bluuebunny/crossref_metadata_2025 huggingface dataset:
Trends in Residency Academic Productivity of Ophthalmic Plastic and Reconstructive Surgery Fellows Between 2012 and 2019
Authors: Huang Austin , Kirby R. Parker , Huang Kevin Y. , Du Tony , Mu Andrew , Wu Samuel , Nguyen Celine , Dang Rachel , Yoon Stephen P. , Yen Michael T. , Al-Mohtaseb Zaina
Published: February 2023

Purpose:

To characterize research productivity of ophthalmic plastic and reconstructive surgery (OPRS) fellows during residency.

Methods:

A database was compiled of OPRS fellows listed on the American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS) Annual Fall Scientific Symposium program books who began their fellowship between 2012 and 2019. PubMed was searched for all publications published between July 1st of the year they began residency and September 30th of the year they began fellowship training. Bibliometric variables captured for each fellow included: the number of publications, first-author publications, and ophthalmology-related publications.

Results:

A total of 197 OPRS fellows who began their fellowship training between 2012 and 2019 published a mean (± SD) of 2.42 ± 2.80 publications, 1.43 ± 1.85 first-author publications, and 2.33 ± 2.74 ophthalmology-related publications during residency. Linear regression revealed that the number of publications (P < 0.001), first-author publications (P < 0.001), and ophthalmology-related publications (P < 0.001)that OPRS fellows published during residency have all significantly increased over the time assessed.

Conclusions:

The academic productivity of OPRS fellows during residency was quantified through bibliometric analysis to establish a national benchmark for the benefit of both prospective applicants and program directors. Residency research output of OPRS fellows has significantly increased between 2012 and 2019. Since ASOPRS program requirements necessitate academic productivity and thesis completion, publication records and involvement in research become valuable considerations when evaluating fellowship applicants. The knowledge of what accepted fellows have published provides the opportunity to make historical comparisons and may prove useful in the evaluation of the competitiveness of a given year’s applicant pool.
The roles of 68Ga-PSMA PET/CT and 18F-FDG PET/CT imaging in patients with triple-negative breast cancer and the association of tissue PSMA and claudin 1, 4, and 7 levels with PET findings
Authors: Arslan Esra , Ergül Nurhan , Beyhan Ediz , Erol Fenercioglu Özge , Sahin Rahime , Cin Merve , Battal Havare Semiha , Can Trabulus Fadime Didem , Mermut Özlem , Akbas Sinem , Fikret Çermik Tevfik
Published: February 2023

Aim

Aim of study is to compare the results of Gallium-68-prostate-specific membrane antigen (68Ga-PSMA) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography(PET)/computed tomography (CT), to evaluate the correlation between PET findings and the level of PSMA, Claudin (Clau) 1, 4, and 7 receptors obtained by immunohistochemical (IHC) analysis, and to determine potential predictive and prognostic values in TNBC.

Methods

Forty-seven lesions of 42 subjects diagnosed TNBC both underwent PET/CT scan for preoperative staging/restaging were prospectively included study. PSMA, Clau 1, 4, and 7 expressions were IHC evaluated from the biopsy samples of the primary tumor (PT). Maximum standardized uptake value(SUV max) of the PT, lymph node, and distant organ metastases (DOMs) on 18F-FDG and 68Ga-PSMA PET/CT were compared with PSMA, Clau 1, 4, and 7 receptor expressions.

Results

IHC analyses on 29 BC lesions to demonstrate Clau expression showed 86% (25/29) Clau 1, 86% (25/29) Clau 4, 45% (13/29) Clau 7, and 48% (14/29) PSMA-positive. The mean DOM (SUVmax) was 15.5 ± 11.6 for 18F-FDG and 6.0 ± 2.9 for 68Ga-PSMA. Axial diameter of BC PT had a significant positive correlation with 18F-FDG SUVmax, 68Ga-PSMA SUVmax, and PSMA scores. BC lesions 68Ga-PSMA SUVmax had a significant negative correlation with the Ki-67 index. Axial diameter of the primary tumor had significant negative correlation with Clau 7 scores (r = −0.409, P = 0.034). Absence of Clau 1 expression found to significantly increase the rate of DOM (100% vs. 28%) (P = 0.014). All patients with axillary lymph node (ALN) metastases (n = 17, 100%) exhibited Clau 4 positivity (P = 0.021). The presence of PSMA expression observed to significantly increase the rate of ALN metastases (64.7% vs. 25%) (P = 0.035).

Conclusion

Confirming PSMA expression with PET imaging would be significant as PSMA, a theranostic agent, may be a considerable potential agent for radionuclide treatment strategies, in addition to its additional diagnostic contribution to FDG, especially in patients with metastatic TNBC, which is an aggressive, heterogeneous disease.
Factors Affecting Presentation and Treatment of Pediatric/Adolescent Cancer Patients Diagnosed With SARS-CoV-2
Authors: Sharma Ishna , Hamby Tyler , Noorani Sahil , Liu Angela , Omar Salma , Ahmad Hufsa , Watts Shelley , Hoeft Alice , Whitworth Suzanne , Ray Anish
Published: February 2023

Background:

It is thought that the clinical course of actively treated pediatric/adolescent cancer patients diagnosed with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is more severe than experienced by the general pediatric population. We describe the clinical course, risk factors affecting presentation, and management of coronavirus disease 2019 (COVID-19) infection for these patients.

Methods:

Patients at a single institution receiving cancer therapy while diagnosed with SARS-CoV-2 between January 2020 and June 2021 were retrospectively reviewed. Data collected included age at SARS-CoV-2 diagnosis, sex, ethno-race, adjusted body mass index, and active therapies.

Results:

Twenty-nine patients met inclusion criteria, with 16 (55.2%) experiencing symptoms. Twenty-three (79.3%) patients required no institutional support; 10 (34.4%) required hospitalization, of which 80.0% required oxygen, 30.0% required intensive care, and 10.0% required intubation. Three (10.3%) patients developed MIS-C. Obesity increased odds of hospitalization (odds ratio=25.5; P=0.002) and oxygenation (odds ratio=14.88; P=0.012).

Conclusions:

Hospitalization and MIS-C rates were significantly higher than, whereas mortality rates and symptom presentations were consistent with, rates in the general pediatric population. Obesity was the only risk factor predictive of clinical severity. Cancer treatment modifications and pre-emptive administration of COVID-19 treatment did not modify clinical course.
Ring formation byVibriofusion protein composed of FliF and FliG, MS-ring and C-ring component of bacterial flagellar motor in membrane
Authors: Takahashi Kanji , Nishikino Tatsuro , Kajino Hiroki , Kojima Seiji , Uchihashi Takayuki , Homma Michio
Published: February 2023

The marine bacteriumVibrio alginolyticushas a single flagellum as a locomotory organ at the cell pole, which is rotated by the Na+-motive force to swim in a liquid. The base of the flagella has a motor composed of a stator and rotor, which serves as a power engine to generate torque through the rotor–stator interaction coupled to Na+influx through the stator channel. The MS-ring, which is embedded in the membrane at the base of the flagella as part of the rotor, is the initial structure required for flagellum assembly. It comprises 34 molecules of the two-transmembrane protein FliF. FliG, FliM, and FliN form a C-ring just below the MS-ring. FliG is an important rotor protein that interacts with the stator PomA and directly contributes to force generation. We previously found that FliG promotes MS-ring formation inE. coli. In the present study, we constructed afliF–fliGfusion gene, which encodes an approximately 100 kDa protein, and the successfully production of this protein effectively formed the MS-ring inE. colicells. We observed fuzzy structures around the ring using either electron microscopy or high-speed atomic force microscopy (HS-AFM), suggesting that FliM and FliN are necessary for the formation of a stable ring structure. The HS-AFM movies revealed flexible movements at the FliG region. We speculate that this flexibility plays a crucial role in facilitating the interaction between the cytoplasmic region of PomA and FliG to generate force.

IMPORTANCE

MS-ring is the initial structure to be assembled in flagellar motors. It comprises a complex two-ring (M and S) structure composed of 34 FliF molecules. We prepared a FliF–FliG fusion protein, which is directly involved in force generation. We observed it enabled the efficient formation of the MS-ring. The FliG portion that usually comprises the C-ring along with FliM and FliN displayed high flexibility likely due to the lack of FliM and FliN in the fusion protein. This study represents a significant milestone in thein vitroreconstruction of Na+-driven motor complexes.
Abnormal Intraepidermal Nerve Fiber Density in Disease: A Scoping Review
Authors: Thomas SJ , Enders J , Kaiser A , Rovenstine L , Heslop L , Hauser W , Chadwick A , Wright DE
Published: February 2023

Background

Intraepidermal nerve fiber density (IENFD) has become an important biomarker for neuropathy diagnosis and research. The consequences of reduced IENFD can include sensory dysfunction, pain, and a significant decrease in quality of life. We examined the extent to which IENFD is being used as a tool in human and mouse models and compared the degree of fiber loss between diseases to gain a broader understanding of the existing data collected using this common technique.

Methods

We conducted a scoping review of publications that used IENFD as a biomarker in human and non-human research. PubMed was used to identify 1,004 initial articles that were then screened to select articles that met the criteria for inclusion. Criteria were chosen to standardize publications so they could be compared rigorously and included having a control group, measuring IENFD in a distal limb, and using protein gene product 9.5 (PGP9.5).

Results

We analyzed 397 articles and collected information related to publication year, the condition studied, and the percent IENFD loss. The analysis revealed that the use of IENFD as a tool has been increasing in both human and non-human research. We found that IENFD loss is prevalent in many diseases, and metabolic or diabetes-related diseases were the most studied conditions in humans and rodents. Our analysis identified 74 human diseases in which IENFD was affected, with 71 reporting IENFD loss and an overall average IENFD change of -47%. We identified 28 mouse and 21 rat conditions, with average IENFD changes of -31.6 % and - 34.7% respectively. Additionally, we present data describing sub-analyses of IENFD loss according to disease characteristics in diabetes and chemotherapy treatments in humans and rodents.

Interpretation

Reduced IENFD occurs in a surprising number of human disease conditions. Abnormal IENFD contributes to important complications, including poor cutaneous vascularization, sensory dysfunction, and pain. Our analysis informs future rodent studies so they may better mirror human diseases impacted by reduced IENFD, highlights the breadth of diseases impacted by IENFD loss, and urges exploration of common mechanisms that lead to substantial IENFD loss as a complication in disease.
A Systematic Review of the Association between the Age of Onset of Spinal-Bulbar Muscular Atrophy (Kennedy’s Disease) and the Length of CAG Repeats in the Androgen Receptor Gene
Authors: Bellai Dante J. , Rae Mark G.
Published: February 2023

Background

Spinal bulbar muscular atrophy (SBMA) is an X-linked recessive motor neuron disorder which is caused by the presence of ≥ 38 CAG repeats in the androgen receptor gene. Relatively little is known about SBMA, but existing literature indicates a relationship between CAG repeat number and the onset age of some motor symptoms of SBMA. This literature review explored the effect of larger CAG repeats on the age of weakness onset compared to shorter length CAG repeats in male SBMA patients.

Methods

Three databases were searched (MEDLINE, SCOPUS, and Web of Science; Oct 2021) along with targeted searches in Cambridge University Press and Annals of Neurology. 514 articles were initially identified, of which 13 were included for qualitative synthesis.

Results

Eleven of the thirteen articles identified a statistically significant inverse correlation between CAG repeat length and age of weakness onset in SBMA. Five studies indicated that SBMA patients with fewer CAG repeats (e.g. 35-37) had an older age of weakness onset than patients with a greater number (e.g. >40) of CAG repeats. The minimum number of CAG repeats associated with weakness was numbered in the mid-to-late thirties.

Conclusion

Identification of a relationship between CAG repeat number and weakness may enable earlier detection and intervention for SBMA.

Limitations of this review include the restriction to English-only studies and differences in statistical methodology used in each study. We recommend that future studies use interviews, chart reviews, and standardized scoring methods to reduce effects of retrospective bias on reporting SBMA signs and symptoms.
Lysis cassette-mediated exoprotein release inYersinia entomophagais controlled by a PhoB- like regulator
Authors: Schoof Marion , O’Callaghan Maureen , Hefer Charles , Glare Travis R. , Paulson Amber R. , Hurst Mark R.H.
Published: February 2023

Secretion of exoproteins is a key component of bacterial virulence and is tightly regulated in response to environmental stimuli and host-dependent signals. The entomopathogenic bacteriumYersinia entomophagaMH96 produces a wide range of exoproteins including its main virulence factor, the 2.46 MDa insecticidal Yen-Tc toxin complex. Previously, a high-throughput transposon-based screening assay identified the region of exoprotein release (YeRER) as essential to exoprotein release in MH96. The current study defines the role of the YeRER-associatedambiguous holin/endolysin-based lysiscluster (ALC) and the novel RoeA regulator in the regulation and release of exoproteins in MH96. A mutation in the ALC region abolished exoprotein release and caused cell elongation, a phenotype able to be restored throughtrans-complementation with an intact ALC region. Endogenous ALC did not impact cell growth of the wild type, while artificial expression of an optimised ALC caused cell lysis. Using HolA-sfGFP and Rz1-sfGFP reporter, Rz1 expression was observed in all cells while HolA expression was limited to a small proportion of cells, which increased over time. Transcriptomic assessments found expression of the genes encoding the prominent exoproteins, including the Yen-Tc, was reduced in theroeAmutant and identified a 220 ncRNA of the YeRER intergenic that, whentranscomplemented in the wildtype, abolished exoprotein release. A model forY. entomophagamediated exoprotein regulation and release is proposed.

Importance

While theoretical models exist, there is not yet any empirical data that links ALC phage-like lysis cassettes with the release of large macro-molecular toxin complexes such as Yen-Tc in Gram-negative bacteria. In this study, we demonstrate that the novelY. entomophagaRoeA activates the production of exoproteins (including Yen-Tc) and the ALC at the transcriptional level. The translation of the ALC holin is confined to a subpopulation of cells that then lyse over time, indicative of a complex hierarchical regulatory network. The presence of orthologous RoeA orthologue and a HolA like holin 5’ of an eCIS Afp element inPseudomonas chlororaphiscombined with the presented data suggests a shared mechanism is required for the release of some large macromolecular protein assemblies such as the Yen-Tc, and further supports classification of phage-like lysis clusters as type 10 secretion systems.
aweMAGs: a fully automated workflow for quality assessment and annotation of eukaryotic genomes from metagenomes
Authors: Albanese Davide , Coleine Claudia , Selbmann Laura , Donati Claudio
Published: February 2023

Metagenomics is one of the most promising approaches to identify and characterize novel microbial species from environmental samples. While a large amount of prokaryotic metagenome assembled genomes (MAGs) have been published, only a few examples of eukaryotic MAGs have been reported. This is in part due to the absence of dedicated and easy-to-use processing pipelines. Quality assessment, annotation and phylogenomic placement of eukaryotic MAGs involve the use of several computational tools and reference databases that are often difficult to collect and maintain. We present metashot/aweMAGs, a fully automated workflow capable of performing all these steps. metashot/aweMAGs can run out-of-the-box on any platform that supports Docker, Singularity and Nextflow, including computing clusters or batch systems in the cloud.
Targeting the cell and non-cell autonomous regulation of 47S synthesis by GCN2 in colon cancer
Authors: Piecyk Marie , Triki Mouna , Laval Pierre-Alexandre , Duret Cedric , Fauvre Joelle , Cussonneau Laura , Machon Christelle , Guitton Jerôme , Rama Nicolas , Gibert Benjamin , Ichim Gabriel , Catez Frederic , Bourdelais Fleur , Durand Sebastien , Diaz Jean-Jacques , Coste Isabelle , Renno Toufic , Manié Serge N , Aznar Nicolas , Ansieau Stephane , Ferraro-Peyret Carole , Chaveroux Cedric
Published: February 2023

Nutrient availability is a key determinant of tumor cell behavior. While nutrient-rich conditions favor proliferation and tumor growth, scarcity, and particularly glutamine starvation, promotes cell dedifferentiation and chemoresistance. Here, linking ribosome biogenesis plasticity with tumor cell fate, we uncover that the amino acid sensor GCN2 represses the expression of the precursor of ribosomal RNA, 47S, under metabolic stress. We show that blockade of GCN2 triggers cell death by an irremediable nucleolar stress and subsequent TP53-mediated apoptosis in patient-derived models of colon adenocarcinoma (COAD). In nutrient-rich conditions, GCN2 activity supports cell proliferation through the transcription stimulation of 47S rRNA, independently of the canonical ISR axis. However, impairment of GCN2 activity prevents nuclear translocation of the methionyl tRNA synthetase (MetRS) underlying the generation of a nucleolar stress, mTORC1 inhibition and autophagy induction. Inhibition of the GCN2-MetRS axis drastically improves the cytotoxicity of RNA pol I inhibitors, including the first-line chemotherapy oxaliplatin, on patient-derived COAD tumoroids. Our data thus reveal that GCN2 differentially controls the ribosome biogenesis according the nutritional context. Furthermore, pharmacological co-inhibition of the two GCN2 branches and the RNA pol I activity may represent a valuable strategy for elimination of proliferative and metabolically-stressed COAD cell.
Comparative proteomics of vesicles essential for the egress ofPlasmodium falciparumgametocytes from red blood cells
Authors: Sassmannshausen Juliane , Bennink Sandra , Distler Ute , Küchenhoff Juliane , Minns Allen M. , Lindner Scott E. , Burda Paul-Christian , Tenzer Stefan , Gilberger Tim W. , Pradel Gabriele
Published: February 2023

Transmission of malaria parasites to the mosquito is mediated by sexual precursor cells, the gametocytes. Upon entering the mosquito midgut, the gametocytes egress from the enveloping erythrocyte while passing through gametogenesis. Egress follows an inside-out mode during which the membrane of the parasitophorous vacuole ruptures prior to the erythrocyte membrane. Membrane rupture requires the exocytosis of specialized secretory vesicles of the parasites; i.e. the osmiophilic bodies (OBs) involved in rupturing the parasitophorous vacuole membrane, and vesicles (here termed g-exonemes) that harbour the perforin-like protein PPLP2 required for erythrocyte lysis. While several OB proteins are known, like G377 and MDV1/Peg3, the protein composition of the g-exonemes remains unclear. Here, we used high- resolution imaging and BioID methods to study the two types of egress vesicles inPlasmodium falciparumgametocytes. We show that OB exocytosis precedes discharge of the g-exonemes and that exocytosis of the g-exonemes, but not of the OBs, is calcium-sensitive. Further, the two types of vesicles exhibit distinct proteomes. In addition to known egress-related proteins, our analyses revealed novel components of OBs and g-exonemes, including proteins involved in vesicle trafficking. Our data provide insight into the immense molecular machinery required for the inside-out egress ofP. falciparumgametocytes.
A novel HERC4-dependent glue degrader targeting STING
Authors: Mutlu Merve , Schmidt Isabel , Morrison Andrew I. , Goretzki Benedikt , Freuler Felix , Begue Damien , Pythoud Nicolas , Ahrne Erik , Kapps Sandra , Roest Susan , Bonenfant Debora , Jeanpierre Delphine , Tran Thi-Thanh-Thao , Maher Rob , An Shaojian , Rietsch Amandine , Nigsch Florian , Hofmann Andreas , Reece-Hoyes John , Parker Christian N. , Guerini Danilo
Published: February 2023

Stimulator of interferon genes (STING) is a central component of the pathway sensing the presence of cytosolic nucleic acids, having a key role in type I interferon innate immune response. Localized at the endoplasmic reticulum (ER), STING becomes activated by cGAMP, which is generated by the intracellular DNA sensor cyclic GMP-AMP synthase (cGAS). Due to its critical role in physiological function and its ‘ involvement in a variety of diseases, STING has been a notable focus for drug discovery. Recent advances in drug discovery allow the targeting of proteins previously considered “un-druggable” by novel mechanism of actions. Molecular glue degraders are defined as the compounds leading targeted protein degradation (TPD) by creating novel ligase-substrate interactions. Here, we identified AK59 as a novel molecular glue degrader for STING. A genome-wide, CRISPR/Cas9 knockout screen showed that the compound-mediated degradation of STING by AK59 is compromised by the loss of HECT and RLD domain containing E3 ubiquitin protein ligase 4 (HERC4), ubiquitin-like modifier activating enzyme 5 (UBA5) and ubiquitin like modifier activating enzyme 6 (UBA6). While UBA5 and UBA6 could be the auxiliary factors for AK59 activity, our results indicate that HERC4 is the main E3 ligase for the observed degradation mechanism. Validation by individual CRISPR knockouts, co-immunoprecipitations, as well as proximity mediated reporter assays suggested that AK59 functions as a glue degrader by forming a novel interaction between STING and HERC4. Furthermore, our data reveals that AK59 was effective on the most common pathological STING mutations that cause STING-associated vasculopathy with onset in infancy (SAVI), suggesting a potential clinical application of this mechanism. Thus, these findings not only reveal a novel mechanism for compound-induced degradation of STING but also utilize HERC4 as potential E3 ligase that for TPD, enabling novel therapeutic applications.
Field and genetic evidence support the photosynthetic performance index (PIABS) as an indicator of rice grain yield
Authors: Rodríguez Andrés Alberto , Vilas Juan Manuel , Sartore Gustavo Daniel , Bezus Rodolfo , Colazo José , Maiale Santiago Javier
Published: February 2023

The effective increase of the rice breeding process for grain yield could be sustained by developing efficient tools to accelerate plant selection through the rapid determination of reliable predictors. Here, we have described different associations between grain yield and photosynthetic parameters simply and fast obtainable by a non-invasive technique in flag leaf during the anthesis stage. Among the analyzed photosynthetic parameters, the photosynthetic performance index (PIABS) stood out for its strong association with grain yield. A genome-wide association analysis determined in plants from a rice diversity panel at tillering stage indicated the presence of a quantitative trait locus on chromosome 9 characterized by a set of candidate chloroplastic genes with contrasting haplotypes for PIABS. An analysis of these haplotypes indicated a separation into two groups. One with haplotypes linked to high values of PIABS, which were associated almost exclusively withJaponicaspp. subpopulations, and another with haplotypes linked to low values of PIABS, which were associated exclusively withIndicaspp. subpopulations. Genotypes of theJaponicaspp. subpopulations showed high values in panicle weight, a yield components parameter, compared with theIndicaspp. subpopulations genotypes. The results of this work suggested that PIABScould be an early predictor of grain yield at the tillering stage in rice breeding processes.
8-channel Tx dipole and 20-channel Rx loop coil array for MRI of the cervical spinal cord at 7 Tesla
Authors: Rios Nibardo Lopez , Gilbert Kyle M. , Papp Daniel , Cereza Gaspard , Foias Alexandru , Rangaprakash D. , May Markus W. , Guerin Bastien , Wald Lawrence L. , Keil Boris , Stockmann Jason P. , Barry Robert L. , Cohen-Adad Julien
Published: February 2023

The quality of cervical spinal cord images can be improved by the use of tailored radiofrequency coil solutions for ultra-high field imaging; however, very few commercial and research 7 Tesla radiofrequency coils currently exist for the spinal cord, and in particular those with parallel transmit capabilities. This work presents the design, testing and validation of a pTx/Rx coil for the human neck and cervical/upper-thoracic spinal cord. The pTx portion is composed of 8 dipoles to ensure high homogeneity over this large region of the spinal cord. The Rx portion is made of 20 semi-adaptable overlapping loops to produce high Signal-to-noise ratio (SNR) across the patient population. The coil housing is designed to facilitate patient positioning and comfort, while being tight fitting to ensure high sensitivity. We demonstrate RF shimming capabilities to optimize B1+uniformity, power efficiency and/or specific absorption rate (SAR) efficiency. B1+homogeneity, SNR and g-factor was evaluated in adult volunteers and demonstrated excellent performance from the occipital lobe down to the T4-T5 level. We compared the proposed coil with two state-of-the-art head and head/neck coils, confirming its superiority in the cervical and upper-thoracic regions of the spinal cord. This coil solution therefore provides a convincing platform for producing the high image quality necessary for clinical and research scanning of the upper spinal cord.
Out of sight, out of mind: Responses in primate ventral visual cortex track individual fixations during natural vision
Authors: Xiao Will , Sharma Saloni , Kreiman Gabriel , Livingstone Margaret S.
Published: February 2023

During natural vision, primates shift their gaze several times per second with large, ballistic eye movements known as saccades. Open questions remain as to whether visual neurons retain their classical retinotopic response properties during natural vision or whether neurons integrate information across fixations and predict the consequences of impending saccades. Answers are especially wanting for vision in complex scenes relevant to natural behavior. We let 13 monkeys freely view thousands of large natural images, recorded over 883 hours of neuronal responses throughout the ventral visual pathway across 4.7 million fixations, and designed flexible analyses to reveal the spatial, temporal, and feature selectivity of the responses. Ventral visual responses followed each fixation and did not become gaze-invariant as monkeys examined an image over seconds. Computational models revealed that neuronal responses corresponded to eye-centered receptive fields. The results suggest that ventral visual cortex remains predominantly retinotopic during natural vision and does not establish a gaze-independent representation of the world.
The impossible challenge of estimating non-existent moments of the Chemical Master Equation
Authors: Wagner Vincent , Radde Nicole
Published: February 2023

Motivation

The Chemical Master Equation is a set of linear differential equations that describes the evolution of the probability distribution on all possible configurations of a (bio-)chemical reaction system. Since the number of configurations and therefore the dimension of the CME rapidly increases with the number of molecules, its applicability is restricted to small systems. A widely applied remedy for this challenge are moment-based approaches which consider the evolution of the first few moments of the distribution as summary statistics for the complete distribution. Here, we investigate the performance of two moment-estimation methods for reaction systems whose equilibrium distributions encounter heavy-tailedness and hence do not possess statistical moments.

Results

We show that estimation via Stochastic Simulation Algorithm trajectories lose consistency over time and estimated moment values span a wide range of values even for large sample sizes. In comparison, the Method of Moments returns smooth moment estimates but is not able to indicate the nonexistence of the allegedly predicted moments. We furthermore analyze the negative effect of a CME solution’s heavy-tailedness on SSA run times and explain inherent difficulties.

While moment estimation techniques are a commonly applied tool in the simulation of (bio-)chemical reaction networks, we conclude that they should be used with care, as neither the system definition nor the moment estimation techniques themselves reliably indicate the potential heavy-tailedness of the CME’s solution.
P53 Acetylation Exerts Critical Roles In Pressure Overload Induced Coronary Microvascular Dysfunction and Heart Failure
Authors: He Xiaochen , Cantrell Aubrey C , Williams Quinesha A , Gu Wei , Chen Yingjie , Chen Jian-Xiong , Zeng Heng
Published: February 2023

Coronary microvascular dysfunction (CMD) has been shown to contribute to cardiac hypertrophy and heart failure with preserved ejection fraction. At this point, there are no proven treatments for CMD. We have shown that histone acetylation may play a critical role in the regulation of CMD. By using a mouse model that replaces lysine with arginine at residues K98/117/161/162R of p53 (p534KR), preventing acetylation at these sites, we test the hypothesis that acetylation-deficient p534KRcould improve coronary microvascular dysfunction and prevent the progression of hypertensive cardiac hypertrophy and heart failure. Wild-type (WT) and p534KRmice were subjected to pressure overload (PO) by transverse aortic constriction to induce cardiac hypertrophy and heart failure (HF). Echocardiography measurements revealed improved cardiac function together with reduction of apoptosis and fibrosis in p534KRmice. Importantly, myocardial capillary density and coronary flow reserve (CFR) were significantly improved in p534KRmice. Moreover, p534KRupregulated the expression of cardiac glycolytic enzymes and glucose transporters, as well as the level of fructose-2,6-biphosphate; increased PFK-1 activity; and attenuated cardiac hypertrophy. These changes were accompanied by increased expression of HIF-1α and proangiogenic growth factors. Additionally, the levels of SERCA-2 were significantly upregulated in sham p534KRmice as well as in p534KRmice after TAC.In vitro, p534KRsignificantly improved endothelial cell (EC) glycolytic function and mitochondrial respiration, and enhanced EC proliferation and angiogenesis. Similarly, acetylation-deficient p534KRsignificantly improved CFR and rescued cardiac dysfunction in SIRT3 KO mice. Our data reveal the importance of p53 acetylation in coronary microvascular function, cardiac function, and remodeling, and may provide a promising approach to improve hypertension-induced coronary microvascular dysfunction (CMD) and to prevent the transition of cardiac hypertrophy to heart failure.
WITHDRAWN: Enhancing Mutational Hotspot Predictions: The Role of Atomic Fluctuations
Authors: Martis Elvis A. F. , Coutinho Evans C.
Published: February 2023

Withdrawal Statement

The authors have withdrawn this manuscript because the reviewers have suggested significant revision of the manuscript. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Rice plants alter their yield component parameters based on their tolerance to low temperatures determined by a non-invasive method during the vegetative stage
Authors: Carolina Michelini María , Gazquez Ayelén , Checovich Mariana Leonela , Maiale Santiago Javier , Menéndez Ana Bernardina , Rodríguez Andrés Alberto
Published: February 2023

The first rice phenological stages are commonly subjected to low temperatures (LT) in temperate crop areas. Here, plants of rice genotypes were analyzed according to their LT tolerance at seedling stage, using a realistic experimental temperatures range, and measuring quantitative and operator-independent parameters, fast-obtainable by non-invasive techniques. The ratios between values of these parameters determined in plants under LT condition with respect to the control condition were statistically analyzed. We have found a discriminant formula based on two parameters that allowed to differentiate between genotypes previously described as tolerant and sensitive to LT, with a very low general classification error. The application of the discriminant formula to score plants under LT, using all genotypes from the Rice Diversity Panel 1 which comprehensively represents the genetic variability of theO. sativaspecies, resulted in LT tolerance levels of its subspecies and subpopulations consistent with previous reports. In turn, a strong association between the LT tolerance score at the seedling stage and the panicle weight in plants under field LT during the vegetative stage, suggested that this scoring could be used as an indirect selection factor of genotypes with good yield traits and suited to LT prone environments.
A Non-Canonical IRAK Signaling Pathway Triggered by DNA Damage
Authors: Li Yuanyuan , Shah Richa B. , Sarti Samanta , Belcher Alicia L. , Lee Brian J. , Gorbatenko Andrej , Nemati Francesca , Yu Ian , Stanley Zoe , Shao Zhengping , Silva Jose M. , Zha Shan , Sidi Samuel
Published: February 2023

Interleukin-1 receptor (IL-1R)-associated kinases (IRAKs) are core effectors of Toll-like receptor (TLR) and IL-1R signaling, with no reported roles outside of innate immunity. We find that vertebrate cells exposed to ionizing radiation (IR) sequentially activate IRAK4 and IRAK1 through a phosphorylation cascade mirroring that induced by TLR/IL-1R, resulting in a potent anti-apoptotic response. However, IR-induced IRAK1 activation does not require the receptors or the IRAK4/1 adaptor protein MyD88, and instead of remaining in the cytoplasm, the activated kinase is immediately transported to the nucleus via a conserved nuclear localization signal. We identify: double-strand DNA breaks (DSBs) as the biologic trigger for this pathway; the E3 ubiquitin ligase Pellino1 as the scaffold enabling IRAK4/1 activation in place of TLR/IL-1R-MyD88; and the pro-apoptotic PIDDosome (PIDD1-RAIDD-caspase-2) as a critical downstream target in the nucleus. The data delineate a non-canonical IRAK signaling pathway derived from, or ancestral to, TLR signaling. This DSB detection pathway, which is also activated by genotoxic chemotherapies, provides multiple actionable targets for overcoming tumor resistance to mainstay cancer treatments.
Maturation of Nucleus Accumbens Synaptic Transmission Signals a Critical Period for the Rescue of Social Deficits in a Mouse Model of Autism Spectrum Disorder
Authors: Matthiesen Melina , Khlaifia Abdessattar , Steininger Carl Frank David , Dadabhoy Maryam , Mumtaz Unza , Arruda-Carvalho Maithe
Published: February 2023

Social behavior emerges early in development, a time marked by the onset of neurodevelopmental disorders featuring social deficits, including autism spectrum disorder (ASD). Although deficits in social interaction and communication are at the core of the clinical diagnosis of ASD, very little is known about their neural correlates at the time of clinical onset of the disorder. The nucleus accumbens (NAc), a brain region extensively implicated in social behavior, undergoes synaptic, cellular and molecular alterations in early life, and is particularly affected in ASD mouse models. To explore a link between the maturation of the NAc and neurodevelopmental deficits in social behavior, we compared age-dependent changes in spontaneous synaptic transmission in NAc shell medium spiny neurons (MSNs) between the highly social C57BL/6J mouse strain and the idiopathic ASD mouse model BTBRT+Itpr3tf/Jat postnatal day (P) 4, P6, P8, P12, P15, P21 and P30. We found that MSNs from both C57BL/6J and BTBR mice display age-dependent increases in spontaneous excitatory and inhibitory synaptic currents between P4 and P30. Comparison of NAc spontaneous transmission between strains showed that BTBR MSNs display increased excitatory transmission during the first postnatal week, and increased inhibition across the first, second and fourth postnatal weeks, suggesting accelerated maturation of excitatory and inhibitory synaptic inputs onto BTBR MSNs compared to C57BL/6J mice. These early life changes in synaptic transmission are consistent with a potential critical period in the maturation of the NAc, which could maximize the efficacy of interventions affecting social behavior. To test this possibility, we treated BTBR mice in either early life (P4-P8) or adulthood (P60-P64) with the mTORC1 antagonist rapamycin, a well-established rescue intervention for ASD-like behavior. We found that rapamycin treatment rescued social interaction deficits in BTBR mice when injected in infancy, but not in adulthood. These data emphasize the importance of studying brain regions involved in the pathophysiology of neurodevelopmental disorders at clinically-relevant time points, which may offer novel insight into the timing and targets of therapeutic interventions to maximize positive outcomes.
Hippocampal mechanisms support cortisol-induced memory enhancements
Authors: Sherman Brynn E. , Harris Bailey B. , Turk-Browne Nicholas B. , Sinha Rajita , Goldfarb Elizabeth V.
Published: February 2023

Stress can powerfully influence episodic memory, often enhancing memory encoding for emotionally salient information. These stress-induced memory enhancements stand at odds with demonstrations that stress and the stress-related hormone cortisol can negatively affect the hippocampus, a brain region important for episodic memory encoding. To resolve this apparent conflict and determine whether and how the hippocampus supports memory encoding under cortisol, we combined behavioral assays of associative memory, high-resolution functional magnetic resonance imaging (fMRI), and pharmacological manipulation of cortisol in a within-participant, double-blinded procedure. Hydrocortisone led to enhanced functional connectivity between hippocampal subregions, which predicted subsequent memory enhancements for emotional information. Cortisol also modified the relationship between hippocampal representations and memory: whereas hippocampal signatures of distinctiveness predicted memory under placebo, relative integration predicted memory under cortisol. Together, these data provide novel evidence that the human hippocampus contains the necessary machinery to support emotional memory enhancements under stress.
Fast And Accurate Population Level Transcranial Magnetic Stimulation via Low-Rank Probabilistic Matrix Decomposition (PMD)
Authors: Hasan Nahian I. , Wang Dezhi , Gomez Luis J.
Published: February 2023

Transcranial magnetic stimulation (TMS) is used to study brain function and treat mental health disorders. During TMS, a coil placed on the scalp induces an E-field in the brain that modulates its activity. TMS is known to stimulate regions that are exposed to a large E-field. Clinical TMS protocols prescribe a coil placement based on scalp landmarks. There are inter-individual variations in brain anatomy that result in variations in the TMS-induced E-field at the targeted region and its outcome. These variations across individuals could in principle be minimized by developing a large database of head subjects and determining scalp landmarks that maximize E-field at the targeted brain region while minimizing its variation using computational methods. However, this approach requires repeated execution of a computational method to determine the E-field induced in the brain for a large number of subjects and coil placements. We developed a probabilistic matrix decomposition-based approach for rapidly evaluating the E-field induced during TMS for a large number of coil placements. Our approach can determine the E-field induced in over 1 Million coil placements in 9.5 hours, in contrast, to over 5 years using a bruteforce approach. After the initial set-up stage, the E-field can be predicted over the whole brain within 2-3 milliseconds and to 2% accuracy. We tested our approach in over 200 subjects and achieved an error of < 2% in most and < 3.5% in all subjects. We will present several examples of bench-marking analysis for our tool in terms of accuracy and speed across and its applicability for population level optimization of coil placement.

Graphical Abstract

Highlights

A method for practical E-field informed population-level TMS coil placement strategies is developed.

This algorithm enables the determination of E-field informed optimal coil placement in seconds enabling it’s use for close-loop and on-the-fly reconfiguration of TMS.

After the initial set-up stage of less than 10 hours, the E-field can be predicted for any coil placement across the whole brain within in 2-3 milliseconds.
Proteome-wide comparison of tertiary protein structures reveal extensive molecular mimicry inPlasmodium-human interactions
Authors: Muthye Viraj , Wasmuth James D.
Published: February 2023

Molecular mimicry is a strategy used by parasites to escape the host immune system and successfully transmit to a new host. To date, high-throughput examples of molecular mimicry have been limited to comparing protein sequences. However, with advances in the prediction of tertiary structural models, led by Deepmind’s AlphaFold, it is now possible to compare the tertiary structures of thousands of proteins from parasites and their hosts, to identify more subtle mimics. Here, we present the first proteome-level search for tertiary structure similarity between the proteins fromPlasmodium falciparumand human. Of 206P. falciparumproteins that have previously been proposed as mediators ofPlasmodium-human interactions, we propose that seven evolved to molecularly mimic a human protein. By expanding the approach to allP. falciparumproteins, we identified a further 386 potential mimics, with 51 proteins corroborated by additional biological data. These findings demonstrate a valuable application of AlphaFold-derived tertiary structural models, and we discuss key considerations for its effective use in other host-parasite systems.
Phytochrome higher order mutants reveal a complex set of light responses in the mossPhyscomitrium patens
Authors: Yuan Jinhong , Xu Tengfei , Hiltbrunner Andreas
Published: February 2023

Phytochromes are photoreceptors enabling plants to respond to various light conditions. Independent gene duplication events resulted in small phytochrome gene families in mosses, ferns, and seed plants. This phytochrome diversity is hypothesised to be critical for sensing and adapting to different light conditions, but experimental evidence for this idea is lacking for mosses and ferns.

The model moss speciesPhyscomitrium patenscontains seven phytochromes grouped into three clades, PHY1/3, PHY2/4, and PHY5. Here, we used CRISPR/Cas9 generated single and higher order mutants to investigate their role in light-regulation of protonema and gametophore growth, protonema branching, and induction of gametophores.

We found both specific and partially overlapping roles for the three clades of moss phytochromes in regulating these responses in different light conditions, and we identified a mechanism for sensing simulated canopy shade different from the mechanism in seed plants. PHY1/3 clade phytochromes act as primary far-red light receptors, while PHY5 clade phytochromes are the primary red light receptors. PHY2/4 clade phytochromes have functions in both red and far-red light.

Similar to seed plants, gene duplication events in the phytochrome lineage in mosses were followed by functional diversification into red and far-red light sensing phytochromes.
Enzyme-less nanopore detection of post-translational modifications within long polypeptides
Authors: Martin-Baniandres Pablo , Lan Wei-Hsuan , Board Stephanie , Romero-Ruiz Mercedes , Garcia-Manyes Sergi , Qing Yujia , Bayley Hagan
Published: February 2023

Means to sequence DNA and RNA quickly and cheaply have revolutionized biology and medicine. The ability to analyse cellular proteins and their millions of variants would be an advance of comparable importance, but requires a fresh technical approach. We use electroosmosis for the non-enzymatic capture, unfolding and translocation of individual polypeptides of more than 1200 residues by a protein nanopore. By monitoring the ionic current carried by the nanopore, we locate post-translational modifications deep within the polypeptide chains, and thereby lay the groundwork for obtaining inventories of the proteoforms in cells and tissues.
Long-term responses of Icelandic Arctic foxes to changes in marine and terrestrial ecosystems
Authors: Berthelot Fanny , Unnsteinsdóttir Ester R. , Carbonell Ellgutter Jennifer A. , Ehrich Dorothee
Published: February 2023

The long-term dynamics of predator populations may be driven by fluctuations in resource availability and reflect ecosystem changes such as those induced by climate change. The Icelandic Arctic fox (Vulpes lagopus) population has known major fluctuations in size since the 1950s. Using stable isotopes analysis of bone collagen over a long-time series (1979-2018), we aimed at identifying the main resources used by Icelandic Arctic foxes during periods of growth and decline to assess if the variations in their population size are linked to fluctuations in the availability of resources. We hypothesized that (1) the decline in Seabirds abundance was responsible for the decrease in the fox population; and (2) that the growth in the fox population combined to fluctuations in main resources would lead to an increase in intra-specific competition, ultimately leading to variations in their isotopic niches at the population scale. The isotopic signatures of Arctic foxes as well as their temporal trends differed clearly between inland and coast. Inland foxes showed an overall shift towards more terrestrial preys, whereas coastal foxes displayed a relatively stable use of marine resources over the years. Stable isotopes mixing models suggested that marine resources and rock ptarmigans were the most important food source and highlighted a rather stable diet in coastal habitats compared to inland habitats where more fluctuations in dietary composition were observed. Coastal foxes had a broader niche than inland foxes, and there was more variation in niche size in the inland habitat. Our results are in agreement with a general decline in seabird populations driving the decline in Arctic foxes, especially in coastal habitats. For the inland foxes, our results suggest that the lack of marine resources might have led to an increased use of ptarmigans as well as other terrestrial resources such as geese and waders, especially during the most recent period.