bluuebunny/crossref_metadata_2025_split huggingface dataset:
Resource allocation to cell envelopes and the scaling of bacterial growth rate
Authors: Trickovic Bogi , Lynch Michael 
Published: January 2022

1AbstractAlthough various empirical studies have reported a positive correlation between the specific growth rate and cell size across bacteria, it is currently unclear what causes this relationship. We conjecture that such scaling occurs because smaller cells have a larger surface-to-volume ratio and thus have to allocate a greater fraction of the total resources to the production of the cell envelope, leaving fewer resources for other biosynthetic processes. To test this theory, we developed a coarse-grained model of bacterial physiology composed of the proteome that converts nutrients into biomass, with the cell envelope acting as a resource sink. Assuming resources are partitioned to maximize the growth rate, the model yields expected scalings. Namely, the growth rate and ribosomal mass fraction scale negatively, while the mass fraction of envelope-producing enzymes scales positively with surface-to-volume. These relationships are compatible with growth measurements and quantitative proteomics data reported in the literature.
Cancer-driving mutations are enriched in genic regions intolerant to germline variation
Authors: Vitsios Dimitrios , Dhindsa Ryan S. , Mitchell Jonathan , Matelska Dorota , Zou Zoe , Armenia Joshua , Wang Quanli , Sidders Ben , Harper Andrew R. , Petrovski Slavé 
Published: January 2022

AbstractLarge reference datasets of protein-coding variation in human populations have allowed us to determine which genes and genic sub-regions are intolerant to germline genetic variation. There is also a growing number of genes implicated in severe Mendelian diseases that overlap with genes implicated in cancer. Here, we hypothesized that mitotically mutable genic sub-regions that are intolerant to germline variation are enriched for cancer-driving mutations. We introduce a new metric, OncMTR, which uses 125,748 exomes in the gnomAD database to identify genic sub-regions intolerant to germline variation but enriched for hematologic somatic variants. We demonstrate that OncMTR can significantly predict driver mutations implicated in hematologic malignancies. Divergent OncMTR regions were enriched for cancer-relevant protein domains, and overlaying OncMTR scores on protein structures identified functionally important protein residues. Finally, we performed a rare variant, gene-based collapsing analysis on an independent set of 394,694 exomes from the UK Biobank and find that OncMTR dramatically improves genetic signals for hematologic malignancies. Our web app enables easy visualization of OncMTR scores for each protein-coding gene (https://astrazeneca-cgr-publications.github.io/OncMTR-Viewer/).
Isolation and Characterization of Extracellular Vesicles from the Fungal PhytopathogenColletotrichum higginsianum
Authors: Rutter Brian D. , Chu Thi-Thu-Huyen , Zajt Kamil K. , Dallery Jean-Félix , O’Connell Richard J. , Innes Roger W. 
Published: January 2022

AbstractFungal phytopathogens secrete extracellular vesicles (EVs) associated with enzymes and phytotoxic metabolites. While these vesicles are thought to promote infection, defining the true contents and functions of fungal EVs, as well as suitable protein markers, is an ongoing process. To expand our understanding of fungal EVs and their possible roles during infection, we purified EVs from the hemibiotrophic phytopathogenColletotrichum higginsianum, the causative agent of anthracnose disease in multiple plant species, includingArabidopsis thaliana. EVs were purified in large numbers from the supernatant of protoplasts but not the supernatant of intact mycelial cultures. We purified two separate populations of EVs, each associated with over 700 detected proteins, including proteins involved in vesicle transport, cell wall biogenesis and the synthesis of secondary metabolites. We selected two SNARE proteins (Snc1 and Sso2) and one 14-3-3 protein (Bmh1) as potential EV markers and generated transgenic lines expressing fluorescent fusions. Each marker was confirmed to be protected inside EVs. Fluorescence microscopy was used to examine the localization of each marker during infection onArabidopsisleaves. These findings further our understanding of EVs in fungal phytopathogens and will help build an experimental system to study EV inter-kingdom communication between plants and fungi.
Sex differences in the alcohol-mediated modulation of BLA network states
Authors: DiLeo Alyssa , Antonodiou Pantelis , Ha Spencer , Maguire Jamie L. 
Published: January 2022

AbstractAbout 85% of adults in the United States report drinking alcohol in their lifetime. Mood disorders, like generalized anxiety disorder and major depression, are highly comorbid with alcohol use. The basolateral amygdala (BLA) is an area of the brain that is heavily implicated in both mood disorders and alcohol use disorder. Importantly, modulation of BLA network/oscillatory states via parvalbumin-positive (PV) GABAergic interneurons has been shown to control the behavioral expression of fear and anxiety. Further, PV interneurons express a high density of δ-subunit-containing GABAAreceptors (GABAARs), which are sensitive to low concentrations of alcohol. Our lab previously demonstrated that δ-subunit-containing GABAARs on PV interneurons in the BLA influence voluntary ethanol intake and anxiety-like behavior in withdrawal. Therefore, we hypothesized that the effects of alcohol may modulate BLA network states that have been associated with fear and anxiety behaviors via δ-GABAARs on PV interneurons in the BLA. Given the impact of ovarian hormones on the expression of δ-GABAARs, we examined the ability of alcohol to modulate local field potentials (LFPs) in the BLA from male and female C57BL/6J andGabrd-/-mice after acute and repeated exposure to alcohol. Here, we demonstrate that acute and repeated alcohol can differentially modulate oscillatory states in male and female C57BL/6J mice, a process which involves δ-GABAARs. This is the first study to demonstrate that alcohol is capable of altering network states implicated in both anxiety and alcohol use disorders.Significance StatementAlcohol use disorder and mood disorders are highly comorbid. The basolateral amygdala (BLA) is implicated in both of these disorders, but the mechanisms contributing to their shared pathophysiology remain uncertain. Here we demonstrate that acute and repeated alcohol exposure can alter network oscillations in the BLA which control the behavioral expression of fear and anxiety. These data suggest that alcohol may directly influence network states associated with mood. Further, we demonstrate sex differences in alcohol’s ability to modulate BLA network states, an effect involving δ-GABAAreceptors, which may contribute to sex differences in alcohol intake and comorbid mood disorders. These data potentially point to a novel mechanism mediating the effects of alcohol on affective states.
Glucocorticoid receptor dysregulation underlies 5-HT2Areceptor-dependent synaptic and behavioral deficits in a mouse neurodevelopmental disorder model
Authors: Saunders Justin M. , Muguruza Carolina , Sierra Salvador , Moreno José L. , Callado Luis F. , Meana J. Javier , Beardsley Patrick M. , González-Maeso Javier 
Published: January 2022

ABSTRACTPrenatal environmental insults increase the risk of neurodevelopmental psychiatric conditions in the offspring. Structural modifications of dendritic spines are central to brain development and plasticity. Using maternal immune activation (MIA) as a rodent model of prenatal environmental insult, previous results have reported dendritic structural deficits in the frontal cortex. However, very little is known about the molecular mechanism underlying MIA-induced synaptic structural alterations in the offspring. Using prenatal (E12.5) injection with poly-(I:C) as a mouse MIA model, we show that upregulation of the serotonin 5-HT2Areceptor (5-HT2AR) is at least in part responsible for some of the effects of prenatal insults on frontal cortex dendritic spine structure and sensorimotor gating processes. Mechanistically, we report that this upregulation of frontal cortex 5-HT2AR expression is associated with MIA-induced reduction of nuclear translocation of the glucocorticoid receptor (GR) and, consequently, a decrease in the enrichment of GR at the5-HT2ARpromoter. The translational significance of these preclinical findings is supported by data in postmortem human brain samples suggesting dysregulated nuclear GR translocation in frontal cortex of schizophrenia subjects. Repeated (twice a day for 4 days) corticosterone administration augmented frontal cortex5-HT2ARexpression and reduced GR binding to the5-HT2ARpromoter. However, virally (AAV)-mediated augmentation of GR function reduced frontal cortex5-HT2ARexpression and improved sensorimotor gating processes via 5-HT2AR. Together, these data support a negative regulatory relationship between GR signaling and5-HT2ARexpression in mouse frontal cortex that may carry implications for the pathophysiology underlying5-HT2ARdysregulation in neurodevelopmental psychiatric disorders.
Antibiotic action revealed by real-time imaging of the mycobacterial membrane
Authors: Wuo Michael G. , Dulberger Charles L. , Brown Robert A. , Sturm Alexander , Ultee Eveline , Bloom-Ackermann Zohar , Choi Catherine , Garner Ethan C. , Briegel Ariane , Hung Deborah T. , Rubin Eric J. , Kiessling Laura L. 
Published: January 2022

AbstractThe current understanding of mycobacterial cell envelope remodeling in response to antibiotics is limited. Chemical tools that report on phenotypic changes with minimal cell wall perturbation are critical to understanding such time-dependent processes. We employed a fluorogenic chemical probe to image how antibiotics perturb mycobacterial cell envelope assembly in real-time. Time-lapse microscopy revealed that differential antibiotic treatment elicited unique cellular phenotypes, providing a platform for simultaneously monitoring cell envelope construction and remodeling responses. Our data show that rifampicin, which does not directly inhibit cell wall biosynthesis, affords a readily detected mycomembrane phenotype. The fluorogenic probe revealed the production of extracellular vesicles in response to antibiotics, and analyses of these vesicles indicate that antibiotic treatment elicits the release of agents that attenuate macrophage activation.
Mild respiratory SARS-CoV-2 infection can cause multi-lineage cellular dysregulation and myelin loss in the brain
Authors: Fernández-Castañeda Anthony , Lu Peiwen , Geraghty Anna C. , Song Eric , Lee Myoung-Hwa , Wood Jamie , Yalçın Belgin , Taylor Kathryn R. , Dutton Selena , Acosta-Alvarez Lehi , Ni Lijun , Contreras-Esquivel Daniel , Gehlhausen Jeff R. , Klein Jon , Lucas Carolina , Mao Tianyang , Silva Julio , Peña-Hernández Mario A. , Tabachnikova Alexandra , Takahashi Takehiro , Tabacof Laura , Tosto-Mancuso Jenna , Breyman Erica , Kontorovich Amy , McCarthy Dayna , Quezado Martha , Hefti Marco , Perl Daniel , Folkerth Rebecca , Putrino David , Nath Avi , Iwasaki Akiko , Monje Michelle 
Published: January 2022

AbstractSurvivors of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection frequently experience lingering neurological symptoms, including impairment in attention, concentration, speed of information processing and memory. This long-COVID cognitive syndrome shares many features with the syndrome of cancer therapy-related cognitive impairment (CRCI). Neuroinflammation, particularly microglial reactivity and consequent dysregulation of hippocampal neurogenesis and oligodendrocyte lineage cells, is central to CRCI. We hypothesized that similar cellular mechanisms may contribute to the persistent neurological symptoms associated with even mild SARS-CoV-2 respiratory infection. Here, we explored neuroinflammation caused by mild respiratory SARS-CoV-2 infection – without neuroinvasion - and effects on hippocampal neurogenesis and the oligodendroglial lineage. Using a mouse model of mild respiratory SARS-CoV-2 infection induced by intranasal SARS-CoV-2 delivery, we found white matter-selective microglial reactivity, a pattern observed in CRCI. Human brain tissue from 9 individuals with COVID-19 or SARS-CoV-2 infection exhibits the same pattern of prominent white matter-selective microglial reactivity. In mice, pro-inflammatory CSF cytokines/chemokines were elevated for at least 7-weeks post-infection; among the chemokines demonstrating persistent elevation is CCL11, which is associated with impairments in neurogenesis and cognitive function. Humans experiencing long-COVID with cognitive symptoms (48 subjects) similarly demonstrate elevated CCL11 levels compared to those with long-COVID who lack cognitive symptoms (15 subjects). Impaired hippocampal neurogenesis, decreased oligodendrocytes and myelin loss in subcortical white matter were evident at 1 week, and persisted until at least 7 weeks, following mild respiratory SARS-CoV-2 infection in mice. Taken together, the findings presented here illustrate striking similarities between neuropathophysiology after cancer therapy and after SARS-CoV-2 infection, and elucidate cellular deficits that may contribute to lasting neurological symptoms following even mild SARS-CoV-2 infection.
Application of sequential cyclic compression on cancer cells in a flexible microdevice
Authors: Onal Sevgi , Alkaisi Maan M. , Nock Volker 
Published: January 2022

AbstractMechanical forces shape physiological structure and function within cell and tissue microenvironments, during which cells strive to restore their shape or develop an adaptive mechanism to maintain cell integrity depending on strength and type of the mechanical loading. While some cells are shown to experience permanent plastic deformation after a repetitive mechanical tensile loading and unloading, the impact of such repetitive compression on plastic deformation of cells is yet to be understood. As such, the ability to apply cyclic compression is crucial for any experimental setup aimed at the study of mechanical compression taking place in cell and tissue microenvironments. Here, we demonstrate such cyclic compression using a microfluidic compression platform on live cell actin in SKOV-3 ovarian cancer cells. Live imaging of the actin cytoskeleton dynamics of the compressed cells was performed for varying pressures applied sequentially in ascending order during cell compression. Additionally, recovery of the compressed cells was investigated by capturing actin cytoskeleton and nuclei profiles of the cells at zero time and 24 h-recovery after compression in end point assays. This was performed for a range of mild pressures within the physiological range. Results showed that the phenotypical response of compressed cells during recovery after compression with 20.8 kPa differed observably from that for 15.6 kPa. This demonstrated the ability of the platform to aid in the capture of minute differences in cell behaviour as a result of being compressed at various pressures in physiologically relevant manner. Differences observed between compressed cells fixed at zero time or after 24 h-recovery suggest that SKOV-3 cells exhibit deformations at the time of the compression, a proposed mechanism cells use to prevent mechanical damage. The extent of recovery of compressed cells, inferred by imaging cell membrane bulges and actin cytoskeleton and measuring the shape descriptors of cell nuclei, can give insights into the plasticity of cancer cells. Thus, biomechanical responses of SKOV-3 ovarian cancer cells to sequential cyclic compression and during recovery after compression could be revealed in a flexible microdevice. As demonstrated in this work, the microfluidic platform could control the strength and duration of cyclic compression, while enabling the observation of morphological, cytoskeletal and nuclear changes and recovery in compressed cells, thus providing a powerful new tool for the study of mechanobiological processes in cancer and cell biology.
Deviation from the Residue-Based Linear Free Energy Relationship Reveals a Non-Native Structure in Protein Folding
Authors: Fujinami Daisuke , Hayashi Seiichiro , Kohda Daisuke 
Published: January 2022

AbstractMultiprobe measurements, such as NMR and hydrogen exchange study, can provide the equilibrium constant K and kinetic rate constant k of the structural changes of a polypeptide on a per-residue basis. We previously found a linear relationship between residue-specific log K values and residuespecific log k values for the two-state topological isomerization of a 27-residue peptide. To test the general applicability of the residue-based linear free energy relationship (rbLEFR), we performed a literature search to collect residue-specific equilibrium and kinetic constants in various exchange processes, including protein folding, coupled folding and binding of intrinsically disordered peptides, and structural fluctuations of folded proteins. The good linearity in a substantial number of log-log plots proved that the rbLFER holds for the structural changes in a wide variety of protein-related phenomena. Protein molecules quickly fold into their native structures and change their conformations smoothly. Theoretical studies and molecular simulations advocate that the physicochemical basis is the consistency principle and the minimal frustration principle: Non-native structures/interactions are absent or minimized along the folding pathway. The linearity of the residue-based free energy relationship demonstrates experimentally the absence of non-native structures in transition states. In this context, the hydrogen exchange study of apomyoglobin folding intermediates is particularly interesting. We found that the residues that deviated from the linear relationship corresponded to the non-native structure, which had been identified by other experiments. The rbLFER provides a unique and practical method to probe the dynamic aspects of the transition states of protein molecules.HighlightsA collection of equilibrium and kinetic constants of structural changes of proteinsResidue-based linear free energy relationship widely holds between the two constantsrbLFER indicates the absence of non-ground state structures in transition statesrbLFER is an experiment proof of the consistency principle of protein foldingDeviations from the linear relation suggest special structures in transition statesAbstract Figure
Fluorescence visualization of deep-buried hollow organs
Authors: Feng Zhe , Li Yuanyuan , Chen Siyi , Yu Xiaoming , Ying Yanyun , Zheng Junyan , Wu Tianxiang , Li Jin , Fan Xiaoxiao , Zhang Dan , Qian Jun 
Published: January 2022

AbstractHigh-definition fluorescence imaging of deep-buried organs is still challenging. Here, we develop bright fluorophores emitting to 1700 nm by enhancing electron donating ability and reducing donor-acceptor distance. In parallel, the heavy water functions as the solvent of the delicately designed fluorophores, effectively reducing the fluorescent signal loss caused by the absorption by water. The near-infrared-II (NIR-II, 900-1880 nm) emission is eventually recovered and extended beyond 1400 nm. Compared with the spectral range beyond 1500 nm, the one beyond 1400 nm gives a more accurate fluorescence visualization of the hollow organs, owing to the absorption-induced scattering suppression. In addition, the intraluminal lesions containing much water are simultaneously negatively stained, leading to a stark contrast for precise diagnosis. Eventually, the intraluminally perfused fluorescent probes are excreted from mice and thus no obvious side effects emerge. This general method can provide new avenues for future biomedical imaging of deep and highly scattering tissues.
Intravenous gene transfer throughout the brain of infant Old World primates using AAV
Authors: Chuapoco Miguel R. , Flytzanis Nicholas C. , Goeden Nick , Octeau J. Christopher , Roxas Kristina M. , Chan Ken Y. , Scherrer Jon , Winchester Janet , Blackburn Roy J. , Campos Lillian J. , Arokiaraj Cynthia M. , Miles Timothy F. , Jang Min J. , Vendemiatti Julia , Deverman Benjamin E. , Pickel James , Fox Andrew S. , Gradinaru Viviana 
Published: January 2022

AbstractAdeno-associated viruses (AAVs) can enable robust and safe gene delivery to the mammalian central nervous system (CNS). While the scientific community has developed numerous neurotropic AAV variants for systemic gene-transfer to the rodent brain, there are few AAVs that efficiently access the CNS of higher order primates. We describe here AAV.CAP-Mac, an engineered AAV variant that enables systemic, brain-wide gene delivery in infants of two Old World primate species—the rhesus macaque (Macaca mulatta) and the green monkey (Chlorocebus sabaeus). We identified CAP-Mac using a multi-species selection strategy, initially screening our library in the adult common marmoset (Callithrix jacchus) and narrowing our pool of test-variants for another round of selection in infant macaques. In individual characterization, CAP-Mac robustly transduces human neurons in vitro and Old World primate neurons in vivo, where it targets all lobes of cortex, the cerebellum, and multiple subcortical regions of disease relevance. We use CAP-Mac for Brainbow-like multicolor labeling of macaque neurons throughout the brain, enabling morphological reconstruction of both medium spiny neurons and cortical pyramidal cells. Because of its broad distribution throughout the brain and high neuronal efficiency in infant Old World primates compared to AAV9, CAP-Mac shows promise for researchers and clinicians alike to unlock novel, noninvasive access to the brain for efficient gene transfer.