bluuebunny/crossref_metadata_2025_split huggingface dataset:
A robust Reeb graph model of white matter fibers with application to Alzheimer’s disease progression⋆
Authors: Shailja S. , Grafton Scott T. , Manjunath B. S. 
Published: March 2022

AbstractTractography generates billions of complex curvilinear fibers (streamlines) in 3D that exhibit the geometry of white matter pathways. Analysis of raw streamlines on such a large scale is time-consuming and intractable. Further, it is well known that tractography computations produce noisy streamlines, and this in turn severely affect their use in structural brain connectivity analysis. Prompted by these challenges, we propose a novel method to model the bundling structures of streamlines using the construct of a Reeb graph. Three key parameters in our method capture the geometry and topology of the streamlines: (i) ϵ – distance between a pair of streamlines in a bundle that defines its sparsity; (ii) α – spatial length of the bundle that introduces persistence; and (iii) δ – the bundle thickness. Together, these parameters control the robustness and granularity of the model to provide a compact signature of the streamlines and their underlying anatomic fiber structure. We validate the robustness of the bundling structure using synthetic and ISMRM datasets. Next, we demonstrate the potential of this approach as a tool for efficient tractogram comparison by quantifying the fiber densities in the progression of Alzheimer’s disease. Our results on ADNI data localize the maximal bundles of various brain regions and show a significant depletion in the fiber density as Alzheimer’s disease progresses. The source code for the implementation is available on GitHub.
IRONMAN interacts with OsHRZ1 and OsHRZ2 to maintain Fe homeostasis
Authors: Peng Feng , Li Chenyang , Lu Chengkai , Li Yang , Xu Peng , Liang Gang 
Published: March 2022

AbstractIRONMAN is a family of small peptides which positively regulate the Fe deficiency response. However, the molecular mechanism by which OsIMA1 and OsIMA2 regulate Fe homeostasis was unclear. Here, we reveal that OsIMA1 and OsIMA2 interact with the potential Fe sensors, OsHRZ1 and OsHRZ2. OsIMA1 and OsIMA2 contain a conserved 17-amino acid C-terminal region which is responsible for the interactions with OsHRZ1 and OsHRZ2. The OsIMA1 overexpressing plants have the increased seed Fe concentration and the reduced fertility, as observed in the hrz1-2 loss-of-function mutant plants. Moreover, the expression trends of Fe deficiency inducible genes in the OsIMA1 overexpressing plants are the same to those in the hrz1-2. Co-expression assays suggest that OsHRZ1 and OsHRZ2 promote the degradation of OsIMA1 proteins. As the interaction partners of OsHRZ1, the OsPRI proteins also interact with OsHRZ2. The conserved C-terminal region of four OsPRIs contributes to the interactions with OsHRZ1 and OsHRZ2. An artificial IMA (aIMA) derived from the C-terminal of OsPRI1 can be also degraded by OsHRZ1. Moreover, the aIMA overexpressing rice plants accumulate more Fe without reduction of fertility. This work establishes the link between OsIMAs and OsHRZs, and develops a new strategy for Fe fortification in rice.
Combining two Genetic Sexing Strains allows sorting of non-transgenic males forAedesgenetic control
Authors: Lutrat Célia , Burckbuchler Myriam , Olmo Roenick Proveti , Beugnon Rémy , Fontaine Albin , Akbari Omar S. , Argilés-Herrero Rafael , Baldet Thierry , Bouyer Jérémy , Marois Eric 
Published: March 2022

SummaryChemical control of disease vectoring mosquitoesAedes albopictusandAedes aegyptiis costly, unsustainable, and increasingly ineffective due to the spread of insecticide resistance. The Sterile Insect Technique is a valuable alternative but is limited by the slow, error-prone, and wasteful sex-separation requirement. Here, we present four Genetic Sexing Strains (two for eachAedesspecies) based on fluorescence markers linked to the m and M sex loci, allowing for the isolation of transgenic males. Furthermore, we demonstrate how combining these sexing strains enables the production of non-transgenic males. Scaling-up would allow the sorting of 100,000 first instar male larvae in under 1.5 hours with an estimated 0.01-0.1% female contamination. Cost-efficiency analyses revealed that using these strains could result in important savings while setting up and running a mass-rearing facility. Altogether, these Genetic Sexing Strains should enable a major upscaling in control programmes against these important vectors.Graphical abstract
Co-release of histamine and GABA in prefrontal cortex excites fast-spiking interneurons and causes divisive gain change in pyramidal cells; an effect that is enhanced in older mice
Authors: Lucaci Diana , Yu Xiao , Chadderton Paul , Wisden William , Brickley Stephen G 
Published: March 2022

AbstractWe studied how co-release of histamine/GABA from axons originating from the hypothalamic tuberomammillary nucleus (TMN) and projecting to the prefrontal cortex (PFC) influences circuit processing. We opto-stimulated histamine/GABA co-release from genetically defined TMN axons that express the histidine decarboxylase gene (TMNHDC axons). Whole-cell recordings were used to monitor excitability of visually identified PFC neurons in layer 2/3 of prelimbic (PL), anterior cingulate (AC) and infralimbic (IL) regions before and after opto-stimulated histamine/GABA release. We found that histamine-GABA co-release influences the PFC through actions on distinct neuronal types: histamine stimulates fast-spiking interneurons; and co-released GABA enhances tonic (extrasynaptic) inhibition on pyramidal cells (PyrNs). For fast spiking non-accommodating interneurons, opto-stimulation increased excitability, an effect blocked by histamine H1 and H2 receptor antagonists. The excitability of other interneuron types in the PFC was not altered. In contrast, the combined action of histamine and GABA co-release from TMNHDC axons produced predominantly divisive gain changes in PyrNs, increasing their resting input conductance, and decreasing the slope of the input-output relationship. The direct inhibitory effect of TMNHDC axon activation on PyrNs was not blocked by histamine receptor antagonists but was blocked by GABAA receptor antagonists. Across the adult lifespan (from 3 months to over 2 years of age), stimulation of TMNHDC axons in the PFC inhibited PyrN excitability significantly more in older mice. For individuals that maintain cognitive performance into later life, increases in TMNHDC modulation of PyrNs could enhance information processing and be an adaptive mechanism to buttress cognition.
EZH2 endorses cell plasticity to carcinoma cells facilitating mesenchymal to epithelial transition and tumour colonization
Authors: Gallardo Amador , Molina Aldara , Asenjo Helena G , Lopez-Onieva Lourdes , Alvarez-Perez Juan Carlos , Martorell-Marugán Jordi , Cara Francisca E , Espinosa-Martinez Mencia , Carmona-Sáez Pedro , Granados-Principal Sergio , Medina Pedro P , Sanchez-Pozo Antonio , Landeira David 
Published: March 2022

SummaryReversible transition between the epithelial and mesenchymal states are key aspects of carcinoma cell dissemination and the metastatic disease, and thus, characterizing the molecular basis of the epithelial to mesenchymal transition (EMT) is crucial to find druggable targets and more effective therapeutic approaches in cancer. Emerging studies suggest that epigenetic regulators might endorse cancer cells with the cell plasticity required to conduct dynamic changes in cell state during EMT. However, epigenetic mechanisms involved remain mostly unknown. Polycomb Repressive Complexes (PRCs) proteins are well-established epigenetic regulators of development and stem cell differentiation, but their role in different cancer systems is inconsistent and sometimes paradoxical. In this study, we have analysed the role of the PRC2 protein EZH2 in lung carcinoma cells. We found that besides its described role in CDKN2A-dependent cell proliferation, EZH2 upholds the epithelial state of cancer cells by repressing the transcription of hundreds of mesenchymal genes. Chemical inhibition or genetic removal of EZH2 promotes the residence of cancer cells in the mesenchymal state during reversible epithelial-mesenchymal transition. In fitting, analysis of human patient samples and tumour xenograft models indicate that EZH2 is required to efficiently repress mesenchymal genes and facilitate tumour colonization in vivo. Overall, this study discloses a novel role of PRC2 as a master regulator of EMT in carcinoma cells. This finding has important implications for the design of therapies based on EZH2 inhibitors in human cancer patients.
Cold-induced [Ca2+]cytelevations function to support osmoregulation in marine diatoms
Authors: Kleiner Friedrich H. , Helliwell Katherine E. , Chrachri Abdul , Hopes Amanda , Parry-Wilson Hannah , Gaikwad Trupti , Mieszkowska Nova , Chrachri Abdul , Mock Thomas , Wheeler Glen L. , Brownlee Colin 
Published: March 2022

AbstractDiatoms are a group of microalgae that are important primary producers in a range of open ocean, freshwater and intertidal environments. The latter can experience significant long- and short-term variability in temperature, from seasonal variations to rapid temperature shifts caused by tidal immersion and emersion. As temperature is a major determinant in the distribution of diatom species, their temperature sensory and response mechanisms likely have important roles in their ecological success. We have examined the mechanisms diatoms use to sense rapid changes in temperature, such as those experienced in the intertidal zone. We find that the diatomsPhaeodactylum tricornutumandThalassiosira pseudonanaexhibit a transient cytosolic Ca2+([Ca2+]cyt) elevation in response to rapid cooling, similar to those observed in plant and animal cells. However, [Ca2+]cytelevations were not observed in response to rapid warming. The kinetics and magnitude of cold-induced [Ca2+]cytelevations correlate with the rate of temperature decrease. We do not find a role for the [Ca2+]cytelevations in enhancing cold tolerance, but show that cold shock induces a Ca2+-dependent K+efflux and reduces mortality ofP. tricornutumduring a simultaneous hypo-osmotic shock. As inter-tidal diatom species may routinely encounter simultaneous cold and hypo-osmotic shocks during tidal cycles, we propose that cold-induced Ca2+signalling interacts with osmotic signalling pathways to aid in the regulation of cell volume. Our findings provide insight into the nature of temperature perception in diatoms and highlight that cross-talk between signalling pathways may play an important role in their cellular responses to multiple simultaneous stressors.
BrainQCNet: a Deep Learning attention-based model for the automated detection of artifacts in brain structural MRI scans
Authors: Garcia Mélanie , Dosenbach Nico , Kelly Clare 
Published: March 2022

AbstractAnalyses of structural MRI (sMRI) data depend on robust upstream data quality control (QC). It is also crucial that researchers seek to retain maximal amounts of data to ensure reproducible, generalizable models and to avoid wasted effort, including that of participants. The time-consuming and difficult task of manual QC evaluation has prompted the development of tools for the automatic assessment of brain sMRI scans. Existing tools have proved particularly valuable in this age of Big Data; as datasets continue to grow, reducing execution time for QC evaluation will be of considerable benefit. The development of Deep Learning (DL) models for artifact detection in structural MRI scans offers a promising avenue toward fast, accurate QC evaluation. In this study, we trained an interpretable Deep Learning model, ProtoPNet, to classify minimally preprocessed 2D slices of scans that had been manually annotated with a refined quality assessment (ABIDE 1;n= 980 scans). To evaluate the best model, we applied it to 2141 ABCD scans for which gold-standard manual QC annotations were available. We obtained excellent accuracy: 82.4% for good quality scans (Pass), 91.4% for medium to low quality scans (Fail). Further validation using 799 scans from ABIDE 2 and 750 scans from ADHD-200 confirmed the reliability of our model. Accuracy was comparable to or exceeded that of existing ML models, with fast processing and prediction time (1 min per scan, GPU machine, CUDA-compatible). Our attention model also performs better than traditional DL (i.e., convolutional neural network models) in detecting poor quality scans. To facilitate faster and more accurate QC prediction for the neuroimaging community, we have shared the model that returned the most reliable global quality scores as a BIDS-app (https://github.com/garciaml/BrainQCNet).
The rostral medial frontal cortex is crucial for engagement in consummatory behavior
Authors: White Samantha R. , Laubach Mark 
Published: March 2022

ABSTRACTThe medial frontal cortex (MFC) in rodents emits rhythmic activity that is entrained to the animal’s licking cycle during consumption and encodes the value of consumed fluids (Horst and Laubach, 2013; Amarante et al., 2017; Amarante and Laubach, 2021). These signals are especially prominent in the rostral half of the MFC. This region is located above an orbitofrontal region where mu opioid receptors regulate intake (Mena et al., 2011; Castro and Berridge, 2017) and reversible inactivation reduces behavioral measures associated with the incentive value and palatability of liquid sucrose (Parent et al., 2015a). Here, we examined the effects of reversible inactivation and stimulation of mu opioid receptors in rostral MFC on behavior in an incentive contrast licking task. Adult male rats licked to receive access to liquid sucrose, which alternated between high (16%) and low (4%) values over 30 sec periods. Bilateral infusion of muscimol reduced the total number of licks emitted over the 30 min test sessions, the time spent actively consuming sucrose, and the ratio of licks for the higher and lower value fluids. Inactivation did not alter licking frequency or variability or microstructural measures such as the duration of licking bouts that are classically associated with the palatability of a liquid reward. Infusions of DAMGO (1μg/μL) at the same sites had inconsistent behavioral effects across different subjects. Our findings suggest that the rostral MFC has a distinct role in the control of consummatory behavior and contributes to peristent consumption and not to the expression of palatability.SIGNIFICANCE STATEMENTThe medial frontal cortex (MFC) of rodents has received attention in recent years and is considered as a singular cortical region with a potential unitary function. Increasing evidence suggests that MFC is composed of distinct subregions, with unique roles in the control of behavior. The present study adds to this literature by showing unique effects of reversibly inactivating the most rostral part of the medial frontal cortex and a lack of consistent effects of stimulating mu opioid receptors in the subregion. Findings are in contrast to previous reports on the more ventral orbitofrontal cortex and caudal medial frontal cortex and are important for understanding the general role of the rodent frontal cortex and how opioids may act to control behavior.
The pore-forming protein gasdermin D is a cellular redox sensor
Authors: Devant Pascal , Boršić Elvira , Ngwa Elsy M. , Thiagarajah Jay R. , Hafner-Bratkovič Iva , Evavold Charles L. , Kagan Jonathan C. 
Published: March 2022

AbstractReactive oxygen species (ROS) affect inflammation and immunity in a multitude of ways, in particular in the context of the signaling pathways that determine cell fate. Inflammasomes are multiprotein cytoplasmic complexes whose pyroptosis-inducing activities are controlled by ROS. Our knowledge of how ROS mediates inflammasome activities is largely based on studies of the initiating events in these pathways. Herein, we show that ROS controls the terminal events in the pyroptosis pathways. We found that ROS oxidizes the protein gasdermin D (GSDMD) and promotes its assembly into a death-inducing pore forming complex. Mechanistically, ROS enhances GSDMD-mediated pyroptosis in an intrinsic manner, likely through oxidative modification of a specific cysteine residue (C192). Diverse ROS sources promote GSDMD oxidation, ranging from homeostatic control via the Ragulator-Rag complex, to inducible control via diverse microbial products and environmental toxins. These findings expand the steps in the inflammasome pathway that are controlled by ROS and suggest that GSDMD operates as a pyroptosis-inducing redox sensor.
Identification of unusually disulphide-bonded insulin forms using mass spectrometry and thermolysin cleavage
Authors: Jevon Dillon , Moon Kyung-Mee , Foster Leonard J. , Johnson James D. 
Published: March 2022

ABSTRACTInsulin is an essential hormone made by the pancreatic beta-cells in the islets of Langerhans. Beta-cells produce more insulin protein than virtually all other cellular proteins combined. Dysfunction in the process of insulin synthesis can lead to disease, including rare forms of monogenic diabetes. Specifically, aberrant intra-insulin and inter-insulin disulphide bonds have been implicated in the pathology of type 1 diabetes and type 2 diabetes, respectively. In type 1 diabetes, misprocessed insulin isoforms may be neoepitopes that kick-start and/or exacerbate the auto-immune response. In type 2 diabetes, aberrant disulphides form insulin dimers that can clog the endoplasmic reticulum and contribute to beta cell dysfunction. To facilitate the study of novel and known insulin neoepitopes and dimers, we present an unbiased and rapid technique for identifying insulin disulphide patterns from pancreatic islet extracts. The basis of this method is the cleavage between insulin’s cysteine residues with the metalloprotease, thermolysin, and subsequent identification of cysteine containing fragments and their partner peptides by LC-MS/MS. Using this technique, we identify 6 aberrant disulphide bonded insulin species, including a previously described type 1 diabetes neoepitope, as well as inter-chain disulphide bonded insulin dimers. Furthermore, using the endoplasmic stress inducer, thapsigargin, we observe increased disulphide errors in a patient donor sample. This approach lays foundations to identify the scope and cause of aberrant insulin disulphide formation in health and disease.
Profiling Mouse Brown and White Adipocytes to Identify Metabolically Relevant Small ORFs and Functional Microproteins
Authors: Martinez Thomas F. , Lyons-Abbott Sally , Bookout Angie L. , Donaldson Cynthia , Vaughan Joan M. , Lau Calvin , Abramov Ariel , Baquero Arian F. , Baquero Karalee , Friedrich Dave , Huard Justin , Davis Ray , Kim Bong , Koch Ty , Mercer Aaron J. , Misquith Ayesha , Murray Sara A. , Perry Sakara , Pino Lindsay K. , Sanford Christina , Simon Alex , Zhang Yu , Zipp Garrett , Shokhirev Maxim N. , Whittle Andrew J. , Searle Brian C. , MacCoss Michael J. , Saghatelian Alan , Barnes Christopher A. 
Published: March 2022

SUMMARYThe absence of thousands of recently annotated small open reading frame (smORF)-encoded peptides and small proteins (microproteins) from databases has precluded their analysis in metabolism and metabolic disease. Given the outsized importance of small proteins and peptides such as insulin, leptin, amylin, glucagon, and glucagon-like peptide-1 (GLP-1) in metabolism, microproteins are a potentially rich source of uncharacterized metabolic regulators. Here, we annotate smORFs in primary differentiated brown, white, and beige mouse adipose cells. Ribosome profiling (Ribo-Seq) detected a total of 3,877 unannotated smORFs. Analysis of RNA-Seq datasets revealed diet-regulated smORF expression in adipose tissues, and validated the adipose translation of the feeding-neuron marker gene Gm8773. Gm8773 encodes the mouse homolog of FAM237B, a neurosecretory protein that stimulates food intake and promotes weight gain in chickens. Testing of recombinant mFAM237B produced similar orexigenic activity in mice further supporting a role for FAM237B as a metabolic regulator and potentially part of the brain-adipose axis. Furthermore, we demonstrated that data independent acquisition mass spectrometry (DIA-MS) proteomics can provide a sensitive, flexible, and quantitative platform for identifying microproteins by mass spectrometry. Using this system led to the detection of 58 microproteins from cell culture and an additional 33 from mouse plasma. The proteomics data established the anti-inflammatory microprotein AW112010 as a circulating factor, and found that plasma levels of a microprotein translated from a FRS2 uORF is elevated in older obese mice. Together, the data highlight the value of this database in examining understudied smORFs and microproteins in metabolic research and identifying additional regulators of metabolism.
Assessing cats’ (Felis catus) sensitivity to human pointing gestures
Authors: Mäses Margaret , Wascher Claudia A.F. 
Published: March 2022

AbstractA wide range of non-human animal species have been shown to be able to respond to human referential signals, such as pointing gestures. The aim of the present study was to replicate previous findings showing cats to be sensitive to human pointing cues (Miklósi et al. 2005). In our study, we presented two types of human pointing gestures - momentary ipsilateral (direct pointing) and momentary cross-body pointing. We tested nine rescue cats in a two-way object choice task. On a group level, the success rate of cats was 74.4 percent. Cats performed significantly above chance level in both the ipsilateral and cross-body pointing condition. Trial number, rewarded side and type of gesture did not significantly affect the cats’ performances in the experiment. On an individual level, 5 out of 7 cats who completed 20 trials, performed significantly above chance level. Two cats only completed 10 trials. One of them succeeded in 8, the other in 6 of these. The results of our study replicate previous findings of cats being responsive to human ipsilateral pointing cues and add additional knowledge about their ability to follow cross-body pointing cues. Our results highlight that a domestic species, socialised in a group setting, may possess heterospecific communication skills. Further research is needed to exclude alternative parsimonious explanations, such as local and stimulus enhancement.
Visualization of conformational changes and membrane remodeling leading to genome delivery by viral class-II fusion machinery
Authors: Prasad Vidya Mangala , Blijleven Jelle S. , Smit Jolanda M. , Lee Kelly K. 
Published: March 2022

AbstractChikungunya virus (CHIKV) is a human pathogen that delivers its genome to the host cell cytoplasm through endocytic low pH-activated membrane fusion mediated by class-II fusion proteins. Though structures of prefusion, icosahedral CHIKV are available, structural characterization of virion interaction with membranes has been limited. Here, we have used cryo-electron tomography to visualize CHIKV’s complete membrane fusion pathway, identifying key intermediary glycoprotein conformations coupled to membrane remodeling events. Using sub-tomogram averaging, we elucidate features of the low pH-exposed virion, nucleocapsid and full-length E1-glycoprotein’s post-fusion structure. Contrary to class-I fusion systems, CHIKV achieves membrane apposition by protrusion of extended E1-glycoprotein homotrimers into the target membrane. The fusion process also features a large hemifusion diaphragm that transitions to a wide pore for intact nucleocapsid delivery. Our analyses provide comprehensive ultrastructural insights into the class-II virus fusion system function and direct mechanistic characterization of the fundamental process of protein-mediated membrane fusion.