bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of Postoperative Delirium With Incident Dementia and Graft Outcomes Among Kidney Transplant Recipients
Authors: Ruck Jessica M. , Chu Nadia M. , Liu Yi , Li Yiting , Chen Yusi , Mathur Aarti , Carlson Michelle C. , Crews Deidra C. , Chodosh Joshua , Segev Dorry L. , McAdams-DeMarco Mara
Published: August 2023

Background.

Kidney transplant (KT) recipients have numerous risk factors for delirium, including those shared with the general surgical population (eg, age and major surgery) and transplant-specific factors (eg, neurotoxic immunosuppression medications). Evidence has linked delirium to long-term dementia risk in older adults undergoing major surgery. We sought to characterize dementia risk associated with post-KT delirium.

Methods.

Using the United States Renal Data System datasets, we identified 35 800 adult first-time KT recipients ≥55 y. We evaluated risk factors for delirium using logistic regression. We evaluated the association between delirium and incident dementia (overall and by subtype: Alzheimer’s, vascular, and other/mixed-type), graft loss, and death using Fine and Gray’s subhazards models and Cox regression.

Results.

During the KT hospitalization, 0.9% of recipients were diagnosed with delirium. Delirium risk factors included age (OR = 1.40, 95% CI, 1.28-1.52) and diabetes (OR = 1.38, 95% CI, 1.10-1.73). Delirium was associated with higher risk of death-censored graft loss (aHR = 1.52, 95% CI, 1.12-2.05) and all-cause mortality (aHR = 1.53, 95% CI, 1.25-1.89) at 5 y post-KT. Delirium was also associated with higher risk of dementia (adjusted subhazard ratio [aSHR] = 4.59, 95% CI, 3.48-6.06), particularly vascular dementia (aSHR = 2.51, 95% CI, 1.01-6.25) and other/mixed-type dementia (aSHR = 5.58, 95% CI, 4.24-7.62) subtypes. The risk of all-type dementia associated with delirium was higher for younger recipients aged between 55 and 64 y (P
interaction = 0.01).

Conclusions.

Delirium is a strong risk factor for subsequent diagnosis of dementia among KT recipients, particularly those aged between 55 and 64 y at the time of transplant. Patients experiencing posttransplant delirium might benefit from early interventions to enhance cognitive health and surveillance for cognitive impairment to enable early referral for dementia care.
Calcineurin Inhibition in Deceased Organ Donors: A Systematic Review and Meta-analysis of Preclinical Studies
Authors: D’Aragon Frédérick , Rousseau William , Breau Ruth , Aminaei Daniel , Ichai Carole , Boyd Gordon J. , Burns Karen E. A. , Cardinal Héloïse , Carrier François-Martin , Chassé Michaël , Chaudhury Prosanto , Dhanani Sonny , English Shane W. , Frenette Anne Julie , Hanna Steven , Knoll Gregory , Lauzier François , Oczkowski Simon , Rochwerg Bram , Shamseddin Khaled , Slessarev Marat , Treleaven Darin , Turgeon Alexis F. , Weiss Matthew J. , Selzner Markus , Meade Maureen O.
Published: August 2023

Background.

Preconditioning deceased organ donors with calcineurin inhibitors (CNIs) may reduce ischemia–reperfusion injury to improve transplant outcomes.

Methods.

We searched MEDLINE, EMBASE, Cochrane Library, and conference proceedings for animal models of organ donation and transplantation, comparing donor treatment with CNIs with either placebo or no intervention, and evaluating outcomes for organ transplantation. Reviewers independently screened and selected studies, abstracted data, and assessed the risk of bias and clinical relevance of included studies. Where possible, we pooled results using meta-analysis; otherwise, we summarized findings descriptively.

Results.

Eighteen studies used various animals and a range of CNI agents and doses and evaluated their effects on a variety of transplant outcomes. The risk of bias and clinical applicability were poorly reported. Pooled analyses suggested benefit of CNI treatment on early graft function in renal transplants (3 studies; serum creatinine: ratio of means [RoM] 0.54; 95% confidence interval [CI], 0.34-0.86) but not for liver transplants (2 studies; serum alanine transaminase: RoM 0.61; 95% CI, 0.30-1.26; and serum aspartate aminotransferase: RoM 0.58; 95% CI, 0.26-1.31). We found no reduction in graft loss at 7 d (2 studies; risk ratio 0.54; 95% CI, 0.08-3.42). CNI treatment was associated with reduced transplant recipient levels of interleukin-6 (4 studies; RoM 0.36; 95% CI, 0.19-0.70), tumor necrosis factor-alpha (5 studies; RoM 0.36; 95% CI, 0.12-1.03), and cellular apoptosis (4 studies; RoM 0.30; 95% CI, 0.19-0.47).

Conclusions.

Although this compendium of animal experiments suggests that donor preconditioning with CNIs may improve early kidney graft function, the limited ability to reproduce a true clinical environment in animal experiments and to assess for risk of bias in these experiments is a serious weakness that precludes current clinical application.
John Robert Lawrence Allen. 25 October 1932—18 October 2020
Authors: Worsley Peter , Bell Martin , Fulford Michael
Published: August 2023

John Allen was one of the leading British geologists of the late twentieth century, who changed his primary research focus in mid career from clastic sedimentology to geoarchaeology. He read for a BSc degree in geology at the University of Sheffield, graduating with first class honours in 1955. He continued at Sheffield as a postgraduate student researching the geology of the Old Red Sandstone of the Clee Hills in Shropshire, but never submitted a PhD thesis. However, in 1958 the University of Reading offered him a research fellowship to investigate the geology of the hydrocarbon-rich River Niger delta region. In 1961 he became a lecturer in geology and a member of the new purpose-built Sedimentology Research Laboratory at Reading. The international renown of the laboratory was largely based on his prodigious sedimentological research output relating to sedimentary structures, river and coastal environments and Devonian continental deposits. He was appointed reader in 1967 and professor in 1972. In 1974 he led the founding of a taught MSc course in ‘Sedimentology and its applications’, which soon became a world leader. In 1988, in the context of the rationalization of university geology departments, Reading's department was selected for closure. However, John Allen's research esteem was such that a special case was made and a postgraduate-only institute specializing in sedimentology was established with him as director. He resigned the directorship after five years in favour of a research professorship. His objectives changed from orthodox old-rock studies to research on recent muddy estuarine sediments. By selecting the estuary of the River Severn as his new field area, he soon realized that this opened up a rich area of collaboration with colleagues in archaeology. His geological skills were subsequently applied to a range of archaeological problems. He became a key contributor to a new MSc degree course in geoarchaeology.
A unifying mechanism for protein transport through the core bacterial Sec machinery
Authors: Allen William J. , Collinson Ian
Published: August 2023

Encapsulation and compartmentalization are fundamental to the evolution of cellular life, but they also pose a challenge: how to partition the molecules that perform biological functions—the proteins—across impermeable barriers into sub-cellular organelles, and to the outside. The solution lies in the evolution of specialized machines, translocons, found in every biological membrane, which act both as gate and gatekeeper across and into membrane bilayers. Understanding how these translocons operate at the molecular level has been a long-standing ambition of cell biology, and one that is approaching its denouement; particularly in the case of the ubiquitous Sec system. In this review, we highlight the fruits of recent game-changing technical innovations in structural biology, biophysics and biochemistry to present a largely complete mechanism for the bacterial version of the core Sec machinery. We discuss the merits of our model over alternative proposals and identify the remaining open questions. The template laid out by the study of the Sec system will be of immense value for probing the many other translocons found in diverse biological membranes, towards the ultimate goal of altering or impeding their functions for pharmaceutical or biotechnological purposes.
Bacillus thuringiensisbioinsecticide influencesDrosophilaoviposition decision
Authors: Babin Aurélie , Gatti Jean-Luc , Poirié Marylène
Published: August 2023

Behavioural avoidance has obvious benefits for animals facing environmental stressors such as pathogen-contaminated foods. Most current bioinsecticides are based on the environmental and opportunistic bacteriumBacillus thuringiensis(Bt) that kills targeted insect pests upon ingestion. While food and oviposition avoidance ofBtbioinsecticide by targeted insect species was reported, this remained to be addressed in non-target organisms, especially those affected by chronic exposure toBtbioinsecticide such asDrosophilaspecies. Here, using a two-choice oviposition test, we showed that female flies of threeDrosophilaspecies (four strains ofD. melanogaster,D. busckiiandD. suzukii) avoided laying eggs in the presence ofBtvar.kurstakibioinsecticide, with potential benefits for the offspring and female's fitness. Avoidance occurred rapidly, regardless of the fraction of the bioinsecticide suspension (spores and toxin crystals versus soluble toxins/compounds) and independently of the female motivation for egg laying. Our results suggest that, in addition to recent findings of developmental and physiological alterations upon chronic exposure to non-targetDrosophila, this bioinsecticide may modify the competitive interactions betweenDrosophilaspecies in treated areas and the interactions with their associated natural enemies.
On the scope of scientific hypotheses
Authors: Thompson William Hedley , Skau Simon
Published: August 2023

Hypotheses are frequently the starting point when undertaking the empirical portion of the scientific process. They state something that the scientific process will attempt to evaluate, corroborate, verify or falsify. Their purpose is to guide the types of data we collect, analyses we conduct, and inferences we would like to make. Over the last decade, metascience has advocated for hypotheses being in preregistrations or registered reports, but how to formulate these hypotheses has received less attention. Here, we argue that hypotheses can vary in specificity along at least three independent dimensions: the relationship, the variables, and the pipeline. Together, these dimensions form the scope of the hypothesis. We demonstrate how narrowing the scope of a hypothesis in any of these three ways reduces the hypothesis space and that this reduction is a type of novelty. Finally, we discuss how this formulation of hypotheses can guide researchers to formulate the appropriate scope for their hypotheses and should aim for neither too broad nor too narrow a scope. This framework can guide hypothesis-makers when formulating their hypotheses by helping clarify what is being tested, chaining results to previous known findings, and demarcating what is explicitly tested in the hypothesis.
Prediction of the next major outbreak of COVID-19 in Mainland China and a vaccination strategy for it
Authors: Wu Yuanyuan , Zhou Weike , Tang Sanyi , Cheke Robert A. , Wang Xia
Published: August 2023

After the widespread prevalence of COVID-19 at the end of 2022 in Mainland China, a major concern is when will the second major outbreak occur and with what prevalence and fatality rates will it be associated with, as peoples' immunity from natural infection subsides. To address this, we established an age-structured model considering vaccine and infection-derived immunity, fitted an immunity-waning curve, and calibrated the model using the epidemic and vaccination data from Hong Kong in 2022. The model and the situation of the first major epidemic in Mainland China were then used to predict the prevalence rate, fatality rate and peak time of the second wave. In addition, the controlling effects of different vaccination strategies on the second major outbreak are discussed. Finally, a characterization indicator for the level of population immunity was provided. We conclude that if the prevalence of the first major epidemic was 80%, the prevalence rate of the second major outbreak would be about 37.64%, and the peak time would have been July 2 2023. Strengthening vaccination can effectively delay the peak of the second wave of the epidemic and reduce the prevalence.
Enhancing energy absorption through sequential instabilities in mechanical metamaterials
Authors: Bekele Adam , Wadee M. Ahmer , Phillips Andrew T. M.
Published: August 2023

Structural components designed to absorb energy and shield a more valuable structure ideally require mechanical properties that combine a relatively high load-carrying capacity followed by a practically zero stiffness. This ensures that a specified energy quantity may be absorbed within a limited displacement and that any stress transfer to the valuable structure is minimized. Material damage has been historically mobilized to provide such properties, but this obviously renders such components to be single-use. By contrast, mobilization of elastic instability can also provide the desired combination of properties but without necessarily damaging the material. This reveals an intriguing possibility of such components being potentially repairable and theoretically re-usable with no significant loss in performance. A series of analytical, finite-element and experimental studies are presented for a bespoke mechanical metamaterial arrangement that is designed to buckle sequentially and behave with the desired ‘high strength–low stiffness’ characteristic. It is found that the various axial and rotational stiffnesses associated with the geometric arrangement and its constituent connections may be tuned to provide the desired mechanical behaviour within the elastic range and delay the onset of significant damage, thereby rendering the concept of harnessing instability to be feasible.
Bourbon virus, a newly discovered zoonotic thogotovirus
Authors: Bendl Elias , Fuchs Jonas , Kochs Georg
Published: August 2023

The recent discovery of Bourbon virus (BRBV) put a new focus on the genus of thogotoviruses as zoonotic, tick-transmitted pathogens within the orthomyxovirus family. Since 2014, BRBV has been linked to several human cases in the Midwest United States with severe acute febrile illness and a history of tick bites. The detection of the virus in the Lone Star tick, Amblyomma americanum, and a high sero-prevalence in wild animals suggest widespread circulation of BRBV. Phylogenetic analysis of the viral RNA genome classified BRBV into the subgroup of Dhori-like thogotoviruses. Strikingly, BRBV is apathogenic in mice, contrasting not only with the fatal disease in affected patients but also with the severe disease in mice caused by other members of the thogotovirus genus. To gain insights into this intriguing discrepancy, we will review the molecular biology and pathology of BRBV and its unique position within the thogotovirus genus. Lastly, we will discuss the zoonotic threat posed by this newly discovered pathogen.
Cell–cell communication in African trypanosomes
Authors: McWilliam K. R.
Published: August 2023

Years of research have shown us that unicellular organisms do not exist entirely in isolation, but rather that they are capable of an altogether far more sociable way of living. Single cells produce, receive and interpret signals, coordinating and changing their behaviour according to the information received. Although this cell–cell communication has long been considered the norm in the bacterial world, an increasing body of knowledge is demonstrating that single-celled eukaryotic parasites also maintain active social lives. This communication can drive parasite development, facilitate the invasion of new niches and, ultimately, influence infection outcome. In this review, I present the evidence for cell–cell communication during the life cycle of the African trypanosomes, from their mammalian hosts to their insect vectors, and reflect on the many remaining unanswered questions in this fascinating field.
Clinical Utility of EsoGuard® as an Efficient Triage Test for Diagnosing Barrett’s Esophagus in On-Duty Firefighters
Authors: Hamblin Rachelle , Lee Victoria T. , deGuzman Brian J. , Verma Suman , Aklog Lishan
Published: August 2023

Background

Firefighters have frequent exposure to compounds shown to increase risk of esophageal neoplasia. EsoGuard® (EG) is a DNA biomarker assay that can be utilized with efficiency and high tolerability as a triage to endoscopy for diagnosis of patients with Barrett’s Esophagus (BE), a known precursor to esophageal adenocarcinoma (EAC). This diagnostic tool may facilitate disease testing among busy at-risk firefighters.

Methods

Retrospective analysis of prospectively collected clinical utility (CU) data for use of EG as a triage to more invasive endoscopic evaluation. EG was performed on esophageal cell samples collected with the nonendoscopic EsoCheck® (EC) device during two large cancer and pre-cancer screening events for firefighters in San Antonio, TX, in January 2023. CU was evaluated by provider impact assessment.

Results

388 firefighters were identified for EG testing, of which >99% (385/388) successfully completed EC cell collection. Over 96% (372/385) of tests had binary results; the remaining <4% failed analysis due to insufficient DNA. The EG positivity rate was 7.3% (28/385), all of whom were referred for specialist and upper endoscopy evaluation. Among those who tested negative, none were referred for further diagnostic workup. This represented a 100% concordance between EG results and physician management decisions.

Conclusions

This study capturing real-world data on use of EG in a population of firefighters demonstrates its ability to test many individuals rapidly and efficiently in a well-tolerated fashion, and reliable use of the test to triage individuals prior to pursuing more invasive and time-consuming diagnostic approaches.
Developing tree improvement strategies for challenging environmental stresses under global climate change: a review from traditional tree breeding to genomics of adaptive traits for the quaking aspen
Authors: Mu Deyu , Ding Chen , Chen Hao , Li Yang , Raley Earl M. (Fred)
Published: August 2023

Quaking or trembling aspen in North America and Euro-Asia(Populus tremuloidesandP. tremula,respectively) are both widely distributed species with a long history of scientific research and tree improvement work in areas such as carbon sequestration, biomass, bioenergy, wood, and fiber, as well as studies evaluating the social, economic, and ecological benefits of the species. This chapter reviews the ecological genetics and genomics of quaking aspen’s adaptive traits with a broad perspective of the relationship between phenotypic variation and genetic (G) and environmental (E) effects as well as their interactions (GxE). Based on recent studies, several adaptive traits are discussed, including spring and fall phenology and stress tolerance to environmental factors such as frost, salinity, drought, heat, UV radiation, etc. We also conducted a meta-analysis of empirical studies on adaptive traits ofP. tremuloidesand its sister species, as research usingP. tremuloidesas a true “model species” is currently limited. However, molecular tools and experimental designs in the form of different common gardens constitute an integrated pathway for the development of traits and varieties/populations to promote reforestation under changing climatic conditions.
Learning with filopodia and spines
Authors: Albesa-González Albert , Clopath Claudia
Published: August 2023

Filopodia are thin synaptic protrusions that have been long known to play an important role in early development. It has recently been found that they are more abundant in the adult cortex than previously thought, and more plastic than spines (button-shaped mature synapses). Inspired by these findings, we introduce a new model of synaptic plasticity that jointly describes learning of filopodia and spines. The model assumes that filopodia exhibit additive learning, which is highly competitive and volatile. At the same time, it proposes that if filopodia undergo sufficient potentiation they consolidate into spines, and start following multiplicative learning dynamics. This makes spines more stable and sensitive to the fine structure of input correlations. We show that our learning rule has a selectivity comparable to additive spike-timing-dependent plasticity (STDP) and represents input correlations as well as multiplicative STDP. We also show how it can protect previously formed memories and act as a synaptic consolidation mechanism. Overall, our results provide a mechanistic explanation of how filopodia and spines could cooperate to overcome the difficulties that these separate forms of learning (additive and multiplicative) each have.

Author Summary

Changes in the strength of synaptic connections between neurons are the basis of learning in biological and artificial networks. In animals, these changes can only depend on locally available signals, and are usually modeled withlearning rules. Based on recent discoveries onfilopodia, a special type of synaptic structure, we propose a new learning rule called Filopodium-Spine spike-timing-dependent-plasticity. Our rule proposes that filopodia follow additive STDP and spines (mature synapses) multiplicative STDP. We show that our model overcomes classic difficulties that these learning rules have separately, like the absence of stability or specificity, and can also be seen as a first stage of synaptic consolidation.
Adaptive Artificial Intelligence to Teach Interactive Molecular Dynamics in the Context of Human-Computer Interaction
Authors: Demir Mustafa , Leahy Sean M. , Mishra Punya , Chen Chun Kit , Singharoy Abhishek
Published: August 2023

Artificial Intelligence (AI) can be easily integrated into virtual education to drive adaptive instruction and real-time constructive feedback to students, offering a possible conduit for fostering discovery curiosity in learners. This study examines and characterizes Human-AI-Teaming (HAT) coordination dynamics to monitor the inception of discovery curiosity in online laboratories of interactive molecular dynamics (IMD). We used molecular physics measures (kinetic/ potential energy and action) obtained from simple and complex examples of simulated mouse tracking datasets in IMD log files as a proxy for understanding the context of molecular sciences and developing novel interactions for inquiry. These measures are good features of our HAT context because kinetic energy reflects the system’s atoms’ overall motion regarding the individual atoms’ speed. While kinetic energy represents if a learner applies artificial forces to the task, potential energy can be AI’s response to these forces. The action is a systems-level reaction to the changes during the task. By applying nonlinear dynamical systems methods to the physics measures, we extracted the Largest Lyapunov Exponent and Determinism metrics as HATs’ coordination stability and predictability, respectively. The findings underline that while the more complex IMD task required less stable and predictable HAT coordination dynamics, the simple task is more. One explanation is that AI needs to anticipate the learner by providing feedback at the right time and place during the more complex IMD task to initiate and sustain the learner’s discovery curiosity. In IMD, future HAT design should consider coordination dynamics for fostering ‘discovery curiosity’ and practical learning.
Travelling waves or sequentially activated discrete modules: mapping the granularity of cortical propagation
Authors: Orsher Yuval , Rom Ariel , Perel Rotem , Lahini Yoav , Blinder Pablo , Shein-Idelson Mark
Published: August 2023

Numerous studies have identified travelling waves in the cortex and suggested they play important roles in brain processing. These waves are most often measured using macroscopic methods that are unable to assess the local spiking activity underlying wave dynamics. Here we investigated the possibility that waves may not be travelling at the single neuron scale. We first show that sequentially activating two discrete brain areas can appear as travelling waves in EEG simulations. We next reproduce these results using an analytical model of two sequentially activated regions. Using this model, we were able to generate wave-like activity with variable directions, velocities, and spatial patterns, and to map the discriminability limits between travelling waves and modular sequential activations. Finally, we investigated the link between field potentials and single neuron excitability using large-scale measurements from turtle cortex ex-vivo. We found that while field potentials exhibit wave-like dynamics, the underlying spiking activity was better described by consecutively activated spatially adjacent groups of neurons. Taken together, this study suggests caution when interpreting phase delay measurements as continuously propagating wavefronts in two different spatial scales. A careful distinction between modular and wave excitability profiles across scales will be critical for understanding the nature of cortical computations.
Cell competition for cancer treatment with Urine Progenitor Cells
Authors: Bagó Juli R. , Radhakrishnan Dhwani , Hrdinka Matouš , Cichoń Tomasz , Smolarczyk Ryszard , Charvátová Sandra , Motais Benjamin , Giebel Sebastian , Hájek Roman
Published: August 2023

Here, we provide evidence that urine progenitor cells (UPCs) might offer a novel therapeutic strategy for treating different types of cancer. We found that UPCs have inherent antitumor properties due to cell-cell competition, and we described their mechanism of action against different tumor cell lines.In vitrotime-lapse analysis showed that the UPCs have tumor tropic properties, homing to various tumor-conditioned mediums. Besides, UPCs engineered for the expression of cytotoxic agents (the Tumor Necrosis Factor ligand superfamily member 10 and Herpesvirus-thymidine kinase) significantly increased their antitumor properties against several tumor cell lines and proved to serve as highly effective drug-delivery vehicles. Finally, using a mouse model of human triple-negative breast cancer, we observed a 150-fold decrease in tumor volumes in mice treated with engineered UPCs compared to controls. Collectively, our findings demonstrate for the first time the antitumor properties of the UPCs and form a foundation to continue exploring the new concept of cell-cell competition in progenitor cells to treat different types of cancer.
Functional annotation of a divergent genome using sequence and structure-based homology
Authors: Svedberg Dennis , Winiger Rahel R. , Berg Alexandra , Sharma Himanshu , Tellgren-Roth Christian , Debrunner-Vossbrinck Bettina A. , Vossbrinck Charles R. , Barandun Jonas
Published: August 2023

Background

Microsporidia are a large taxon of intracellular pathogens characterized by extraordinarily streamlined genomes with unusually high sequence divergence and many species-specific adaptations. These unique factors pose challenges for traditional genome annotation methods based on sequence homology. As a result, many of the microsporidian genomes sequenced to date contain numerous genes of unknown function. Recent innovations in rapid and accurate structure prediction and comparison, together with the growing amount of data in structural databases, provide new opportunities to assist in the functional annotation of newly sequenced genomes.

Results

In this study, we established a workflow that combines sequence and structure-based functional gene annotation approaches employing a ChimeraX plugin, allowing for visual inspection and manual curation. We employed this workflow on a high-quality telomere-to-telomere sequenced tetraploid genome ofVairimorpha necatrix. First, the 3080 predicted open reading frames, of which 89 % were confirmed with RNA sequencing data, were used as input. Next, ColabFold was used to create protein structure predictions, followed by a Foldseek search for structural matching to the PDB and AlphaFold databases. The subsequent manual curation, using sequence and structure-based hits, increased the accuracy and quality of the functional genome annotation compared to results using only traditional annotation tools. Our workflow resulted in a comprehensive description of theV. necatrixgenome, along with a structural summary of the most prevalent protein groups, such as the ricin B lectin family. In addition, and to test our tool, we identified the functions of several previously uncharacterizedEncephalitozoon cuniculigenes.

Conclusion

We provide a new functional annotation tool for divergent organisms and employ it on a newly sequenced, high-quality microsporidian genome to shed light on this uncharacterized intracellular pathogen of Lepidoptera. The addition of a structure-based annotation approach can serve as a valuable template for studying other microsporidian or similarly divergent species.
Prior Uncertainty Impedes Discrete Locomotor Adaptation
Authors: Jiang Aojun , Grover Francis M. , Bucklin Mary , Deol Jasjit , Shafer Anna , Gordon Keith E.
Published: August 2023

The impact of environmental uncertainty on locomotor adaptation remains unclear. Environmental uncertainty could either aid locomotor adaptation by prompting protective control strategies that stabilize movements to assist learning or impede adaptation by reducing error sensitivity and fostering hesitance to pursue corrective movements. To explore this, we investigated participants’ adaptation to a consistent viscous force field after experiencing environmental uncertainty in the form of unpredictable balance perturbations. We compared the performance of this group (Perturbation) to the adaptive performance of a Control group that did not experience any unpredictable perturbations. Perturbations were delivered using a cable-driven robotic device applying lateral forces to the pelvis. We assessed whole-body center of mass (COM) trajectory (COM signed deviation), anticipatory postural adjustments (COM lateral offset), and first step width. The Perturbation group exhibited larger disruptions in COM trajectory (greater COM signed deviations) than the Control group when first walking in the force field. While the COM signed deviations of both groups decreased towards baseline values, only the Control group returned to baseline levels. The Perturbation groups COM signed deviations remained higher, indicating they failed to fully adapt to the force field before the end. The Perturbation group also did not adapt their COM lateral offset to counter the predictable effects of the force field as the Control group did, and their first step width increased more slowly. Our findings suggest that exposure to unpredictable perturbations impeded future sensorimotor adaptations to consistent perturbations.
A novel, N2-fixing cyanobacterium present and active in the global oceans
Authors: Cleveland Catie S. , Turk-Kubo Kendra A. , Zhao Yiming , Zehr Jonathan P. , Webb Eric A.
Published: August 2023

Marine N2-fixing cyanobacteria, including the unicellular genusCrocosphaera, are considered keystone species in marine food webs.Crocosphaeraare globally distributed and provide new sources of nitrogen (N) and carbon (C), which fuel oligotrophic microbial communities and upper trophic levels. Despite their ecosystem importance, only one species,Crocosphaera watsonii, has ever been identified and characterized as widespread in the oligotrophic oceans. Herein, we present a novel species, candidatusCrocosphaera waterburyi(C. waterburyihereafter), enriched from the North Pacific Ocean, activein situ, and globally distributed in environmental datasets.C. waterburyiis morphologically, phylogenetically, and physiologically distinct fromC. watsonii; therefore, description of this novel species provides a new window into previously uncharacterized diversity and ecology of unicellular N2-fixing cyanobacterial taxa and further highlights their importance in the global N cycle.
Endothelial mechanobiology under controlled disturbed flows
Authors: Paddillaya Neha , Mahulkar Suyog , Arakeri Jaywant H , Gundiah Namrata
Published: August 2023

Early atherosclerotic lesions often develop in areas of disturbed flow within arterial curvatures and bifurcations. Complex flows alter the signaling of inflammatory and other signaling molecules that may exacerbate the disease phenotype. Microfluidic platforms to assess changes in endothelial mechanobiology generally employ laminar unidirectional or oscillatory flows generated in straight channels; such platforms do not however mimic the complex time-varying bi-directional shear patterns on arterial walls. We fabricated an endothelium-on-chip device to generate “controlled” disturbed flows, characterized using a wall shear rosette, such as those reported in aneurysmal vessels and in regions with atherosclerotic plaques. We cultured human aortic endothelial cells (HAEC) in the device and subjected the monolayer to a circular shear rosette which represents bidirectional and oscillatory shear stresses. Immunofluorescence results show large cuboidal cells with significantly higher nuclear areas, changes in the localization of VE-Cadherin, elevated actin and NF-kB expressions in the device as compared to cell monolayers subjected to laminar flow, unidirectional oscillatory flow, and No-flow conditions. The creation of a dysfunctional endothelial monolayer due to bidirectional oscillatory flows also correlated with dramatic changes to the lamin A/C distribution and heterochromatin organization in the nucleus that have not been reported earlier. Such studies are potentially useful to assess novel therapeutics, mitigate effects of vascular disease for personalized medicine, study thrombus creation in the vicinity of inflamed endothelial monolayers, and reduce ourreliance on animal trials. Our device and analytical method represent the first successful demonstration of generating controlled disturbed flows in microfluidic devices
Prolonged survival of a patient with active MDR-TB HIV co-morbidity: Insights from a Mycobacterium tuberculosis strain with a unique genomic deletion
Authors: Rubinstein Mor , Makhon Andrei , Losev Yelena , Valenci Gal Zizelski , Gatt Yair E. , Margalit Hanah , Fass Ephraim , Kutikov Ina , Murik Omer , Zeevi David A. , Savyon Michal , Tau Luba , Shwartz Hasia Kaidar , Dveyrin Zeev , Rorman Efrat , Nissan Israel
Published: August 2023

Coinfection of HIV and multidrug-resistant tuberculosis (MDR-TB) presents significant challenges in terms of the treatment and prognosis of tuberculosis, leading to complexities in managing the disease and impacting the overall outcome for TB patients. This study presents a remarkable case of a patient with MDR-TB and HIV coinfection who survived for over eight years, despite poor treatment adherence and comorbidities. Whole genome sequencing (WGS) of the infectingMycobacterium tuberculosis(Mtb) strain revealed a unique genomic deletion, spanning 18 genes, including key genes involved in hypoxia response, intracellular survival, immunodominant antigens and dormancy. This deletion, that we have called “Del-X”, potentially exerts a profound influence on the bacterial physiology and its virulence. Only few similar deletions were detected in other non-relatedMtbgenomes worldwide.In vivoevolution analysis identified drug resistance and metabolic adaptation mutations and their temporal dynamics during the patient’s treatment course.
A platform for standardized, online delivered, clinically applicable neurocognitive assessment: Webneuro
Authors: Williams Leanne M.
Published: August 2023

We are in the midst of a paradigm shift in which we see a precision mental health and the emergence of brain-based assessments for personalizing treatments. The precision emphasis of precision mental health includes a focus on measurement. Within the biopsychosocial domains of measurement, objective measures of cognitive function have an important role in disorders of mental health. Here, data integrating the development, norming, validation, psychometric testing and clinical application of a web-delivered neurocognitive assessment (WebNeuro) are presented. Data are from 1,000 healthy participants and over 500 clinical participants across diagnoses. Results provide norms across nine decades, and demonstrate the construct validity, internal consistency, and test-retest reliability of WebNeuro. Findings also show that WebNeuro identifies neurocognitive impairments across multiple neuropsychiatric disorders.
Brain-Derived CCN3 Is An Osteoanabolic Hormone That Sustains Bone in Lactating Females
Authors: Babey Muriel E. , Krause William C. , Herber Candice B. , Chen Kun , Nikkanen Joni , Rodriquez Ruben , Zhang Xiao , Castro-Navarro Fernanda , Wang Yuting , Villeda Saul , Lane Nancy E. , Scheller Erica L. , Chan Charles K.F. , Ambrosi Thomas H. , Ingraham Holly A.
Published: August 2023

In lactating mothers, the high calcium (Ca2+) demand for milk production triggers significant bone resorption. While estrogen would normally counteract excessive bone loss and maintain sufficient bone formation during this postpartum period, this sex steroid drops precipitously after giving birth. Here, we report that brain-derived CCN3 (Cellular Communication Network factor 3) secreted from KISS1 neurons of the arcuate nucleus (ARCKISS1) fills this void and functions as a potent osteoanabolic factor to promote bone mass in lactating females. Using parabiosis and bone transplant methods, we first established that a humoral factor accounts for the female-specific, high bone mass previously observed by our group after deleting estrogen receptor alpha (ERα) from ARCKISS1neurons1. This exceptional bone phenotype in mutant females can be traced back to skeletal stem cells (SSCs), as reflected by their increased frequency and osteochondrogenic potential. Based on multiple assays, CCN3 emerged as the most promising secreted pro-osteogenic factor from ARCKISS1neurons, acting on mouse and human SSCs at low subnanomolar concentrations independent of age or sex. That brain-derived CCN3 promotes bone formation was further confirmed by in vivo gain- and loss-of-function studies. Notably, a transient rise in CCN3 appears in ARCKISS1neurons in estrogen-depleted lactating females coincident with increased bone remodeling and high calcium demand. Our findings establish CCN3 as a potentially new therapeutic osteoanabolic hormone that defines a novel female-specific brain-bone axis for ensuring mammalian species survival.
Discovery and engineering of AiEvo2, a novel Cas12a nuclease for human gene editing applications
Authors: Sharrar Allison , Arake de Tacca Luisa , Meacham Zuriah , Staples-Ager Johanna , Collingwood Trevor , Rabuka David , Schelle Michael
Published: August 2023

The precision of gene editing technology is critical to creating safe and effective therapies for treating human disease. While the programmability of CRISPR-Cas systems has allowed for rapid innovation of new gene editing techniques, the off-target activity of these enzymes has hampered clinical development for novel therapeutics. Here we report the identification and characterization of a novel CRISPR-Cas12a enzyme fromAcinetobacter indicus(AiCas12a). We then engineer the nuclease (termed AiEvo2) for increased specificity, PAM recognition, and efficacy on a variety of human clinical targets. AiEvo2 is highly precise and able to efficiently discriminate between normal and disease-causing alleles in Huntington’s patient derived cells by taking advantage of a single nucleotide polymorphism on the disease-associated allele. AiEvo2 efficiently edits several liver-associated target genes including PCSK9 and TTR when delivered to primary hepatocytes as mRNA encapsulated in a lipid nanoparticle. The enzyme also engineers an effective CD19 CAR-T therapy from primary human T cells using multiplexed simultaneous editing and CAR insertion. To further ensure precise editing, we engineered an anti-CRISPR protein (ErAcr) to selectively inhibit off-target gene editing while retaining therapeutic on-target editing. The engineered AiEvo2 nuclease coupled with a novel ErAcr protein represents a new way to control the fidelity of editing and improve the safety and efficacy of gene editing therapies.
Dark adaptation is not necessary to drive the proliferative regeneration response in the adult zebrafish retina
Authors: Hemerson Marlo , Muhr Jeremy , Pferdmenges Lauren , Jiudice Sarah , Ackerman Kristin M.
Published: August 2023

Macular degeneration, retinal detachment, and retinitis pigmentosa are eye diseases which cause damage to the photoreceptors and are considered leading causes of vision loss worldwide (National Eye Institute, 2022). Thus, developing animal models to study processes related to retinal damage, specifically loss of photoreceptors and their pending degeneration/regeneration is critical. This study aims to modify current light-induced retinal degeneration (LIRD) protocols within the zebrafish model to more efficiently replicate the proliferative response that drives regeneration. The most common LIRD model incorporates a 10-14 day dark adaptation period followed by multiple days of constant intense light exposure designed to damage the retinas and induce a proliferation response (Thomas et al., 2012; Vihtelic & Hyde, 2000). Modified procedures have been published and demonstrate that shortened 24-hour dark adaptation periods still result in cellular damage via apoptosis, but the proliferation response (i.e., pending regeneration) was not examined (Khan et al., 2020). Therefore, our study aims to fully eliminate dark adaptation and will use changes in retinal morphology and proliferation as the hallmark of a successfully initiated regeneration response. Dark-adapted (DA-control fish) and non-dark-adapted (NDA-experimental fish) were taken off their housing system and exposed to constant intense light for 24, 36, and 48 hr. to ensure enough time for damage and proliferation to proceed. Retinas were cross-sectioned to include dorsal and ventral retina, immunohistochemically labeled, and the outer nuclear layer (ONL), inner nuclear layer (INL), cones, and proliferation cell nuclear antigen (PCNA)-positive cells were analyzed to determine the level of structural integrity, if cell photoreceptor numbers were altered, and if proliferation occurred in response to light exposure. Dark-adapted (DA) and non-dark-adapted (NDA) zebrafish retinas displayed similar damage and increased proliferation responses to the constant intense light, indicating that the 10–14-day dark adaptation period is not necessary to induce regeneration in adult zebrafish retinas, reducing experimental timing by two weeks.
MoMA: Large scale network model of Microbes, Metabolites and Aging hallmarks
Authors: Menon Sarvesh , Bapatdhar Nishad , Kumar Bipin Pradeep , Ghosh Samik
Published: August 2023

The gut microbiome is known to be a driver of age-related health decline. Various studies have shone light on the role of the gut microbiome as a marker as well as modulator of aging processes. However, the mechanisms by which the microbiome affects aging are still unclear. We have developed a Microbiome Metabolite Aging (MMA) fusion network by building upon a metabolic interaction network of gut microbiota to develop associations with the hallmarks of aging. The MMA, consisting of 238 metabolite-aging hallmark interactions serves as a tool to investigate the mammalian (and in particular human) gut microbiome as an effector of aging at a systems-level. The network further identifies 249 microbes that unequivocally affect the hallmarks of aging. The results highlight how the underlying biology of microbial metabolite mediated interactions, in conjunction with the topological properties at a network level, differentially regulate the aging hallmarks. This detailed microbial and metabolite association to the hallmarks of aging provides a foundation which is envisaged to be instrumental in advancing our knowledge of the physiology of aging, and for the development of novel therapeutic tools.
The utility of CRISPR activation as a platform to identify interferon stimulated genes with anti-viral function
Authors: Kirby Emily N. , Montin Xavier B. , Allen Timothy P. , Densumite Jaslan , Trowbridge Brooke N. , Beard Michael R.
Published: August 2023

Interferon Stimulated Genes (ISGs) play key roles in the control of viral replication and dissemination. Understanding this dynamic relationship between the pathogen and host is critical to our understanding of viral life-cycles and development of potential novel anti-viral strategies. Traditionally, plasmid based exogenous prompter driven expression of ISGs has been used to investigate anti-viral ISG function, however there are deficiencies in this approach. To overcome this, we investigated the utility of CRISPR activation (CRISPRa), which allows for targeted transcriptional activation of a gene from its endogenous promoter. Using the CRISPRa-SAM system to induce targeted expression of a panel of anti-viral ISGs we showed robust induction of mRNA and protein expression. We then employed our CRISPRa-SAM ISG panel in several antiviral screen formats to test for the ability of ISGs to prevent viral induced cytopathic cell death (CPE) and replication of Dengue Virus (DENV), Zika Virus (ZIKV), West Nile Virus Kunjin (WNVKUNV), Hepatitis A Virus (HAV) and Human Coronavirus 229E (HCoV-229E). Our CRISPRa approach confirmed the anti-viral activity of ISGs like IFI6, IFNβ and IFNλ2 that prevented viral induced CPE, which was supported by high-content immunofluorescence imaging analysis. This work highlights CRISPRa as a rapid, agile, and powerful methodology to identify and characterise ISGs and viral restriction factors.
The human AMPKγ3 R225W mutation does neither enhance basal AMPKγ3-associated activity nor glycogen in human or mouse skeletal muscle
Authors: Eskesen Nicolas O. , Kjøbsted Rasmus , Birk Jesper B. , Henriksen Nicolai S. , Andersen Nicoline R. , Ringholm Stine , Pilegaard Henriette , Pehmøller Christian K. , Wojtaszewski Jørgen F. P.
Published: August 2023

Background

AMP-activated protein kinase (AMPK) is activated during cellular energy perturbation. AMPK is composed of three subunits and several variants of AMPK complexes are expressed in skeletal muscle. The regulatory AMPKγ3 subunit is predominantly expressed in fast-twitch muscle fibers. A human AMPKγ3 R225W mutation has been described in two families. In cultured cells derived from R225W carrier muscle, the mutation was reported to increase total AMPK activity. In addition, elevated glycogen levels were observed in skeletal muscle. This led to the idea of AMPKγ3 being involved in glycogen levels in skeletal muscle. Evidence for such a causative link has never been provided.

Results

We studied newly obtained muscle biopsies from three human carriers of the AMPKγ3 R225W mutation and matched controls and we developed a novel knock-in mouse model carrying the AMPKγ3 R225W mutation (KI HOM). In all three human pairs, the basal AMPKγ3-associated activity was reduced when assayed in the absence of exogenous AMP. No difference was observed when assayed under AMP saturation, which was supported by findings in muscle of KI HOM mice. Furthermore, the well-established stimulatory effects of AICAR/muscle contraction on AMPKγ3-associated activity were absent in muscle from KI HOM mice. Muscle glycogen levels were not affected by the mutation in human carriers or in KI HOM mice.

Conclusions

The AMPKγ3 R225W mutation does not impact AMPK-associated activity in mature human skeletal muscle and the mutation is not linked to glycogen accumulation. The R225W mutation ablates AMPKγ3-associated activation by AICAR/muscle contractions, presumably through loss of nucleotide binding.