bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diagnostic performance of serum CA-125 for overall and complicated acute appendicitis: a systematic review and meta-analysis
Authors: Arredondo Montero Javier , Pérez Riveros Blanca Paola , Bueso Asfura Oscar Emilio 
Published: December 2023

ABSTRACTBackgroundThis study aimed to analyze the diagnostic performance of serum CA-125 in acute appendicitis (AA).MethodsThis review was registered in PROSPERO (CRD42023450988). We included prospective or retrospective original clinical studies evaluating the diagnostic performance of serum CA-125 in AA. A search was conducted in PubMed, Web of Science, Scopus, and OVID. Search terms and keywords were: (appendicitis OR appendectomy) AND (CA-125 OR CA125). Two independent reviewers selected the articles and extracted relevant data. Methodological quality was assessed using the QUADAS2 index. A synthesis of the results, standardization of the metrics, and three random-effect meta-analyses were performed.ResultsFive studies with data from 533 participants (including 219 patients with a confirmed diagnosis of AA and 107 controls) were included in this review. The random-effect meta-analysis of serum CA-125 (AA vs controls) included 5 articles (125 AA and 70 controls) and resulted in a non-significant mean difference [95% CI] of −6.80 [−20.51,6.92] U/mL (p=0.33). The meta-analysis by subgroups that included only male patients resulted in a significant mean difference [95% CI] of 3.48 [0.46,6.49] U/mL (p=0.02)ConclusionsAlthough serum CA-125 does not appear to be a good overall marker for the diagnosis of AA, our subgroup analyses show that this marker could be useful for diagnosing AA in males. It also appears to be a potentially useful tool for discriminating complicated and uncomplicated AA. However, the limited number of included studies precludes drawing generalizable conclusions. Future prospective studies focused on males are required to confirm these findings.FundingNoneRegistrationPROSPERO (CRD42023450988).
Stage-specific expression patterns and co-targeting relationships among miRNAs in the developing mouse cerebral cortex
Authors: Todorov Hristo , Weißbach Stephan , Schlichtholz Laura , Mueller Hanna , Hartwich Dewi , Gerber Susanne , Winter Jennifer 
Published: December 2023

AbstractmicroRNAs are particularly important during brain development, however, the composition and temporal dynamics of miRNA regulatory networks are not sufficiently characterized. Here, we performed small RNA sequencing of mouse embryonic cortical samples at E14, E17, and P0 as well as in neural progenitor cells differentiatedin vitrointo neurons. Using co-expression network analysis, we detected clusters of miRNAs that were co-regulated at distinct developmental stages. miRNAs such as miR-92a/b acted as hubs during early, and miR-124 and miR-137 during late neurogenesis. Notably, validated targets of P0 hub miRNAs were enriched for down-regulated genes related to stem cell proliferation, negative regulation of neuronal differentiation and RNA splicing, among others, suggesting that miRNAs are particularly important for modulating transcriptional programs of crucial factors that guide the switch to neuronal differentiation. As most genes contain binding sites for more than one miRNA, we furthermore constructed a co-targeting network where numerous miRNAs shared more targets than expected by chance. Using luciferase reporter assays, we demonstrated that simultaneous binding of miRNA pairs to neurodevelopmentally relevant genes exerted an enhanced transcriptional silencing effect compared to single miRNAs. Taken together, our study provides a comprehensive resource of miRNA longitudinal expression changes during corticogenesis. Furthermore, we highlight several potential mechanisms through which miRNA regulatory networks can shape embryonic brain development.
Transcriptional memory is conferred by combined heritable maintenance and local removal of selective chromatin modifications
Authors: Mikulski Pawel , Tehrani Sahar S.H. , Kogan Anna , Abdul-Zani Izma , Shell Emer , Ryan Brent J. , Jansen Lars E.T. 
Published: December 2023

AbstractInterferon-γ (IFNγ) transiently activates genes involved in inflammation and innate immunity. A subset of targets maintain a mitotically heritable memory of prior IFNγ exposure resulting in hyperactivation upon reexposure. Here we discovered that the active chromatin marks H3K4me1, H3K14Ac and H4K16Ac are established during IFNγ priming and selectively maintained on a cluster of GBP genes for at least 7 days in dividing cells in the absence of transcription. The histone acetyltransferase KAT7 is required for the accelerated GBP reactivation upon reexposure to IFNγ. In naïve cells, we find the GBP cluster is maintained in low-level repressive chromatin marked by H3K27me3 limiting priming in a PRC2-dependent manner. Unexpectedly, IFNγ results in transient accumulation of this repressive mark but is then selectively depleted from primed GBP genes during the memory phase facilitating hyperactivation of primed cells. Furthermore, we identified a cis-regulatory element that makes transient, long-range contacts across the GBP cluster and acts as a repressor, primarily to curb the hyperactivation of previously IFNγ-primed cells. Combined our results identify the putative chromatin basis for long-term transcriptional memory of interferon signalling that may contribute to enhanced innate immunity.
Chromatin phase separation and nuclear shape fluctuations are correlated in a polymer model of the nucleus
Authors: Attar Ali Goktug , Paturej Jaroslaw , Banigan Edward J. , Erbas Aykut 
Published: December 2023

ABSTRACTAbnormalities in the shapes of mammalian cell nuclei are hallmarks of a variety of diseases, including progeria, muscular dystrophy, and various cancers. Experiments have shown that there is a causal relationship between chromatin organization and nuclear morphology. Decreases in heterochromatin levels, perturbations to heterochromatin organization, and increases in euchromatin levels all lead to misshapen nuclei, which exhibit deformations, such as nuclear blebs and nuclear ruptures. However, the polymer physical mechanisms of how chromatin governs nuclear shape and integrity are poorly understood. To investigate how heterochromatin and euchromatin, which are thought to microphase separatein vivo, govern nuclear morphology, we implemented a composite coarse-grained polymer and elastic shell model. By varying chromatin volume fraction (density), heterochromatin levels and structure, and heterochromatin-lamina interactions, we show how the spatial organization of chromatin polymer phases within the nucleus could perturb nuclear shape in some scenarios. Increasing the volume fraction of chromatin in the cell nucleus stabilizes the nuclear lamina against large fluctuations. However, surprisingly, we find that increasing heterochromatin levels or heterochromatin-lamina interactions enhances nuclear shape fluctuations in our simulations by a “wetting”-like interaction. In contrast, shape fluctuations are largely insensitive to the internal structure of the heterochromatin, such as the presence or absence of chromatin-chromatin crosslinks. Therefore, our simulations suggest that heterochromatin accumulation at the nuclear periphery could perturb nuclear morphology in a nucleus or nuclear region that is sufficiently soft, while stabilization of the nucleus via heterochromatin likely occurs through mechanisms other than chromatin microphase organization.
Building synthetic biosensors using red blood cell proteins
Authors: Dolberg Taylor B. , Gunnels Taylor F. , Ling Te , Sarnese Kelly A. , Crispino John D. , Leonard Joshua N. 
Published: December 2023

AbstractAs the use of engineered cell therapies expands from pioneering efforts in cancer immunotherapy to other applications, an attractive but less explored approach is the use of engineered red blood cells (RBCs). Compared to other cells, RBCs have a very long circulation time and reside in the blood compartment, so they could be ideally suited for applications as sentinel cells that enablein situsensing and diagnostics. However, we largely lack tools for converting RBCs into biosensors. A unique challenge is that RBCs remodel their membranes during maturation, shedding many membrane components, suggesting that an RBC-specific approach may be needed. Towards addressing this need, here we develop a biosensing architecture built on RBC membrane proteins that are retained through erythropoiesis. This biosensor employs a mechanism in which extracellular ligand binding is transduced into intracellular reconstitution of a split output protein (including either a fluorophore or an enzyme). By comparatively evaluating a range of biosensor architectures, linker types, scaffold choices, and output signals, we identify biosensor designs and design features that confer substantial ligand-induced signalin vitro. Finally, we demonstrate that erythroid precursor cells engineered with our RBC protein biosensors functionin vivo.This study establishes a foundation for developing RBC-based biosensors that could ultimately address unmet needs including non-invasive monitoring of physiological signals for a range of diagnostic applications.
Developmentally unique cerebellar processing prioritizes self- over other-generated movements
Authors: Richardson Angela M. , Sokoloff Greta , Blumberg Mark S. 
Published: December 2023

AbstractAnimals must distinguish the sensory consequences of self-generated movements (reafference) from those of other-generated movements (exafference). Only self- generated movements entail the production of motor copies (i.e., corollary discharges), which are compared with reafference in the cerebellum to compute predictive or internal models of movement. Internal models emerge gradually over the first three postnatal weeks in rats through a process that is not yet fully understood. Previously, we demonstrated in postnatal day (P) P8 and P12 rats that precerebellar nuclei convey corollary discharge and reafference to the cerebellum during active (REM) sleep when pups produce limb twitches. Here, recording from a deep cerebellar nucleus (interpositus, IP) in P12 rats of both sexes, we compared reafferent and exafferent responses to twitches and limb stimulations, respectively. As expected, most IP units showed robust responses to twitches. However, in contrast with other sensory structures throughout the brain, relatively few IP units showed exafferent responses. Upon finding that exafferent responses occurred in pups under urethane anesthesia, we hypothesized that urethane inhibits cerebellar cortical cells, thereby disinhibiting exafferent responses in IP. In support of this hypothesis, ablating cortical tissue dorsal to IP mimicked the effects of urethane on exafference. Finally, the results suggest that twitch-related corollary discharge and reafference are conveyed simultaneously and in parallel to cerebellar cortex and IP. Based on these results, we propose that twitches provide opportunities for the nascent cerebellum to integrate somatotopically organized corollary discharge and reafference, thereby enabling the development of closed-loop circuits and, subsequently, internal models.SignificanceStatementFor adult animals to produce flexible and adaptive movements, they must distinguish self- from other-generated movements and learn to anticipate how their body moves through space. The computations required for this capacity occur within the cerebellar system. In early infancy, these computations are not yet established and must develop through sensorimotor experience. Here, we found that self-generated movements—particularly those movements occurring during active sleep—are a preferred source of that sensorimotor experience to the infant cerebellum. This preference appears to be unique to the infant cerebellum and helps us understand how that structure establishes its neural circuitry and functions.
Molecular Disambiguation of Heart Rate Control by the Nucleus Ambiguus
Authors: Jalil Maira , Coverdell Tatiana C. , Gutierrez Veronica A. , Crook Maisie E. , Shi Jiachen , Stornetta Daniel. S. , Schwalbe Dana C. , Abbott Stephen B. G. , Campbell John N. 
Published: December 2023

SUMMARYThe nucleus ambiguus (nAmb) provides parasympathetic control of cardiorespiratory functions as well as motor control of the upper airways and striated esophagus. A subset of nAmb neurons innervates the heart through the vagus nerve to control cardiac function at rest and during key autonomic reflexes such as the mammalian diving reflex. These cardiovagal nAmb neurons may be molecularly and anatomically distinct, but how they differ from other nAmb neurons in the adult brain remains unclear. We therefore classified adult mouse nAmb neurons based on their genome-wide expression profiles, innervation of cardiac ganglia, and ability to control HR. Our integrated analysis of single-nucleus RNA-sequencing data predicted multiple molecular subtypes of nAmb neurons. Mapping the axon projections of one nAmb neuron subtype,Npy2r-expressing nAmb neurons, showed that they innervate cardiac ganglia. Optogenetically stimulating all nAmb vagal efferent neurons dramatically slowed HR to a similar extent as selectively stimulatingNpy2r+ nAmb neurons, but not other subtypes of nAmb neurons. Finally, we trained mice to perform voluntary underwater diving, which we use to showNpy2r+ nAmb neurons are activated by the diving response, consistent with a cardiovagal function for this nAmb subtype. These results together reveal the molecular organization of nAmb neurons and its control of heart rate.
In vivooptimized three-photon imaging of intact mouse tibia links plasma cell motility to functional states in the bone marrow
Authors: Rakhymzhan Asylkhan , Fiedler Alexander F. , Günther Robert , Domingue Scott , Wooldridge Laura , Leben Ruth , Cao Yu , Bias Anne , Roodselaar Jay , Köhler Ralf , Ulbricht Carolin , Heidelin Judith , Andresen Volker , Beckers Ingeborg , Haibel Astrid , Duda Georg , Hauser Anja E. , Niesner Raluca A. 
Published: December 2023

AbstractIntravital multi-photon imaging of the bone marrow is crucial to the study of cellular dynamics, communication with the microenvironment and functions, however, imaging of deep tissue areas is challenging and minimally invasive methods for deep-marrow imaging in intact long bones are needed. We developed a high pulse energy 1650 nm laser prototype, which permits to surpass >100 µm thick cortical bone and to perform three-photon microscopy (3PM) in more than 400 µm depth in the marrow cavity of intact mouse tibiain vivo. Its unique 3 and 4 MHz laser repetition rates allowed us to analyze motility patterns of rare cells over large fields of view deep within the unperturbed marrow. In this way, we found a bi-modal migratory behavior of marrow plasma cells. Besides, the analysis of third harmonics generation (THG) in the tibia identified this signal to be a label-free indicator of the abundance of cellular organelles, in particular the endoplasmic reticulum, reflecting protein biosynthesis capacity. We found that only one third of the plasma cells in the tibia marrow of adult mice have a strong THG signal and, thus, a high protein synthesis capacity, while the other two thirds of plasma cells display a low THG signal. Finally, we identified an inverse link between migratory behavior and THG signal strength in marrow plasma cells. As in these cells, the protein biosynthesis capacity indicated by a strong THG signal is mainly associated with antibody secretion, we could relate motility to functional states of plasma cellsin vivo. Our 3PM method retains the ability to connect cellular dynamics to protein biosynthesis capacity in various marrow cell types beyond plasma cells, as THG is a ubiquitous signal, opening new perspectives on understanding how tissue microenvironment impacts on cellular functions in the bone marrow.
Discovery of Novel Small Molecule CB2 Agonist for the Treatment of Glioblastoma Tumors
Authors: Kiraly M. , Okwan-Duodu D. , Wong A.J. , Foss J.F. , Giordano T. 
Published: December 2023

AbstractMalignant brain tumors cause over 15,000 deaths per year in the United States. Survival for over five years is only 36%. Nearly 49% of malignant brain tumors are glioblastomas (GBM), and 30% of them have the ability to diffuse and infiltrate. Treatment frequently includes surgery, radiotherapy and chemotherapy. In case of GBM patients, combining temozolomide (TMZ) chemotherapy with radiation improved survival over radiotherapy alone (survival by 2 years: 17% vs. 11%; 5 years: 10% vs. 2%). Most primary GBM tumors from pediatric and adult patients express high levels of cannabinoid type II (CB2) receptors, and that expression correlated with tumor grade. Cannabinoids like (−)-trans-Δ9−tetrahydrocannabinol (Δ9-THC) were shown to suppress GBM tumor growth, trigger apoptosis in GBM stem cells, and slow down angiogenesis, thus cutting GBM cells off of blood supply. These data led to local administration of Δ9-THC in clinical trials in patients with recurrent glioblastomas, although the well-known psychotropic effects of Δ9-THC and related compounds mediated via the CB1 receptors have raised some concerns among clinicians. Thus, the medicinal usage of cannabinoids has been limited. One leading strategy to avoid the side effects is administration of CB2-selective non-psychotic drugs. To create an effective solution, we designed a preclinical study to develop a novel GBM therapy, using NeuroTherapia’s lead molecule, the CB2 agonist NTRX-07. We have already demonstrated that NTRX-07 ameliorates Amyloid β production and deposition in the hippocampus, and thus restored Long-Term Potentiation – the cellular mechanism for learning and memory formation. Consequently, we showed that NTRX-07 has a highly competitive target compound profile, and that is safe in murine models, dogs and humans. NTRX-07 has entered clinical trials for the management of AD as the first orally available CB2 agonist designed to be centrally active. The phase I single ascending dose study in normal volunteers demonstrated targeted plasma levels of the drug after oral administration with no serious adverse events or clinically significant changes in safety examinations or laboratory tests. In this pilot mouse GBM survival study, we found breakthrough evidence that our compound can exert potent anti-cancer activity and significantly extend the survival of GBM animals; even without previously exposing them to radiotherapy or TMZ. Our goal is to bring NTRX-07 into the clinic as a new therapeutic for patients with GBM.
Near infrared spectroscopic characterization of sesamin, a dietary lignan natural product
Authors: Jackson Sara W. , Jang Moon-Hyung , Asani Eliza , Yates C. Ryan , Ng Joseph , Baudry Jerome 
Published: December 2023

AbstractSesamin, a lignan component of sesame seed oil, has shown pharmacologic benefits, such as anti-oxidative and anti-inflammatory qualities. However, the amount of data available to the field is surprisingly sparse, as for instance there is no known spectroscopic characterization of sesamin. This work provides the first experimental near infrared spectrum of sesamin. Sesamin powder was subjected to experimental Fourier-transform infrared spectroscopy, and the resulting spectrum was compared to quantum chemical calculations of sesamin’s stereoisomers in various hydration states. Major peaks of sesamin were assigned vibrational modes through comparison of computed and observed spectra. Multiple sesamin species may be present in a typical powder sample, coexisting with potential trace hydration.
Implementation of an enriched membrane protein carrier channel for enhanced detection of membrane proteins in mass spectrometry-based thermal stability assays
Authors: Phaneuf Clifford G. , Ivanov Alexander R. 
Published: December 2023

AbstractIn this work, we developed a membrane-enriched stable isotope isobaric-labeled carrier channel (meSIILCC) for mass spectrometry-based thermal stability assay (MS-TSA). A proof-of-concept study demonstrated that the meSIILCC method could modestly improve membrane protein (MP) detection in MS-TSA experiments. An enhancement of 10% in identifications of membrane-proteins was observed in the meSIILCC group. Hydrophobicity analysis of the identified and quantified peptides using the grand average of hydropathy index confirmed the meSIILCC approach enriched for peptides of higher hydrophobicity characteristic of membrane-associated proteins.To further improve meSIILCC, four membrane-protein enrichment approaches were compared. Using the selected and optimized workflow that utilized isobaric labeling-mass spectrometry, 8,662 protein groups were quantitatively characterized and then annotated based on their subcellular localization. The corresponding reporter ion intensities were used to construct a heatmap, which revealed an increased representation of proteins corresponding to the “plasma membrane” gene ontology term.In a separate DMSO-only MS-TSA experiment, the optimally performing meSIILCC was added at 10-fold the protein content of the lowest heated aliquot from the MS-TSA, and isotope interference was found to be the highest in the 134N channel, while to a much lesser degree in other channels that were left empty.To further assess the performance of meSIILCC in the DMSO-only MS-TSA experiment, an over-representation analysis was performed, which demonstrated that proteins exclusive to the meSIILCC group had more than a five-fold increase in gene ontology cellular component terms related to the “membrane” term.We found 496 proteins from the DMSO-only MS-TSA experiment, which were identified across all replicates and shared between the meSIILCC and control that were annotated with “plasma membrane.” A close to 28% increase in the set corresponding to unique peptides was realized, using the meSIILCC approach, with a median value of 6.3 peptides per protein, compared to 4.7 in the control.
Age-Related Changes of Dopamine D1 and D2 Receptors Expression in Parvalbumin-Positive Cells of the Orbitofrontal and Prelimbic Cortices of Mice
Authors: Dong Jihui , Wei Xiaoyan , Huang Ziran , Tian Jing , Zhang Wen 
Published: December 2023

AbstractDopamine (DA) plays a pivotal role in reward processing, cognitive functions, and emotional regulation. The prefrontal cortex (PFC) is a critical brain region for these processes. Parvalbumin-positive (PV+) neurons are one of the major classes of inhibitory GABAergic neurons in the cortex, they modulate the activity of neighboring neurons, influencing various brain functions. While DA receptor expression exhibits age-related changes, the age-related changes of these receptors in PV+ neurons, especially in the PFC, remains unclear. To address this, we investigated the expression of DA D1 (D1R) and D2 (D2R) receptors in PV+ neurons within the orbitofrontal (OFC) and prelimbic (PrL) cortices at different postnatal ages (P28, P42, P56, and P365). We found that the expression of D1R and D2R in PV+ neurons showed both age- and region-related changes. PV+ neurons in the OFC expressed a higher abundance of D1 than those in the PrL, and those neurons in the OFC also showed higher co-expression of D1R and D2R than those in the PrL. In both the OFC and PrL, D1R in PV+ neurons increased from P28 and reached a plateau at P42, then receded to express at P365. Meanwhile, D2R did not show significant age-related changes in both regions. These results showed dopamine receptors in the prefrontal cortex exhibit age- and region-specific changes, which may contribute to the difference of these brain regions in reward-related brain functions.