bluuebunny/crossref_metadata_2025 huggingface dataset:
Surgery and Surgical Training Before Graduate Medical Education
Authors: Alseidi Adnan A. , Craver H. William , Dennis Andrew J. , Fingeret Abbey , Fried Gerald M. , Mason Bonnie Simpson , Sudan Ranjan , Yang Stephen C. , Ford Henri R.
Published: July 2024

Objective:

To update and add to the first report commissioned by the Blue Ribbon Committee (BRC) about 20 years prior.

Background:

Following a summit in late 2022 commissioned by the American Board of Surgery regarding competency-based reforms in surgical education and through a partnership with the American College of Surgeons and other stakeholders, a BRC-II on surgical education was formed. The BRC-II would have 7 subcommittees. This paper details the work of the Medical Student Subcommittee within the BRC-II.

Methods:

The subcommittee’s work, supported by staff from the American College of Surgeons, entailed a thorough literature review, which involved collating and aggregating the findings, identifying key challenges and opportunities, and committing to draft recommendations. These recommendations were then presented and refined through discussions with the BRC at large in multiple virtual and in-person settings.

Results:

The subcommittee’s work is detailed below and further summarized in table format. The section below elucidates the medical student education continuum and discusses the pertinent topics of recruitment, surgical engagement in medical student training and the surgical image, training for the current surgical practice model, trainee selection for graduate medical education, and optimizing the transition from undergraduate medical education to graduate medical education.

Conclusions:

The last 2 decades have shown significant changes and shifts in medical education and surgical practice. The findings of BRC-II in this manuscript help to structure the current and future necessary improvements, focusing on different aspects of medical student education.
The Fingerprint of Scalp-EEG in Drug-Resistant Frontal Lobe Epilepsies
Authors: Kalss Gudrun , Pelliccia Veronica , Zimmermann Georg , Trinka Eugen , Tassi Laura
Published: July 2024

Purpose:

Scalp-EEG incompletely covers the frontal lobe cortex. Underrepresentation of frontobasal or frontomesial structures, fast ictal spreading, and false lateralization impede scalp-EEG interpretation. Hence, we investigated the significance of scalp-EEG in the presurgical workup of frontal lobe epilepsy.

Methods:

Using descriptive statistical methods and Pearson chi-squared test for group comparisons, we retrospectively investigated postsurgical outcome, interictal epileptiform discharges (iiEDs), and electrographic seizure patterns on scalp-EEG in 81 consecutive patients undergoing resective epilepsy surgery within the margins of the frontal lobe.

Results:

Postoperatively, patients with frontopolar iiEDs (n = 7) or concordant frontopolar iiED focus and seizure-onset (n = 2) were seizure free (n = 7/7, Engel Ia). MRI-positive patients with frontopolar iiEDs or frontopolar seizure-onset (n = 1/8 Engel Id, n = 7/8 Engel Ia) underwent surgery without stereo-EEG. Thirteen of 16 patients with frontolateral (n = 8/10, Engel Ia), or left frontobasal (n = 5/6, Engel Ia) seizure-onset undergoing further stereo-EEG, were seizure-free postoperatively. Seizure-onset prevalent over one electrode (n = 37/44 Engel I, p = 0.02), fast activity (FA)/flattening at seizure-onset (n = 29/33 Engel I, p = 0.02), FA/flattening during the seizure (n = 38/46 Engel I, p = 0.05), or focal rhythmic sharp-/spike-/polyspike-and-slow waves during the seizure (n = 24/31, Engel Ia, p = 0.05) were favorable prognostic markers. Interictal polyspike waves (p = 0.006 for Engel Ia) and interictal paroxysmal FA (p = 0.02 for Engel I) were unfavorable prognostic markers.

Conclusions:

Frontopolar scalp-EEG findings serve as biomarkers for predicting favorable surgical outcome in lesional frontal lobe epilepsy. Consequently, careful analysis of scalp-EEG assists in bypassing stereo-EEG in these patients.
Comparative genomics sheds new light on the convergent evolution of infrared vision in snakes
Authors: Zou Dahu , Huang Song , Tian Shilin , Kilunda Felista Kasyoka , Murphy Robert W. , Dahn Hollis A. , Zhou Youbing , Lee Ping-Shin , Chen Jin-Min
Published: July 2024

Infrared vision is a highly specialized sensory system that evolved independently in three clades of snakes. Apparently, convergent evolution occurred in the transient receptor potential ankyrin 1 (
TRPA1
) proteins of infrared-sensing snakes. However, this gene can only explain how infrared signals are received, and not the transduction and processing of those signals. We sequenced the genome of
Xenopeltis unicolor
, a key outgroup species of pythons, and performed a genome-wide analysis of convergence between two clades of infrared-sensing snakes. Our results revealed pervasive molecular adaptation in pathways associated with neural development and other functions, with parallel selection on loci associated with trigeminal nerve structural organization. In addition, we found evidence of convergent amino acid substitutions in a set of genes, including
TRPA1
and
TRPM2
. The analysis also identified convergent accelerated evolution in non-coding elements near 12 genes involved in facial nerve structural organization and optic nerve development. Thus, convergent evolution occurred across multiple dimensions of infrared vision in vipers and pythons, as well as amino acid substitutions, non-coding elements, genes and functions. These changes enabled independent groups of snakes to develop and use infrared vision.
Wild raccoons demonstrate flexibility and individuality in innovative problem-solving
Authors: Stanton Lauren A. , Cooley-Ackermann Carissa , Davis Emily C. , Fanelli Rachel E. , Benson-Amram Sarah
Published: July 2024

Cognitive skills, such as innovative problem-solving, are hypothesized to aid animals in urban environments. However, the significance of innovation in wild populations, and its expression across individuals and socio-ecological conditions, is poorly understood. To identify how and when innovation arises in urban-dwelling species, we used advanced technologies and new testing and analytical methods to evaluate innovative problem-solving abilities of wild raccoons (
Procyon lotor
). We deployed multi-compartment puzzle boxes with either one or multiple solution types and identified raccoons using radio frequency identification. Raccoons solved these novel extractive foraging tasks, and their success was influenced by age and exploratory diversity. Successful raccoons always discovered multiple different solution types, highlighting flexible problem-solving. Using a unique, comparative sequence analysis approach, we found that variation in raccoon solving techniques was greater between individuals than within individuals, and this self-similarity intensified during times of competition. Finally, the inclusion of an easier solution in the multi-solution trials enabled previously unsuccessful raccoons to bootstrap their learning and successfully open multiple difficult solutions. Our study suggests that innovative problem-solving is probably influenced by many factors and has provided novel field and analytical methods, as well as new insights on the socio-ecological dynamics of urban populations.
High-quality PacBio draft genome sequences of 17 free-living Bradyrhizobium and four related Nitrobacteraceae strains isolated from arid soils in the Santa Catalina Mountains of Southern Arizona.
Authors: Kridler Melanie R , Howe Amanda , Legins Jimaree A , Guerrero Christina , Bartelme Ryan P. , Taylor Bridget , Carini Paul
Published: July 2024

Non-symbiotic Bradyrhizobium are among the most abundant and ubiquitous microbes in bulk soils globally. Despite this, most available genomic resources for Bradyrhizobium are derived from plant-associated strains. We present high-quality draft genomes for 17 Bradyrhizobium and four Nitrobacteraceae cultures isolated from bulk semiarid soils in Arizona, USA. The genome sizes range from 5.99 to 10.4 Mbp. Phylogenomic analysis of the 21 genomes indicates they fall into four clades. Two of the clades are nested within the Bradyrhizobium genus. The other two clades were associated with Nitrobacteraceae outgroups basal to Bradyrhizobium. All genomes lack genes coding for molybdenum or vanadium nitrogenases, and nod genes that code for proteins involved in nodulation, suggesting these isolates are free-living, non-symbiotic, and do not fix dinitrogen gas. These genomes offer new resources for investigating free-living Bradyrhizobium lineages.
The interpretation attributed to observed gaze shifts affects their social-cueing effect
Authors: Zehngut Amit , Yuval-Greenberg Shlomit
Published: July 2024

In an environment busy with abundant stimulation, individuals must rely on attentional cues to select the most relevant targets. As social creatures, a crucial strategy involves monitoring where others are focusing their attention and following them, assuming that locations attended by others are more likely to yield benefits than other locations. Given that gaze shifts represent a visible shift in attention, mirroring the gaze shifts of others can serve as an effective, social-attentional strategy. Indeed, research demonstrates that observing others redirect their gaze results in a reflexive shift of attention, reflected by improved perceptual performance for objects located at the gazed-at positions. This phenomenon is known as thegaze cueing effect(GCE). However, gaze shifts may not always align with the direction of attention. Individuals often avert their gaze while they are engaged in demanding cognitive tasks. Such gaze shifts signify internal focus rather than shifting attention outward. Here we hypothesize that the response to a gaze-shift cue is not reflexive but is contingent upon social context. In two pre-registered experiments, participants viewed videos of gaze shifts and engaged in a perceptual task, with one group primed to perceive the gaze shifts as reflecting cognitive processing rather than overt attentional shifts. Results indicated that GCE was suppressed in this group, suggesting that GCE is influenced by contextual cues framing the nature of the gaze shifts. These findings suggest that social attention is flexible and depends on the specific interpretation of the social context.
Bona fidecytotoxic iNKT cells with superior antitumour responses identified in mice and humans
Authors: de Amat Herbozo Carolina , Wong Stephanie WY , Kuypers Meggie , Ilango Guy , Liu Zhewei , Mathews Jessica A , Nguyen Albert , Veillette André , Gommerman Jennifer L , Baranek Thomas , Crome Sarah Q , Tsao Ming Sound , Sacher Adrian G , Paget Christophe , Mallevaey Thierry
Published: July 2024

Adoptive cell therapies (ACT) using unmodified or engineered invariant Natural Killer T (iNKT) cells are in clinical trials for cancer treatment. While promising, outcomes are still suboptimal, possibly due to iNKT cell heterogeneity. This study identified unique iNKT cell populations with strong cytotoxic activity in mice and humans. In mice, iNKT1c cells showed potent CD1d-dependent and -independent antitumor functions, with responses influenced by NK receptors. IL-15 enhances their cytolytic activity, while retinoic acid is essential for their generation. In humans, terminally differentiated CD57+iNKT cells showed marked NK-receptor expression and most effectively killed C1R tumor cellsin vitro. These cells appeared activated/exhausted within tumors of non-small cell lung cancer patients. Additionally, a central memory-like CD62L+CD4-iNKT subset efficiently expanded and generated cytotoxic CD57+iNKT cellsin vitro, making them an appealing candidate for ACT. This study paves the way for the design of more effective iNKT cell-based immunotherapies.
γ-aminobutyric acid receptor B signaling drives glioblastoma in females in an immune-dependent manner
Authors: Pathak Asmita , Palasalava Sravya , Knott Maxon V. , Colon Bruno , Ciervo Erika , Zhou Yadi , Mitchell Jonathan , Pumar Oriana Teran , Wong Harrison K. A. , Zhang Li , Susic Nikola , Shah Khushi Hemendra , Kay Kristen , Chin Diana , Johnson Sadie , Cheng Feixiong , Lyssiotis Costas A. , Watson Dionysios C. , Ceccarelli Michele , Shah Ashish , Wahl Daniel R. , Lathia Justin D. , Bayik Defne
Published: July 2024

Sex differences in immune responses impact cancer outcomes and treatment response, including in glioblastoma (GBM). However, host factors underlying sex specific immune-cancer interactions are poorly understood. Here, we identify the neurotransmitter γ-aminobutyric acid (GABA) as a driver of GBM-promoting immune response in females. We demonstrated that GABA receptor B (GABBR) signaling enhances L-Arginine metabolism and nitric oxide synthase 2 (NOS2) expression in female granulocytic myeloid-derived suppressor cells (gMDSCs). GABBR agonist and GABA analog promoted GBM growth in females in an immune-dependent manner, while GABBR inhibition reduces gMDSC NOS2 production and extends survival only in females. Furthermore, female GBM patients have enriched GABA transcriptional signatures compared to males, and the use of GABA analogs in GBM patients is associated with worse short-term outcomes only in females. Collectively, these results highlight that GABA modulates anti-tumor immune response in a sex-specific manner, supporting future assessment of GABA pathway inhibitors as part of immunotherapy approaches.
AlphaFold Model Quality Self-Assessment Improvement Via Deep Graph Learning
Authors: Verburgt Jacob , Zhang Zicong , Kihara Daisuke
Published: July 2024

In the past several years significant advances have been made in the field of deep-learning based computational modeling of proteins, with DeepMind’s AlphaFold2 being among the most prominent. Alongside the atom coordinates, these computationally modeled protein structures typically contain self-confidence metrics that can be used to gauge the relative modeling quality of individual residues, or the protein as a whole. Unfortunately, these scores are not always accurate, and may sometimes annotate poorly modeled regions of the protein as high confidence. Here, we introduce EQA-Fold to address this problem. EQA-Fold overhauls the LDDT prediction head of AlphaFold to provide more accurate self-confidence scores. We show that EQA-Fold is able to provide more accurate self-confidence scores than the standard AlphaFold architectures, as well as recent Model Quality Assessment protocols.
Precuneus activity during retrieval is positively associated with amyloid burden in cognitively normal olderAPOE4carriers
Authors: Fischer Larissa , Molloy Eóin N. , Binette Alexa Pichet , Vockert Niklas , Marquardt Jonas , Pilar Andrea Pacha , Kreissl Michael C. , Remz Jordana , Poirier Judes , Rajah M. Natasha , Villeneuve Sylvia ,   PREVENT-AD Research Group, Maass Anne
Published: July 2024

The precuneus is an early site of amyloid-beta (Aβ) accumulation. Previous cross-sectional studies reported increased precuneus fMRI activity in older adults with mild cognitive deficits or elevated Aβ. However, longitudinal studies in early Alzheimer’s disease (AD) risk stages are lacking and the interaction with Apolipoprotein-E (APOE) genotype is unclear. In the PREVENT-AD cohort, we assessed how precuneus activity during successful memory retrieval at baseline and over time relates to future Aβ and tau burden and to change in memory performance. We further studied the moderation byAPOE4genotype. We included 165 older adults (age: 62.8±4.4 years; 113 female; 66APOE4carriers) who were cognitively normal at baseline and had a family history of AD. All participants performed task-fMRI at baseline and underwent18F-flortaucipir-PET and18F-NAV4694-Aβ-PET on average 5 years later. We found that higher baseline activity and greater longitudinal change in activity in precuneus were associated with higher subsequent Aβ inAPOE4 carriers but not non-carriers. There were no effects of precuneus activity on tau burden. Finally,APOE4non-carriers with low baseline activity in the precuneus exhibited better longitudinal performance in an independent memory test compared toAPOE4non-carriers with high baseline activity andAPOE4carriers. Our findings suggest that higher task-related precuneus activity at baseline and over time are associated with subsequent Aβ burden in cognitively normalAPOE4carriers. Our results further indicate that the absence of hyperactivation and the absence of theAPOE4allele is related with the best future cognitive outcome in cognitively normal older adults at risk for AD.

Significance Statement

The precuneus is a brain region involved in episodic memory function and is an early site of amyloid-beta (Aβ) accumulation. Alterations in task-related activity occur in the precuneus with ageing as well as with Alzheimer’s disease (AD) pathology even in the absence of cognitive symptoms; however, their course and implications are not well understood. We demonstrate that higher precuneus activity at baseline and its change over time during successful memory retrieval is associated with higher Aβ burden on average 5 years after baseline in Apolipoprotein-E4 (APOE4)carriers. Lower precuneus baseline activation was related to better memory performance over time inAPOE4non-carriers. Our findings provide novel longitudinal evidence that increased activity in posterior midline regions is linked to early AD pathology in dependence ofAPOE4genotype.
NLRP1B allele 2 does not respond to Val-boro-Pro (VbP) in the intestinal epithelium
Authors: Mazzone Ryan J. , Winsor Nathaniel J. , Li Lu Yi , Barry Kristian T. , Ranger Adrienne , Goyal Shawn , Meade Justin J. , Bruce Jessica , Philpott Dana J. , Mogridge Jeremy , Girardin Stephen E.
Published: July 2024

The intestinal mucosa must balance tolerance to commensal microbes and luminal antigens with rapid detection of enteric pathogens in order to maintain homeostasis. This balance is facilitated through the regulation of epithelial layer integrity by innate immune receptors. Certain NOD-like receptors (NLRs) expressed in intestinal epithelial cells, including NLRC4 and NLRP9B, form inflammasomes that protect against pathogens by activating caspase-1 to cause extrusion of infected cells. NLRP1B is a murine NLR encoded by five alleles of a highly polymorphic gene homologous to human NLRP1. NLRP1B forms inflammasomes in response to a variety of pathogens that cause intestinal infections, but it has almost exclusively been studied in immune cells and has not been characterized in cells of the intestinal epithelium. Here, we show thatNlrp1bis expressed in ileal and colonic organoids derived for C57BL/6J mice.Nlrp1bwas upregulated by interleukin-13 in organoids and by the protozoanTritrichomonas murisin vivo, suggesting that NLRP1B may be involved in defense against enteric parasites. Surprisingly, while Val-boro-Pro (VbP) activated NLRP1B in bone marrow-derived macrophages, it did not activate NLRP1B in organoids. We furthermore did not detectNlrp1bin organoids derived from Balb/cJ mice, which express a different allele than the one expressed in C57BL/6J mice. Together, our results suggest that NLRP1B may have an allele-dependent function in murine IECs whose regulation is distinct from that of macrophages.
ARGX-119, a therapeutic agonist antibody targeting MuSK
Authors: Vanhauwaert Roeland , Oury Julien , Vankerckhoven Bernhardt , Steyaert Christophe , Jensen Stine Marie , Vergoossen Dana L.E. , Kneip Christa , Santana Leah , Lim Jamie L. , Plomp Jaap J. , Augustinus Roy , Koide Shohei , Blanchetot Christophe , Ulrichts Peter , Huijbers Maartje G. , Silence Karen , Burden Steven J.
Published: July 2024

ARGX-119 is a novel, humanized, agonist monoclonal SIMPLE Antibody™ specific for muscle-specific kinase (MuSK) that is being developed for treatment of patients with neuromuscular diseases. ARGX-119 is the first monoclonal antibody (mAb) that binds with high affinity to the Frizzled-like domain of human, non-human primate, rat and mouse MuSK, without off-target binding, making it suitable for clinical development. Within the Fc-region, ARGX-119 harbors L234A, L235A mutations to diminish potential immune-activating effector functions. Its mode-of-action is to activate MuSK without interfering with its natural ligand neural Agrin, and cluster acetylcholine receptors (AChRs) in a dose-dependent manner, thereby stabilizing neuromuscular function. In a mouse model forDOK7congenital myasthenia (CM), ARGX-119 prevented early postnatal lethality and reversed disease relapse by restoring neuromuscular function and reducing muscle weakness and fatigability in a dose-dependent manner. Pharmacokinetic (PK) studies in non-human primates, rats and mice revealed non-linear PK behavior of ARGX-119, indicative of target-mediated-drug disposition (TMDD) andin vivotarget engagement. Instability of neuromuscular synapses contributes to symptoms in many neuromuscular diseases for example congenital myasthenia (CM), amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). ARGX-119 is a novel, first-in-class MuSK agonist mAb in clinical development. Based on this proof-of-concept study, it has the potential to alleviate neuromuscular diseases hallmarked by impaired neuromuscular synaptic function.

One sentence summary

ARGX-119 is a novel first-in-class MuSK agonist monoclonal antibody in clinical development for treatment of neuromuscular diseases.
Gencube: Efficient retrieval, download, and unification of genomic data from leading biodiversity databases
Authors: Son Keun Hong , Cho Je-Yoel
Published: July 2024

Motivation

With the daily submission of numerous new genome assemblies, associated annotations, and experimental sequencing data to genome archives for various species, the volume of genomic data is growing at an unprecedented rate. Major genomic databases are establishing new hierarchical structures to manage this data influx. However, there is a significant need for tools that can efficiently access, download, and integrate genomic data from these diverse repositories, making it challenging for researchers to keep pace.

Results

We have developedGencube, a command-line tool with two primary functions. First, it facilitates the utility of genome assemblies, related annotations, gene set sequences, and cross-species data from various leading biodiversity databases. Second, it helps researchers intuitively explore experimental sequencing data that meets their needs and consolidates the metadata of the retrieved outputs.

Availability and implementation

Gencubeis a free and open-source tool, with its code available on GitHub:https://github.com/snu-cdrc/gencube.
Exploring the Mechanism of Gentiana in Treating Pancreatic Cancer Based on Network Pharmacology and Molecular Docking Techniques
Authors: Qian Yuanyuan , Wang Zhaojunli , Ji Jiancheng
Published: July 2024

Objective

This study aims to investigate the mechanism of Gentiana in treating pancreatic cancer using network pharmacology and molecular docking techniques.

Methods

Active compounds of Gentiana were screened from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. The 3D structures of the active compounds were downloaded from the PubChem database. Reverse docking was performed using the PharmMapper database to identify potential target proteins. Differential gene expression data related to colorectal cancer were obtained from the Gene Expression Omnibus (GEO) database, and differentially expressed genes were selected. Venn diagram analysis was employed to identify common genes between the protein targets and differentially expressed genes. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were conducted using the Database for Annotation, Visualization, and Integrated Discovery (DAVID) tool. Molecular docking was performed using ChemDraw 20.0, AutoDock, and PyMOL.

Results

A total of 72 common genes and 15 signaling pathways were identified from the reverse docking data of Gentiana and the pancreatic cancer dataset (GSE196009). Molecular docking results demonstrated favorable binding energies between the active compounds of Gentiana and proteins 1og5, 1pq2, 2bxr, 2bk3, 1u3w, 1wma, 1wuu, 1tdi, 1mlw, 1egc, 1s1p, 1f12, 1m51, 1kqu, 1ls6, 1ry0, 1nhx, and 1db4.

Conclusion

Gentiana may exert its therapeutic effects on pancreatic cancer through a multi-component, multi-target, and multi-pathway mechanism.
CytoNormPy enables a fast and scalable removal of batch effects in cytometry datasets
Authors: Exner Tarik , Hackert Nicolaj , Leomazzi Luca , Van Gassen Sofie , Saeys Yvan , Lorenz Hanns-Martin , Grieshaber-Bouyer Ricardo
Published: July 2024

Motivation

We present a python implementation of the widely used CytoNorm algorithm for the removal of batch effects.

Results

Our implementation ran up to 85% faster than its R counterpart, while being fully compatible with common single-cell data structures and -frameworks of python. We extend the previous functionality by adding common clustering algorithms and provide key visualizations of the algorithm and its evaluation.

Availability and implementation

The CytoNormPy implementation is freely available on GitHub:https://github.com/TarikExner/CytoNormPy.
PLAbDab-nano: a database of camelid and shark nanobodies from patents and literature
Authors: Gordon Gemma L. , Greenshields-Watson Alexander , Agarwal Parth , Wong Ashley , Boyles Fergus , Hummer Alissa , Lujan Hernandez Ana G. , Deane Charlotte M.
Published: July 2024

Nanobodies are essential proteins of the adaptive immune systems of camelid and shark species, complementing conventional antibodies. Properties such as their relatively small size, solubility and high thermostability make VHH and VNAR modalities a promising therapeutic format and a valuable resource for a wide range of biological applications. The volume of academic literature and patents related to nanobodies has risen significantly over the past decade. Here, we present PLAbDab-nano, a nanobody complement to the Patent and Literature Antibody Database (PLAbDab). PLAbDab-nano is a selfupdating, searchable repository containing approximately 5000 annotated VHH and VNAR sequences. We describe the methods used to curate the entries in PLAbDab-nano, and highlight how PLAbDab-nano could be used to design diverse libraries, as well as find sequences similar to known patented or therapeutic entries. PLAbDab-nano is freely available as a searchable web server (opig.stats.ox.ac.uk/webapps/plabdab-nano/).

Graphical Abstract
Glutamine-addiction in cisplatin resistant cancer cells is mediated by SLC7A11 and can be targeted with asparaginase therapy
Authors: Wang Jiantao , Strauss Robert , Bartek Jiri , Rudd Sean G
Published: July 2024

Linking disease phenotypes with molecular targets is key to the rational design of treatment interventions. Resistance to the chemotherapeutic cisplatin is one of the major factors limiting the clinical utility of this therapy, which is central to the treatment of a variety of solid malignancies. In this study, we couple the upregulation of a chemoresistant factor, the glutamate-cystine antiporter SLC7A11, with the addiction of cisplatin-resistant cancer cells to extracellular glutamine. In doing so, we thus provide a putative biomarker for this acquired metabolic dependency of chemoresistance. Subsequently, we evaluate various therapeutic strategies to selectively kill SLC7A11highcisplatin-resistant cancer cells, identifying cross-resistance to ferroptosis-inducing compounds and hypersensitivity to glutaminase inhibitor CB-839. We identify enzymatic depletion of extracellular glutamine using the long-standing anti-leukemic therapy asparaginase (ASNase), which possesses glutaminase activity, as a potential approach, and show this can be successfully combined with cisplatin in cell models. In summary, this study mechanistically links an acquired metabolic dependency of chemoresistant cancer cells with a putative biomarker and provides a potentially actionable strategy to target these drug resistant cells warranting further investigation.
Extending the Acute Skin Response Spectrum to Include the Far-UVC
Authors: Gutierrez-Bayona Natalia E. , Petersen Camryn , Hashmi Raabia H. , Buonanno Manuela , Shuryak Igor , Ponnaiya Brian , Kleiman Norman J. , Brenner David J. , Welch David
Published: July 2024

Guidance on maximal limits for ultraviolet (UV) exposure has been developed by national and international organizations to protect against adverse effects on human skin and eyes. These guidelines consider the risk of both acute effects (i.e. erythema and photokeratitis) and delayed effects (e.g., skin and ocular cancers) when determining exposure limits, and specify the dose a person can safely receive during an 8-hour period without harmful effects. The determination of these exposure limits relies on the action spectra of photobiological responses triggered by UV radiation that quantify the effectiveness of each wavelength at eliciting each of these effects. With growing interest in using far-UVC (200-235 nm) radiation to control the spread of airborne pathogens, recent arguments have emerged about revisiting exposure limits for UV wavelengths. However, the standard erythema action spectra, which provides some of the quantitative basis for these limits, has not been extended below 240 nm. This study assists to expand the erythema action spectrum to far-UVC wavelengths using a hairless albino mice model. We estimate that inducing acute effects on mouse skin with 222 nm radiation requires a dose of 1,162 mJ/cm2, well above the current ACGIH skin exposure limit of 480 mJ/cm2.
A distinct Down state assembly in retrosplenial cortex during slow-wave sleep
Authors: Opalka Ashley N , Dougherty Kimberly J , Wang Dong V
Published: July 2024

Understanding the intricate mechanisms underlying slow-wave sleep (SWS) is crucial for deciphering the brain’s role in memory consolidation and cognitive functions. It is well-established that cortical delta oscillations (0.5–4 Hz) coordinate communications among various cortical, hippocampal, and thalamic regions during SWS. These delta oscillations have periods of Up and Down states, with the latter previously thought to represent complete cortical silence; however, new evidence suggests that Down states serve important functions for information exchange during memory consolidation. The retrosplenial cortex (RSC) stands out for its pivotal role in memory consolidation due to its extensive connectivity with memory-associated regions, although it remains unclear how RSC neurons engage in delta-associated consolidation processes. Here, we employed multi-channelin vivoelectrophysiology to study RSC neuronal activity in freely behaving mice during natural SWS. We discovered that the RSC contains a discrete assembly of putative excitatory neurons (∼20%) that initiated firing at SWS Down states and reached maximal firing at the Down-to-Up transitions. Therefore, we termed these RSC neurons the Down state assembly (DSA), and the remaining RSC excitatory neurons as non-DSA. Compared to non-DSA, DSA neurons exhibit a higher firing rate, larger cell body size, and no connectivity with nearby RSC neurons. Subsequently, we investigated RSC neuronal activity during a contextual fear conditioning paradigm and found that both DSA and non-DSA neurons exhibited increased firing activity during post-training sleep compared to pre-training sleep, indicating their roles in memory consolidation. Lastly, optogenetics combined with electrophysiology revealed that memory-associated inputs differentially innervated RSC excitatory neurons. Collectively, these findings provide insight on distinct RSC neuronal subpopulation activity in sleep and memory consolidation.
Long-lived adult-born hippocampal neurons promote successful cognitive aging
Authors: Blin Nicolas , Charrier Vanessa , Farrugia Fanny , Cartier Estelle , Pacary Emilie , Koehl Muriel , Lois Carlos , Lie Dieter Chichung , Masachs Nuria , Abrous Djoher Nora
Published: July 2024

Aging is commonly associated with a decline in memory abilities, yet some individuals remain resilient with preserved memory abilities. Memory processing is critically dependent on adult neurogenesis, a unique form of plasticity in the hippocampus. However, it remains unknown if cognitive aging influences the integration and role of adult-born hippocampal neurons (ABNs) generated early in adult life. Here, we investigated the role of long-lived ABNs in rats characterized as either resilient or vulnerable to cognitive aging using a peudo-longitudinal approach. Our findings reveal that long-lived ABNs support successful cognitive aging by preserving their synaptic inputs onto the proximal segments of their dendrites, and that these proximal synaptic sites also demonstrate a maintenance of their mitochondrial homeostasis. Furthermore, by-passing the reduced inputs of ABNs in vulnerable rats through direct optogenetic stimulation successfully improved their memory abilities. Overall, our data indicate that the maintenance of long-lived ABNs integration within the neuronal network is essential for successful cognitive aging, highlighting their potential as a therapeutic target for restoring cognitive functions in old age.

Graphical abstract
Mitochondria affect photosynthesis through altered tissue levels of oxygen
Authors: Punkkinen Matleena , Blokhina Olga , Peralta Ogorek Lucas León , Kim Minsoo , Fagerstedt Kurt , Vierling Elizabeth , Pedersen Ole , Shapiguzov Alexey
Published: July 2024

Interactions between plant energy organelles, the chloroplasts and the mitochondria, are crucial for plant development and acclimation. These interactions occur at different levels including exchange of metabolites and reducing power, organelle signaling pathways and intracellular gas exchange. Mitochondrial retrograde stress signaling activates expression of nuclear genes encoding mitochondrial components, including alternative oxidases. High abundances of these respiratory enzymes coincide not only with the changes in plant respiration but also with alterations in the chloroplast. For example, plants that overexpress alternative oxidases are tolerant to methyl viologen, a redox-active compound that catalyzes transfer of electrons from Photosystem I to molecular oxygen. The mechanism of this inter-organelle interaction is unclear but could be related to diminished availability of tissue oxygen. Here we assessed respiration, photosynthesis andin vivolevels of oxygen in a set of Arabidopsis lines with perturbations in diverse mitochondrial functions, including defects in respiratory complex I, mitochondrial protein processing, transcription, nucleoid organization, altered fission and architecture or suppressed ATP synthase activity. In these lines, the increased abundance and activity of alternative oxidases strongly correlated with higher oxygen consumption in darkness, lower oxygen re-accumulation in light, and diminished effects of methyl viologen in chloroplasts. These results support the hypothesis that increased mitochondrial oxygen sink capacity affects photosynthesis by decreasing oxygen levels in tissues. This phenomenon can be one of the reasons for the impact that stressed mitochondria have on chloroplasts and photosynthesis. It contributes to our understanding of the mechanisms of hypoxia establishment and acclimation in plants.
Assessing Assembly Errors in Immunoglobulin Loci: A Comprehensive Evaluation of Long-read Genome Assemblies Across Vertebrates
Authors: Zhu Yixin , Watson Corey T. , Safonova Yana , Pennell Matt , Bankevich Anton
Published: July 2024

Long-read sequencing technologies have revolutionized genome assembly producing near-complete chromosome assemblies for numerous organisms, which are invaluable to research in many fields. However, regions with complex repetitive structure continue to represent a challenge for genome assembly algorithms, particularly in areas with high heterozygosity. Robust and comprehensive solutions for the assessment of assembly accuracy and completeness in these regions do not exist. In this study we focus on the assembly of biomedically important antibody-encoding immunoglobulin (IG) loci, which are characterized by complex duplications and repeat structures. High-quality full-length assemblies for these loci are critical for resolving haplotype-level annotations of IG genes, without which, functional and evolutionary studies of antibody immunity across vertebrates are not tractable. To address these challenges, we developed a pipeline, "CloseRead", that generates multiple assembly verification metrics for analysis and visualization. These metrics expand upon those of existing quality assessment tools and specifically target complex and highly heterozygous regions. Using CloseRead, we systematically assessed the accuracy and completeness of IG loci in publicly available assemblies of 74 vertebrate species, identifying problematic regions. We also demonstrated that inspecting assembly graphs for problematic regions can both identify the root cause of assembly errors and illuminate solutions for improving erroneous assemblies. For a subset of species, we were able to correct assembly errors through targeted reassembly. Together, our analysis demonstrated the utility of assembly assessment in improving the completeness and accuracy of IG loci across species.
A Ketogenic Diet Sensitizes Pancreatic Cancer to Inhibition of Glutamine Metabolism
Authors: Hajihassani Omid , Zarei Mehrdad , Roichman Asael , Loftus Alexander , Boutros Christina S. , Hue Jonathan , Naji Parnian , Boyer Jacob , Tahan Soubhi , Gallagher Peter , Beegan William , Choi James , Lei Shihong , Kim Christine , Rathore Moeez , Nakazzi Faith , Shah Ishan , Lebo Kevin , Cheng Helen , Mudigonda Anusha , Alibeckoff Sydney , Ji Karen , Graor Hallie , Miyagi Masaru , Vaziri-Gohar Ali , Brunengraber Henri , Wang Rui , Lund Peder J. , Rothermel Luke D. , Rabinowitz Joshua D. , Winter Jordan M.
Published: July 2024

Pancreatic cancer is the third leading cause of cancer death in the United States, and while conventional chemotherapy remains the standard treatment, responses are poor. Safe and alternative therapeutic strategies are urgently needed1. A ketogenic diet has been shown to have anti-tumor effects across diverse cancer types but will unlikely have a significant effect alone. However, the diet shifts metabolism in tumors to create new vulnerabilities that can be targeted (1). Modulators of glutamine metabolism have shown promise in pre-clinical models but have failed to have a marked impact against cancer in the clinic. We show that a ketogenic diet increases TCA and glutamine-associated metabolites in murine pancreatic cancer models and under metabolic conditions that simulate a ketogenic dietin vitro.The metabolic shift leads to increased reliance on glutamine-mediated anaplerosis to compensate for low glucose abundance associated with a ketogenic diet. As a result, glutamine metabolism inhibitors, such as DON and CB839 in combination with a ketogenic diet had robust anti-cancer effects. These findings provide rationale to study the use of a ketogenic diet with glutamine targeted therapies in a clinical context.

Graphical Abstract

Graphical Abstract Description:Mechanistic rationale for combining a ketogenic diet and glutamine metabolism inhibitors.The combination of low glucose from a ketogenic diet and pharmacologic glutamine inhibition impairs nutrient input to mitochondria, reducing cancer growth.
Deletion of wheat alpha-gliadins from chromosome 6D improves gluten strength and reduces immunodominant celiac disease epitopes
Authors: Rottersman Maria G. , Zhang Wenjun , Zhang Junli , Grigorian Gabriela , Burguener German , Carter Claudia , Vang Teng , Hegarty Joshua , Zhang Xiaoqin , Dubcovsky Jorge
Published: July 2024

Wheat gliadins and glutenins confer valuable end-use characteristics but include amino acid sequences (epitopes) that can elicit celiac disease (CeD) in genetically predisposed individuals. The onset of CeD in these individuals is affected by the amount and duration of the exposure to immunogenic epitopes. Therefore, a reduction of epitopes that result in high immune responses in the majority of CeD patients (immunodominant epitopes) can reduce the incidence of CeD at a population level. We identified deletions encompassing the α-gliadins at the three wheat genomes, designated hereafter asΔgli-A2(PI 704906),Δgli-B2(PI 704907), andΔgli-D2(PI 704908). TheΔgli-D2deletion, which eliminates major immunodominant epitopes, significantly increases gluten strength, improves breadmaking quality, and has no negative effects on grain yield or grain protein content. By contrast,Δgli-A2andΔgli-B2showed limited effects on breadmaking quality. The stronger effect of theΔgli-D2deletion on gluten strength is associated with the presence of α-gliadins with seven cysteines inGLI-D2that are absent inGLI-A2andGLI-B2loci, which all have α-gliadins with six cysteines. We show that α-gliadins with seven cysteines are incorporated into the gluten polymer, where they likely function as chain-terminators limiting the expansion of the gluten polymer and reducing its strength. In summary, the publicly availableΔgli-D2deletion developed in this study can be used to simultaneously improve wheat gluten strength and reduce immunodominant CeD epitopes.
Advances in Estimating Level-1 Phylogenetic Networks from Unrooted SNPs
Authors: Warnow Tandy , Tabatabaee Yasamin , Evans Steven N.
Published: July 2024

We address the problem of how to estimate a phylogenetic network when given SNPs (i.e., single nucleotide polymorphisms, or bi-allelic markers that have evolved under the infinite sites assumption). We focus on level-1 phylogenetic networks (i.e., networks where the cycles are node-disjoint), since more complex networks are unidentifiable. We provide a polynomial time quartet-based method that we prove correct for reconstructing the unrooted topology of any level-1 phylogenetic networkN, if we are given a set of SNPs that covers all the bipartitions ofN, even if the ancestral state is not known, provided that the cycles are of length at least 5; we also prove that an algorithm developed by Dan Gusfield in JCSS 2005 correctly recovers the unrooted topology in polynomial time in this case. To the best of our knowledge, this is the first result to establish that the unrooted topology of a level-1 network is uniquely recoverable from SNPs without known ancestral states. We also present a stochastic model for DNA evolution, and we prove that the two methods (our quartet-based method and Gusfield’s method) are statistically consistent estimators of the unrooted topology of the level-1 phylogenetic network. For the case of multi-state homoplasy-free characters, we prove that our quartet-based method correctly constructs the unrooted topology of level-1 networks under the required conditions (all cycles of length at least five), while Gusfield’s algorithm cannot be used in that condition. These results assume that we have access to an oracle for indicating which sites in the DNA alignment are homoplasy-free, and we show that the methods are robust, under some conditions, to oracle errors.
Controlled pH Alteration Enables Guanine Accumulation and Drives Crystallization within Iridosomes
Authors: Eyal Zohar , Gorelick-Ashkenazi Anna , Deis Rachael , Barzilay Yuval , Broder Yonatan , Kellum Asher Perry , Varsano Neta , Hartstein Michal , Sorrentino Andrea , Kaplan-Ashiri Ifat , Rechav Katya , Metzler Rebecca , Houben Lothar , Kronik Leeor , Rez Peter , Gur Dvir
Published: July 2024

Many animals exhibit remarkable colors produced by the constructive interference of light reflected from arrays of intracellular guanine crystals. These systems are utilized for various purposes, including vision, camouflage, communication, and thermal regulation. Each guanine crystal forms within a membrane-bound organelle called an iridosome, where precise control over crystal formation occurs. While the presence of guanine crystals in iridosomes is well-documented, the mechanisms facilitating the accumulation of water-insoluble guanine and driving its crystallization remain unclear. Here, we employ advanced imaging and spectroscopy techniques to characterize the maturation of iridosomes in zebrafish iridophores during development. Using cryo-electron microscopy, we found that amorphous guanine accumulates in early-stage iridosomes. Synchrotron-based soft X-ray microscopy studies revealed that, unlike mature crystals, the accumulated guanine is initially in its protonated state. Live imaging with a pH sensor demonstrated that early-stage iridosomes are acidic and that their pH gradually approaches neutrality during maturation. Additionally, the application of a V-ATPase inhibitor reduced the acidity of iridosomes and significantly decreased crystal formation, suggesting the involvement of V-ATPase in regulating the organelle pH. Our findings reveal new insights into the molecular mechanisms facilitating guanine accumulation and crystallization within iridosomes, emphasizing the pivotal role of pH alternations in the precise formation of biogenic crystals.
Lung structural cells are altered by influenza virus leading to rapid immune protection following re-challenge
Authors: Worrell Julie C. , Hargrave Kerrie E. , Finney George E. , Hansell Chris , Cole John , Nijjar Jagtar Singh , Morton Fraser , Pingen Marieke , Purnell Tom , Mitchelson Kathleen , Brennan Euan , Allan Jay , Ilia Georgios , Herder Vanessa , Dietrich Claire Kennedy , Doncheva Yoana , Jamieson Nigel B. , Palmarini Massimo , MacLeod Megan K.L
Published: July 2024

Lung structural cells, including epithelial cells and fibroblasts, form barriers against pathogens and trigger immune responses following infections such as influenza A virus. This response leads to the recruitment of innate and adaptive immune cells required for viral clearance. Some of these recruited cells remain within the lung following infection and contribute to enhanced viral control following subsequent infections. There is growing evidence that structural cells can also display long-term changes following infection or insults. Here we investigate long-term changes to mouse lung epithelial cells, fibroblasts, and endothelial cells following influenza virus infection and find that all three cell types maintain an imprint of the infection, particularly in genes associated with communication with T cells. Lung epithelial cells from IAV-infected mice display functional changes by more rapidly controlling influenza virus than cells from naïve animals. This rapid anti-viral response and increased expression of molecules required to communicate with T cells demonstrates sustained and enhanced functions following infection. These data suggest lung structural cells could be effective targets for vaccines to boost durable protective immunity.

Graphical Abstract

Highlights

Lung epithelial cells, fibroblasts, and blood endothelial cells maintain an inflammatory imprint of influenza A virus (IAV) infection for at least 40 days post-infection.

In vivore-infection leads to a more spatially restricted anti-viral response compared to primary IAV-infected animals.

T cells are not required for enhanced viral control early after re-infectionin vivo

Ex vivolung epithelial cells from IAV-infected mice more rapidly control IAV than cells from naïve animals in the absence of immune cells.