bluuebunny/crossref_metadata_2025_split huggingface dataset:
Optic Neuropathy Associated with POLG Mutations: A Case Series and Literature Review
Authors: Reitinger Jeremy C. , Mackay Devin D. 
Published: January 2024

Background:
The clinical characteristics of patients with polymerase gamma (POLG) mutation-associated optic neuropathy remain incompletely characterized.

Methods:
We describe the clinical characteristics of 3 patients with POLG-associated optic neuropathy. We performed a literature review of optic neuropathy cases associated with POLG mutations and compared them with our cohort.

Results:
Many published cases of POLG-associated optic neuropathy in our literature review lacked details regarding severity of vision loss, visual field defects, and optical coherence tomography analysis. The clinical presentation of POLG mutations remains widely variable in age (from pediatric cases to adults) and associated systemic findings. All patients in our literature review presented with systemic symptoms, most commonly muscle weakness, ptosis, and ophthalmoplegia, whereas many young patients had severe systemic symptoms. In our case series, all 3 cases had isolated optic neuropathy affecting the papillomacular bundle, with signs such as reduced visual acuity and color vision, central visual field defects, temporal retinal nerve fiber layer loss with temporal optic disc pallor, and retinal ganglion cell complex loss. In addition, 2 of the 3 cases had added mitochondrial stressors in addition to the POLG mutation.

Conclusions:
Clinicians should be aware that POLG mutations can present as isolated optic neuropathy primarily affecting the papillomacular bundle. With mitochondrial failure being the likely underlying pathogenic mechanism in POLG-associated optic neuropathy, helping affected patients eliminate mitochondrial stressors may be important in reducing the risk for progressive vision loss in this otherwise currently untreatable disorder.
Aged Tendons Exhibit Altered Mechanisms of Strain-Dependent Extracellular Matrix Remodeling
Authors: Aggouras Anthony N. , Stowe Emma J. , Mlawer Samuel J. , Connizzo Brianne K. 
Published: January 2024

ABSTRACTAging is a primary risk factor for degenerative tendon injuries, yet the etiology and progression of this degeneration is poorly understood. While aged tendons have innate cellular differences that support a reduced ability to maintain mechanical tissue homeostasis, the response of aged tendons to altered levels of mechanical loading has not yet been studied. To address this question, we subjected young and aged murine flexor tendon explants to various levels ofin vitrotensile strain. We first compared the effect of static and cyclic strain on matrix remodeling in young tendons, finding that cyclic strain is optimal for studying remodelingin vitro. We then investigated the remodeling response of young and aged tendon explants after 7 days of varied mechanical stimulus (stress-deprivation, 1%, 3%, 5%, or 7% cyclic strain) via assessment of tissue composition, biosynthetic capacity, and degradation profiles. We hypothesized that aged tendons would show muted adaptive responses to changes in tensile strain and exhibit a shifted mechanical setpoint, at which the remodeling balance is optimal. Interestingly, we found 1% cyclic strain best maintains native physiology while promoting ECM turnover for both age groups. However, aged tendons display fewer strain-dependent changes, suggesting a reduced ability to adapt to altered levels of mechanical loading. This work has significant impact in understanding the regulation of tissue homeostasis in aged tendons, which can inform clinical rehabilitation strategies for treating elderly patients.
Archaeological Ivories: A practical guide for identifying elephant and hippo ivory in the archaeological record
Authors: Shochat Harel 
Published: January 2024

AbstractThe use of osseous materials for crafting various artifacts is well-attested in the archaeological record of the ancient Near East. While bone, the most common and available material, was used more frequently, ivory was highly valued as an exotic material for fashioning exquisite prestige items designed for ostentatious display and linked to society’s elite strata. Therefore, reliably distinguishing between the taxonomic origins of the osseous artifacts is significant for interpreting the archaeological data. In the Near East, the demand for ivory products reached its zenith during the mid-2ndto mid-1stmillennia BCE, producing one of the largest assemblages unearthed anywhere in the world. Using state-of-the-art bio-molecular analyses to study this collection is costly, time-consuming, and entails damaging the highly-curated artifacts. This paper provides an essential, simple, non-destructive, and validated method to distinguish bone from elephant or hippo ivory (the most common osseous materials attested in the Near East record). However, following similar guidelines can help index other biological sources of ivory.
The Flash Mode of Proton Irradiation in the Bragg Peak Partly Spares the Embryogenesis of the Quail
Authors: Akulinichev Sergey V. , Glukhov Segrey I. , Gavrilov Yury K. , Kokontsev Dmitry A. , Kuznetsova Elena A. , Martynova Valeriia V. , Yakovlev Ivan A. 
Published: January 2024

AbstractThe study of biological effects of high-dose-rate ionizing radiation using animal models remains an urgent problem. In the work, a comparison of proton-induced damage to embryos (the 9thpost-fertilization day) and 1-day-old baby chicks (the 18thpost-fertilization day) from irradiated eggs of Japanese quail (Coturnix coturnix japónica) irradiated in and outside the Bragg peak with the conventional and ultra-high dose rate D (CONV D < 1 Gy/s, FLASH D ∼100 Gy/s and single-pulse flash - SPLASH D ∼106Gy/s, respectively) was carried out. The following criteria were used: survival, body weight and body length of embryos, weight of chicks, percentage of erythrocytes with anomalies (with micronuclei, without nuclei, with two nuclei), and the speed of movement of 1-day-old chicks in the open field test. The largest number of dead embryos was recorded after irradiation with 7 and 14 Gy in the plateau region of the proton trajectory. By the criteria of body weight and length, as well as the number of erythrocytes with micronuclei in 9-day-old embryos from eggs irradiated with a dose of 8.5 Gy in the Bragg peak, FLASH and SPLASH modes were found to be the least traumatic compared with the CONV mode. The weight of chicks from eggs irradiated with a dose of 4 Gy in the Bragg peak did not differ from the control and did not depend on the irradiation mode. The lowest death incidence and the smallest number of abnormal erythrocytes were recorded after FLASH and SPLASH irradiation; in chicks that hatched from eggs irradiated in the CONV mode, a tendency for an increase in the number of abnormal erythrocytes was observed. The speed of movement of chicks from FLASH- and SPLASH-irradiated eggs was comparable with that from unirradiated eggs, and chicks from eggs irradiated in the CONV mode were less active than chicks from unirradiated eggs and eggs irradiated in the other regimes. Thus, the irradiation of eggs with a beam of accelerated protons in the Bragg peak in the FLASH/SPLASH modes is less damaging for healthy tissues and for the development of embryos and chicks on the cellular, anatomical, and physiological levels.
Transdifferentiation of epithelial cells and fibroblasts induced by IL-1β fuels neutrophil recruitment in chronic rhinosinusitis
Authors: Xie Xinyu , Wang Pin , Jin Min , Wang Yue , Qi Lijie , Wu Changhua , Guo Shu , Li Changqing , Zhang Xiaojun , Yuan Ye , Ma Xinyi , Liu Fangying , Liu Weiyuan , Liu Heng , Duan Chen , Ye Ping , Li Xuezhong , Borish Larry , Zhao Wei , Feng Xin 
Published: January 2024

AbstractNeutrophilic inflammation contributes to multiple chronic inflammatory airway diseases, including asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), and is associated with an unfavorable prognosis. Here, using single-cell RNA sequencing (scRNA-seq) to profile human nasal mucosa obtained from the inferior turbinates, middle turbinates, and nasal polyps of CRSwNP patients, we identified two IL-1 signaling-induced cell subsets—LY6D+club cells andIDO1+fibroblasts—that promote neutrophil recruitment by respectively releasing S100A8/A9 and CXCL1/2/3/5/6/8 into inflammatory regions. IL-1β, a pro-inflammatory cytokine involved in IL-1 signaling, induces the transdifferentiation ofLY6D+club cells andIDO1+fibroblasts from primary epithelial cells and fibroblasts, respectively. In an LPS-induced neutrophilic CRSwNP mouse model, blocking IL-1β activity with a receptor antagonist significantly reduced the numbers ofLY6D+club cells andIDO1+fibroblasts and mitigated nasal inflammation. This study reveals the roles of two cell subsets in neutrophil recruitment and demonstrates an IL-1-based intervention for mitigating neutrophilic inflammation in CRSwNP.
β-Catenin associates with a Wnt signaling mRNA network in myeloid cells through canonical RBP binding
Authors: Wagstaff M , Sevim O , Goff A , Raynor M , Park H , Mancini E , Nguyen DTT , Chevassut T , Blair A , Castellano L , Newbury S , Towler B , Morgan RG 
Published: January 2024

AbstractWnt/β-catenin signaling is important for normal hematopoietic stem/progenitor cell (HSPC) biology and heavily implicated in acute myeloid leukaemia (AML). The central mediator β-catenin is an attractive therapeutic target in AML however its targeting has been hampered by poor characterisation of its molecular interactions in haematopoietic cells. Our previous β-catenin interactome study identified the significant enrichment of RNA-binding proteins (RBP) implying post-transcriptional roles for β-catenin in myeloid cells. To identify β-catenin-associated mRNAs we performed β-catenin RNA-immunoprecipitation coupled to RNA-sequencing (RIP-seq) and identified significantly enriched Wnt signalling pathway transcripts. Using β-catenin cross-linking immunoprecipitation (CLIP) we demonstrated a limited capacity for β-catenin to bind RNA directly implying dependence on other RBPs. β-Catenin was found to interact with MSI2 in both myeloid cell lines and AML patient samples, where expression was significantly correlated. MSI2 knockdown reduced Wnt signalling output (TCF/LEF activity), through suppression of LEF-1 expression and nuclear localization. Through both RIP and CLIP we demonstrate MSI2 bindsLEF1mRNA in a partly β-catenin dependent fashion, and may impact the post-transcriptional control of LEF-1 expression. Finally, we show that MSI2-mediated expansion of human HSPCs could be partly driven throughLEF1regulation. This is the first study to show functional crosstalk between MSI2 and Wnt signalling in human cells, and indicates potential novel post-transcriptional roles for β-catenin in a haematological context.
An integrated signaling threshold initiates IgG response towards virus-like immunogens
Authors: Wholey Wei-Yun , Meyer Alexander R. , Yoda Sekou-Tidiane , Mueller James L. , Mathenge Raisa , Chackerian Bryce , Zikherman Julie , Cheng Wei 
Published: January 2024

AbstractClass-switched neutralizing antibody (nAb) production is rapidly induced upon many viral infections. However, due to the presence of multiple components in typical virions, the precise biochemical and biophysical signals from viral infections that initiate nAb responses remain inadequately defined. Using a reductionist system of synthetic virus-like structures (SVLS) containing minimal, highly purified biochemical components commonly found in enveloped viruses, here we show that a foreign protein on a virion-sized liposome can serve as a stand-alone danger signal to initiate class-switched nAb responses in the absence of cognate T cell help or Toll-like receptor signaling but requires CD19, the antigen (Ag) coreceptor on B cells. Introduction of internal nucleic acids (iNAs) obviates the need for CD19, lowers the epitope density (ED) required to elicit the Ab response and transforms these structures into highly potent immunogens that rival conventional virus-like particles in their ability to elicit strong Ag-specific IgG. As early as day 5 after immunization, structures harbouring iNAs and decorated with just a few molecules of surface Ag at doses as low as 100 ng induced all IgG subclasses of Ab known in mice and reproduced the IgG2a/2c restriction that has been long observed in live viral infections. These findings reveal a shared mechanism for nAb response upon viral infection. High ED is capable but not necessary for driving Ab secretionin vivo. Instead, even a few molecules of surface Ag, when combined with nucleic acids within these structures, can trigger strong antiviral IgG production. As a result, the signaling threshold for the induction of neutralizing IgG is set by dual signals originating from both ED on the surface and the presence of iNAs within viral particulate immunogens.One-sentence summaryReconstitution of minimal viral signals necessary to initiate antiviral IgG
A systematic evaluation of computational methods for cell segmentation
Authors: Wang Yuxing , Zhao Junhan , Xu Hongye , Han Cheng , Tao Zhiqiang , Zhou Dawei , Geng Tong , Liu Dongfang , Ji Zhicheng 
Published: January 2024

ABSTRACTCell segmentation is a fundamental task in analyzing biomedical images. Many computational methods have been developed for cell segmentation and instance segmentation, but their performances are not well understood in various scenarios. We systematically evaluated the performance of 18 segmentation methods to perform cell nuclei and whole cell segmentation using light microscopy and fluorescence staining images. We found that general-purpose methods incorporating the attention mechanism exhibit the best overall performance. We identified various factors influencing segmentation performances, including image channels, choice of training data, and cell morphology, and evaluated the generalizability of methods across image modalities. We also provide guidelines for choosing the optimal segmentation methods in various real application scenarios. We developed Seggal, an online resource for downloading segmentation models already pre-trained with various tissue and cell types, substantially reducing the time and effort for training cell segmentation models.
DysregulatedSASS6expression promotes increased ciliogenesis and cell invasion phenotypes
Authors: Hargreaves Eleanor , Jenks Andrew D , Staszewski Adina , Tsalikis Athanasios , Bodoque Raquel , Arias-Garcia Mar , Abdi Yasmin , Al-Malki Abdulaziz , Yuan Yinyin , Natrajan Rachael , Haider Syed , Iskratsch Thomas , Wang Won-Jing , Godinho Susana , Palaskas Nicolaos J , Calvo Fernando , Zech Tobias , Tanos Barbara 
Published: January 2024

AbstractCentriole and/or cilia defects are characteristic of cancer cells and have been linked to cancer cell invasion. However, the mechanistic basis of these effects is unknown. Spindle assembly abnormal protein 6 homolog (SAS-6) is essential for centriole biogenesis and cilia formation. In cycling cells, SAS-6 undergoes APCCdh1-mediated targeted degradation by the 26S proteasome at the end of mitosis. Little is known about the function of SAS-6 outside of centrosome biogenesis. To examine this, we expressed a non-degradable SAS-6 mutant (SAS-6ND). Expression of SAS-6ND led to an increase in ciliation and cilia-dependent cell invasion, and caused an upregulation of the YAP/TAZ pathway. YAP/TAZ or ciliogenesis inhibition prevented SAS-6-induced invasion. SAS-6ND caused increased actin alignment and stress fiber coherency, and nuclear flattening known to promote YAP nuclear import. Finally, data from The Cancer Genome Atlas showed that SAS-6 overexpression is associated with poor prognosis in various cancers. Our data provide evidence for a defined role of SAS-6 in cancer cell invasion and offers mechanistic insight into the role of YAP/TAZ in this cilia-sensitive process.SynopsisSAS-6 overexpressing cells show increased ciliation, actin cytoskeleton reorganization, cell flattening, YAP pathway activation and increased invasion
BioXNet: a biologically inspired neural network for deciphering anti-cancer drug response in precision medicine
Authors: Yang Jiannan , Kei Wu William Ka , Man Hui Rina Yee , Kei Wong Ian Chi , Zhang Qingpeng 
Published: January 2024

AbstractAccurate prediction of anti-cancer drug responses in preclinical and clinical studies is crucial for drug discovery and personalized medicine. While machine learning models have demonstrated promising prediction accuracy in this task, their translational value in cancer therapy is constrained by the lack of model interpretability and insufficient patients’ data with genomic profiles to calibrate models. The rich cell line data has the potential to supplement patients’ data, but the difference between the drug response mechanisms in cell lines and human body needs to be characterized quantitatively. To address these challenges, we proposed the BioXNet, which captures drug response mechanisms by seamlessly integrating drug target information with genomic profiles (genetic and epigenetic modifications) into a single biologically inspired neural network. BioXNet exhibited superior performance in drug response prediction tasks in both preclinical and clinical settings. An analysis of BioXNet’s interpretability revealed its ability to identify significant differences in drug response mechanisms between cell lines and the human body. Notably, the key factor of drug response is the drug targeting genes in cell lines but methylation modifications in the human body. Furthermore, we developed an online human-readable interface of BioXNet for drug response exploration by medical professionals and laymen. BioXNet represents a step further towards unifying drug, cell line and patients’ data under a holistic interpretable machine learning framework for precision medicine in cancer therapy.
Diving into broad-scale and high-resolution population genomics to decipher drivers of structure and climatic vulnerability in a marine invertebrate
Authors: Bourret Audrey , Leung Christelle , Puncher Gregory N. , Corre Nicolas Le , Deslauriers David , Skanes Katherine , Bourdages Hugo , Ros Manon Cassista-Da , Walkusz Wojciech , Jeffery Nicholas W. , Stanley Ryan R. E. , Parent Geneviève J. 
Published: January 2024

AbstractSpecies with widespread distributions play a crucial role in our understanding of climate change impacts on population structure. In marine species, population structure is often governed by both high connectivity potential and selection across strong environmental gradients. Despite the complexity of factors influencing marine populations, studying species with broad distribution can provide valuable insights into the relative importance of these factors and the consequences of climate-induced alterations across environmental gradients. We used the northern shrimpPandalus borealisand its wide latitudinal distribution to identify current drivers of population structure and predict the species vulnerability to climate change. Individuals sampled across 24° latitude were genotyped at high geographic-(54 stations) and genetic-(14,331 SNPs) resolutions to assess genetic variation and environmental correlations. Four populations were identified in addition to finer substructure associated to local adaptation. Geographic patterns of neutral population structure reflected predominant oceanographic currents, while a significant proportion of the genetic variation was associated with gradients in salinity and temperature. Adaptive landscapes generated using climate projections suggest a larger genomic offset in the southern extent of theP. borealisrange, where shrimp had the largest adaptive standing genetic variation. Our genomic results combined with recent observations point to the non-recovery in southern regions and an impending vulnerable status in the regions at higher latitude forP. borealis. They also provide rare insights into the drivers of population structure and climatic vulnerability of a widespread meroplanktonic species, which is crucial to understand future challenges associated with invertebrates essential to ecosystem functioning.
Chloride binding to prestin does not influence very high-frequency complex nonlinear capacitance (cNLC) in the mouse outer hair cell
Authors: Bai Jun-Ping , Zhang Chenou , Bahader Iman , Strenzke Nicola , Renigunta Vijay , Oliver Dominik , Navaratnam Dhasakumar , Beckstein Oliver , Santos-Sacchi Joseph 
Published: January 2024

AbstractPrestin (SLC26a5) function evolved to enhance auditory sensitivity and frequency selectivity by providing mechanical feedback via outer hair cells (OHC) into the organ of Corti. Its effectiveness is governed by the voltage-dependent kinetics of the protein’s charge movements, namely, nonlinear capacitance (NLC). We study the frequency response of NLC in the mouse OHC, a species with ultrasonic hearing. We find that the characteristic frequency cut-off (Fis) for the mouse in near 27 kHz. Single point mutations within the chloride binding pocket of prestin (e.g., S396E, S398E) lack the protein’s usual anion susceptibility. In agreement, we now show absence of anion binding in these mutants through molecular dynamics (MD) simulations. NLC Fisin the S396E knock-in mouse is unaltered, indicating that high frequency activity is not governed by chloride, but more likely by viscoelastic loads within the membrane. We also show that the allosteric action of chloride does not underlie piezoelectric-like behavior in prestin, since tension sensitivity of S396E NLC is comparable to that of WT. Because prestin structures of all species studied to-date are essentially indistinguishable, with analogous chloride binding pockets, auditory requirements of individual species for cochlear amplification likely evolved to enhance prestin performance by modifying, not its protein-anion interaction, but instead external mechanical loads on the protein.SignificancePrestin is believed to provide cochlear amplification in mammals that possess a wide range of frequency sensitivities. Previously, chloride anions have been shown to control prestin kinetics at frequencies below 10 kHz. However, now we find that chloride binding is not influential for prestin kinetics in the very high range of the mouse. We suggest that such high frequency prestin performance is governed by impinging mechanical loads within the membrane, and not interactions with anions.
Repairing a deleterious domestication variant in a floral regulator gene of tomato by base editing
Authors: Glaus Anna N. , Brechet Marion , Swinnen Gwen , Lebeigle Ludivine , Iwaszkiewicz Justyna , Ambrosini Giovanna , Julca Irene , Zhang Jing , Roberts Robyn , Iseli Christian , Guex Nicolas , Jiménez-Gómez José , Glover Natasha , Martin Gregory B. , Strickler Susan , Soyk Sebastian 
Published: January 2024

ABSTRACTCrop genomes accumulated deleterious mutations, a symptom known as the cost of domestication. Precision genome editing has been proposed to eliminate such potentially harmful mutations, however, experimental demonstration is lacking. Here, we identified a deleterious mutation in the tomato transcription factorSUPPRESSOR OF SP2(SSP2), which became prevalent in the domesticated germplasm and diminished DNA-binding to genome-wide targets. We found thatSSP2acts partially redundant with its paralogSSPto regulate shoot and inflorescence architecture. However, redundancy was compromised during tomato domestication and completely lost in the closely-related speciesPhysalis grisea, in which a single ortholog regulates shoot branching. We applied base editing to directly repair the deleterious mutation in cultivated tomato and obtained plants with compact growth that provide an early fruit yield. Our work shows how deleterious variants sensitized modern genotypes for phenotypic tuning and illustrates how repairing deleterious mutations with genome editing may allow predictable crop improvement.