and a case group, consisted of 52 T1DM children with VDD (< 20 ng/ml). Both groups had comparable gender, age, BMI, and disease duration. The laboratory measurements included analysis of blood indices, markers of iron metabolism, hepcidin and inflammatory markers included interleukin 6 (IL-6) and C-reactive protein (CRP). Compared to control group, T1DM children with VDD differs specifically in terms of some markers of blood indices, such as decreased hemoglobin and increased red blood cell distribution width. Moreover, decreased serum iron, ferritin, total iron-binding capacity and transferrin along with elevated inflammatory markers were observed in case group. Results of the study indicated that VDD had increased the risk of iron deficiency anemia in children with T1DM as well as inflammatory related anemia. Furthermore, in T1DM children, VDD had raised the incidence of both absolute and functional iron deficiency, with greater incidence of the former. This study may indicate that VDD may be a risk factor that may worsen iron deficiency anemia in T1DM.
New sulfonamide-based glycosides incorporated 1,2,3-triazole as cytotoxic agents through VEGFR-2 and carbonic anhydrase inhibitory activity
Authors: Abbas Hebat-Allah S. , Nossier Eman S. , El-Manawaty May A. , El-Bayaa Mohamed N.
Published: June 2024

New sulfonamide-triazole-glycoside hybrids derivatives were designed, synthesised, and investigated for anticancer efficacy. The target glycosides’ cytotoxic activity was studied with a panel of human cancer cell lines. Sulfonamide-based derivatives, 4, 7 and 9 exhibited promising activity against HepG-2 and MCF-7 (IC50 = 8.39–16.90 μM against HepG-2 and 19.57–21.15 μM against MCF-7) comparing with doxorubicin (IC50 = 13.76 ± 0.45, 17.44 ± 0.46 μM against HepG-2 and MCF-7, rescpectively). To detect the probable action mechanism, the inhibitory activity of these targets was studied against VEGFR-2, carbonic anhydrase isoforms hCA IX and hCA XII. Compoumds 7 and 9 gave favorable potency (IC50 = 1.33, 0.38 μM against VEGFR-2, 66, 40 nM against hCA IX and 7.6, 3.2 nM against hCA XII, respectively), comparing with sorafenib and SLC-0111 (IC50 = 0.43 μM, 53 and 4.8 nM, respectively). Moreover, the docking simulation was assessed to supply better rationalization and gain insight into the binding affinity between the promising derivatives and their targeted enzymes that was used for further modification in the anticancer field.
Maternal diet quality with child allergic and respiratory multimorbidity in the Elfe birth cohort
Authors: Delvert Rosalie , Charles Marie-Aline , Leynaert Bénédicte , Kadawathagedara Manik , Adel-Patient Karine , Divaret-Chauveau Amandine , Dufourg Marie-Noëlle , Raherison Chantal , Varraso Raphaëlle , de Lauzon-Guillain Blandine , Bédard Annabelle
Published: June 2024

Evidence linking maternal diet during pregnancy to allergic or respiratory diseases in children remains sparse, and outcomes were mainly studied separately. We aim to investigate these associations by considering clusters of allergic and respiratory multimorbidity among 9679 mother–child pairs from the Elfe birth cohort. Maternal diet quality was evaluated using a food-based score (Diet Quality score), a nutrient-based score (PANDiet score) and food group intakes. Adjusted multinomial logistic regressions on allergic and respiratory multimorbidity clusters up to 5.5 years were performed. Child allergic and respiratory diseases were described through five clusters: “asymptomatic” (43%, reference), “early wheeze without asthma” (34%), “asthma only” (7%), “allergies without asthma” (7%), “multi-allergic” (9%). A higher PANDiet score and an increased legume consumption were associated with a reduced risk of belonging to the “early wheeze without asthma” cluster. A U-shaped relationship was observed between maternal fish consumption and the “allergies without asthma” cluster. To conclude, adequate nutrient intake during pregnancy was weakly associated with a lower risk of “early wheeze without asthma” in children. No association was found with food groups, considered jointly or separately, except for legumes and fish, suggesting that maternal adherence to nutritional guidelines might be beneficial for allergic and respiratory diseases prevention.
Characterization of heavy metal contamination in groundwater of typical mining area in Hunan Province
Authors: Hao Wenjie , Liu Huan , Hao Shuli , Mao Kuanzhen
Published: June 2024

Heavy metal pollution in mining areas is a major cause of groundwater contamination, characterized by high toxicity, difficult degradability, and easy accumulation, and the source of pollution is not easily identified. Relying on the results of groundwater quality analysis tests in a typical mining area, this paper uses the SPSS 18.0 statistical analysis model to analyze the statistical characteristics of different indicator factors in the antimony mining area. The conclusions play a crucial role in implementing health and safety measures for the mining area and its surrounding residents. The statistical study results show that Mn, Se, As, and Sb are closely related to human mining activities and are polluted to varying degrees; the principal component analysis model indicates that the upstream monitoring points 26#, 22#, and 25# in the mining area groundwater are less polluted. The five monitoring points with a comprehensive principal component F > 1 are all located within the range of the metal mine cluster, indicating that the groundwater in the mining area is particularly sensitive to the impact of anthropogenic mineral extraction. This research summarizes the hydrogeological and geochemical statistical characteristics of the groundwater in the mining area, providing a reference for groundwater pollution risk diagnosis, ecological restoration, and heavy metal pollution prevention and control in this and similar mining areas.
Deterioration in cognitive control related mPFC function underlying development of treatment resistance in early psychosis
Authors: Crisp Charlotte M. , Sahni Angad , Pang Sze W. , Vanes Lucy D. , Szentgyorgyi Timea , Averbeck Bruno , Moran Rosalyn J. , Shergill Sukhwinder S.
Published: June 2024

One third of people with psychosis become antipsychotic treatment-resistant and the underlying mechanisms remain unclear. We investigated whether altered cognitive control function is a factor underlying development of treatment resistance. We studied 50 people with early psychosis at a baseline visit (mean < 2 years illness duration) and follow-up visit (1 year later), when 35 were categorized at treatment-responsive and 15 as treatment-resistant. Participants completed an emotion-yoked reward learning task that requires cognitive control whilst undergoing fMRI and MR spectroscopy to measure glutamate levels from Anterior Cingulate Cortex (ACC). Changes in cognitive control related activity (in prefrontal cortex and ACC) over time were compared between treatment-resistant and treatment-responsive groups and related to glutamate. Compared to treatment-responsive, treatment-resistant participants showed blunted activity in right amygdala (decision phase) and left pallidum (feedback phase) at baseline which increased over time and was accompanied by a decrease in medial Prefrontal Cortex (mPFC) activity (feedback phase) over time. Treatment-responsive participants showed a negative relationship between mPFC activity and glutamate levels at follow-up, no such relationship existed in treatment-resistant participants. Reduced activity in right amygdala and left pallidum at baseline was predictive of treatment resistance at follow-up (67% sensitivity, 94% specificity). The findings suggest that deterioration in mPFC function over time, a key cognitive control region needed to compensate for an initial dysfunction within a social-emotional network, is a factor underlying development of treatment resistance in early psychosis. An uncoupling between glutamate and cognitive control related mPFC function requires further investigation that may present a future target for interventions.
Advanced environmental scanning electron microscopy reveals natural surface nano-morphology of condensed mitotic chromosomes in their native state
Authors: Neděla Vilém , Tihlaříková Eva , Cápal Petr , Doležel Jaroslav
Published: June 2024

The challenge of in-situ handling and high-resolution low-dose imaging of intact, sensitive and wet samples in their native state at nanometer scale, including live samples is met by Advanced Environmental Scanning Electron Microscopy (A-ESEM). This new generation of ESEM utilises machine learning-based optimization of thermodynamic conditions with respect to sample specifics to employ a low temperature method and an ionization secondary electron detector with an electrostatic separator. A modified electron microscope was used, equipped with temperature, humidity and gas pressure sensors for in-situ and real-time monitoring of the sample. A transparent ultra-thin film of ionic liquid is used to increase thermal and electrical conductivity of the samples and to minimize sample damage by free radicals. To validate the power of the new method, we analyze condensed mitotic metaphase chromosomes to reveal new structural features of their perichromosomal layer, and the organization of chromatin fibers, not observed before by any microscopic technique. The ability to resolve nano-structural details of chromosomes using A-ESEM is validated by measuring gold nanoparticles with achievable resolution in the lower nanometre units.
Multinational proficiency tests for EGFR exon 20 insertions reveal that the assay design matters
Authors: Ihle Michaela A. , Heydt Carina , Schultheis Anne Maria , Stöhr Robert , Haller Florian , Herold Sylvia , Aust Daniela , Dietmaier Wolfgang , Evert Matthias , Eszlinger Markus , Haak Anja , Laßmann Silke , Vorholt Daniela , Breitenbücher Frank , Werner Martin , Streubel Anna , Mairinger Thomas , Grassow-Narlik Maja , Merkelbach-Bruse Sabine
Published: June 2024

Insertion mutations in exon 20 of the epidermal growth factor receptor gene (EGFR exon20ins) are rare, heterogeneous alterations observed in non-small cell lung cancer (NSCLC). With a few exceptions, they are associated with primary resistance to established EGFR tyrosine kinase inhibitors (TKIs). As patients carrying EGFR exon20ins may be eligible for treatment with novel therapeutics—the bispecific antibody amivantamab, the TKI mobocertinib, or potential future innovations—they need to be identified reliably in clinical practice for which quality-based routine genetic testing is crucial. Spearheaded by the German Quality Assurance Initiative Pathology two international proficiency tests were run, assessing the performance of 104 participating institutes detecting EGFR exon20ins in tissue and/or plasma samples. EGFR exon20ins were most reliably identified using next-generation sequencing (NGS). Interestingly, success rates of institutes using commercially available mutation-/allele-specific quantitative (q)PCR were below 30% for tissue samples and 0% for plasma samples. Most of these mutation-/allele-specific (q)PCR assays are not designed to detect the whole spectrum of EGFR exon20ins mutations leading to false negative results. These data suggest that NGS is a suitable method to detect EGFR exon20ins in various types of patient samples and is superior to the detection spectrum of commercially available assays.
Pediatric health service utilization at tertiary hospitals in Denmark 2000–2018
Authors: Madsen Pi Vejsig , Jensen Andreas , Eriksson Frank , Stensballe Lone Graff
Published: June 2024

Pediatric health service differs between and within countries. To prioritize limited resources, data-driven studies on pediatric tertiary hospital contacts are warranted. This population-based register study identified all contacts with four Danish tertiary hospitals 2000–2018 by 0–17-year-old patients. During 2000–2018, 2,496,001 individuals resided in Denmark while 0–17 years old, and the study described 829,562 inpatient and 3,932,744 outpatient contacts at tertiary hospitals by hospital, sex, age, diagnosis, department, and residence. Male patients accounted for more contacts overall (inpatient 55.51%, outpatient 52.40%) and more contacts with severe chronic disease (inpatient 56.24%, outpatient 54.41%). Median (interquartile range) patient age was 3.09 (0.26–9.96) and 8.48 (2.78–13.70) years for in- and outpatient contacts. Overall, 28.23% and 21.02% of in- and outpatient contacts included a diagnosis of a severe chronic disease, but the proportions differed across hospitals. A pattern of pediatric healthcare directed towards less severe diseases was observed: While the total number of outpatient visits at tertiary hospitals increased from 2000 to 2018, the proportion of these contacts which had a diagnosis of a severe chronic disease decreased. Future comparisons between hospitals regarding pediatric outcomes should consider potential differences in terms of uptake and diagnosis severity. Such findings may have implications for future pediatric organization, nationally and internationally.
Exploring the relationship between heavy metals and diabetic retinopathy: a machine learning modeling approach
Authors: Gui Yanchao , Gui Siyu , Wang Xinchen , Li Yiran , Xu Yueyang , Zhang Jinsong
Published: June 2024

Diabetic retinopathy (DR) is one of the leading causes of adult blindness in the United States. Although studies applying traditional statistical methods have revealed that heavy metals may be essential environmental risk factors for diabetic retinopathy, there is a lack of analyses based on machine learning (ML) methods to adequately explain the complex relationship between heavy metals and DR and the interactions between variables. Based on characteristic variables of participants with and without DR and heavy metal exposure data obtained from the NHANES database (2003–2010), a ML model was developed for effective prediction of DR. The best predictive model for DR was selected from 11 models by receiver operating characteristic curve (ROC) analysis. Further permutation feature importance (PFI) analysis, partial dependence plots (PDP) analysis, and SHapley Additive exPlanations (SHAP) analysis were used to assess the model capability and key influencing factors. A total of 1042 eligible individuals were randomly assigned to two groups for training and testing set of the prediction model. ROC analysis showed that the k-nearest neighbour (KNN) model had the highest prediction performance, achieving close to 100% accuracy in the testing set. Urinary Sb level was identified as the critical heavy metal affecting the predicted risk of DR, with a contribution weight of 1.730632 ± 1.791722, which was much higher than that of other heavy metals and baseline variables. The results of the PDP analysis and the SHAP analysis also indicated that antimony (Sb) had a more significant effect on DR. The interaction between age and Sb was more significant compared to other variables and metal pairs. We found that Sb could serve as a potential predictor of DR and that Sb may influence the development of DR by mediating cellular and systemic senescence. The study revealed that monitoring urinary Sb levels can be useful for early non-invasive screening and intervention in DR development, and also highlighted the important role of constructed ML models in explaining the effects of heavy metal exposure on DR.
Unraveling the relationship between serum parathyroid hormone levels and trabecular bone score: a cross-sectional study
Authors: Zhao Tingxiao , Li Yanlei , Tian Jinlong , Kang Yao , Xu Jiongnan , Shao Haiyu , Zhou Jinlei , Xia Chen , Wang Yongguang , Zhang Jun
Published: June 2024

The TBS is a new method for clinicians to assess the bone quality. It is directly related to the mechanical strength of bone and helps predict fracture risk. The present analysis aimed to investigate the associations between serum PTH levels and TBS by analyzing data from the National Health and Nutrition Examination Survey (NHANES). A total of 3516 participants from the NHANES 2005–2006 were included in this cross-sectional study. The independent variable was serum PTH, and the outcome variable was TBS. The associations of serum PTH levels with TBS were examined using multivariable linear regression models. After adjusting for covariates, there was a negative association between serum PTH level and TBS (β = − 0.0034; 95% confidence interval, − 0.0050 to − 0.0017). However, in the subgroup analysis stratified by gender, race, and age, this association became negative only in Non-Hispanic White (β =  − 0.0047, 95% CI:  −  0.0071 to  −  0.0048) and young people (age < 60) (β = − 0.0036, 95% CI: − 0.0057, − 0.0016), regardless of gender. In addition, the association of serum PTH with TBS was an U-shaped curve, with a point of inflection at 6.71 pmol/L. This study showed that serum PTH level was negatively associated with TBS. Maintaining PTH levels in a lower reasonable clinical range may be beneficial to bone health, especially for young non-Hispanic white.