bluuebunny/crossref_metadata_2025 huggingface dataset:
A bipolar disorder-associated missense variant alters adenylyl cyclase 2 activity and promotes mania-like behavior
Authors: Sen Paromita , Ortiz Oskar , Brivio Elena , Menegaz Danusa , Sotillos Elliott Laura , Du Ying , Ries Clemens , Chen Alon , Wurst Wolfgang , Lopez Juan Pablo , Eder Matthias , Deussing Jan M.
Published: July 2024

Abstract

The single nucleotide polymorphism rs13166360, causing a substitution of valine (Val) 147 to leucine (Leu) in the adenylyl cyclase 2 (ADCY2), has previously been associated with bipolar disorder (BD). Here we show that the disease-associated ADCY2 missense mutation diminishes the enzyme´s capacity to generate the second messenger 3’,5’-cylic adenosine monophosphate (cAMP) by altering its subcellular localization. We established mice specifically carrying the Val to Leu substitution using CRISPR/Cas9-based gene editing. Mice homozygous for the Leu variant display symptoms of a mania-like state accompanied by cognitive impairments. Mutant animals show additional characteristic signs of rodent mania models, i.e., they are hypersensitive to amphetamine, the observed mania-like behaviors are responsive to lithium treatment and the Val to Leu substitution results in a shifted excitatory/inhibitory synaptic balance towards more excitation. Exposure to chronic social defeat stress switches homozygous Leu variant carriers from a mania- to a depressive-like state, a transition which is reminiscent of the alternations characterizing the symptomatology in BD patients. Single-cell RNA-seq (scRNA-seq) revealed widespread Adcy2 mRNA expression in numerous hippocampal cell types. Differentially expressed genes particularly identified from glutamatergic CA1 neurons point towards ADCY2 variant-dependent alterations in multiple biological processes including cAMP-related signaling pathways. These results validate ADCY2 as a BD risk gene, provide insights into underlying disease mechanisms, and potentially open novel avenues for therapeutic intervention strategies.
Prevalence and correlates of common mental disorders among participants of the Uganda Genome Resource: Opportunities for psychiatric genetics research
Authors: Kalungi Allan , Kinyanda Eugene , Akena Dickens Howard , Gelaye Bizu , Ssembajjwe Wilber , Mpango Richard Steven , Ongaria Terry , Mugisha Joseph , Makanga Ronald , Kakande Ayoub , Kimono Beatrice , Amanyire Philip , Kirumira Fred , Lewis Cathryn M. , McIntosh Andrew M. , Kuchenbaecker Karoline , Nyirenda Moffat , Kaleebu Pontiano , Fatumo Segun
Published: July 2024

Genetics research has potential to alleviate the burden of mental disorders in low- and middle-income-countries through identification of new mechanistic pathways which can lead to efficacious drugs or new drug targets. However, there is currently limited genetics data from Africa. The Uganda Genome Resource provides opportunity for psychiatric genetics research among underrepresented people from Africa. We aimed at determining the prevalence and correlates of major depressive disorder (MDD), suicidality, post-traumatic stress disorder (PTSD), alcohol abuse, generalised anxiety disorder (GAD) and probable attention-deficit hyperactivity disorder (ADHD) among participants of the Uganda Genome Resource. Standardised tools assessed for each mental disorder. Prevalence of each disorder was calculated with 95% confidence intervals. Multivariate logistic regression models evaluated the association between each mental disorder and associated demographic and clinical factors. Among 985 participants, prevalence of the disorders were: current MDD 19.3%, life-time MDD 23.3%, suicidality 10.6%, PTSD 3.1%, alcohol abuse 5.7%, GAD 12.9% and probable ADHD 9.2%. This is the first study to determine the prevalence of probable ADHD among adult Ugandans from a general population. We found significant association between sex and alcohol abuse (adjusted odds ratio [AOR] = 0.26 [0.14,0.45], p < 0.001) and GAD (AOR = 1.78 [1.09,2.49], p = 0.019) respectively. We also found significant association between body mass index and suicidality (AOR = 0.85 [0.73,0.99], p = 0.041), alcohol abuse (AOR = 0.86 [0.78,0.94], p = 0.003) and GAD (AOR = 0.93 [0.87,0.98], p = 0.008) respectively. We also found a significant association between high blood pressure and life-time MDD (AOR = 2.87 [1.08,7.66], p = 0.035) and probable ADHD (AOR = 1.99 [1.00,3.97], p = 0.050) respectively. We also found a statistically significant association between tobacco smoking and alcohol abuse (AOR = 3.2 [1.56,6.67], p = 0.002). We also found ever been married to be a risk factor for probable ADHD (AOR = 2.12 [0.88,5.14], p = 0.049). The Uganda Genome Resource presents opportunity for psychiatric genetics research among underrepresented people from Africa.
Brain volume and neurodevelopment at 13 years following sepsis in very preterm infants
Authors: Thompson Deanne K. , Cai Shirley , Kelly Claire E. , Alexander Bonnie , Matthews Lillian G. , Mainzer Rheanna , Doyle Lex W. , Cheong Jeanie L. Y. , Inder Terrie E. , Yang Joseph Y. M. , Anderson Peter J.
Published: July 2024

Background

Associations of neonatal infection with brain growth and later neurodevelopmental outcomes in very preterm (VP) infants are unclear. This study aimed to assess associations of neonatal sepsis in VP infants with (1) brain growth from term-equivalent age to 13 years; and (2) 13-year brain volume and neurodevelopmental outcomes.

Methods

224 infants born VP ( < 30 weeks’ gestation/<1250 g birthweight) were recruited. Longitudinal brain volumes for 68 cortical and 14 subcortical regions were derived from MRI at term-equivalent, 7 and/or 13 years of age for 216 children (79 with neonatal sepsis and 137 without). 177 children (79%) had neurodevelopmental assessments at age 13. Of these, 63 with neonatal sepsis were compared with 114 without. Brain volumetric growth trajectories across time points were compared between sepsis and no-sepsis groups using mixed effects models. Linear regressions compared brain volume and neurodevelopmental outcome measures at 13 years between sepsis and no sepsis groups.

Results

Growth trajectories were similar and there was little evidence for differences in brain volumes or neurodevelopmental domains at age 13 years between those with or without sepsis.

Conclusions

Neonatal sepsis in children born VP does not appear to disrupt subsequent brain development, or to have functional consequences in early adolescence.

Impact statement

Neonatal sepsis has been associated with poorer short-term neurodevelopmental outcomes and reduced brain volumes in very preterm infants.

This manuscript provides new insights into the long-term brain development and neurodevelopmental outcomes of very preterm-born children who did or did not have neonatal sepsis.

We found that regional brain volumes up to 13 years, and neurodevelopmental outcomes at age 13, were similar between those with and without neonatal sepsis.

The links between neonatal sepsis and long-term neurodevelopment remain unclear.
IL-4/IL-4R axis signaling drives resistance to immunotherapy by inducing the upregulation of Fcγ receptor IIB in M2 macrophages
Authors: Zhang Jiayu , Dong Yu , Yu Shan , Hu Keshu , Zhang Lingyun , Xiong Min , Liu Mengling , Sun Xun , Li Suyao , Yuan Yitao , Zhang Chi , Zhu Mengxuan , Wei Yichou , Zhu Yanjing , Yu Yiyi , Zhang Pengfei , Liu Tianshu
Published: July 2024

In recent years, immunotherapy, particularly PD-1 antibodies, have significantly enhanced the outcome of gastric cancer patients. Despite these advances, some patients do not respond well to treatment, highlighting the need to understand resistance mechanisms and develop predictive markers of treatment effectiveness. This study retrospectively analyzed data from 106 patients with stage IV gastric cancer who were treated with first-line immunotherapy in combination with chemotherapy. By comparing plasma cytokine levels between patients resistant and sensitive to PD-1 antibody therapy, the researchers identified elevated IL-4 expression in the resistant patients. Mechanical investigations revealed that IL-4 induces metabolic changes in macrophages that activate the PI3K/AKT/mTOR pathway. This alteration promotes ATP production, enhances glycolysis, increases lactic acid production, and upregulates FcγRIIB expression in macrophages. Ultimately, these changes lead to CD8+ T cell dysfunction and resistance to PD-1 antibody therapy in gastric cancer. These findings highlight the role of IL-4-induced macrophage polarization and metabolic reprogramming in immune resistance and verify IL-4 as potential targets for improving treatment outcomes in gastric cancer patients.
The addition of mycoprotein to a mixed-meal impacts postprandial glucose kinetics without altering blood glucose concentrations: a randomised controlled trial
Authors: Whelehan Gráinne , West Sam , Abdelrahman Doaa R. , Murton Andrew J. , Finnigan Tim J. A. , Wall Benjamin T. , Stephens Francis B.
Published: July 2024

Background

Mycoprotein is a high-fibre food previously shown to reduce postprandial glucose concentrations when ingested within a mixed-meal. We applied a dual stable isotope tracer approach to determine whether this is due to a reduced rate of appearance of glucose, in participants of ranging BMI.

Methods

Twenty-four adults (F = 8, BMI 30 ± 6 kg·m−2) attended 2 trials in a double-blind, randomised, cross-over design. Participants ingested two energy and macronutrient matched milk-based drinks (enriched with 1000 mg [U-13C6] glucose in a subset of 12 participants), containing 50 g glucose and either 0 (CON) or 20 g (MYC) mycoprotein. A primed continuous intravenous infusion of D-[6,6-2H2] glucose determined plasma glucose kinetics over 6 h. Postprandial time-course, and AUC, of glucose and insulin concentration, rate of disappearance (RdT) and appearance of exogenous (RaEx), endogenous (EGP), and total (RaT) plasma glucose were assessed using two- and one-way ANOVA.

Results

Drink ingestion increased blood glucose and serum insulin concentrations (P < 0.05) and were comparable between conditions (P > 0.05). Both RaT and RdT were higher with MYC compared with CON over 6 h (mean 6 h glucose appearance and disappearance increased by 5 and 9%, respectively, P < 0.05). RaEx was not affected by MYC ingestion over 6 h (P > 0.05). The mean contribution of EGP to total glucose appearance was 15% greater with MYC, with a trend towards significance (P = 0.05). There was no relationship between BMI and the response to MYC ingestion for any of the variables (P < 0.05).

Conclusion

The ingestion of mycoprotein within a mixed-meal impacted postprandial glucose kinetics, but not blood glucose or serum insulin concentrations, in individuals of ranging BMI.

Clinical trial registry number and website

This trial was registered at clinicaltrials.gov as NCT04084639 and can be accessed at https://clinicaltrials.gov/ct2/show/NCT04084639.
Psychological and ethical issues raised by genomic in paediatric care pathway, a qualitative analysis with parents and childhood cancer patients
Authors: Droin-Mollard Marion , de Montgolfier Sandrine , Gimenez-Roqueplo Anne-Paule , Flahault Cécile , Petit Arnaud , Bourdeaut Franck , Julia Sophie , Rial-Sebbag Emmanuelle , Coupier Isabelle , Simaga Fatoumata , Brugières Laurence , Guerrini-Rousseau Léa , Claret Béatrice , Cavé Hélène , Strullu Marion , Hervouet Lucile , Lahlou-Laforêt Khadija
Published: July 2024

In paediatric oncology, genomics raises new ethical, legal and psychological issues, as somatic and constitutional situations intersect throughout the care pathway. The discovery of potential predisposition in this context is sometimes carried out outside the usual framework. This article focuses on the views of children, adolescents, and young adults (AYA) with cancer and their parents about their experience with genomic testing. Forty-eight semi-structured interviews were performed with children or AYAs with cancer and one of their parents, before and/or after receiving the genetic test results. The interviews were fully transcribed, coded and thematically analysed using an inductive method. This analysis revealed several themes that are key issues: perceived understanding and consenting, apprehension about the test outcomes (expectations and fears), perception and attitude towards incidental findings. The main expectation was an aetiological explanation. Children and AYAs also emphasised the altruistic meaning of genetic testing, while parents seemed to expect a therapeutic and preventive approach for their child and the rest of the family. Parents were more concerned about a family risk, while patients were more afraid of cancer relapse or transmission to their descendants. Both groups suggested possible feelings of guilt concerning family transmission and imaginary representations of what genomics may allow. Incidental findings were not understood by patients, while some parents perceived the related issues and hesitated between wanting or not to know. A multidisciplinary approach would be an interesting way to help parents and children and AYAs to better grasp the complexity of genetic and/or genomic testing.
Inter-zonal epithelial thickness differences for early keratoconus detection using optical coherence tomography
Authors: Naujokaitis Tadas , Khoramnia Ramin , Friedrich Maximilian , Son Hyeck-Soo , Auffarth Gerd U. , Augustin Victor A.
Published: July 2024

Purpose

To develop and test a parameter for early keratoconus screening by quantifying the localized epithelial thickness differences in keratoconic eyes.

Methods

The cross-sectional study included 189 eyes of 116 subjects in total: 86 eyes of 54 keratoconus patients with bilateral ectasia and 40 eyes of 20 healthy subjects in the parameter-development dataset and 42 eyes of 21 keratoconus patients with asymmetric ectasia and 21 eyes of 21 healthy subjects in the parameter-validation dataset. Epithelial thickness maps were obtained using anterior segment optical coherence tomography and the inter-zonal epithelial thickness differences were calculated. The developed parameter was tested in keratoconus patients with asymmetric ectasia.

Results

Compared to healthy controls, the inferior-temporal and global inter-zonal epithelial thickness differences were higher not only in eyes with tomographically significant keratoconus (median [interquartile range] of 4.42 [3.13] µm vs. 0.78 [0.42] µm, p < 0.001, and 3.05 [1.51] µm vs. 1.07 [0.26] µm, p < 0.001, respectively), but also in tomographically normal keratoconus fellow eyes (1.36 [0.85] µm vs. 0.78 [0.42] µm, p = 0.005, and 1.31 [0.32] µm vs. 1.07 [0.26] µm, p = 0.01, respectively). The inferior-temporal inter-zonal epithelial thickness differences had an area under the receiver operating characteristic curve (95% confidence interval) of 0.991 (0.972–1) for detecting tomographically significant keratoconus and 0.749 (0.598–0.901) for differentiating between tomographically normal keratoconus fellow eyes and healthy controls.

Conclusions

The inter-zonal epithelial thickness differences are increased in keratoconus fellow eyes which still have a normal Scheimpflug corneal tomography, and therefore may serve as a useful parameter to detect early ectatic changes.
Voxelated bioprinting of modular double-network bio-ink droplets
Authors: Zhu Jinchang , He Yi , Wang Yong , Cai Li-Heng
Published: July 2024

Analogous of pixels to two-dimensional pictures, voxels—in the form of either small cubes or spheres—are the basic building blocks of three-dimensional objects. However, precise manipulation of viscoelastic bio-ink voxels in three-dimensional space represents a grand challenge in both soft matter science and biomanufacturing. Here, we present a voxelated bioprinting technology that enables the digital assembly of interpenetrating double-network hydrogel droplets made of polyacrylamide/alginate-based or hyaluronic acid/alginate-based polymers. The hydrogels are crosslinked via additive-free and biofriendly click reaction between a pair of stoichiometrically matched polymers carrying norbornene and tetrazine groups, respectively. We develop theoretical frameworks to describe the crosslinking kinetics and stiffness of the hydrogels, and construct a diagram-of-state to delineate their mechanical properties. Multi-channel print nozzles are developed to allow on-demand mixing of highly viscoelastic bio-inks without significantly impairing cell viability. Further, we showcase the distinctive capability of voxelated bioprinting by creating highly complex three-dimensional structures such as a hollow sphere composed of interconnected yet distinguishable hydrogel particles. Finally, we validate the cytocompatibility and in vivo stability of the printed double-network scaffolds through cell encapsulation and animal transplantation.
Room temperature catalytic upgrading of unpurified lignin depolymerization oil into bisphenols and butene-2
Authors: Subbotina Elena , Souza Layra Rodrigues , Zimmerman Julie , Anastas Paul
Published: July 2024

Lignin is the largest source of renewable aromatics on earth. Despite numerous techniques for lignin depolymerization into mixtures of valuable monomers, methods for their upgrading into final products are scarce. The state of the art upgrading methods generally rely on catalytic funneling, requiring high temperatures, catalyst loadings and hydrogen pressure, and lead to the loss of functionality and bio-based carbon content. Here an alternative approach is presented, whereby the target monomers are selectively converted in unpurified mixtures into easily separable final products under mild conditions. We use reductive catalytic fractionation of wood to convert lignin into iso-eugenol and propenyl syringol enriched oil followed by an olefin metathesis to yield bisphenols and butene-2, thus, valorizing all bio-based carbons. To further demonstrate the synthetic utility of the obtained bisphenols we converted them into polyesters with a high glass transition temperature (Tg = 140.3 °C) and thermal stability (Td50% = 330 °C).
An electricity-driven mobility circular economy with lifecycle carbon footprints for climate-adaptive carbon neutrality transformation
Authors: Song Aoye , Dan Zhaohui , Zheng Siqian , Zhou Yuekuan
Published: July 2024

Under the carbon neutrality targets and sustainable development goals, emergingly increasing needs for batteries are in buildings and electric vehicles. However, embodied carbon emissions impose dialectical viewpoints on whether the electrochemical battery is environmentally friendly or not. In this research, a community with energy paradigm shifting towards decentralization, renewable and sustainability is studied, with multi-directional Vehicle-to-Everything (V2X) and lifecycle battery circular economy. Approaches are proposed to quantify the lifecycle carbon intensity of batteries. Afterwards, pathways for zero-carbon transformation are proposed to guide the economic feasibility of energy, social and governance investment behaviors. Results show that lifecycle zero-carbon battery can be achieved under energy paradigm shifting to positive, V2X interaction, battery cascade utilization and battery circular economy in various climate regions. This study proposes an approach for lifecycle battery carbon intensity quantification for sustainable pathways transition on zero-carbon batteries and carbon-neutral communities.
DropBlot: single-cell western blotting of chemically fixed cancer cells
Authors: Liu Yang , Herr Amy E.
Published: July 2024

Archived patient-derived tissue specimens play a central role in understanding disease and developing therapies. To address specificity and sensitivity shortcomings of existing single-cell resolution proteoform analysis tools, we introduce a hybrid microfluidic platform (DropBlot) designed for proteoform analyses in chemically fixed single cells. DropBlot serially integrates droplet-based encapsulation and lysis of single fixed cells, with on-chip microwell-based antigen retrieval, with single-cell western blotting of target antigens. A water-in-oil droplet formulation withstands the harsh chemical (SDS, 6 M urea) and thermal conditions (98 °C, 1-2 hr) required for effective antigen retrieval, and supports analysis of retrieved protein targets by single-cell electrophoresis. We demonstrate protein-target retrieval from unfixed, paraformaldehyde-fixed (PFA), and methanol-fixed cells. Key protein targets (HER2, GAPDH, EpCAM, Vimentin) retrieved from PFA-fixed cells were resolved and immunoreactive. Relevant to biorepositories, DropBlot profiled targets retrieved from human-derived breast tumor specimens archived for six years, offering a workflow for single-cell protein-biomarker analysis of sparing biospecimens.
Electron stochastic acceleration in laboratory-produced kinetic turbulent plasmas
Authors: Yuan Dawei , Lei Zhu , Wei Huigang , Zhang Zhe , Zhong Jiayong , Li Yifei , Ping Yongli , Zhang Yihang , Li Yutong , Wang Feilu , Liang Guiyun , Qiao Bin , Fu Changbo , Liu Huiya , Zhang Panzheng , Zhu Jianqiang , Zhao Gang , Zhang Jie
Published: July 2024

The origin of energetic charged particles in universe remains an unresolved issue. Astronomical observations combined with simulations have provided insights into particle acceleration mechanisms, including magnetic reconnection acceleration, shock acceleration, and stochastic acceleration. Recent experiments have also confirmed that electrons can be accelerated through processes such as magnetic reconnection and collisionless shock formation. However, laboratory identifying stochastic acceleration as a feasible mechanism is still a challenge, particularly in the creation of collision-free turbulent plasmas. Here, we present experimental results demonstrating kinetic turbulence with a typical spectrum k−2.9 originating from Weibel instability. Energetic electrons exhibiting a power-law distribution are clearly observed. Simulations further reveal that thermal electrons undergo stochastic acceleration through collisions with multiple magnetic islands-like structures within the turbulent region. This study sheds light on a critical transition period during supernova explosion, where kinetic turbulences originating from Weibel instability emerge prior to collisionless shock formation. Our results suggest that electrons undergo stochastic acceleration during this transition phase.
Unlocking the potential of biogas systems for energy production and climate solutions in rural communities
Authors: Luo Tao , Shen Bo , Mei Zili , Hove Anders , Ju Keyi
Published: July 2024

On-site conversion of organic waste into biogas to satisfy consumer energy demand has the potential to realize energy equality and mitigate climate change reliably. However, existing methods ignore either real-time full supply or methane escape when supply and demand are mismatched. Here, we show an improved design of community biogas production and distribution system to overcome these and achieve full co-benefits in developing economies. We take five existing systems as empirical examples. Mechanisms of synergistic adjusting out-of-step biogas flow rates on both the plant-side and user-side are defined to obtain consumption-to-production ratios of close to 1, such that biogas demand of rural inhabitants can be met. Furthermore, carbon mitigation and its viability under universal prevailing climates are illustrated. Coupled with manure management optimization, Chinese national deployment of the proposed system would contribute a 3.77% reduction towards meeting its global 1.5 °C target. Additionally, fulfilling others’ energy demands has considerable decarbonization potential.
PDX1+ cell budding morphogenesis in a stem cell-derived islet spheroid system
Authors: Zhao Jia , Liang Shenghui , Cen Haoning Howard , Li Yanjun , Baker Robert K. , Ruprai Balwinder , Gao Guang , Zhang Chloe , Ren Huixia , Tang Chao , Chen Liangyi , Liu Yanmei , Lynn Francis C. , Johnson James D. , Kieffer Timothy J.
Published: July 2024

Remarkable advances in protocol development have been achieved to manufacture insulin-secreting islets from human pluripotent stem cells (hPSCs). Distinct from current approaches, we devised a tunable strategy to generate islet spheroids enriched for major islet cell types by incorporating PDX1+ cell budding morphogenesis into staged differentiation. In this process that appears to mimic normal islet morphogenesis, the differentiating islet spheroids organize with endocrine cells that are intermingled or arranged in a core-mantle architecture, accompanied with functional heterogeneity. Through in vitro modelling of human pancreas development, we illustrate the importance of PDX1 and the requirement for EphB3/4 signaling in eliciting cell budding morphogenesis. Using this new approach, we model Mitchell-Riley syndrome with RFX6 knockout hPSCs illustrating unexpected morphogenesis defects in the differentiation towards islet cells. The tunable differentiation system and stem cell-derived islet models described in this work may facilitate addressing fundamental questions in islet biology and probing human pancreas diseases.
An extended interaction site determines binding between AP180 and AP2 in clathrin mediated endocytosis
Authors: Naudi-Fabra Samuel , Elena-Real Carlos A. , Vedel Ida Marie , Tengo Maud , Motzny Kathrin , Jiang Pin-Lian , Schmieder Peter , Liu Fan , Milles Sigrid
Published: July 2024

The early phases of clathrin mediated endocytosis are organized through a highly complex interaction network mediated by clathrin associated sorting proteins (CLASPs) that comprise long intrinsically disordered regions (IDRs). AP180 is a CLASP exclusively expressed in neurons and comprises a long IDR of around 600 residues, whose function remains partially elusive. Using NMR spectroscopy, we discovered an extended and strong interaction site within AP180 with the major adaptor protein AP2, and describe its binding dynamics at atomic resolution. We find that the 70 residue-long site determines the overall interaction between AP180 and AP2 in a dynamic equilibrium between its bound and unbound states, while weaker binding sites contribute to the overall affinity at much higher concentrations of AP2. Our data suggest that this particular interaction site might play a central role in recruitment of adaptors to the clathrin coated pit, whereas more transient and promiscuous interactions allow reshaping of the interaction network until cargo uptake inside a coated vesicle.
Kdm4a is an activity downregulated barrier to generate engrams for memory separation
Authors: Guo Xiuxian , Hong Pengfei , Xiong Songhai , Yan Yuze , Xie Hong , Guan Ji-Song
Published: July 2024

Memory engrams are a subset of learning activated neurons critical for memory recall, consolidation, extinction and separation. While the transcriptional profile of engrams after learning suggests profound neural changes underlying plasticity and memory formation, little is known about how memory engrams are selected and allocated. As epigenetic factors suppress memory formation, we developed a CRISPR screening in the hippocampus to search for factors controlling engram formation. We identified histone lysine-specific demethylase 4a (Kdm4a) as a negative regulator for engram formation. Kdm4a is downregulated after neural activation and controls the volume of mossy fiber boutons. Mechanistically, Kdm4a anchors to the exonic region of Trpm7 gene loci, causing the stalling of nascent RNAs and allowing burst transcription of Trpm7 upon the dismissal of Kdm4a. Furthermore, the YTH domain containing protein 2 (Ythdc2) recruits Kdm4a to the Trpm7 gene and stabilizes nascent RNAs. Reducing the expression of Kdm4a in the hippocampus via genetic manipulation or artificial neural activation facilitated the ability of pattern separation in rodents. Our work indicates that Kdm4a is a negative regulator of engram formation and suggests a priming state to generate a separate memory.
Early human fetal lung atlas reveals the temporal dynamics of epithelial cell plasticity
Authors: Quach Henry , Farrell Spencer , Wu Ming Jia Michael , Kanagarajah Kayshani , Leung Joseph Wai-Hin , Xu Xiaoqiao , Kallurkar Prajkta , Turinsky Andrei L. , Bear Christine E. , Ratjen Felix , Kalish Brian , Goyal Sidhartha , Moraes Theo J. , Wong Amy P.
Published: July 2024

Studying human fetal lungs can inform how developmental defects and disease states alter the function of the lungs. Here, we sequenced >150,000 single cells from 19 healthy human pseudoglandular fetal lung tissues ranging between gestational weeks 10–19. We capture dynamic developmental trajectories from progenitor cells that express abundant levels of the cystic fibrosis conductance transmembrane regulator (CFTR). These cells give rise to multiple specialized epithelial cell types. Combined with spatial transcriptomics, we show temporal regulation of key signalling pathways that may drive the temporal and spatial emergence of specialized epithelial cells including ciliated and pulmonary neuroendocrine cells. Finally, we show that human pluripotent stem cell-derived fetal lung models contain CFTR-expressing progenitor cells that capture similar lineage developmental trajectories as identified in the native tissue. Overall, this study provides a comprehensive single-cell atlas of the developing human lung, outlining the temporal and spatial complexities of cell lineage development and benchmarks fetal lung cultures from human pluripotent stem cell differentiations to similar developmental window.
Ethylene electrosynthesis from low-concentrated acetylene via concave-surface enriched reactant and improved mass transfer
Authors: Chen Fanpeng , Li Li , Cheng Chuanqi , Yu Yifu , Zhao Bo-Hang , Zhang Bin
Published: July 2024

Electrocatalytic semihydrogenation of acetylene (C2H2) provides a facile and petroleum-independent strategy for ethylene (C2H4) production. However, the reliance on the preseparation and concentration of raw coal-derived C2H2 hinders its economic potential. Here, a concave surface is predicted to be beneficial for enriching C2H2 and optimizing its mass transfer kinetics, thus leading to a high partial pressure of C2H2 around active sites for the direct conversion of raw coal-derived C2H2. Then, a porous concave carbon-supported Cu nanoparticle (Cu-PCC) electrode is designed to enrich the C2H2 gas around the Cu sites. As a result, the as-prepared electrode enables a 91.7% C2H4 Faradaic efficiency and a 56.31% C2H2 single-pass conversion under a simulated raw coal-derived C2H2 atmosphere (~15%) at a partial current density of 0.42 A cm−2, greatly outperforming its counterpart without concave surface supports. The strengthened intermolecular π conjugation caused by the increased C2H2 coverage is revealed to result in the delocalization of π electrons in C2H2, consequently promoting C2H2 activation, suppressing hydrogen evolution competition and enhancing C2H4 selectivity.
Transient shuttle for a widespread neural probe with minimal perturbation
Authors: Roh Yeonwook , Kim Hyeongseok , Kim Eun-A , Ji Kyungbin , Kang Minji , Gong Dohyeon , Im Sunghoon , Hong Insic , Park Jieun , Park Soo Jung , Bae Yiseul , Park Jae-Il , Koh Je-Sung , Han Seungyong , Lee Eun Jeong , Kang Daeshik
Published: July 2024

Bioelectronic implants in the deep brain provide the opportunity to monitor deep brain activity with potential applications in disease diagnostics and treatment. However, mechanical mismatch between a probe and brain tissue can cause surgical trauma in the brain and limit chronic probe-based monitoring, leading to performance degradation. Here, we report a transient shuttle-based probe consisting of a PVA and a mesh-type probe. A rigid shuttle based on PVA implants an ultrathin mesh probe in the target deep brain without a tangle, while creating both a sharp edge for facile penetration into the brain and an anti-friction layer between the probe and brain tissue through dissolving its surface. The capability to shuttle dissolved materials can exclude the retracted process of the shuttle in the brain. Complete dissolution of the shuttle provides a dramatic decrease (~1078-fold) in the stiffness of the probe, which can therefore chronically monitor a wide area of the brain. These results indicate the ability to use a simplistic design for implantation of wide and deep brain probes while preventing unnecessary damage to the brain and probe degradation during long-term use.
Reassortment incompetent live attenuated and replicon influenza vaccines provide improved protection against influenza in piglets
Authors: Graaf-Rau Annika , Schmies Kathrin , Breithaupt Angele , Ciminski Kevin , Zimmer Gert , Summerfield Artur , Sehl-Ewert Julia , Lillie-Jaschniski Kathrin , Helmer Carina , Bielenberg Wiebke , grosse Beilage Elisabeth , Schwemmle Martin , Beer Martin , Harder Timm
Published: July 2024

Swine influenza A viruses (swIAV) cause an economically important respiratory disease in modern pig production. Continuous virus transmission and antigenic drift are difficult to control in enzootically infected pig herds. Here, antibody-positive piglets from a herd enzootically infected with swIAV H1N2 (clade 1 A.3.3.2) were immunized using a homologous prime-boost vaccination strategy with novel live attenuated influenza virus (LAIV) based on a reassortment-incompetent bat influenza-swIAV chimera or a vesicular stomatitis virus-based replicon vaccine. Challenge infection of vaccinated piglets by exposure to H1N2 swIAV-infected unvaccinated seeder pigs showed that both LAIV and replicon vaccine markedly reduced virus replication in the upper and lower respiratory tract, respectively, compared to piglets immunized with commercial heterologous or autologous adjuvanted whole-inactivated virus vaccines. Our novel vaccines may aid in interrupting continuous IAV transmission chains in large enzootically infected pig herds, improve the health status of the animals, and reduce the risk of zoonotic swIAV transmission.
Towards an Interoperability Landscape for a National Research Data Infrastructure for Personal Health Data
Authors: Vorisek Carina Nina , Klopfenstein Sophie Anne Inès , Löbe Matthias , Schmidt Carsten Oliver , Mayer Paula Josephine , Golebiewski Martin , Thun Sylvia
Published: July 2024

The German initiative “National Research Data Infrastructure for Personal Health Data” (NFDI4Health) focuses on research data management in health research. It aims to foster and develop harmonized informatics standards for public health, epidemiological studies, and clinical trials, facilitating access to relevant data and metadata standards. This publication lists syntactic and semantic data standards of potential use for NFDI4Health and beyond, based on interdisciplinary meetings and workshops, mappings of study questionnaires and the NFDI4Health metadata schema, and literature search. Included are 7 syntactic, 32 semantic and 9 combined syntactic and semantic standards. In addition, 101 ISO Standards from ISO/TC 215 Health Informatics and ISO/TC 276 Biotechnology could be identified as being potentially relevant. The work emphasizes the utilization of standards for epidemiological and health research data ensuring interoperability as well as the compatibility to NFDI4Health, its use cases, and to (inter-)national efforts within these sectors. The goal is to foster collaborative and inter-sectoral work in health research and initiate a debate around the potential of using common standards.
A high-quality chromosome-level genome assembly of the endangered tree Kmeria septentrionalis
Authors: Shi Chen-Yu , Qin Guo-Le , Qin Ying-Can , Lu Lin-Yuan , Guan De-Long , Gao Li-Xia
Published: July 2024

Kmeria septentrionalis is a critically endangered tree endemic to Guangxi, China, and is listed on the International Union for Conservation of Nature’s Red List. The lack of genetic information and high-quality genome data has hindered conservation efforts and studies on this species. In this study, we present a chromosome-level genome assembly of K. septentrionalis. The genome was initially assembled to be 2.57 Gb, with a contig N50 of 11.93 Mb. Hi-C guided genome assembly allowed us to anchor 98.83% of the total length of the initial contigs onto 19 pseudochromosomes, resulting in a scaffold N50 of 135.08 Mb. The final chromosome-level genome, spaning 2.54 Gb, achieved a BUSCO completeness of 98.9% and contained 1.67 Gb repetitive elements and 35,927 coding genes. This high-quality genome assembly provides a valuable resource for understanding the genetic basis of conservation-related traits and biological properties of this endangered tree species. Furthermore, it lays a critical foundation for evolutionary studies within the Magnoliaceae family.
Asymptomatic malaria and predictors among migrant farmworkers East Shewa zone Oromia Ethiopia
Authors: Legesse Gudeta , Tafesse Weynshet , Kenea Dagaga , Subussa Bereket Wake , Alemayehu Gezahegn Solomon , Kebede Tadesse , Golassa Lemu , Ali Musa Mohammed , Hailu Asrat
Published: July 2024

Asymptomatic malaria can impact existing malaria control and elimination efforts around the world, particularly in Africa, where the majority of malaria cases and death occurs. This is a cross-sectional study aimed to determine the prevalence and predictors of asymptomatic malaria among migrant farmworkers from June to July 2020 in the Upper Awash Agro-industry, East Shewa zone, Oromia Regional State, Ethiopia. A total of 254 migrant farmworkers without signs and symptoms of malaria were enrolled. Data on socio-demographic characteristics and malaria prevention practices were obtained through a structured questionnaire. Venous blood samples were collected and diagnosed using microscopy, rapid diagnostic tests, and polymerase chain reaction (PCR). Data were coded, entered, and analyzed using SPSS version-21 statistical software. Multivariable logistic regression was used to assess associated factors. A p < 0.05 was considered statistically significant. The overall prevalence of asymptomatic malaria among farmworkers in this study was 5.1% [95% CI 1.6, 6.7]. The proportions of Plasmodium falciparum was 90.0% (9/10) while it was 10.0% (1/10) for Plasmodium vivax. Out of the microscopy and/or RDT-confirmed malaria cases, (n = 9; 100%) were confirmed to be P. falciparum by nested PCR, while (n = 3/122; 2.46%) were found to be P. falciparum among 50% negative cases with the microscopy and/or RDT. The gametocyte stage was detected in 40% of microscopically positive cases out of which 44.4% belongs to P. falciparum. Home area/origin of migrant laborers [AOR = 6.08, (95% CI 1.08, 34.66)], family history of malaria [AOR = 8.15, (95% CI 1.43, 46.44)], and outdoor sleeping [AOR = 10.14, (95% CI 1.15, 89.14)] were significantly associated with asymptomatic malaria. In conclusion, asymptomatic malaria was detected among farmworkers in the study area and it was significantly associated with outdoor sleeping, home area, and family history of malaria. Prevention tools and control strategies, particularly focusing on migrant farmworkers, should be considered to support the ongoing malaria control and elimination effort in Ethiopia.
Breast cancer, viruses, and human leukocyte antigen (HLA)
Authors: James Lisa M. , Georgopoulos Apostolos P.
Published: July 2024

Several viruses have been implicated in breast cancer, including human herpes virus 4 (HHV4), human herpes virus 5 (HHV5), human papilloma virus (HPV), human JC polyoma virus (JCV), human endogenous retrovirus group K (HERVK), bovine leukemia virus (BLV) and mouse mammary tumor virus (MMTV). Human leukocyte antigen (HLA) is involved in virus elimination and has been shown to influence breast cancer protection/susceptibility. Here we investigated the hypothesis that the contribution of a virus to development of breast cancer would depend on the presence of the virus, which, in turn, would be inversely related to the success of its elimination. For that purpose, we estimated in silico predicted binding affinities (PBA) of proteins of the 7 viruses above to 127 common HLA alleles (69 Class I [HLA-I] and 58 Class II HLA-II]) and investigated the association of these binding affinities to the breast cancer—HLA (BC-HLA) immunogenetic profile of the same alleles. Using hierarchical tree clustering, we found that, for HLA-I, viruses BLV, JCV and MMTV were grouped with the BC-HLA, whereas, for HLA-II, viruses BLV, HERVK, HPV, JCV, and MMTV were grouped with BC-HLA. Finally, for both HLA classes, the average PBAs of the viruses grouped with the BC-HLA profile were significantly lower than those of the other, non BC-HLA associated viruses. Assuming that low PBAs are likely associated with slower viral elimination, these findings support the hypothesis that a defective/slower elimination and, hence, longer persistence and inefficient/delayed production of antibodies against them underlies the observed association of the low-PBA group with breast cancer.
Role of serum complement C3 and C4 on kidney outcomes in IgA nephropathy
Authors: Tringali Edoardo , Vetrano Daniele , Tondolo Francesco , Maritati Federica , Fabbrizio Benedetta , Pasquinelli Gianandrea , Provenzano Michele , La Manna Gaetano , Baraldi Olga
Published: July 2024

IgA Nephropathy (IgAN) is the most prevalent glomerular disease worldwide. Complement system activation is crucial in its pathogenesis. Few studies correlated serum C3 and C4 with disease activity and prognosis. This retrospective study investigated the prognostic value of serum complement at the time of diagnosis in patients with IgAN. Specifically we evaluated whether adding serum C3 and C4 levels to established predictive models-one based on variables related to chronic kidney disease (CKD) progression and another incorporating variables from the International IgA Prediction Tool (IntIgAPT)-enhances the accuracy of outcome prediction. A composite renal outcome was defined as 50% decline in eGFR or onset of kidney failure. 101 patients were stratified according to baseline C3 levels in three groups (Low, Medium and High). During a median follow-up of 54 months, the Low group exhibited higher incidence of primary outcome (16.3 events vs 2.9 and 1.7 events × 100 pts/year, p = 0.0026). Model-1 (M1), consisting of CKD progression variables, and Model-3 (M3), comprising IntIgANPT variables, were implemented with baseline C3 and C4 to create Model-2 (M2) and Model-4 (M4), respectively. M2 demonstrated better predictive performance over M1, showing higher discrimination (lower AIC and BIC, higher C-index and NR2). Similarly, M4 outperformed M3, showing enhanced outcome prediction when C3 and C4 levels were added. Implementation of serum C3 and C4 can enhance prediction accuracy of already-validated prognostic models in IgAN. Lower C3 and higher C4 levels were associated with poorer prognosis, highlighting a more 'Complement-Pathic' subset of patients.
A comprehensive analysis of germline predisposition to early-onset ovarian cancer
Authors: Horackova Klara , Zemankova Petra , Nehasil Petr , Vocka Michal , Hovhannisyan Milena , Matejkova Katerina , Janatova Marketa , Cerna Marta , Kleiblova Petra , Jelinkova Sandra , Stastna Barbora , Just Pavel , Dolezalova Tatana , Nemcova Barbora , Urbanova Marketa , Koudova Monika , Hazova Jana , Machackova Eva , Foretova Lenka , Stranecky Viktor , Zikan Michal , Kleibl Zdenek , Soukupova Jana
Published: July 2024

The subset of ovarian cancer (OC) diagnosed ≤ 30yo represents a distinct subgroup exhibiting disparities from late-onset OC in many aspects, including indefinite germline cancer predisposition. We performed DNA/RNA-WES with HLA-typing, PRS assessment and survival analysis in 123 early-onset OC-patients compared to histology/stage-matched late-onset and unselected OC-patients, and population-matched controls. Only 6/123(4.9%) early-onset OC-patients carried a germline pathogenic variant (GPV) in high-penetrance OC-predisposition genes. Nevertheless, our comprehensive germline analysis of early-onset OC-patients revealed two divergent trajectories of potential germline susceptibility. Firstly, overrepresentation analysis highlighted a connection to breast cancer (BC) that was supported by the CHEK2 GPV enrichment in early-onset OC(p = 1.2 × 10–4), and the presumably BC-specific PRS313, which successfully stratified early-onset OC-patients from controls(p = 0.03). The second avenue pointed towards the impaired immune response, indicated by LY75-CD302 GPV(p = 8.3 × 10–4) and diminished HLA diversity compared with controls(p = 3 × 10–7). Furthermore, we found a significantly higher overall GPV burden in early-onset OC-patients compared to controls(p = 3.8 × 10–4). The genetic predisposition to early-onset OC appears to be a heterogeneous and complex process that goes beyond the traditional Mendelian monogenic understanding of hereditary cancer predisposition, with a significant role of the immune system. We speculate that rather a cumulative overall GPV burden than specific GPV may potentially increase OC risk, concomitantly with reduced HLA diversity.
Green method for 17-hydroxyprogesterone extraction and determination using PDMS stir bar sorptive extraction coupled with HPLC: optimization by response surface methodology
Authors: Noori Maedeh , Talebpour Zahra
Published: July 2024

Quantifying small amounts of the 17-hydroxyprogesterone in various matrix is crucial for different purposes. In this study, a commercial polydimethylsiloxane stir bar was used to extract hormone from water and urine samples. Analysis was performed by high-performance liquid chromatography using a UV detector. The response surface methodology was used to optimize the desorption and extraction steps, with predicted optimal point relative errors of 1.25% and 6.40%, respectively. The optimized method was validated with a linear range of 1.21–1000.00 for aqueous and 2.43–2000.00 ng mL–1 for urine samples. The coefficient of determination was 0.9998 and 0.9967, and the detection limit of the proposed method was obtained to be 0.40 and 0.80 ng mL–1 for aqueous and urine samples, respectively. The recovery percentage and relative standard deviation within a day and between three days after the addition of three different concentration levels of the standard to the control sample were 87–103% and 0.4–3.6% for aqueous and 87.5–101% and 0.1–5.2% for urine samples, respectively. The results show that the proposed method can be appropriate and cost-effective for extracting and analyzing this hormone. In addition, using three different tools, the greenness of the proposed method was proven.
Effects of different afforestation years on soil moisture and nutrient content in Maxian Mountain of the Loess Plateau
Authors: Mao Liang , Miao Yugu , Ge Yiru , Wei Shaochong , Yang Xuanyi , Li Shijie , Si Li , Gou Yu-Ping , Quandahor Peter
Published: July 2024

In the area of “returning farmland to forest” on the Loess Plateau in China, it is difficult to cultivate artificially planted trees into forests. In the current study, abandoned cultivated land after 10 years of natural restoration served as controls (CK), while the treatments included afforestation periods of 2, 4, 6, 8, and 10 years. Soil samples were collected from various depths: 0–20, 20–40, 40–60, 60–80, to 80–100 cm. The findings revealed that with increasing years of artificial afforestation, soil pH gradually increased, and soil moisture content rose in the 0–20 cm layer while declining in deeper layers (20–100 cm) in the Maxian Mountain region of the Loess Plateau. Moreover, the total carbon, nitrogen, phosphorus, and potassium content initially increased and then decreased with the duration of artificial afforestation, reaching peak values after 8 years. Contents of organic matter, ammonium nitrogen, nitrate nitrogen, available phosphorus, and available potassium in the same soil layer increased with each year of afforestation. However, upon reaching 10 years of artificial afforestation, the effective nutrient content in the 60–80 and 80–100 cm soil layers exhibited a decrease. The values of Integrated Fertility Index (IFI) in different afforestation years were ranked as follows: 8 years > 6 years > 10 years > 4 years > 2 year, but all of them were significantly smaller than those of natural restoration plot CK (P < 0.05). Overall, soil fertility in the Maxian Mountain area of the Loess Plateau increases with each additional year of artificial afforestation. However, when the artificial afforestation period is 10 years, soil fertility decreases and marking a shift from enhancement to decline beyond this duration.