bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical implications of changes in metabolic syndrome status after kidney transplantation: a nationwide prospective cohort study
Authors: Lee Yu Ho , Song Sang Heon , Song Seung Hwan , Shin Ho Sik , Yang Jaeseok , Kim Myoung Soo , Hwang Hyeon Seok ,   the KOTRY Study Group, Ahn Curie , Yang Jaeseok , Kong Jin Min , Kwon Oh Jung , Kim Deok Gie , Jung Cheol-Woong , Kim Yeong Hoon , Kim Joong Kyung , Kim Chan-Duck , Min Ji Won , Park Sung Kwang , Park Yeon Ho , Berm Park Jae , Park Jung Hwan , Park Jong-Won , Ban Tae Hyun , Song Sang Heon , Song Seung Hwan , Shin Ho Sik , Yang Chul Woo , Yoon Hye Eun , Lee Kang Wook , Lee Dong Ryeol , Lee Dong Won , Lee Sam Yeol , Lee Sang-Ho , Lee Su Hyung , Lee Jung Jun , Lee Jung Pyo , Lee Jeong-Hoon , Jeon Jin Seok , Jun Heungman , Jeong Kyung Hwan , Chung Ku Yong , Cho Hong Rae , Ki Ju Man , Chae Dong-Wan , Choi Soo Jin Na , Han Duck Jong , Han Seungyeup , Ha Kyu
Published: May 2023

Background

Metabolic syndrome (MetS) is prevalent in patients with end-stage kidney disease, and kidney transplantation is expected to modify the metabolic status. However, whether changes in metabolic status at the time of transplantation affect recipient outcomes remains unclear.

Methods

We analyzed 4187 recipients registered in a nationwide prospective cohort from 2014 to 2020. MetS was defined as the presence of three or more components of the metabolic syndrome. Patients were classified based on the pre- and post-transplant MetS status: MetS-free, MetS-developed, MetS-recovered and MetS-persistent. Study outcomes were occurrence of death-censored graft loss and a composite of cardiovascular events and death.

Results

Among recipients without pre-transplant MetS, 19.6% (419/2135) developed post-transplant MetS, and MetS disappeared in 38.7% (794/2052) of the recipients with pre-transplant MetS. Among the four groups, the MetS-developed group showed the worst graft survival rate, and the MetS-persistent group had a poorer composite event-free survival rate. Compared with the MetS-free group, the MetS-developed group was associated with an increased risk of graft loss [adjusted hazard ratio (aHR) 2.35; 95% confidence interval (CI) 1.17–4.98] and the risk of graft loss increased with increasing numbers of dysfunctional MetS components. MetS-persistent was associated with increased risks of cardiovascular events and death (aHR 2.46; 95% CI 1.12–5.63), but changes in the number of dysfunctional MetS components was not.

Conclusion

Kidney transplantation significantly alters the metabolic status. Newly developed MetS after transplantation was associated with an increased risk of graft loss, whereas persistent MetS exposure before and after transplantation was associated with increased risks cardiovascular events and patient survival.
Reducing meat and/or dairy consumption in adults: a systematic review and meta-analysis of effects on protein intake, anthropometric values, and body composition
Authors: Habumugisha Theogene , Engebretsen Ingunn Marie Stadskleiv , Måren Inger Elisabeth , Kaiser Carl Walter Matthias , Dierkes Jutta
Published: May 2023

Context

Consumers are increasingly encouraged to reduce meat and dairy consumption. However, few meta-analyses of randomized controlled trials (RCTs) on the effect of reducing meat and/or dairy on (absolute) protein intake, anthropometric values, and body composition are available.

Objective

The aim of this systematic review and meta-analysis was to evaluate the effect of reducing meat and/or dairy consumption on (absolute) protein intake, anthropometric values, and body composition in adults aged ≥ 45 years.

Data Sources

The MEDLINE, Cochrane CENTRAL, Embase, ClinicalTrials.gov, and International Clinical Trials Registry Platform databases were searched up to November 24, 2021.

Data Extraction

Randomized controlled trials reporting protein intake, anthropometric values, and body composition were included.

Data Analysis

Data were pooled using random-effects models and expressed as the mean difference (MD) with 95%CI. Heterogeneity was assessed and quantified using Cochran’s Q and I2 statistics. In total, 19 RCTs with a median duration of 12 weeks (range, 4–24 weeks) and a total enrollment of 1475 participants were included. Participants who consumed meat- and/or dairy-reduced diets had a significantly lower protein intake than those who consumed control diets (9 RCTs; MD, −14 g/d; 95%CI, −20 to −8; I2 = 81%). Reducing meat and/or dairy consumption had no significant effect on body weight (14 RCTs; MD, −1.2 kg; 95%CI, −3 to 0.7; I2 = 12%), body mass index (13 RCTs; MD, −0.3 kg/m2; 95%CI, −1 to 0.4; I2 = 34%), waist circumference (9 RCTs; MD, −0.5 cm; 95%CI, −2.1 to 1.1; I2 = 26%), amount of body fat (8 RCTs; MD, −1.0 kg; 95%CI, −3.0 to 1.0; I2 = 48%), or lean body mass (9 RCTs; MD, −0.4 kg; 95%CI, −1.5 to 0.7; I2 = 0%).

Conclusion

Reduction of meat and/or dairy appears to reduce protein intake. There is no evidence of a significant impact on anthropometric values or body composition. More long-term intervention studies with defined amounts of meat and dairy are needed to investigate the long-term effects on nutrient intakes and health outcomes.

Systematic Review Registration

PROSPERO registration no. CRD42020207325.
Economic Consequences of Kinship: Evidence From U.S. Bans on Cousin Marriage
Authors: Ghosh Arkadev , Hwang Sam Il Myoung , Squires Munir
Published: May 2023

Close-kin marriage, by sustaining tightly knit family structures, may impede development. We find support for this hypothesis using U.S. state bans on cousin marriage. Our measure of cousin marriage comes from the excess frequency of same-surname marriages, a method borrowed from population genetics that we apply to millions of marriage records from the eighteenth to the twentieth century. Using census data, we first show that married cousins are more rural and have lower-paying occupations. We then turn to an event study analysis to understand how cousin marriage bans affected outcomes for treated birth cohorts. We find that these bans led individuals from families with high rates of cousin marriage to migrate off farms and into urban areas. They also gradually shift to higher-paying occupations. We observe increased dispersion, with individuals from these families living in a wider range of locations and adopting more diverse occupations. Our findings suggest that these changes were driven by the social and cultural effects of dispersed family ties rather than genetics. Notably, the bans also caused more people to live in institutional settings for the elderly, infirm, or destitute, suggesting weaker support from kin.
Labor Market Dynamics and Development
Authors: Donovan Kevin , Lu Will Jianyu , Schoellman Todd
Published: May 2023

We provide new evidence on how labor market dynamics vary with development. We build a new data set consisting of harmonized microdata from rotating panel labor force surveys covering 80 million people from 49 countries. Labor market flows, such as the job-finding or employment exit rate, are higher in developing economies. These higher flows largely reflect a slippery job ladder: workers transition frequently to and from marginal employment without climbing to or persisting in better-paying jobs. Subsistence self-employment and different patterns of selection for wage workers each play a role in our findings and are useful avenues for future theories of labor market frictions.
Search Frictions and Efficiency in Decentralized Transport Markets
Authors: Brancaccio Giulia , Kalouptsidi Myrto , Papageorgiou Theodore , Rosaia Nicola
Published: May 2023

We explore efficiency and optimal policy in decentralized transport markets, such as taxis, trucks, and bulk shipping. We show that in these markets, search frictions distort the transportation network and the dynamic allocation of carriers over space. We derive explicit and intuitive conditions for efficiency and show how they translate into efficient pricing rules, or optimal taxes and subsidies for the planner who cannot set prices directly. The results imply that destination-based pricing is essential to attain efficiency. Then, using data from dry bulk shipping, we demonstrate that search frictions lead to a sizable social loss and substantial misallocation of ships over space. Optimal policy can eliminate about half of the welfare loss. Can a centralizing platform, often arising as a market-based solution to search frictions, do better? Interestingly, the answer is no; although the platform eradicates frictions, it exerts market power, thus eroding the welfare gains. Finally, we use two recent interventions in the industry (China’s Belt and Road Initiative and the environmental initiative IMO 2020) to demonstrate that taking into account the efficiency properties of transport markets is germane to any proposed policy.
Exclusion of older adults from randomized controlled trials in rheumatoid arthritis
Authors: Mańko Anna , Raczkiewicz Anna , Górski Andrzej , Borysowski Jan , Wiland Piotr
Published: May 2023

Objectives

To assess eligibility criteria that either explicitly or implicitly exclude older patients from randomized controlled trials (RCTs) in RA.

Methods

Our analysis included RCTs of pharmacological interventions registered with ClinicalTrials.gov and started between 2013 and 2022. Co-primary outcomes were proportions of trials with an upper age limit and the eligibility criteria indirectly increasing risk of the exclusion of older adults.

Results

A total of 143/290 (49%) trials had an upper age limit of 85 years or less. Multivariable analysis showed that the odds of an upper age limit were significantly lower in trials performed in the USA [adjusted odds ratio (aOR), 0.34; CI, 0.12–0.99; P = 0.04] and intercontinental trials (aOR, 0.4; CI, 0.18–0.87; P = 0.02). In total, 154/290 (53%) trials had at least one eligibility criterion implicitly excluding older adults. These included specific comorbidities (n = 114; 39%), compliance concerns (n = 67; 23%), and broad and vague exclusion criteria (n = 57; 20%); however, we found no significant associations between these criteria and trial characteristics. Overall, 217 (75%) trials either explicitly or implicitly excluded older patients; we also noted a trend towards increasing proportion of these trials over time. Only one trial (0.3%) enrolled solely patients aged 65 and older.

Conclusion

Older adults are commonly excluded from RCTs in RA based on both age limits and other eligibility criteria. This seriously limits the evidence base for the treatment of older patients in clinical practice. Given the growing prevalence of RA in older adults, relevant RCTs should be more inclusive to them.
Close to me but unreachable: spotting the link between peripersonal space and empathy
Authors: Schiano Lomoriello Arianna , Cantoni Chiara , Ferrari Pier Francesco , Sessa Paola
Published: May 2023

The space surrounding the body [i.e. peripersonal space (PPS)] has a crucial impact on individuals’ interactions with the environment. Research showed that the interaction within the PPS increases individuals’ behavioral and neural responses. Furthermore, individuals’ empathy is affected by the distance between them and the observed stimuli. This study investigated empathic responses to painfully stimulated or gently touched faces presented within the PPS depending on the presence vs absence of a transparent barrier erected to prevent the interaction. To this aim, participants had to determine whether faces were painfully stimulated or gently touched, while their electroencephalographic signals were recorded. Brain activity [i.e. event-related potentials (ERPs) and source activations] was separately compared for the two types of stimuli (i.e. gently touched vs painfully stimulated faces) across two barrier conditions: (i) no-barrier between participants and the screen (i.e. no-barrier) and (ii) a plexiglass barrier erected between participants and the screen (i.e. barrier). While the barrier did not affect performance behaviorally, it reduced cortical activation at both the ERP and source activation levels in brain areas that regulate the interpersonal interaction (i.e. primary, somatosensory, premotor cortices and inferior frontal gyrus). These findings suggest that the barrier, precluding the possibility of interacting, reduced the observer’s empathy.
Promising or Predatory? Online Education in Non-Profit and For-Profit Universities
Authors: Smith Christian Michael , Villalobos Amber D , Hamilton Laura T , Eaton Charlie
Published: May 2023

Online education is a rapidly growing segment of the postsecondary system, and recent growth is concentrated at non-profit universities. Research shows that Black and low-income students are disproportionately represented in online programs; however, research on the outcomes of exclusively online education, especially at four-year non-profit universities, has been limited. Two narratives have emerged about the consequences of the access that online education provides: one describing it as promising and the other describing it as predatory. We harness both institution-level data and individual-level data to intervene in this debate. We show that online education is related to worse educational outcomes in non-profit and for-profit sectors, including lower retention and graduation rates. A sensitivity analysis suggests that selection into online education is unlikely to explain these results. Attending online is also related to some less desirable student loan repayment outcomes across sectors. Our results suggest that online education is a form of “predatory inclusion,” in that access is coupled with increased risks for students relative to comparable peers attending in-person. In light of our findings, we propose that the provision of online education by for-profit entities—even in the non-profit sector—may play a central role in producing poor student outcomes.
The prediction model of the aortic bifurcation
Authors: Khamanarong Kimaporn , Amnatbuddee Siriruthai , Sae-Jung Surachai , Mahiphot Jarupon , Chaisiwamongkol Kowit
Published: May 2023

  

Key Findings: The aortic bifurcation can be predetermined using the prediction model. The left common iliac artery (LCIA) was longer, more vertical, and closer to the lumbar spine than the right common iliac artery (RCIA). The formula of the diameter of the aorta, RCIA and LCIA is file:///C:/Users/ortho/AppData/Local/Temp/msohtmlclip1/01/clip_image002.png (D, diameter; a, aorta; r, RCIA; l, LCIA). The formula for the angle of aortic bifurcation is file:///C:/Users/ortho/AppData/Local/Temp/msohtmlclip1/01/clip_image004.png. Surgeons can use these formulas to predict and solve the problem when dealing with these arteries.
Acute Bilateral Dislocation of the Temporomandibular Joint With Left Old Zygomaticomaxillary Complex Fracture Treated With Coronoidectomy Authors
Authors: Song Baixuan , Du Zhaojie , Shao Xiaojun
Published: May 2023

The majority of various types of temporomandibular joint dislocation can be easily reduced to normal position through nontraumatic procedures. We present a rare case of temporomandibular joint dislocation with a left old zygomaticomaxoid complex fracture in a 48-year-old hemiplegic male. Due to the lock-in state of dislocated coronoid process and deformed zygomaticomaxoid complex, this type of dislocation combined with an old fracture is rare and difficult to reduce with conservative therapy. Therefore, coronoidectomy was performed to release the lock and reduce the condylar.
Liquid-liquid extraction of lipidated peptides for direct identification of lipidation sites
Authors: Tsumagari Kazuya , Isobe Yosuke , Ishihama Yasushi , Seita Jun , Arita Makoto , Imami Koshi
Published: May 2023

Proteins can be modified by lipids in various ways, for example by myristoylation, palmitoylation, farnesylation, and geranylgeranylation—these processes are collectively referred to as lipidation. Current chemical proteomics using alkyne lipids has enabled the identification of lipidated protein candidates but does not identify endogenous lipidation sites and is not readily applicable toin vivosystems. Here, we introduce a proteomic methodology for global analyses of endogenous lipidation sites that combines liquid-liquid extraction of hydrophobic lipidated peptides with liquid chromatography-tandem mass spectrometry using a gradient program of acetonitrile in the high concentration range. We applied this method to explore lipidation sites in HeLa cells, and identified a total of 90 lipidation sites, including 75 protein N-terminal myristoylation sites, which is more than the number of high-confidence lipidated proteins identified by myristic acid analog-based chemical proteomics. Isolation of lipidated peptides from digests prepared with different proteases enabled the identification of different lipidated sites, extending the coverage. Moreover, our peptide-centric approach successfully identified dually modified peptides having myristoylation and palmitoylation. Finally, we analyzedin vivomyristoylation sites in mouse tissues and found that the lipidation profile is tissue-specific. This simple method (not requiring chemical labeling or affinity purification) should be a promising tool for global profiling of various protein lipidations.
Unveiling the three-step model for the interaction of imidazolium-based ionic liquids on albumin
Authors: Raw Juliana , Franco Leandro R. , Rodrigues Luiz Fernando de C. , Barbosa Leandro R. S.
Published: May 2023

The effect of the ionic liquids (ILs) 1-methyl-3-tetradecyl imidazolium chloride ([C14MIM][Cl]), 1-dodecyl-3-methylimidazolium chloride ([C12MIM][Cl]) and 1-decyl-methylimidazolium chloride ([C10MIM][Cl]) on the structure of bovine serum albumin (BSA) was investigated by fluorescence spectroscopic, UV-Vis spectroscopy, small an-gle X-ray scattering and molecular dynamics simulations. Concerning the fluorescence measurements, we observed a blue shift and a fluorescence quenching as IL concen-tration increased in the solution. Such behavior was observed for all three studied imidazolium-based IL, being larger as the number of methylene groups in the alkyl chain grew. UV-Vis absorbance measurements indicate that even at relatively small IL:protein ratios, like 1:1, or 1:2 ([C14MIM][Cl]) is able to change, at least partially, the sample turbidity. SAXS results agree with the spectroscopic techniques and sug-gest that the proteins underwent a partial unfolding, evidenced by an increase in the radius of gyration (Rg) of the scattering particle. In the absence and presence of ([C14MIM][Cl])=3mM BSARg, increases from 29.1 to 45.1 Å, respectively. Together, these results indicate that the interaction of BSA with IL is divided into three stages: the first stage is characterized by the protein in its native form. It takes place for IL:protein≤1:2 and the interaction is predominantly due to the electrostatic forces, provided by the negative charges on the surface of the BSA and the cationic polar head of the ILs. In the second stage, higher IL concentrations induce the unfolding of the protein, most likely inducing the unfolding of domains I and III, in such a way that the protein’s secondary structure is kept almost unaltered. In the last stage, IL micelles start to form and, therefore, interaction with protein reaches a saturation point and free micelles may be formed. We believe this work provides new information about the interaction of ILs with BSA.

Graphical Abstract
Urinary protein changes during the short-term growth and development of rats
Authors: Liu Yuqing , Yang Minhui , Wang Haitong , Chen Yuzhen , Gao Youhe
Published: May 2023

Can the urine proteome reflect short-term changes in the growth and development of animals? Do short-term developmental effects on urinary protein need to be considered when performing urine marker studies using model animals with faster growing periods? In this study, urine samples were collected from 10 Wistar rats aged 6-8 weeks 3 and 6 days apart. The results showed that the urine proteome could sensitively reflect short-term growth and development in rats. For example, comparing the urine proteome of Day 0 and Day 6, 195 differential proteins were identified after screening (FC ≥ 1.5 or ≤ 0.67, P < 0.05), and verified by randomization, the average number of randomly generated differential proteins was 17.99. At least 90.77% of the differential proteins were not randomly generated. This finding demonstrates that the differential proteins identified in the samples collected at different time points were not randomly generated. A large number of biological processes and pathways related to growth and development were enriched, which shows that the urine proteome reflects the short-term growth and development of rats, and provides a means for in-depth and meticulous study of growth and development. Moreover, an interfering factor in animal experiments using 6-to 8-week-old rats to construct models was identified. The results of this study demonstrated that there were differences in the urinary proteome in rats aged 6-8 weeks only 3-6 days apart, which suggests that the sensitivity of urinary proteomics is high and shows the sensitive and precise response of the urinary proteome to body changes.
Differential correction of gender imbalance for top-cited scientists across scientific subfields over time
Authors: Ioannidis John P.A. , Boyack Kevin W. , Collins Thomas A. , Baas Jeroen
Published: May 2023

We evaluated how the gender composition of top-cited authors within different subfields of research has evolved over time. We considered 9,071,122 authors with at least 5 full papers in Scopus as of September 1, 2022. Using a previously validated composite citation indicator, we identified the 2% top-cited authors for each of 174 science subfields (Science-Metrix classification) in 4 separate publication age cohorts (first publication pre-1992, 1992-2001, 2002-2011, post-2011). Using NamSor we assigned 3,784,507 authors as men, and 2,011,616 as women (for 36.1% gender assignment uncertain). Men outnumbered women 1.88-fold among all authors, decreasing from 3.93-fold to 1.36-fold over time. Men outnumbered women 3.21-fold among top-cited authors, decreasing from 6.41-fold to 2.28-fold over time. In the youngest (post-2011) cohort, 32/174 (18%) subfields had >=50% women, 97/174 (56%) subfields had >=30% women, and 3 subfields had =<10% women among the top-cited authors. Gender imbalances in author numbers decreased sharply over time in both high-income countries (including the USA) and other countries, but the latter had little improvement in gender imbalances for top-cited authors. In random samples of 100 women and 100 men from the youngest (post-2011) cohort, in-depth assessment showed that most were currently (April 2023) working in academic environments. 32 women and 44 men had some faculty appointment, but only 2 women and 2 men were full professors. Our analysis shows large heterogeneity across scientific disciplines in the amelioration of gender imbalances with more prominent imbalances persisting among top-cited authors and slow promotion pathways even for the most-cited young scientists.
Sequences at gene segment termini inclusive of untranslated regions and partial open reading frames play a critical role in mammalian orthoreovirus S gene packaging
Authors: Dhar Debarpan , Mehanovic Samir , Moss Walter , Miller Cathy L.
Published: May 2023

Mammalian orthoreovirus (MRV) is a prototypic member of theSpinareoviridaefamily and has ten double-stranded RNA segments. One copy of each segment must be faithfully packaged into the mature virion, and prior literature suggests that nucleotides (nts) at the terminal ends of each gene likely facilitate their packaging. However, little is known about the precise packaging sequences required or how the packaging process is coordinated. Using a novel approach, we have determined that 200 nts at each terminus, inclusive of untranslated regions (UTR) and parts of the open reading frame (ORF), are sufficient for packaging each S gene segment (S1-S4) individually and together into replicating virus. Further, we mapped the minimal sequences required for packaging the S1 gene segment to 25 5′ nts and 50 3′ nts. The S1 UTRs alone are not sufficient, but are necessary for packaging, as mutations of the 5′ or 3′ UTRs led to a complete loss of virus recovery. Using a second novel assay, we determined that 50 5′nts and 50 3′ nts of S1 are sufficient to package a non-viral gene segment into MRV. The 5′ and 3′ termini of the S1 gene are predicted to form a panhandle structure and specific mutations within the predicted stem of the panhandle region led to a significant decrease in viral recovery. Additionally, mutation of six nts that are conserved in the three major serotypes of MRV and are predicted to form an unpaired loop in the S1 3′UTR, led to a complete loss of viral recovery. Overall, our data provide strong experimental proof that MRV packaging signals lie at the terminal ends of the S gene segments and offer support that the sequence requirements for efficient packaging of the S1 segment include a predicted panhandle structure and specific sequences within an unpaired loop in the 3′ UTR.
Structure-Activity Relationship Study Identifies a Novel Lipophilic Amiloride Derivative that Efficiently Kills Chemoresistant Breast Cancer Cells
Authors: Hu Michelle , Liu Ruiwu , Castro Noemi , Sanchez Liliana Loza , Learn Julie , Huang Ruiqi , Lam Kit S. , Carraway Kermit L.
Published: May 2023

Derivatives of the potassium-sparing diuretic amiloride are preferentially cytotoxic toward tumor cells relative to normal cells, and have the capacity to target tumor cell populations resistant to currently employed therapeutic agents. However, a major barrier to clinical translation of the amilorides is their modest cytotoxic potency, with estimated IC50values in the high micromolar range. Here we report the synthesis of ten novel amiloride derivatives and the characterization of their cytotoxic potency toward MCF7 (ER/PR-positive), SKBR3 (HER2-positive) and MDA-MB-231 (triple negative) cell line models of breast cancer. Comparisons of derivative structure with cytotoxic potency toward these cell lines underscore the importance of an intact guanidine group, and uncover a strong link between drug-induced cytotoxicity and drug lipophilicity. We demonstrate that our most potent derivative called LLC1 is preferentially cytotoxic toward mouse mammary tumor over normal epithelial organoids, acts in the single digit micromolar range on breast cancer cell line models representing all major subtypes, acts on cell lines that exhibit both transient and sustained resistance to chemotherapeutic agents, but exhibits limited anti-tumor effects in a mouse model of metastatic breast cancer. Nonetheless, our observations offer a roadmap for the future optimization of amiloride-based compounds with preferential cytotoxicity toward breast tumor cells.
Mapping memories: pulse-chase labeling reveals AMPA receptor dynamics during memory formation
Authors: Kim Doyeon , Park Pojeong , Li Xiuyuan , Campos J. David Wong , Tian He , Moult Eric M. , Grimm Jonathan B. , Lavis Luke , Cohen Adam E.
Published: May 2023

A tool to map changes in synaptic strength during a defined time window could provide powerful insights into the mechanisms governing learning and memory. We developed a technique, Extracellular Protein Surface Labeling in Neurons (EPSILON), to map α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) insertionin vivoby pulse-chase labeling of surface AMPARs with membrane-impermeable dyes. This approach allows for single-synapse resolution maps of plasticity in genetically targeted neurons during memory formation. We investigated the relationship between synapse-level and cell-level memory encodings by mapping synaptic plasticity and cFos expression in hippocampal CA1 pyramidal cells upon contextual fear conditioning (CFC). We observed a strong correlation between synaptic plasticity and cFos expression, suggesting a synaptic mechanism for the association of cFos expression with memory engrams. The EPSILON technique is a useful tool for mapping synaptic plasticity and may be extended to investigate trafficking of other transmembrane proteins.
DNA replication is not a limiting factor for rapid growth ofVibrio natriegens
Authors: Ramming Lea , Stukenberg Daniel , Sánchez Olmos María del Carmen , Becker Anke , Schindler Daniel
Published: May 2023

DNA replication prior to cell division is essential for the proliferation of all cells. Bacterial chromosomes are replicated bidirectionally from a single origin of replication, with replication proceeding at about 1000 bp per second. For the best-studied model organism,Escherichia coli, this translates into a replication time of about 40 min for its 4.6 Mb chromosome. Nevertheless,E. colican propagate by overlapping replication cycles with a maximum short doubling time of 20 min. The fastest growing bacterium known today,Vibrio natriegens, is able to replicate with a generation time of less than 10 min. It has a bipartite genome with chromosome sizes of 3.2 and 1.9 Mb. Is simultaneous replication from two origins a prerequisite for its rapid growth? We fused the two chromosomes ofV. natriegensto create a strain carrying a 5.2 Mb chromosome with a single origin of replication. Compared to the wild-type, this strain showed little deviation in growth rate. This suggests that the split genome is not a prerequisite for rapid growth, and that DNA replication is not an important growth rate-limiting factor.
MINI-AC: Inference of plant gene regulatory networks using bulk or single-cell accessible chromatin profiles
Authors: Manosalva Pérez Nicolás , Ferrari Camilla , Engelhorn Julia , Depuydt Thomas , Nelissen Hilde , Hartwig Thomas , Vandepoele Klaas
Published: May 2023

Gene regulatory networks (GRNs) represent the interactions between transcription factors (TF) and their target genes. GRNs control transcriptional programs involved in growth, development and stress responses, ultimately affecting diverse agricultural traits. While recent developments in accessible chromatin (AC) profiling technologies make it possible to identify context-specific regulatory DNA, learning the underlying GRNs remains a major challenge. We developed MINI-AC (Motif-Informed Network Inference based on Accessible Chromatin), a method that combines AC data from bulk or single-cell experiments with TF binding site information to learn GRNs in plants. We benchmarked MINI-AC using bulk AC datasets from differentArabidopsis thalianatissues and showed that it outperforms other methods to identify correct TFs binding sites. In maize, a crop with a complex genome and abundant distal AC regions, MINI-AC successfully inferred leaf GRNs with experimentally confirmed, both proximal and distal, TF-target gene interactions. Furthermore, we showed that both AC regions and footprints are valid alternatives to infer AC-based GRNs with MINI-AC. Finally, we combined MINI-AC predictions from bulk and single-cell AC datasets to identify general and cell-type specific maize leaf regulators. Focusing on C4 metabolism, we identified diverse regulatory interactions in specialized cell types for this photosynthetic pathway. MINI-AC represents a powerful tool for inferring accurate AC-derived GRNs in plants and identifying known and novel candidate regulators, improving our understanding of gene regulation in plants.
Low soil moisture induces recruitment of Actinobacteria in the rhizosphere of a drought-sensitive and Rhizobiales in a drought-tolerant potato cultivar
Authors: Martins Benoit R. , Siani Roberto , Treder Krzysztof , Michałowska Dorota , Radl Viviane , Pritsch Karin , Schloter Michael
Published: May 2023

Growing evidence suggests that soil microbes can improve plant fitness under drought. However, in potato, the world’s most important non-cereal crop, the role of the rhizosphere microbiome under drought has been poorly studied. Using a cultivation independent metabarcoding approach, we examined the rhizosphere microbiome of two potato cultivars with different drought tolerance as a function of water regime (continuous versus reduced watering) and manipulation of soil microbial diversity (i.e., natural (NSM), vs. disturbed (DSM) soil microbiome). Water regime and soil pre-treatment showed a significant interaction with bacterial community composition of the drought-sensitive (HERBST) but not the drought-resistant cultivar (MONI). Depending on the cultivar, different taxa responded to reduced watering. Under NSM conditions, these were mostly rhizobiales order representative in MONI, andStreptomyces,Glycomyces,Marmoricola,Aeromicrobium,Mycobacterium, amongst Actinobacteriota, and the root endophytic fungusFalciphorain HERBST. Under DSM conditions and reduced watering,Bradyrhizobium,Ammoniphilus,Symbiobacteriumand unclassified Hydrogenedensaceae responded in the rhizosphere of MONI compared to the continuous, while in HERBST, fewer taxa of Actinobacteriota and no fungi responded to reduced vs. continuous watering. Overall, our results indicate a strong cultivar specific relationship between potato and their associated rhizosphere microbiomes under reduced soil moisture.
Histone lactylation antagonizes senescence and skeletal muscle aging via facilitating gene expression reprogramming
Authors: Zhang Xuebin , Meng Fanju , Lyu Wencong , He Jianuo , Wei Ran , Du Zhehao , Zhang Chao , Guan Yiting , Huang Xiaoke , Lyu Guoliang , Tian Xiao-Li , Zhang Lijun , Tao Wei
Published: May 2023

One of the prominent drivers of cellular senescence and/or aging is epigenetic alteration, through which orchestrated regulation of gene expression is achieved during the processes. Accumulating endeavors have been devoted to identifying histone modifications-related mechanisms underlying senescence and aging. Here, we show that histone lactylation, a recently identified histone modification bridging metabolism, epigenetic regulation of gene expression and cellular activities in response to internal and external cues, plays a crucial role in counteracting senescence as well as mitigating dysfunctions of skeletal muscle in aged mice. Mechanistically, the abundance of histone lactylation is markedly decreased during senescence and aging but restored following manipulation of the metabolic environment. Genome-wide distribution profiling and gene expression network analysis uncover that the maintenance of histone lactylation level is critical for suppressing senescence and aging programs via targeting of proliferation- and homeostasis-related pathways. We also confirmed that the level of histone lactylation is not only controlled by glycolysis but also regulated by NAD+contentin vivo. More intriguingly, running exercise enhances the level of histone lactylation and reconstructs the cell landscape and communications of mouse skeletal muscle, leading to rejuvenation and functional improvement. Our study highlights the role of histone lactylation in regulating senescence as well as aging-related tissue function, implying that this modification could be used as a novel marker of senescence, and provides a potential target for aging intervention via metabolic manipulation.
Pan-tissue Transcriptome Analysis Reveals Sex-dimorphic Human Aging
Authors: Wang Siqi , Dong Danyue , Li Xin , Wang Zefeng
Published: May 2023

Complex diseases often exhibit sex-dimorphism in morbidity and prognosis, many of which are age-related. However, the underlying mechanisms of the sex-dimorphic aging remain foggy, with limited studies across multiple tissues. We systematically analyzed ∼17,000 transcriptomes from 35 human tissues to quantitatively evaluate the individual and combined contributions of sex and age to transcriptomic variations. We discovered extensive sex-dimorphisms during aging with distinct patterns of change in gene expression and alternative splicing (AS). Intriguingly, the male-biased age-associated AS events have a stronger association with Alzheimer’s disease, and the females-biased events are often regulated by several sex-biased splicing factors that may be controlled by estrogen receptors. Breakpoint analysis showed sex-dimorphic aging rates that are significantly associated with decline of sex hormones, with males having a larger and earlier transcriptome change. Collectively, this study uncovered an essential role of sex during aging at the molecular and multi-tissue levels, providing insight into sex-dimorphic regulatory patterns.
Elucidating human ageing-related phenotypic abnormalities with a novel hierarchical feature selection-based knowledge discovery framework
Authors: Wan Cen , Barton Carl
Published: May 2023

Ageing is a complex biological process involving multiple genes that are also related to phenotypic abnormalities. However, the micro view of the associations between ageing and human phenotypic abnormalities is still under-studied. We propose a new hierarchical feature selection method namely HIP+, which selects positive hierarchical information-preserving features according to pre-defined hierarchical ontology information. The experimental results confirm that HIP+obtained better performance than the state-of-the-art hierarchical feature selection method in predicting human phenotypic abnormalities annotations. We further propose a HIP+-based knowledge discovery framework that also successfully highlights some important associations between biological processes and human phenotypic abnormalities.
Viral modulation of type II interferon increases T cell adhesion and virus spread
Authors: Jürgens Carina , Ssebyatika George , Beyer Sarah , Plückebaum Nina , Kropp Kai A. , González-Motos Víctor , Ritter Birgit , Böning Heike , Nikolouli Eirini , Kinchington Paul R. , Lachmann Nico , Depledge Daniel Pearce , Krey Thomas , Viejo-Borbolla Abel
Published: May 2023

During primary infection, varicella zoster virus (VZV) infects epithelial cells in the respiratory lymphoid organs and mucosa. Subsequent infection of lymphocytes, T cells in particular, causes primary viremia allowing systemic spread throughout the host, including the skin. This results in the expression of cytokines, including interferons (IFNs) which partly limit primary infection. VZV also spreads from skin keratinocytes to lymphocytes prior to secondary viremia. How VZV infects lymphocytes from epithelial cells while evading the cytokine response has not been fully established. Here, we show that VZV glycoprotein C (gC) binds IFN-γ and modifies its activity. Transcriptomic analysis revealed that gC in combination with IFN-γ increased the expression of a small subset of IFN-stimulated genes (ISGs), including intercellular adhesion molecule 1 (ICAM1), as well as several chemokines and immunomodulatory genes. The higher ICAM1 protein level at the plasma membrane of epithelial cells resulted in lymphocyte function-associated antigen 1 (LFA-1)-dependent T cell adhesion. This gC activity required a stable interaction with IFN-γ and signalling through the IFN-γ receptor. Finally, the presence of gC during infection increased VZV spread from epithelial cells to peripheral blood mononuclear cells. This constitutes the discovery of a novel strategy to modulate the activity of IFN-γ, inducing the expression of a subset of ISGs, leading to enhanced T cell adhesion and virus spread.
KMT2C knockout generates ASD-like behaviors in mice
Authors: Brauer Bastian , Merino-Veliz Nicolas , Ahumada Constanza , Arriagada Gloria , Bustos Fernando J
Published: May 2023

Neurodevelopmental disorders have been associated with genetic mutations that affect cellular function, including chromatin regulation and epigenetic modifications. Recent studies in humans have identified mutations in KMT2C, an enzyme responsible for modifying histone tails and depositing H3K4me1 and H3K4me3, as being associated with Kleefstra syndrome 2 and autism spectrum disorder (ASD). However, the precise role of KMT2C mutations in brain disorders remains poorly understood. Here we employed CRISPR/Cas9 gene editing to analyze the effects of KMT2C knockout on animal behavior. Knocking out KMT2C expression in cortical neurons and the mouse brain resulted in decreased KMT2C levels. Importantly, KMT2C knockout animals exhibited repetitive behaviors, social deficits, and intellectual disability resembling ASD. Our findings shed light on the involvement of KMT2C in neurodevelopmental processes and establish a valuable model for elucidating the cellular and molecular mechanisms underlying KMT2C mutations and their relationship to Kleefstra syndrome 2 and ASD.
Sequence-independent, site-specific incorporation of chemical modifications to generate light-activated plasmids
Authors: Chung Khoa , Booth Michael J.
Published: May 2023

Plasmids are ubiquitous in biology, where they are used to study gene-function relationships and intricate molecular networks, and hold potential as therapeutic devices. Developing methods to control their function will advance their application in research and may also expedite their translation to clinical settings. Light is an attractive stimulus to conditionally regulate plasmid expression as it is non-invasive, and its properties such as wavelength, intensity, and duration can be adjusted to minimise cellular toxicity and increase penetration. Herein, we have developed a method to site-specifically introduce photocages into plasmids, by resynthesizing one strand in a manner similar to Kunkel mutagenesis. Unlike alternative approaches to chemically-modify plasmids, this method is sequence independent at the site of modification and uses commercially available phosphoramidites. To generate our light-activated (LA) plasmids, photocleavable biotinylated nucleobases were introduced at specific sites across the T7 and CMV promoters on plasmids and bound to streptavidin to sterically block access. These LA-plasmids were then successfully used to control expression in both cell-free systems (T7 promoter) and mammalian cells (CMV promoter). These light-activated plasmids might be used to remotely-control cellular activity and reduce off-target toxicity for future medical use. Our simple approach to plasmid modification might also be used to introduce novel chemical moieties for advanced function.

Abstract Figure
The protein-bound uremic solute 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF) increases erythrocyte osmotic fragility through interaction with the mechanosensitive channel Piezo1
Authors: Kondo Van Spitzenbergen Beatriz Akemi , Bohnen Gabriela , Dias Erika Sousa , Monte Alegre Júlia B. , Ferreira Dias Gabriela , Grobe Nadja , Moreno-Amaral Andrea Novais , Kotanko Peter
Published: May 2023

Jedi1, a chemical activator of the mechanosensitive cation channel Piezo1, shares structural similarities with the uremic solute 3-carboxy-4-methyl-5-propyl-2-furanpropionate (CMPF). We explored the hypothesis that CMPF at a concentration seen in uremia activates Piezo1 located on red blood cells (RBC). We incubated RBC from five healthy individuals with either Jedi1 or CMPF (both 87 μM), with or without the Piezo1 inhibitor GsMTx-4 (2 μM), and quantified the cells’ osmotic fragility. Our results indicate that compared to controls (i.e., RBC incubated with buffer), both Jedi1 and CMPF increase the osmotic fragility of RBC (i.e., reduce their resistance to osmotic stress). Effects of Jedi1 and CMPF were reversed to the control level by GsMTx-4. These results indicate a role of Piezo1 in augmenting RBC osmotic fragility and modulation of this effect by Jedi1 and CMPF. Our findings open the possibility that CMPF may act as an endogenous chemical activator of Piezo1.
Self-Assembly of a Repeatable DNA Nanohinge System Supporting Higher Order Structure Formation
Authors: Law Melanie , Susham Charlie , Mackay David , Nguyen Stephanie , Nicholas Rachael , Tsai Miguel Roberto G. , Rajkumar Ethan , Inaba Fumiya , Maheden Kieran , Abdi Immanuel , Ho Joe C.H. , Kieft Brandon , Hallam Steven J.
Published: May 2023

DNA base pairs can both encode biological information and be used as a programmable material to build nanostructures with potential application in nanofabrication, data processing and storage, biosensing and drug delivery. Over several decades development of these DNA origami nanostructures has led to increasingly advanced self-assembling nanostructures and molecular machines actuated by various mechanisms such as toehold-mediated strand displacement (TMSD), magnetism and even light. However, scalability remains challenging as using larger scaffold strands can increase the likelihood of kinetic traps and misfolded conformations. Here we describe a repeatable DNA nanohinge system to increase the scalability of existing nanohinge designs for hierarchical assembly of more complex structures with greater degrees of mobility and functionality. The components of this system, comprising two distinct nanohinges, were designed in caDNAno. Structure conformation and stability were simulated using CanDo and MrDNA, and hinge assembly was validated by TEM. Electron micrographs revealed hinge-shaped nanostructures capable of self-assembly into more complex structures, as well as actuation using TMSD through a reversible locking mechanism incorporated into the design. Our work expands the existing utility of DNA nanohinges as building blocks for scalable DNA nanostructures and demonstrates the feasibility of polymerizing hinges in a novel manner for higher order assembly. The enhanced functionality of our dual hinge systems can be employed in future applications requiring greater control and mobility of DNA nanostructures.
Super-resolution imaging of neuronal structure with structured illumination microscopy
Authors: Paul Tristan C. , Johnson Karl A. , Hagen Guy M.
Published: May 2023

Super-resolution structured illumination microscopy (SR-SIM) is a method in optical fluorescence microscopy which is suitable for imaging a wide variety of cells and tissues in biological and biomedical research. Typically, SIM methods use high spatial frequency illumination patterns generated by laser interference. This approach provides high resolution but is limited to thin samples such as cultured cells. Using a different strategy for processing the raw data and coarser illumination patterns, we imaged through a 150 µm thick coronal section of a mouse brain expressing GFP in a subset of neurons. The resolution reached 144 nm, an improvement of 1.7 fold beyond conventional widefield imaging.
Low oscillatory shear stress regulates Weibel-Palade body size and vWF release
Authors: Money Ashley , Todd Harriet J , Jo Hanjoong , Beech David J , McKeown Lynn
Published: May 2023

Blood flow regulates vascular function by generating wall shear stress which impacts endothelial cell (EC) physiology. Whilst high laminar shear stress (HSS) maintains the functional integrity of the vasculature, low oscillatory shear stress (LOSS) evokes secretion of pro-thrombotic and pro-inflammatory components from ECs, thus promoting the development of cardiovascular disease (CVD). Pro-thrombotic and pro-inflammatory cargo are readily stored in endothelial-specific organelles termed Weibel-Palade bodies (WPBs). WPBs form purely due to the multimerization of the pro-thrombotic glycoprotein von Willebrand factor (vWF). Here we investigated if aberrant shear stress, induced by non-uniform oscillatory flow, modulates the biogenesis of WPBs, and the subsequent release of vWF. Ultimately, we demonstrate, using anin vitromodel, that LOSS has no effect on the level of vWF expression, however, LOSS promotes endothelial thrombotic potential by increasing WPB size, which impacts the length of the vWF strings that are released upon stimulation. Thus, wall shear stress can confer functional plasticity to WPBs by manipulating their biogenesis. Further understanding of the underlying mechanisms could aid generation of novel therapeutics in CVD.