bluuebunny/crossref_metadata_2025 huggingface dataset:
Identifying different types of tumors in human brain, breast, and uterus according to their optical properties in the red to near-infrared region
Authors: Hamdy Omnia
Published: April 2020

Optical diagnosis techniques are gaining validity due to their competitive advantages including safety and functionality. These methods probe the tissue using light in the red to near-infrared region that shows relatively high penetration in biological tissues. The reflected light which is controlled by tissue absorption and scattering parameters can provide significant information about its pathology. In the present work, a method for identifying different types of tumors in human brain, breast and uterus based on their absorption and scattering characteristics in the red to near-infrared spectra is proposed. The classification method depends on studying the red to near-infrared light diffusion through the examined tissues using Monte-Carlo simulation and finite element solution of the light diffusion equation. The obtained tissue reflectance profiles, optical fluence rate distribution and absorbed faction in each tumor type show different characteristics along the selected wavelengths. The variation in these three features can be considered as an alternative approach of medical diagnosis or can assist with other conventional diagnosis methods.
Prospects for detecting early warning signals in discrete event sequence data: application to epidemiological incidence data
Authors: Southall Emma , Tildesley Michael J. , Dyson Louise
Published: April 2020

Early warning signals (EWS) identify systems approaching a critical transition, where the system undergoes a sudden change in state. For example, monitoring changes in variance or autocorrelation offers a computationally inexpensive method which can be used in real-time to assess when an infectious disease transitions to elimination. EWS have a promising potential to not only be used to monitor infectious diseases, but also to inform control policies to aid disease elimination. Previously, potential EWS have been identified for prevalence data, however the prevalence of a disease is often not known directly. In this work we identify EWS for incidence data, the standard data type collected by the Centers for Disease Control and Prevention (CDC) or World Health Organization (WHO). We show, through several examples, that EWS calculated on simulated incidence time series data exhibit vastly different behaviours to those previously studied on prevalence data. In particular, the variance displays a decreasing trend on the approach to disease elimination, contrary to that expected from critical slowing down theory; this could lead to unreliable indicators of elimination when calculated on real-world data. We derive analytical predictions which can be generalised for many epidemiological systems, and we support our theory with simulated studies of disease incidence. Additionally, we explore EWS calculated on the rate of incidence over time, a property which can be extracted directly from incidence data. We find that although incidence might not exhibit typical critical slowing down properties before a critical transition, the rate of incidence does, presenting a promising new data type for the application of statistical indicators.

Author summary

The threat posed by infectious diseases has a huge impact on our global society. It is therefore critical to monitor infectious diseases as new data become available during control campaigns. One obstacle in observing disease emergence or elimination is understanding what influences noise in the data and how this fluctuates when near to zero cases. The standard data type collected is the number of new cases per day/month/year but mathematical modellers often focus on data such as the total number of infectious people, due to its analytical properties. We have developed a methodology to monitor the standard type of data to inform whether a disease is approaching emergence or disease elimination. We have shown computationally how fluctuations change as disease data get closer towards a tipping point and our insights highlight how these observed changes can be strikingly different when calculated on different types of data.
Tadpoles of hybridising fire-bellied toads (B. bombinaandB. variegata) differ in their susceptibility to predation
Authors: Smolinský Radovan , Baláž Vojtech , Nürnberger Beate
Published: April 2020

The role of adaptive divergence in the formation of new species has been the subject of much recent debate. The most direct evidence comes from traits that can be shown to have diverged under natural selection and that now contribute to reproductive isolation. Here, we make the case for differential adaptation of two fire-bellied toads (Anura, Bombinatoridae) to two types of aquatic habitat.Bombina bombinaandB. variegataare two anciently diverged taxa that now reproduce in predator-rich ponds and ephemeral aquatic sites, respectively. Nevertheless, they hybridise extensively wherever their distribution ranges adjoin. We show in laboratory experiments that, as expected,B. variegatatadpoles are at relatively greater risk of predation from dragonfly larvae, even when they display a predator-induced phenotype. These tadpoles spent relatively more time swimming and so prompted more attacks from the visually hunting predators. We predict that genomic regions linked to high activity inB. variegataare barred from introgression into theB. bombinagene pool and thus contribute to gene flow barriers that keep the two taxa from merging into one.
The lack of myelin in the mutanttaieprat induces a differential immune response related to protection to the human parasiteTrichinella spiralis
Authors: Nava-Castro Karen Elizabeth , Cortes Carmen , Eguibar José Ramón , Del Rio-Araiza Víctor Hugo , Hernández-Bello Romel , Morales-Montor Jorge
Published: April 2020

Taieprat is a myelin mutant with a progressive motor syndrome characterized by tremor, ataxia, immobility episodes, epilepsy and paralysis of the hindlimbs, accompanied with differential expression of interleukins and their receptors that correlated with the progressive demyelination that characterize this mutant. Thus, thetaieprat is a suitable model to study neuroimmune alterations. The aim of this study was to investigate the immune alterations present in the mutanttaieprat during the acute infection withTrichinella spiralis. Our results show that there is an important decrease in the number of intestinal larvae in thetaieprat when compared to the Sprague-Dawley control rats. We also found differences in the percentage of innate and adaptive immune cell profile in the mesenteric lymphatic nodes and the spleen associated to the lack of myelin in thetaieprat. Finally, a clear pro-inflammatory cytokine pattern was seen in the infectedtaieprat, which may explain the decrease in larvae number. These results sustain the theory that neuroimmune interaction is a fundamental process capable of modulating the immune response, particularly against the parasiteTrichinella spiralisin a model of progressive demyelination that could be an important mechanism in autoimmune diseases and parasite infection.

Author summary

The complex communication among the brain and the immune system may be certainly altered during an infection and may be determinant in the resolution of this. We analyze the immune response to a parasite in a rat model in which a demyelinization process occur naturally and found that parasite loads were reduced when comparing with control subjects and this was accompanied to changes in the systemic immune response.
Lactobacilli and other gastrointestinal microbiota of Peromyscus leucopus, reservoir host for agents of Lyme disease and other zoonoses in North America
Authors: Milovic Ana , Bassam Khalil , Shao Hanjuan , Chatzistamou Ioulia , Tufts Danielle M. , Diuk-Wasser Maria , Barbour Alan G.
Published: April 2020

The cricetine rodent Peromyscus leucopus is an important reservoir for several human zoonoses, including Lyme disease, in North America. Akin to hamsters, the white-footed deermouse has been unevenly characterized in comparison to the murid Mus musculus. To further understanding of P. leucopus’ total genomic content, we investigated gut microbiomes of an outbred colony of P. leucopus, inbred M. musculus, and a natural population of P. leucopus. Metagenome and whole genome sequencing were combined with microbiology and microscopy approaches. A focus was the genus Lactobacillus, four diverse species of which were isolated from forestomach and feces of colony P. leucopus. Three of the species--L. animalis, L. reuteri, and provisionally-named species “L. peromysci”--were identified in fecal metagenomes of wild P. leucopus but not discernibly in samples from M. musculus. L. johnsonii, the fourth species, was common in M. musculus but absent or sparse in wild P. leucopus. Also identified in both colony and natural populations were a Helicobacter sp. in feces but not stomach, and a Tritrichomonas sp. protozoan in cecum or feces. The gut metagenomes of colony P. leucopus were similar to those of colony M. musculus at the family or higher level and for major subsystems. But there were multiple differences between species and sexes within each species in their gut metagenomes at orthologous gene level. These findings provide a foundation for hypothesis-testing of functions of individual microbial species and for interventions, such as bait vaccines based on an autochthonous bacterium and targeting P. leucopus for transmission-blocking.
C. elegansCLASP/CLS-2 negatively regulates membrane ingression throughout the oocyte cortex and is required for polar body extrusion
Authors: Schlientz Aleesa J. , Bowerman Bruce
Published: April 2020

The requirements for oocyte meiotic cytokinesis during polar body extrusion are not well understood. In particular, the relationship between the oocyte meiotic spindle and polar body contractile ring dynamics remains largely unknown. We have used live cell imaging and spindle assembly defective mutants lacking the function of CLASP/CLS-2, kinesin-12/KLP-18, or katanin/MEI-1 to investigate the relationship between meiotic spindle structure and polar body extrusion inC. elegansoocytes. We show that spindle bipolarity and chromosome segregation are not required for polar body contractile ring formation and chromosome extrusion inklp-18mutants, but oocytes with severe spindle assembly defects due to loss of CLS-2 or MEI-1 have penetrant and distinct polar body extrusion defects: CLS-2 is required early for contractile ring assembly or stability, while MEI-1 is required later for contractile ring constriction. We also show that CLS-2 negatively regulates membrane ingression throughout the oocyte cortex during meiosis I, and we explore the relationship between global cortical dynamics and oocyte meiotic cytokinesis.

Author Summary

The precursor cells that produce gametes—sperm and eggs in animals—have two copies of each chromosome, one from each parent. These precursors undergo specialized cell divisions that leave each gamete with only one copy of each chromosome; defects that produce incorrect chromosome number cause severe developmental abnormalities. In oocytes, these cell divisions are highly asymmetric, with extra chromosomes discarded into small membrane bound polar bodies, leaving one chromosome set within the much larger oocyte. How oocytes assemble the contractile apparatus that pinches off polar bodies remains poorly understood. To better understand this process, we have used the nematodeCaenorhabditis elegansto investigate the relationship between the bipolar structure that separates oocyte chromosomes, called the spindle, and assembly of the contractile apparatus that pinches off polar bodies. We used a comparative approach, examining this relationship in three spindle assembly defective mutants. Bipolar spindle assembly and chromosome separation were not required for polar body extrusion, as it occurred normally in mutants lacking a protein called KLP-18. However, mutants lacking the protein CLS-2 failed to assemble the contractile apparatus, while mutants lacking the protein MEI-1 assembled a contractile apparatus that failed to fully constrict. We also found that CLS-2 down-regulates membrane ingression throughout the oocyte surface, and we explored the relationship between oocyte membrane dynamics and polar body extrusion.
The Mechanosensitive Ion Channel MSL10 Potentiates Responses to Cell Swelling in Arabidopsis Seedlings
Authors: Basu Debarati , Haswell Elizabeth S.
Published: April 2020

The ability to respond to unanticipated increases in volume is a fundamental property of cells, essential for cellular integrity in the face of osmotic challenges. Plants must manage cell swelling during flooding, rehydration, and pathogenesis–but little is known about the mechanisms by which this occurs. It has been proposed that plant cells could sense and respond to cell swelling through the action of mechanosensitive ion channels. Here we develop and characterize a new assay to study the effects of cell swelling onArabidopsis thalianaseedlings and to test the contributions of the mechanosensitive ion channel MscS-Like10 (MSL10). The assay incorporates both cell wall softening and hypo-osmotic treatment to induce cell swelling. We show that MSL10 is required for previously demonstrated responses to hypo-osmotic shock, including a cytoplasmic calcium transient within the first few seconds, accumulation of ROS within the first 30 minutes, and increased transcript levels of mechano-inducible genes within 60 minutes. We also show that cell swelling induces programmed cell death within 3 hours, also in a MSL10-dependent manner. Finally, we show that MSL10 is unable to potentiate cell swelling-induced death when phosphomimetic residues are introduced into its soluble N-terminus. Thus, MSL10 functions as a phospho-regulated membrane-based sensor that connects the perception of cell swelling to a downstream signaling cascade and programmed cell death.
Gain of channel function and modified gating properties in TRPM3 mutants causing intellectual disability and epilepsy
Authors: Van Hoeymissen Evelien , Held Katharina , Nogueira Freitas Ana Cristina , Janssens Annelies , Voets Thomas , Vriens Joris
Published: April 2020

Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of disorders characterized by epilepsy with comorbid intellectual disability. Recently, twode novoheterozygous mutations in the gene encoding TRPM3, a calcium permeable ion channel, were identified as the cause of DEE in eight probands, but the functional consequences of the mutations remained elusive. Here we demonstrate that both mutations (V990M and P1090Q) have distinct effects on TRPM3 gating, including increased basal activity, higher sensitivity to stimulation by the endogenous neurosteroid pregnenolone sulphate (PS) and heat, and altered response to ligand modulation. Most strikingly, the V990M mutation affected the gating of the non-canonical pore of TRPM3, resulting in large inward cation currents via the voltage sensor domain in response to PS stimulation. Taken together, these data indicate that the two DEE mutations in TRPM3 result in a profound gain of channel function, which may lie at the basis of epileptic activity and neurodevelopmental symptoms in the patients.
Emission rates of species-specific volatiles change across communities ofClarkiaspecies: Evidence for character displacement in floral scent
Authors: Eisen Katherine E. , Geber Monica A. , Raguso Robert A.
Published: April 2020

A current frontier of character displacement research is to determine if displacement occurs via multiple phenotypic pathways and varies across communities with different species compositions. Here, we conducted the first test for context-dependent character displacement in multimodal floral signals by analyzing variation in floral scent in a system that exhibits character displacement in flower size, and that has multiple types of sympatric communities. In a greenhouse common garden experiment, we measured quantitative variation in volatile emission rates of the progeny of two species ofClarkiafrom replicated communities that contain one, two, or fourClarkiaspecies. The first two axes of a constrained correspondence analysis, which explained 24 percent of the total variation in floral scent, separated the species and community types, respectively. Of the 23 compounds that were significantly correlated with these axes, nine showed patterns consistent with character displacement. Two compounds produced primarily byC. unguiculataand two compounds produced primarily byC. cylindricawere emitted in higher amounts in sympatry. Character displacement in some volatiles varied across sympatric communities and occurred in parallel with displacement in flower size, demonstrating that this evolutionary process can be context-dependent and may occur through multiple pathways.
Characterizing chemotherapy-induced neutropenia and monocytopenia through mathematical modelling
Authors: Cassidy Tyler , Humphries Antony R. , Craig Morgan , Mackey Michael C.
Published: April 2020

In spite of the recent focus on the development of novel targeted drugs to treat cancer, cytotoxic chemotherapy remains the standard treatment for the vast majority of patients. Unfortunately, chemotherapy is associated with high hematopoietic toxicity that may limit its efficacy. We have previously established potential strategies to mitigate chemotherapy-induced neutropenia (a lack of circulating neutrophils) using a mechanistic model of granulopoiesis to predict the interactions defining the neutrophil response to chemotherapy and to define optimal strategies for concurrent chemotherapy/prophylactic granulocyte colony-stimulating factor (G-CSF). Here, we extend our analyses to include monocyte production by constructing and parameterizing a model of monocytopoiesis. Using data for neutrophil and monocyte concentrations during chemotherapy in a large cohort of childhood acute lymphoblastic leukemia patients, we leveraged our model to determine the relationship between the monocyte and neutrophil nadirs during cyclic chemotherapy. We show that monocytopenia precedes neutropenia by 3 days, and rationalize the use of G-CSF during chemotherapy by establishing that the onset of monocytopenia can be used as a clinical marker for G-CSF dosing post-chemotherapy. This work therefore has important clinical applications as a comprehensive approach to understanding the relationship between monocyte and neutrophils after cyclic chemotherapy with or without G-CSF support.
Resolving host and species boundaries for perithecia-producing nectriaceous fungi across the central Appalachian Mountains
Authors: Stauder Cameron M. , Utano Nicole M. , Kasson Matt T.
Published: April 2020

The Nectriaceae contains numerous canker pathogens. Due to scarcity of ascomata on many hosts, comprehensive surveys are lacking. Here we characterize the diversity of perithecia-producing nectriaceous fungi across the central Appalachians. Ten species from twelve hosts were recovered including a novelCorinectriasp. fromPicea rubens. Neonectria ditissimaandN. faginatawere most abundant and associated withFagus grandifoliawith beech bark disease (BBD).N. ditissimawas also recovered from additional cankered hardwoods, including previously unreportedAcer spicatum, Ilex mucronata, andSorbus americana. Cross-pathogenicity inoculations ofN. ditissimaconfirmed susceptibility ofAcerandBetulaspp.Neonectria magnoliaewas recovered from cankeredLiriodendron tulipiferaandMagnolia fraseriand pathogenicity onL. tulipiferawas confirmed.Fusarium babindawas consistently recovered from beech with BBD, although its role remains unclear. This survey provides a contemporary snapshot of Nectriaceae diversity across the Appalachian Mountains. The following nomenclatural changes are proposed:Neonectria magnoliaecomb. nov.
Prey choice of the common vampire bat on introduced species in an Atlantic forest land-bridge island
Authors: Gonçalves Fernando , Magioli Marcelo , Bovendorp Ricardo S. , de Barros Ferraz Katia Maria Paschoaletto Micchi , Cagnoni Letícia Bulascoschi , Moreira Marcelo Zacharias , Galetti Mauro
Published: April 2020

The proliferation of native, alien, invasive and domestic species provide novel and abundant food resources for the common vampire bat (Desmodus rotundus) that could alter its prey preference. Based on the analysis of carbon and nitrogen stable isotopes, we report the prey choice of D. rotundus on introduced mammals in an tropical land-bridge island where the domestic animals were removed and 100 individuals of 15 mammal species were intentionally introduced. Our analysis shows that, D. rotundus on Anchieta Island were more likely to prey upon species from open habitats (mean value of −14.8‰), i.e., animals with high δ13C values characterized by the consumption of C4 resources. As expected for a top predator species, δ15N values for D. rotundus were higher (mean value of 8.2‰) and overlapped the niche of the capybaras (Hydrochoerus hydrochaeris) from the Anchieta Island, while it was distant from coatis, and also from those potential prey from the preserved area in the mainland, including the capybaras, indicating that among all potential mammalian prey species, they fed exclusively on capybaras, the highest mammalian biomass on island. Based on previous information on human occupation, the domestic animals present on Anchieta island might be the main prey of D. rotundus and responsible for maintaining a viable population. As the capybaras were introduced only 36 years ago, this suggests a rapid prey shift due to anthropogenic disturbances, which has allowed common vampire bats to successfully exploit them. Literature records also show that common vampire bats were not captured in preserved areas of the mainland which are near Anchieta Island indicating that the percentage of capture of D. rotundus is usually low in natural forested habitats where potential prey are scattered. As three individuals of introduced capybaras were confirmed died from bat rabies viruses (RABV) in 2020, we suggest periodic monitoring of bat rabies viruses in common vampire bat populations on Anchieta Island and areas nearby, in order to quantify the magnitude of the outbreak area and develop strategies for controlling, especially considering that the island and areas nearby is frequently visited by tourists. We highlighted that this prey choice is context-dependent, and possibly influenced by the removal of domestic animals, the explosive population growth of introduced capybaras combined with their predictable foraging behavior.
Mechanical and chemical activation of GPR68 (OGR1) probed with a genetically-encoded fluorescent reporter
Authors: Ozkan Alper D , Gettas Tina , Sogata Audrey , Phaychanpheng Wynn , Lacroix Jérôme J
Published: April 2020

G-protein coupled receptor (GPCR) 68 (GPR68, or OGR1) couples extracellular acidifications and mechanical stimuli to G protein signaling and plays important roles in vascular physiology, neuroplasticity and cancer progression. Here, we designed a genetically-encoded fluorescent reporter of GPR68 activation called “iGlow”. iGlow responds to known GPR68 activators including fluid shear stress, extracellular pH and the synthetic agonist ogerin. Remarkably, iGlow activation occurred from both primary cilia-like structures and from intracellular vesicles, showing iGlow senses extracellular flow from within the cell. Flow-induced iGlow activation is not eliminated by pharmacological modulation of G protein signaling, disruption of actin filaments, or the presence of GsMTx4, a non-specific inhibitor of mechanosensitive ion channels. Genetic deletion of the conserved Helix 8, proposed to mediate GPCR mechanosensitivity, did not eliminate flow-induced iGlow activation, suggesting GPR68 uses a hitherto unkonwn, Helix8-independent mechanism to sense mechanical stimuli. iGlow will be useful to investigate the contribution of GPR68-mediated mechanotransduction in health and diseases.
Rapid stimulus-driven modulation of slow ocular position drifts
Authors: Malevich Tatiana , Buonocore Antimo , Hafed Ziad M.
Published: April 2020

The eyes are never still during maintained gaze fixation. When microsaccades are not occurring, ocular position exhibits continuous slow changes, often referred to as drifts. Unlike microsaccades, drifts remain to be viewed as largely random eye movements. Here we found that ocular position drifts can, instead, be very systematically stimulus-driven, and with very short latencies. We used highly precise eye tracking in three well trained macaque monkeys and found that even fleeting (~8 ms duration) stimulus presentations can robustly trigger transient and stimulus-specific modulations of ocular position drifts, and with only approximately 60 ms latency. Such drift responses are binocular, and they are most effectively elicited with large stimuli of low spatial frequency. Intriguingly, the drift responses exhibit some image pattern selectivity, and they are not explained by convergence responses, pupil constrictions, head movements, or starting eye positions. Ocular position drifts have very rapid access to exogenous visual information.
Membrane Proteins Have Distinct Fast Internal Motion and Residual Conformational Entropy
Authors: O’Brien Evan S. , Fuglestad Brian , Lessen Henry J. , Stetz Matthew A. , Lin Danny W. , Marques Bryan S. , Gupta Kushol , Fleming Karen G. , Wand A. Joshua
Published: April 2020

For a variety of reasons, the internal motions of integral membrane proteins have largely eluded comprehensive experiential characterization. Here, the fast side chain dynamics of the 7-transmembrane helix protein sensory rhodopsin II and the beta-barrel bacterial outer membrane channel protein W have been characterized in lipid bilayers and detergent micelles by solution NMR relaxation techniques. Though of quite different topologies, both proteins are found to have a similar and striking distribution of methyl-bearing amino acid side chain motion that is independent of membrane mimetic. The methyl-bearing side chains of both proteins, on average, are more dynamic in the ps-ns time regime than any soluble protein characterized to date. Approximately one third of methyl-bearing side chains exhibit extreme rotameric averaging on this timescale. Accordingly, both proteins retain an extraordinary residual conformational entropy in the folded state, which provides a counterbalance to the absence of the hydrophobic effect that normally stabilizes the folded state of water-soluble proteins. Furthermore, the large reservoir of conformational entropy that is observed provides the potential to greatly influence the thermodynamics underlying a plethora of membrane protein functions including ligand binding, allostery and signaling.
Auditory beat perception is related to speech output fluency in post-stroke aphasia
Authors: Stefaniak James D. , Lambon Ralph Matthew A. , De Dios Perez Blanca , Griffiths Timothy D. , Grube Manon
Published: April 2020

Aphasia affects at least one third of stroke survivors, and there is increasing awareness that more fundamental deficits in auditory processing might contribute to impaired language performance in such individuals. We performed a comprehensive battery of psychoacoustic tasks assessing the perception of tone pairs and sequences across the domains of pitch, rhythm and timbre in 17 individuals with post-stroke aphasia and 17 controls. At the group level, we showed a significant difference in auditory perception in only one test (Dynamic Modulation detection). At the level of individual differences we demonstrated a correlation between metrical pattern (beat) perception and speech output fluency with strong effect (Spearman’s rho = 0.72). This was specific in terms of the auditory tests and dissociated from more basic auditory timing perception, which did not correlate with output fluency. This was also specific in terms of the language and cognitive measures, amongst which phonological, semantic and executive function did not correlate with beat detection. We interpret the data in terms of a requirement for the analysis of the metrical structure of sound to construct fluent output, with both being a function of higher-order “temporal scaffolding”. The beat perception task herein allows measurement of timing analysis without any need to account for motor output deficit, and could be a potential clinical tool to examine this. This work suggests strategies to improve fluency after stroke by training in metrical pattern perception.
A Nimbolide-Based Kinase Degrader Preferentially Degrades Oncogenic BCR-ABL
Authors: Tong Bingqi , Spradlin Jessica N. , Novaes Luiz F.T. , Zhang Erika , Hu Xirui , Moeller Malte , Brittain Scott M. , McGregor Lynn M. , McKenna Jeffrey M. , Tallarico John A. , Schirle Markus , Maimone Thomas J. , Nomura Daniel K.
Published: April 2020

Targeted protein degradation (TPD) and proteolysis-targeting chimeras (PROTACs) have arisen as powerful therapeutic modalities for degrading specific protein targets in a proteasome-dependent manner. However, a major limitation to broader TPD applications is the lack of E3 ligase recruiters. Recently, we discovered the natural product nimbolide as a covalent ligand for the E3 ligase RNF114. When linked to the BET family inhibitor JQ1, the resulting heterobifunctional PROTAC molecule was capable of selectively degrading BRD4 in cancer cells. Here, we show the broader utility of nimbolide as an E3 ligase recruiter for TPD applications. We demonstrate that a PROTAC linking nimbolide to the kinase and BCR-ABL fusion oncogene inhibitor dasatinib, BT1, selectively degrades BCR-ABL over c-ABL in leukemia cancer cells, compared to previously reported cereblon or VHL-recruiting BCR-ABL degraders that show opposite selectivity or in some cases inactivity. Further contrasting from cereblon or VHL-recruiting degradation, we show that BT1 treatment not only leads to BCR-ABL degradation, but also stabilizes the endogenous RNF114 substrate and tumor suppressor substrate p21. This leads to additional anti-proliferative effects in leukemia cancer cells beyond those observed with cereblon or VHL-recruiting BCR-ABL PROTACs. Thus, we further establish nimbolide as an additional general E3 ligase recruiter for PROTACs with unique additional benefits for oncology applications. We also further demonstrate the importance of expanding upon the arsenal of E3 ligase recruiters, as such molecules confer differing and unpredictable selectivity for the degradation of neo-substrate proteins.
Phase alignment of low-frequency neural activity to the amplitude envelope of speech reflects evoked responses to acoustic edges, not oscillatory entrainment
Authors: Oganian Yulia , Kojima Katsuaki , Breska Assaf , Cai Chang , Findlay Anne , Chang Edward , Nagarajan Srikantan
Published: April 2020

The amplitude envelope of speech is crucial for accurate comprehension. Considered a key stage in speech processing, the phase of neural activity in the theta-delta bands (1 - 10 Hz) tracks the phase of the speech amplitude envelope during listening. However, the mechanisms underlying this envelope representation have been heavily debated. A dominant model posits that envelope tracking reflects entrainment of endogenous low-frequency oscillations to the speech envelope. Alternatively, envelope tracking reflects a series of evoked responses to acoustic landmarks within the envelope. It has proven challenging to distinguish these two mechanisms. To address this, we recorded magnetoencephalography while participants listened to natural speech, and compared the neural phase patterns to the predictions of two computational models: An oscillatory entrainment model and a model of evoked responses to peaks in the rate of envelope change. Critically, we also presented speech at slowed rates, where the spectrotemporal predictions of the two models diverge. Our analyses revealed transient theta phase-locking in regular speech, as predicted by both models. However, for slow speech we found transient theta and delta phase-locking, a pattern that was fully compatible with the evoked response model but could not be explained by the oscillatory entrainment model. Furthermore, encoding of acoustic edge magnitudes was invariant to contextual speech rate, demonstrating speech rate normalization of acoustic edge representations. Taken together, our results suggest that neural phase locking to the speech envelope is more likely to reflect discrete representation of transient information rather than oscillatory entrainment.
Transcriptomic entropy benchmarks stem cell-derived cardiomyocyte maturation against endogenous tissue at single cell level
Authors: Kannan Suraj , Farid Michael , Lin Brian L. , Miyamoto Matthew , Kwon Chulan
Published: April 2020

The immaturity of pluripotent stem cell (PSC)-derived tissues has emerged as a universal problem for their biomedical applications. While efforts have been made to generate adult-like cells from PSCs, direct benchmarking of PSC-derived tissues againstin vivodevelopment has not been established. Thus, maturation status is often assessed on anad-hocbasis. Single cell RNA-sequencing (scRNA-seq) offers a promising solution, though cross-study comparison is limited by dataset-specific batch effects. Here, we developed a novel approach to quantify PSC-derived cardiomyocyte (CM) maturation through transcriptomic entropy. Transcriptomic entropy is robust across datasets regardless of differences in isolation protocols, library preparation, and other potential batch effects. With this new model, we analyzed over 45 scRNA-seq datasets and over 52,000 CMs, and established a cross-study, cross-species CM maturation reference. This reference enabled us to directly compare PSC-CMs with thein vivodevelopmental trajectory and thereby to quantify PSC-CM maturation status. We further found that our entropy-based approach can be used for other cell types, including pancreatic beta cells and hepatocytes. Our study presents a biologically relevant and interpretable metric for quantifying PSC-derived tissue maturation, and is extensible to numerous tissue engineering contexts.

Significance Statement

There is significant interest in generating mature cardiomyocytes from pluripotent stem cells. However, there are currently few effective metrics to quantify the maturation status of a single cardiomyocyte. We developed a new metric for measuring cardiomyocyte maturation using single cell RNA-sequencing data. This metric, called entropy score, uses the gene distribution to estimate maturation at the single cell level. Entropy score enables comparing pluripotent stem cell-derived cardiomyocytes directly against endogenously-isolated cardiomyocytes. Thus, entropy score can better assist in development of approaches to improve the maturation of pluripotent stem cell-derived cardiomyocytes.
A Critical Role of Hepatic GABA in The Metabolic Dysfunction and Hyperphagia of Obesity
Authors: Geisler Caroline. E. , Ghimire Susma. , Bruggink Stephanie. M. , Miller Kendra E. , Weninger Savanna. N. , Kronenfeld Jason. M. , Yoshino Jun. , Klein Samuel. , Duca Frank. A. , Renquist Benjamin. J.
Published: April 2020

Hepatic lipid accumulation is a hallmark of type II diabetes (T2D) and associated with hyperinsulinemia, insulin resistance, and hyperphagia. Hepatic synthesis of GABA, catalyzed by GABA-transaminase (GABA-T), is upregulated in obese mice. To assess the role of hepatic GABA production in obesity-induced metabolic and energy dysregulation, we treated mice with two pharmacologic GABA-T inhibitors and knocked down hepatic GABA-T expression using an antisense oligonucleotide. Hepatic GABA-T inhibition and knockdown decreased basal hyperinsulinemia and hyperglycemia, and improved glucose intolerance. GABA-T knockdown improved insulin sensitivity assessed by hyperinsulinemic-euglycemic clamps in obese mice. Hepatic GABA-T knockdown also decreased food intake and induced weight loss without altering energy expenditure in obese mice. Data from people with obesity support the notion that hepatic GABA production and transport are associated with serum insulin, HOMA-IR, T2D, and BMI. These results support a key role for hepatocyte GABA production in the dysfunctional glucoregulation and feeding behavior associated with obesity.
Gene-level, but not chromosome-wide, divergence between a very young house fly proto-Y chromosome and its homologous proto-X chromosome
Authors: Hak Son Jae , Meisel Richard P.
Published: April 2020

X and Y chromosomes are usually derived from a pair of homologous autosomes, which then diverge from each other over time. Although Y-specific features have been characterized in sex chromosomes of various ages, the earliest stages of Y chromosome evolution remain elusive. In particular, we do not know whether early stages of Y chromosome evolution consist of changes to individual genes or happen via chromosome-scale divergence from the X. To address this question, we quantified divergence between young proto-X and proto-Y chromosomes in the house fly,Musca domestica. We compared proto-sex chromosome sequence and gene expression between genotypic (XY) and sex-reversed (XX) males. We find evidence for sequence divergence between genes on the proto-X and proto-Y, including five genes with mitochondrial functions. There is also an excess of genes with divergent expression between the proto-X and proto-Y, but the number of genes is small. This suggests that individual proto-Y genes, but not the entire proto-Y chromosome, have diverged from the proto-X. We identified one gene, encoding an axonemal dynein assembly factor (which functions in sperm motility), that has higher expression in XY males than XX males because of a disproportionate contribution of the proto-Y allele to gene expression. The up-regulation of the proto-Y allele may be favored in males because of this gene’s function in spermatogenesis. The evolutionary divergence between proto-X and proto-Y copies of this gene, as well as the mitochondrial genes, is consistent with selection in males affecting the evolution of individual genes during early Y chromosome evolution.
The Neuroanatomy of Speech Processing: A Large-Scale Lesion Study
Authors: Rogalsky Corianne , Basilakos Alexandra , Rorden Chris , Pillay Sara , LaCroix Arianna N. , Keator Lynsey , Mickelsen Soren , Anderson Steven W. , Love Tracy , Fridriksson Julius , Binder Jeffrey , Hickok Gregory
Published: April 2020

The neural basis of language has been studied for centuries, yet the networks critically involved in simply identifying or understanding a spoken word remain elusive. Several functional-anatomical models of critical neural substrates of receptive speech have been proposed, including (1) auditory-related regions in the leftmid-posteriorsuperior temporal lobe, (2)motor-related regions in the left frontal lobe (in normal and/or noisy conditions), the leftanteriorsuperior temporal lobe, or (4)bilateralmid-posterior superior temporal areas. One difficulty in comparing these models is that they often focus on different aspects of the sound-to-meaning pathway and are supported by different types of stimuli and tasks. Two auditory tasks that are typically used in separate studies—syllable discrimination and word comprehension—often yield different conclusions. We assessed syllable discrimination (words and nonwords) and word comprehension (clear speech and with a noise masker) in 158 individuals with focal brain damage: left (n=113) or right (n=19) hemisphere stroke, left (n=18) or right (n=8) anterior temporal lobectomy, and 26 neurologically-intact controls. Discrimination and comprehension tasks are doubly dissociable both behaviorally and neurologically. In support of a bilateral model, clear speech comprehension was near ceiling in 95% of left stroke cases and right temporal damage impaired syllable discrimination. Lesion-symptom mapping analyses for the syllable discrimination and noisy word comprehension tasks each implicated most of the left superior temporal gyrus (STG). Comprehension but not discrimination tasks also implicated the left pMTG, while discrimination but not comprehension tasks also implicated more dorsal sensorimotor regions in posterior perisylvian cortex.
The QT Interval in Patients with SARS-CoV-2 Infection Treated with Hydroxychloroquine/Azithromycin
Authors: Chorin Ehud , Dai Matthew , Shulman Eric , Wadhwani Lalit , Roi-Bar-Cohen  , Barbhaiya Chirag , Aizer Anthony , Holmes Douglas , Bernstein Scott , Spinelli Michael , Park David S. , Chinitz Larry A. , Jankelson Lior
Published: April 2020

We report the change in the QT interval in 84 adult patients with SARS-CoV-2 infection treated with Hydroxychloroquine/Azithromycin combination. QTc prolonged maximally from baseline between days 3 and 4. in 30% of patients QTc increased by greater than 40ms. In 11% of patients QTc increased to >500 ms, representing high risk group for arrhythmia. The development of acute renal failure but not baseline QTc was a strong predictor of extreme QTc prolongation.
Efficient genome editing in multiple salmonid cell lines using ribonucleoprotein complexes
Authors: Gratacap Remi L. , Jin Ye Hwa , Mantsopoulou Marina , Houston Ross D.
Published: April 2020

Infectious and parasitic diseases have major negative economic and animal welfare impacts on aquaculture of salmonid species. Improved knowledge of the functional basis of host response and genetic resistance to these diseases is key to developing preventative and treatment options. Cell lines provide a valuable model to study infectious diseases in salmonids, and genome editing using CRISPR provides an exciting avenue to evaluate the function of specific genes in those systems. While CRISPR/Cas9 has been successfully performed in a Chinook salmon cell line (CHSE-214), there are no reports to date of editing of cell lines derived from the most commercially relevant salmonid species Atlantic salmon and rainbow trout, which are difficult to transduce and therefore edit using lentivirus-mediated methods. In the current study, a method of genome editing of salmonid cell lines using ribonucleoprotein (RNP) complexes was optimised and tested in the most commonly-used salmonid fish cell lines; Atlantic salmon (SHK-1 and ASK cell lines), rainbow trout (RTG-2) and Chinook salmon (CHSE-214). Electroporation of RNP based on either Cas9 or Cas12a was efficient at targeted editing of all the tested lines (typically > 90 % cells edited), and the choice of enzyme expands the number of potential target sites for editing within the genomes of these species. These optimised protocols will facilitate functional genetic studies in salmonid cell lines, which are widely used as model systems for infectious diseases in aquaculture.
Host-parasite dynamics set the ecological theatre for the evolution of state- and context-dependent dispersal in hosts
Authors: Deshpande Jhelam N. , Kaltz Oliver , Fronhofer Emanuel A.
Published: April 2020

While host-parasite interactions are ubiquitous, the large scale consequences of parasite infections are mainly driven by the spatial context. One trait of pivotal importance for the eco-evolutionary dynamics of such metapopulations is the spatial behaviour of hosts, that is, their dispersal. It is well established that dispersal is not a random process, rather dispersal is informed and may depend on internal and external factors. In host-parasite metapopulations, dispersal may be a function of a host’s infection state, but also of the local context, such as host density or parasite prevalence. Using a dynamical host-parasite metapopulation model, we explore whether host dispersal evolves to be state- and context-dependent and what shapes the evolutionarily stable dispersal reaction norms have. We show that state-dependent dispersal readily evolves in the sense that hosts disperse more when infected. This dispersal bias evolves due to kin selection which is consistent with previous studies. Most importantly, we show that prevalence-dependent dispersal evolves, especially when virulence is high and epidemiological dynamics have predictable signatures. The observed evolutionary outcome, a negatively prevalence-dependent dispersal reaction norm for susceptible hosts, seems counter-intuitive at first. However, our results can be readily explained by the emergent epidemiological dynamics, especially their spatial and temporal correlation patterns. Finally, we show that context-dependency in dispersal may rely on both, prevalence, but also host density cues. Our work provides new insights into the evolution of complex dispersal phenotypes in host-parasite metapopulations as well as on associated feedbacks between ecological dynamics and evolutionary change.
Rv0100, a proposed acyl carrier protein in Mycobacterium tuberculosis: expression, purification and crystallization. Corrigendum
Authors: Bondoc Jasper Marc G. , Gutka Hiten J. , Almutairi Mashal M. , Patwell Ryan , Rutter Maxwell W. , Wolf Nina M. , Samudrala Ram , Mehboob Shahila , Dementiev Alexey , Abad-Zapatero Cele , Movahedzadeh Farahnaz
Published: April 2020

The true identity of the protein found in the crystals reported by Bondoc et al. [(2019), Acta Cryst. F75, 646–651] is given.
Crystal structure, Hirshfeld surface analysis and interaction energy and DFT studies of 2-(2,3-dihydro-1H-perimidin-2-yl)-6-methoxyphenol
Authors: Daouda Ballo , Tuo Nanou Tiéba , Hökelek Tuncer , Niameke Jean-Baptiste Kangah , Charles Guillaume Kodjo , Claude Kablan Ahmont Landry , Essassi El Mokhtar
Published: April 2020

The title compound, C18H16N2O2, consists of perimidine and methoxyphenol units, where the tricyclic perimidine unit contains a naphthalene ring system and a non-planar C4N2 ring adopting an envelope conformation with the NCN group hinged by 47.44 (7)° with respect to the best plane of the other five atoms. In the crystal, O—HPhnl...NPrmdn and N—HPrmdn...OPhnl (Phnl = phenol and Prmdn = perimidine) hydrogen bonds link the molecules into infinite chains along the b-axis direction. Weak C—H...π interactions may further stabilize the crystal structure. The Hirshfeld surface analysis of the crystal structure indicates that the most important contributions for the crystal packing are from H...H (49.0%), H...C/C...H (35.8%) and H...O/O...H (12.0%) interactions. Hydrogen bonding and van der Waals interactions are the dominant interactions in the crystal packing. Computational chemistry indicates that in the crystal, the O—HPhnl...NPrmdn and N—HPrmdn...OPhnl hydrogen-bond energies are 58.4 and 38.0 kJ mol−1, respectively. Density functional theory (DFT) optimized structures at the B3LYP/ 6–311 G(d,p) level are compared with the experimentally determined molecular structure in the solid state. The HOMO–LUMO behaviour was elucidated to determine the energy gap.
Crystal structures of {1,1,1-tris[(salicylaldimino)methyl]ethane}gallium as both a pyridine solvate and an acetonitrile 0.75-solvate and {1,1,1-tris[(salicylaldimino)methyl]ethane}indium dichloromethane solvate
Authors: Ventura Dominic L. , Brennessel William W. , Durfee William S.
Published: April 2020

The sexadentate ligand 1,1,1-tris[(salicylideneamino)methyl]ethane has been reported numerous times in its triply deprotonated form coordinated to transition metals and lanthanides, yet it has been rarely employed with main-group elements, including in substituted forms. Its structures with gallium and indium are reported as solvates, namely, ({[(2,2-bis{[(2-oxidobenzylidene)amino-κ2
N,O]methyl}propyl)imino]methyl}phenololato-κ2
N,O)gallium(III) pyridine monosolvate, [Ga(C26H24N3O3)]·C5H5N, the acetonitrile 0.75-solvate, [Ga(C26H24N3O3)]·0.75C2H3N, and ({[(2,2-bis{[(2-oxidobenzylidene)amino-κ2
N,O]methyl}propyl)imino]methyl}phenololato-κ2
N,O)indium(III) dichloromethane monosolvate, [In(C26H24N3O3)]·CH2Cl2. All three metal complexes are pseudo-octahedral and each structure contains multiple weak C—H...O and/or C—H...N intermolecular hydrogen-bonding interactions. The syntheses and additional characterization in the forms of melting points, high-resolution mass spectra, infra-red (IR) spectra, and 1H and 13C NMR spectra are also reported.