bluuebunny/crossref_metadata_2025 huggingface dataset:
The evolution of cold nociception in drosophilid larvae and identification of a neural basis for cold acclimation
Authors: Himmel Nathaniel J. , Letcher Jamin M. , Sakurai Akira , Gray Thomas R. , Benson Maggie N. , Donaldson Kevin J. , Cox Daniel N.
Published: January 2021

Cold temperatures can be fatal to insects, but many species have evolved the ability to cold acclimate, thereby increasing their cold tolerance. While there is a growing body of knowledge concerning the mechanisms underlying cold tolerance, relatively little is known concerning how insects sense noxious cold (cold nociception), or how cold nociception might function in cold tolerance. It has been previously shown that Drosophila melanogaster larvae perform highly stereotyped, cold-evoked behaviors under the control of noxious cold-sensing neurons (nociceptors) innervating the barrier epidermis. In the present study, we first sought to describe cold-nociceptive behavior among 11 drosophilid species with differing cold tolerances and from differing climates. Behavioral analyses revealed that the predominant cold-evoked response among drosophilid larvae is a head-to-tail contraction (CT) behavior, which is likely inherited from a common ancestor. However, despite lack of phylogenetic signal (suggesting trait lability), the CT behavior was transient and there was no clear evidence that cold sensitivity was related to thermal environment; collectively this suggests that the behavior might not be adaptive. We therefore sought to uncover an alternative way that cold nociception might be protective. Using a combination of cold-shock assays, optogenetics, electrophysiology, and methods to genetically disrupt neural transmission, we demonstrate that cold sensing neurons in Drosophila melanogaster (Class III nociceptors) are sensitized by and critical to cold acclimation. Moreover, we demonstrate that cold acclimation can be optogenetically-evoked, sans cold. Collectively, these findings reveal that cold nociception constitutes a peripheral neural basis for Drosophila larval cold acclimation.

Significance Statement

Many insects adapt to cold in response to developmental exposure to cool temperatures. While there is a growing body of knowledge concerning the mechanisms underlying cold tolerance, it is unknown how sensory neurons might contribute. Here, we show that noxious cold sensing (cold nociception) is widely present among drosophilid larvae, and that cold-sensing neurons (Class III cold nociceptors) are necessary and sufficient drivers of cold acclimation. This suggests that cold acclimation has, at least in part, a neural basis.
Participation in a Science Festival Promotes Inclusive Science Communication around Autism Spectrum Disorder
Authors: Gunter Chris , Sinha Cynthia B , Jaquess David
Published: January 2021

As a high prevalence disorder with limited information about etiology, autism spectrum disorder (ASD) has been marked by confusion and miscommunication around its causes and treatments. To promote high-quality science communication, we participated in a local science festival, both providing information about the brain and ASD and asking passersby questions about their knowledge of ASD. We then asked the booth staffers to evaluate the program and conducted qualitative analyses of public and staffer responses. Public responses to the question “what would you like to know about autism?” most often concerned how the disorder was diagnosed or defined. In contrast, public responses to the question “what would you like others to know about autism?” centered around educating those unaffected by ASD on how to improve interactions and awareness, mentioning inclusivity and intersectionality, and dispelling negative stereotypes. The staffers overwhelmingly reported that in future years, they would include even more science and allow for more in-depth conversations with interested parties, as well as bringing materials in other languages. These responses are in keeping with a trend for more inclusive science communication, particularly in the field of behavioral health and ASD, and a desire to challenge myths around the condition. We conclude that our science festival interactions brought multiple benefits to public and staff.
Homogenization of a Reaction Diffusion Equation can Explain Influenza A Virus Load Data
Authors: Baabdulla Arwa Abdulla , Now Hesung , Park Ju An , Kim Woo-Jong , Jung Sungjune , Yoo Joo-Yeon , Hillen Thomas
Published: January 2021

We study the influence of spatial heterogeneity on the antiviral activity of mouse embryonic fibroblasts (MEF) infected with influenza A. MEF of typeUbe1L−/−are composed of two distinct sub-populations, the strong type that sustains a strong viral infection and the weak type, sustaining a weak viral load. We present new data on the virus load infection ofUbe1L−/−, which have been micro-printed in a checker board pattern of different sizes of the inner squares. Surprisingly, the total viral load at one day after inoculation significantly depends on the sizes of the inner squares. We explain this observation by using a reaction diffusion model and we show that mathematical homogenization can explain the observed inhomogeneities. If the individual patches are large, then the growth rate and the carrying capacity will be the arithmetic means of the patches. For finer and finer patches the average growth rate is still the arithmetic mean, however, the carrying capacity uses the harmonic mean. While fitting the PDE to the experimental data, we also predict that a discrepancy in virus load would be unobservable after only half a day. Furthermore, we predict the viral load in different inner squares that had not been measured in our experiment and the travelling distance the virions can reach after one day.
MYCoverexpression leads to increased chromatin interactions at superenhancers and c-Myc binding sites
Authors: See Yi Xiang , Chen Kaijing , Fullwood Melissa J.
Published: January 2021

The MYC oncogene encodes for the c-Myc protein and is frequently dysregulated across multiple cancer cell types, making it an attractive target for cancer therapy. There have been many difficulties in targeting c-Myc, due to its complex network of regulators and the unstructured nature of its protein. Thus, we are interested in looking at the downstream cancer-specific functions of c-Myc. Overexpression of MYC leads to c-Myc binding at active enhancers, resulting in a global transcriptional amplification of active genes. However, the mechanism underlying this c-Myc enhancer invasion has not been well studied. To that end, we performed ChIP-seq, RNA-seq, 4C-seq and SIQHiC (Spike-in Quantitative Hi-C) on the U2OS osteosarcoma cell line with tetracycline-inducible MYC. MYC overexpression in U2OS cells modulated histone acetylation and increased c-Myc binding at superenhancers. SIQHiC analysis revealed increased global chromatin contact frequency, particularly at chromatin interactions connecting c-Myc binding sites. Our results suggest that c-Myc molecules are recruited to and accumulates within zones of high transcription activity, binding first at stable promoter binding sites at low expression levels, then at superenhancer binding sites when overexpressed. At the same time, the recruitment of c-Myc and other transcription factors may stabilize chromatin interactions to increase chromatin contact frequency. The accumulation of c-Myc at cancer-type specific superenhancers may then drive the expression of interacting oncogenes that each cancer is highly reliant on. By elucidating the chromatin landscape of c-Myc driven cancers, we can potentially target these chromatin interactions for cancer therapy, without affecting physiological c-Myc signaling.
Rv3737 is required forMycobacterium tuberculosisgrowthin vitroandin vivoand correlates with bacterial load and disease severity in human tuberculosis
Authors: Li Qing , Peng Zhangli , Fu Xuefeng , Wang Hong , Zhao Zhaoliang , Pang Yu , Chen Ling
Published: January 2021

Rv3737 is the sole homologue of multifunctional transporter ThrE inMycobacterium tuberculosis(Mtb). In this study, we aimed to investigate whether this transporter participatesin vitroandin vivosurvival ofMtb. To characterize the role of Rv3737, we constructed and characterized anMtbH37RvΔRv3737. This strain was evaluated for altered growth rate and macrophage survival using cell model of infection. In addition, the comparative analysis was conducted to determine the association between Rv3737 mRNA expression and disease severity in active pulmonary TB patients. The H37RvΔRv3737 strain exhibited significant slow growth rate compared to H37Rv-WT strain in standard culture medium. Additionally, the survival rate of H37Rv-WT strain in macrophages was 2 folds higher than that of H37RvΔRv3737 at 72 h. A significant higher level of TNF-α and IL-6 mRNA expression was observed in macrophages infected with H37RvΔRv3737 as compared to H37Rv-WT. Of note, Rv3737 expression was significantly increased in clinicalMtbisolates than H37Rv-WT. The relative expression level of Rv3737 was positively correlated with lung cavity number in TB patients. Similarly, the higher Rv3737 mRNA level resulted in lower C(t) value by Xpert MTB/RIF assay, demonstrating that a positive correlation between Rv3737 expression and bacterial load in TB patients. In conclusion, our data is the first to demonstrate that the transporter Rv3737 is required forin vitrogrowth and survival of bacteria inside macrophages. In addition, the expression level of Rv3737 is associated with bacterial load and disease severity in pulmonary tuberculosis patients.
THE INTESTINAL AND ORAL MICROBIOMES ARE ROBUST PREDICTORS OF COVID-19 SEVERITY THE MAIN PREDICTOR OF COVID-19-RELATED FATALITY
Authors: Ward Doyle V. , Bhattarai Shakti , Rojas-Correa Mayra , Purkayastha Ayan , Holler Devon , Da Qu Ming , Mitchell William G. , Yang Jason , Fountain Samuel , Zeamer Abigail , Forconi Catherine , Fujimori Gavin , Odwar Boaz , Cawley Caitlin , McCormick Beth A. , Moormann Ann , Wessolossky Mireya , Bucci Vanni , Maldonado-Contreras Ana
Published: January 2021

The reason for the striking differences in clinical outcomes of SARS-CoV-2 infected patients is still poorly understood. While most recover, a subset of people become critically ill and succumb to the disease. Thus, identification of biomarkers that can predict the clinical outcomes of COVID-19 disease is key to help prioritize patients needing urgent treatment. Given that an unbalanced gut microbiome is a reflection of poor health, we aim to identify indicator species that could predict COVID-19 disease clinical outcomes. Here, for the first time and with the largest COVID-19 patient cohort reported for microbiome studies, we demonstrated that the intestinal and oral microbiome make-up predicts respectively with 92% and 84% accuracy (Area Under the Curve or AUC) severe COVID-19 respiratory symptoms that lead to death. The accuracy of the microbiome prediction of COVID-19 severity was found to be far superior to that from training similar models using information from comorbidities often adopted to triage patients in the clinic (77% AUC). Additionally, by combining symptoms, comorbidities, and the intestinal microbiota the model reached the highest AUC at 96%. Remarkably the model training on the stool microbiome found enrichment of Enterococcus faecalis, a known pathobiont, as the top predictor of COVID-19 disease severity. Enterococcus faecalis is already easily cultivable in clinical laboratories, as such we urge the medical community to include this bacterium as a robust predictor of COVID-19 severity when assessing risk stratification of patients in the clinic.
Potential Blood Transfusion Adverse Events Can be Found in Unstructured Text in Electronic Health Records using the “Shakespeare Method”
Authors: Bright Roselie A , Rankin Summer K , Dowdy Katherine , Blok Sergey V , Bright-Ponte Susan J , Palmer Lee Anne
Published: January 2021

Background

Text in electronic health records (EHRs) and big data tools offer the opportunity for surveillance of adverse events (patient harm associated with medical care) (AEs) in the unstructured notes. Writers may explicitly state an apparent association between treatment and adverse outcome (“attributed”) or state the simple treatment and outcome without an association (“unattributed”). We chose the case of transfusion adverse events (TAEs) and potential TAEs (PTAEs) because real dates were obscured in the study data, and new TAE types were becoming recognized during the study data period.

Objective

Develop a new method to identify attributed and unattributed potential adverse events using the unstructured text of EHRs.

Methods

We used EHRs for adult critical care admissions at a major teaching hospital, 2001-2012. We formed a transfusion (T) group (21,443 admissions treated with packed red blood cells, platelets, or plasma), excluded 2,373 ambiguous admissions, and formed a comparison (C) group of 25,468 admissions. We concatenated the text notes for each admission, sorted by date, into one document, and deleted replicate sentences and lists. We identified statistically significant words in T vs. C. T documents were filtered to those words, followed by topic modeling on the T filtered documents to produce 45 topics.

For each topic, the three documents with the maximum topic scores were manually reviewed to identify events that occurred shortly after the first transfusion; documents with clear alternative explanations for heart, lung, and volume overload problems (e.g., advanced cancer, lung infection) were excluded. We also reviewed documents with the most topics, as well as 20 randomly selected T documents without alternate explanations.

Results

Topics centered around medical conditions. The average number of significant topics was 6.1. Most PTAEs were not attributed to transfusion in the notes.

Admissions with a top-scoring cardiovascular topic (heart valve repair, tapped pericardial effusion, coronary artery bypass graft, heart attack, or vascular repair) were more likely than random T admissions to have at least one heart PTAE (heart rhythm changes or hypotension, proportion difference = 0.47, p = 0.022). Admissions with a top-scoring pulmonary topic (mechanical ventilation, acute respiratory distress syndrome, inhaled nitric oxide) were more likely than random T admissions (proportion difference = 0.37, p = 0.049) to have at least one lung PTAE (hypoxia, mechanical ventilation, bilateral pulmonary effusion, or pulmonary edema).

Conclusions

The “Shakespeare Method” could be a useful supplement to AE reporting and surveillance of structured EHR data. Future improvements should include automation of the manual review process.
SERF deletion modifies amyloid aggregation in a mouse model of Alzheimer’s disease
Authors: Stroo E. , Janssen L. , Sin O. , Hogewerf W. , Koster M. , Harkema L. , Youssef S.A. , Beschorner N. , Wolters A.H.G. , Bakker B. , Becker Lore , Garrett L , Marschall Susan , Hoelter Sabine M , Wurst Wolfgang , Fuchs Helmut , Gailus-Durner Valerie , de Angelis Martin Hrabe , Thathiah A. , Foijer F. , van de Sluis B. , van Deursen J. , Jucker M. , de Bruin A. , Nollen E.A.A.
Published: January 2021

In age-related neurodegenerative disease, like Alzheimer’s and Parkinson’s disease, disease-specific proteins become aggregation-prone and form amyloid-like deposits. Depletion of SERF proteins ameliorates this toxic process in worm- and human cell models for disease. Whether SERF modifies amyloid pathology in mammalian brain, however, has remained unknown. Here, we generated SERF2 brain-specific knockout mice which, unlike full body knockout mice, were viable, and showed no major behavioral and cognitive abnormalities. We combined these knockout mice with the APPPS1 mouse model for human amyloid beta aggregation. Using structure-specific amyloid dyes, previously used to distinguish amyloid polymorphisms in human brain, we show that knockout of SERF2 alters the structure of amyloid fibrils and deposits. Moreover, scanning transmission electron microscopy revealed thicker, shorter and more densely packed amyloid in absence of SERF2. Altogether, our data reveal pleiotropic functions of SERF in development and aging and support a function as a modifier of amyloid aggregation in mammalian brain. Our results indicate that single cellular factors like SERF can determine the structural outcome of amyloid aggregation, offering possibilities for polymorphism-based disease interventions.
In-Vitro Fluorescence Microscopy Studies Show Retention of Spike-Protein (SARS-Cov-2) on Cell Membrane in the Presence of Amodiaquin Dihydrochloride Dihydrate Drug
Authors: Mondal Partha Pratim , Mandal Subhra
Published: January 2021

The ability of S-glycoprotein (S-protein) in SARS-Cov-2 to bind to the host cell receptor protein (angiotensin-converting enzyme 2 (ACE2)) leading to its entry in the cellular system determines its contagious index and global spread. Three available drugs (Riboflavin, Amodiaquin dihydrochloride dihydrate (ADD), and Remidesivir) were investigated to understand the kinetics of S-protein and its entry inside a cellular environment. Optical microscopy and fluorescence-based assays on 293T cells (transfected with ACE2 plasmid) were used as the preamble for assessing the behavior of S-protein in the presence of these drugs for the first 12 hours post-S-protein - ACE2 binding. Preliminary results suggest relatively long retention of S-protein on the cell membrane in the presence of ADD drug. Evident from the %-overlap and colocalization of S-protein with endosome studies, a significant fraction of S-protein entering the cell escape endosomal degradation process, suggesting S-protein takes non-endocytic mediated entry in the presence of ADD. In contrast, in the presence of Riboflavin, S-protein carries out a normal endocytic pathway, comparable to the control (no drug) group. Therefore, the present study indicates ADD potentially affects S-protein’s entry mechanism (endocytic pathway) in addition to its reported target action mechanism. Hence, ADD substantially interferes with S-protein cellular entrance mechanism. This is further strengthened by 24 hrs study. However, detailed studies at the molecular scale are necessary to clarify our understanding of exact intermediate molecular processes. The present study (based on limited data) reveals ADD could be a potential candidate to manage Covid-19 functions through the yet unknown molecular mechanism.
No Evidence for a Single Oscillator Underlying Discrete Visual Percepts
Authors: Morrow Audrey , Samaha Jason
Published: January 2021

Theories of perception based on discrete sampling posit that visual consciousness is reconstructed based on snapshot-like perceptual moments, as opposed to being updated continuously. According to a model proposed by Schneider (2018), discrete sampling can explain both the flash-lag and the Fröhlich illusion, whereby a lag in the conscious updating of a moving stimulus alters its perceived spatial location in comparison to a stationary stimulus. The alpha-band frequency, which is associated with phasic modulation of stimulus detection and the temporal resolution of perception, has been proposed to reflect the duration of perceptual moments. The goal of this study was to determine whether a single oscillator (e.g., alpha) is underlying the duration of perceptual moments, which would predict that the point of subjective equality (PSE) in the flash-lag and Fröhlich illusions are positively correlated across individuals. Although our displays induced robust flash-lag and Fröhlich effects, virtually zero correlation was seen between the PSE in the two illusions, indicating that the illusion magnitudes are unrelated across observers. These findings suggest that, if discrete sampling theory is true, these illusory percepts either rely on different oscillatory frequencies or not on oscillations at all. Alternatively, discrete sampling may not be the mechanism underlying these two motion illusions or our methods were ill-suited to test the theory.
Corticospinal correlates of hand preference for reaching during whole-body motion
Authors: Wijdenes Leonie Oostwoud , Wynn Syanah C. , Roesink Béla S. , Schutter Dennis J.L.G. , Selen Luc P.J. , Medendorp W. Pieter
Published: January 2021

Behavioral studies have shown that humans account for inertial acceleration in their decisions of hand choice when reaching during body motion. Physiologically, it is unclear at what stage of movement preparation information about body motion is integrated in the process of hand selection. Here, we addressed this question by applying transcranial magnetic stimulation over motor cortex (M1) of human participants who performed a preferential reach task while they were sinusoidally translated on a linear motion platform. If M1 only represents a read-out of the final hand choice, we expect the body motion not to affect the MEP amplitude. If body motion biases the hand selection process prior to target onset, we expect corticospinal excitability to modulate with the phase of the motion, with larger MEP amplitudes for phases that show a bias to using the right hand. Behavioral results replicate our earlier findings of a sinusoidal modulation of hand choice bias with motion phase. MEP amplitudes also show a sinusoidal modulation with motion phase, suggesting that body motion influences corticospinal excitability which may ultimately reflect changes of hand preference. The modulation being present prior to target onset suggests that competition between hands is represented throughout the corticospinal tract. Its phase relationship with the motion profile suggests that other processes after target onset take up time until the hand selection process has been completely resolved, and the reach is initiated. We conclude that the corticospinal correlates of hand preference are modulated by body motion.
The adhesion capability ofStaphylococcus aureuscells is heterogeneously distributed over the cell envelope
Authors: Spengler Christian , Maikranz Erik , Glatz Bernhard , Klatt Michael Andreas , Heintz Hannah , Bischoff Markus , Santen Ludger , Fery Andreas , Jacobs Karin
Published: January 2021

Understanding and controlling microbial adhesion is an important biomedical problem. However, many properties of the adhesion process of bacteria are still unknown, for example the distribution of adhesive strength over the cell wall. While a patchy colloid model for adhesion has been developed recently for Gram-negativeEscherichia colicells, a comparable model for Grampositive cells is unknown. Here, we use single-cell force spectroscopy to measure the adhesion ofStaphylococcus aureusat different positions on tailored surfaces. We find heterogeneous adhesion profiles with varying degrees of intensity. By comparing these results to simulations, we find that locally increased adhesion can be explained by several distinct spots of high adhesion capabilities, similar to the patchy colloid model. Only for the underlying profile without local adhesive spots simple geometric considerations are insufficient. Rather, strong angle-dependent molecule-substratum interactions are necessary to explain the bathtub-like adhesion profiles seen forStaphylococcus aureuson a sinusoidal surface. We discuss implications of our results for the development of new materials and the design and analysis of future studies.
Super-resolution shadow imaging reveals local remodeling of astrocytic microstructures and brain extracellular space after osmotic challenge
Authors: Arizono Misa , Inavalli V.V.G. Krishna , Nägerl U. Valentin
Published: January 2021

The extracellular space (ECS) plays a central role for brain physiology, shaping the time course and spread of neurochemicals, ions and nutrients that ensure proper brain homeostasis and neuronal communication. Astrocytes are the most abundant type of glia cell in the brain, whose processes densely infiltrate the brain’s parenchyma. As astrocytes are highly sensitive to changes in osmotic pressure, they are capable of exerting a potent physiological influence on the ECS.

However, little is known about the spatial distribution and temporal dynamics of the ECS that surrounds astrocytes, owing mostly to a lack of appropriate techniques to visualize the ECS in live brain tissue. Mitigating this technical limitation, we applied the recent SUper-resolution SHadow Imaging technique (SUSHI) to astrocyte-labeled organotypic hippocampal brain slices, which allowed us to concurrently image the complex morphology of astrocytes and the ECS with nanoscale resolution in a live experimental setting.

Focusing on ring-like astrocytic microstructures in the spongiform domain, we found them to enclose sizable pools of interstitial fluid and cellular structures like dendritic spines. Upon an experimental osmotic challenge, these microstructures remodeled and swelled up at the expense of the pools, effectively increasing the physical contact between astrocytic and cellular structures.

Our study reveals novel facets of the dynamic microanatomical relationships between astrocytes, neuropil and the ECS in living brain tissue, which could be of functional relevance for neuronglia communication in a variety of (patho)physiological settings, e.g. LTP induction, epileptic seizures or acute ischemic stroke, where osmotic disturbances are known to occur.
Evidence, evolution and pattern of contractile elements in villous vascular walls and stroma of human placentas of premature infants of different gestational ages. An immuno-morphologic comparative study
Authors: Vellone Valerio Gaetano , Paudice Michele , Bianchi Rita , Scaglione Giulia , Biatta Chiara Maria , Buffi Davide , Buffelli Francesca , Barra Fabio , Ferrero Simone , Fulcheri Ezio
Published: January 2021

The contractile elements of the human placenta villous tree represent a topic of interest and many issues persist still open. Histology of the stroma and muscular wall and their evolution, in relation with the gestational age, remains to be clarified for a deeper understanding of the adaptive potential and pathogenetic mechanisms.

In our study, 56 premature placentas (21-36 wks) were considered, sub-divided into four groups based on age of gestation and compared to 23 at-term placentas (37-40 wks). All cases were tested with anti-smooth muscle actin (SMA) and anti-desmin antibodies to identify the contractile elements in the stroma and in vascular walls of villi.

SMA and desmin staining show evident decreased expressions during the pregnancy (temporal variation) and from proximal to distal part of the villous tree (spatial variation) being higher in the stem villi.

Both pre-term and at-term placentas showed persisting, although variable, positivity for SMA and desmin staining in the stroma and in the vessel walls of the mature intermediate and terminal villi. This represents an unexpected finding and nothing alike has been previously reported in literature.

Both highly premature and term placentas seem to maintain contractile components within each type of villi, represented by both myofibroblasts and mature smooth muscular cells. These components may be present in both villous vascular walls and stroma, albeit with different staining intensity.

This finding allows us to imagine an active function in the regulation of the blood flow, not only in stem and intermediate immature villi but even in smaller villi.
Human induced pluripotent stem cell-derived three-dimensional cardiomyocyte tissues ameliorate the rat ischemic myocardium by remodeling the extracellular matrix and cardiac protein phenotype
Authors: Yokoyama Junya , Miyagawa Shigeru , Akagi Takami , Akashi Mitsuru , Sawa Yoshiki
Published: January 2021

The extracellular matrix (ECM) plays a key role in the viability and survival of implanted human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). We hypothesized that coating of three-dimensional (3D) cardiac tissue-derived hiPSC-CMs with the ECM protein fibronectin (FN) would improve the survival of transplanted cells in the heart and improve heart function in a rat model of ischemic heart failure. To test this hypothesis, we first explored the tolerance of FN-coated hiPSC-CMs to hypoxia in anin vitrostudy. Forin vivoassessments, we constructed 3D-hiPSC cardiac tissues (3D-hiPSC-CTs) using a layer-by-layer technique, and then the cells were implanted in the hearts of a myocardial infarction rat model (3D-hiPSC-CTs, n = 10; sham surgery control group (without implant), n = 10). Heart function and histology were analyzed 4 weeks after transplantation. In thein vitroassessment, cell viability and lactate dehydrogenase assays showed that FN-coated hiPSC-CMs had improved tolerance to hypoxia compared with the control cells.In vivo, the left ventricular ejection fraction of hearts implanted with 3D-hiPSC-CT was significantly better than that of the sham control hearts. Histological analysis showed clear expression of collagen type IV and plasma membrane markers such as desmin and dystrophinin vivoafter implantation of 3D-hiPSC-CT, which were not detected in 3D-hiPSC-CMsin vitro. Overall, these results indicated that FN-coated 3D-hiPSC-CT could improve distressed heart function in a rat myocardial infarction model with a well-expressed cytoskeletal or basement membrane matrix. Therefore, FN-coated 3D-hiPSC-CT may serve as a promising replacement for heart transplantation and left ventricular assist devices and has the potential to improve survivability and therapeutic efficacy in cases of ischemic heart disease.
Transient response of basal ganglia network in healthy and low-dopamine state
Authors: Chakravarty Kingshuk , Roy Sangheeta , Sinha Aniruddha , Nambu Atsushi , Chiken Satomi , Kotaleski Jeanette Hellgren , Kumar Arvind
Published: January 2021

The basal ganglia (BG) are crucial for a variety of motor and cognitive functions. Changes induced by persistent low-dopamine (e.g. in Parkinson’s disease), result in aberrant changes in steady-state population activity (β-band oscillations) and transient response of the BG. Typically, brief cortical stimulation results in a triphasic response in the substantia nigra pars reticulata (SNr, output of the BG). The properties of the triphasic responses are shaped by dopamine levels. While it is relatively well understood how changes in BG result in aberrant steady state activity, it is not clear which BG interactions are crucial for the aberrant transient responses in the BG. Moreover, it is also not clear whether the same or different mechanisms underlie the aberrant changes in steady-state activity and aberrant transient response. Here we used numerical simulations of a network model of BG to identify the key factors that determine the shape of the transient responses. We show that an aberrant transient response of the SNr in low-dopamine state, involves changes in both, the direct pathway and the recurrent interactions within the globus pallidus externa (GPe) and between GPe and sub-thalamic nucleus. We found that the connections from D2-type spiny projection neurons to GPe are most crucial in shaping the transient response and by restoring them to their healthy level, we could restore the shape of transient response even in low-dopamine state. Finally, we show that the changes in BG that result in aberrant transient response are also sufficient to generate pathological oscillatory activity.

Significance statement

To understand how changes induced by low-dopamine (e.g. in Parkinson’s disease, PD) affect basal ganglia (BG) function, we need to identify the factors that determine the shape of BG responses to brief cortical stimuli. We show that transient response of the BG is also affected by recurrent interactions within the subnuclei of the BG, and not just feedforward pathways. We found that input and local connectivity within the globus pallidus externa are crucial for shaping the transient response. We also show that the same network changes may underlie both, pathologicalβ-band oscillations and aberrant transient responses. Our results highlight the importance of the recurrent connectivity within the BG and provide a coherent view of emergence of pathological activity in PD.
Virus-associated organosulfur metabolism in human and environmental systems
Authors: Kieft Kristopher , Breister Adam M. , Huss Phil , Linz Alexandra M. , Zanetakos Elizabeth , Zhou Zhichao , Rahlff Janina , Esser Sarah P. , Probst Alexander J. , Raman Srivatsan , Roux Simon , Anantharaman Karthik
Published: January 2021

Viruses influence the fate of nutrients and human health by killing microorganisms and altering metabolic processes. Organosulfur metabolism and biologically-derived hydrogen sulfide play dynamic roles in manifestation of diseases, infrastructure degradation, and essential biological processes. While microbial organosulfur metabolism is well-studied, the role of viruses in organosulfur metabolism is unknown. Here we report the discovery of 39 gene families involved in organosulfur metabolism encoded by 3,749 viruses from diverse ecosystems, including human microbiomes. The viruses infect organisms from all three domains of life. Six gene families encode for enzymes that degrade organosulfur compounds into sulfide, while others manipulate organosulfur compounds and may influence sulfide production. We show that viral metabolic genes encode key enzymatic domains, are translated into protein, are maintained after recombination, and that sulfide provides a fitness advantage to viruses. Our results reveal viruses as drivers of organosulfur metabolism with important implications for human and environmental health.
Emergent organization of multiple visuotopic maps without a feature hierarchy
Authors: Konkle Talia
Published: January 2021

The primate visual system is comprised of multiple visual areas. Despite their foundational relevance, there are no normative accounts for why there are multiple areas nor why they have their signature “mirrored map” topography. Here I show that the stereotyped cortical organization of multiple mirrored areas naturally emerges in simulated cortex, in which self-organizing processes are used to map a multi-scale representation of visual space smoothly onto a two-dimensional cortical sheet. Predominant accounts of multiple areas emphasize hierarchical processing, where each area extends and elaborates on the previous areas’ representation. Here, no explicit hierarchical relationships were required to manifest this multi-areal organization, suggesting that feature hierarchies may be the derived rather than the driving force of this organization. This modeling work thus provides a simple computational explanation for the hallmark features of early visual topography, and the presence of multiple areas, as emergent from a single functional goal — to smoothly represent the visual field at multiple spatial scales.

One Sentence Summary

This work presents a formal model of simulated cortex with multiple visual areas, where purely spatial relationships underlie the large-scale motifs of visual cortex.
Vangl2, a core component of the WNT/PCP pathway, regulates adult hippocampal neurogenesis and age-related decline in cognitive flexibility
Authors: Koehl M , Ladevèze E , Montcouquiol M , Abrous DN
Published: January 2021

Decline in episodic memory is one of the hallmarks of aging and represents one of the most important health problems facing western societies. A key structure in episodic memory is the hippocampal formation and the dentate gyrus in particular, as the continuous production of new dentate granule neurons in this brain region was found to play a crucial role in memory and in age-related decline in memory. As such, understanding the molecular processes that regulate the relationship between adult neurogenesis and aging of memory function holds great therapeutic potential. Recently, we found that Vang-gogh like 2 (Vangl2), a core component of the planar cell polarity signaling pathway, is enriched in the dentate gyrus of adult mice. In this context, we sought to evaluate the involvement of this effector of the Wnt/PCP pathway in both adult neurogenesis and memory abilities in adult and middle-aged mice. Using a heterozygous mouse model carrying a dominant negative mutation in Vangl2 gene, we show that alteration in Vangl2 expression decreases the survival of adult-born granule cells and advances the onset of decrease in cognitive flexibility. Inability of mutant mice to erase old irrelevant information to the benefit of new relevant ones highlights a key role of Vangl2 in interference-based forgetting. Taken together, our findings show for the first that Vangl2 activity may constitute an interesting target to prevent age-related decline in hippocampal plasticity and memory.
Aurora B phosphorylates Bub1 to promote spindle assembly checkpoint signaling
Authors: Roy Babhrubahan , Han Simon J. Y. , Fontan Adrienne N. , Jema Soubhagyalaxmi , Joglekar Ajit P.
Published: January 2021

Accurate chromosome segregation during cell division requires amphitelic chromosome attachment to the spindle apparatus. It is ensured by the combined activity of the Spindle Assembly Checkpoint1(SAC), a signaling mechanism that delays anaphase onset in response to unattached chromosomes, and an error correction mechanism that eliminates syntelic attachments2. The SAC becomes active when Mps1 kinase sequentially phosphorylates the kinetochore protein Spc105/KNL1 and the signaling proteins that Spc105/KNL1 recruits to facilitate the production of the Mitotic Checkpoint Complex3-8(MCC). The error correction mechanism is regulated by the Aurora B kinase, but Aurora B also promotes SAC signaling via indirect mechanisms9-12. Here we present evidence that Aurora B kinase activity directly promotes MCC production by working downstream of Mps1 in budding yeast and human cells. Using the ectopic SAC activation (eSAC) system, we find that the conditional dimerization of Aurora B in budding yeast, and an Aurora B recruitment domain in HeLa cells, with either Bub1 or Mad1, but not the phosphodomain of Spc105/KNL1, leads to ectopic MCC production and mitotic arrest13-16. Importantly, Bub1 must recruit both Mad1 and Cdc20 for this ectopic signaling activity. These and other data show that Aurora B cooperates with Bub1 to promote MCC production, but only after Mps1 licenses Bub1 recruitment to the kinetochore. This direct involvement of Aurora B in SAC signaling may maintain SAC signaling even after Mps1 activity in the kinetochore is lowered.
Pak1 and PP2A antagonize aPKC function to support cortical tension induced by the Crumbs-Yurt complex
Authors: Biehler Cornélia , Rothenberg Katheryn E. , Jetté Alexandra , Gaudé Hélori-Mael , Fernandez-Gonzalez Rodrigo , Laprise Patrick
Published: January 2021

TheDrosophilapolarity protein Crumbs is essential for the establishment and growth of the apical domain in epithelial cells. The protein Yurt limits the ability of Crumbs to promote apical membrane growth, thereby defining proper apical/lateral membrane ratio that is crucial for forming and maintaining complex epithelial structures such as tubes or acini.Here, we show that Yurt also increases Myosin-dependent cortical tension downstream of Crumbs. Yurt overexpression thus induces apical constriction in epithelial cells.The kinase aPKC phosphorylates Yurt, thereby dislodging the latter from the apical domain and releasing apical tension. In contrast, the kinase Pak1 promotes Yurt dephosphorylation through activation of the phosphatase PP2A. The Pak1– PP2A module thus opposes aPKC function and supports Yurt-induced apical constriction. Hence, the complex interplay between Yurt, aPKC, Pak1 and PP2A contributes to the functional plasticity of Crumbs. Overall, our data increase our understanding of how proteins sustaining epithelial cell polarization and Myosin-dependent cell contractility interact with one another to control epithelial tissue architecture.
Mitochondria biogenesis in the synapse is supported by local translation
Authors: Kuzniewska Bozena , Cysewski Dominik , Wasilewski Michal , Sakowska Paulina , Milek Jacek , Kulinski Tomasz M. , Kozielewicz Pawel , Dadlez Michal , Chacinska Agnieszka , Dziembowski Andrzej , Dziembowska Magdalena
Published: January 2021

Synapses are the regions of the neuron that enable the transmission and propagation of action potentials on the cost of high energy consumption and elevated demand for mitochondrial ATP production. The rapid changes in local energetic requirements at dendritic spines imply the role of mitochondria in the maintenance of their homeostasis. Using global proteomic analysis supported with complementary experimental approaches, we show that an important pool of mitochondrial proteins is locally produced at the synapse indicating that mitochondrial biogenesis takes place locally to maintain the pool of functional mitochondria in axons and dendrites. Furthermore, we show that stimulation of synaptoneurosomes induces the local synthesis of mitochondrial proteins that are transported to the mitochondria and incorporated into the protein supercomplexes of the respiratory chain.

Synopsis

Mitochondria biogenesis in the synapse is supported by local translation

Mitochondrial proteins represent a large pool of proteins synthesized locally at the synapse

Newly synthesized mitochondrial proteins are imported into the mitochondria and incorporated into the respiratory chain complexes

Uncoupling of mitochondria and blocking mitochondrial import inhibits incorporation of de novo synthesized proteins into the mitochondrial protein complexes
Special issue editorial: Advances in understanding the role of morphemes in literacy development
Authors: Breadmore Helen L. , Levesque Kyle , Deacon S. Hélène
Published: January 2021

This special issue, Advances in Understanding the Role of Morphemes in Literacy Development, is composed of one narrative review and 11 empirical papers that contribute new theoretical and empirical evidence to our understanding of how morphemes influence reading and spelling development. Here, we summarise key findings from these papers in terms of what they tell us about the multidimensional nature of morphological knowledge and how morphological information is processed at different levels, including across developmental changes and languages. Throughout this discussion, we draw out the implications for education and highlight targeted areas for further research.
Perceived income inequality increases status seeking among low social class individuals
Authors: Du Hongfei , Chen Anli , Li Yingling , Ma Lijun , Xing Qiang , Nie Yangang
Published: January 2021

Prior correlational research demonstrated that in a society with high income inequality, people are more likely to seek high status. The present study aimed to establish a causal relation between income inequality and status seeking by investigating the effects of perceived income inequality on the pursuit of positional goods. Moreover, we investigated whether the relation between perceived income inequality and the pursuit of positional goods is moderated by subjective social status. We manipulated high versus low income inequality and found that perceived income inequality increased the pursuit of positional goods among participants with low social status, but not among participants with high social status. Theoretical and practical implications of the findings are discussed.
Oncological reasons for performing a complete mesocolic excision: a systematic review and meta‐analysis
Authors: Kong Joseph C. , Prabhakaran Swetha , Choy Kay T. , Larach José T. , Heriot Alexander , Warrier Satish K.
Published: January 2021

Background

While complete mesocolic excision (CME) has been shown to have an oncological benefit as compared to conventional colonic surgery for colon surgery, this benefit must be weighed up against the risk of major intra‐abdominal complications. This paper aimed to assess the comparative oncological benefits of CME.

Methods

Following the Preferred Reporting Items for Systematic Reviews and Meta‐analyses guidelines, a systematic review of the literature until May 2020 was performed. Comparative studies assessing CME versus conventional colonic surgery for colon cancer were compared, and outcomes were pooled.

Results

A total of 700 publications were identified, of which 19 were found to meet the inclusion criteria. A total of 25 886 patients were compared, with 14 431 patients in the CME arm. CME was associated with a significantly higher rate of vascular injury (odds ratio 3, P < 0.001). Rates of local and distant recurrence were lower in the CME group (odds ratio 0.66 and 0.73, respectively, both P < 0.001). CME patients had a significantly higher lymph node yield (P < 0.001). While no significant differences were noted between the two groups in terms of pooled 3‐ or 5‐year disease‐free survival, pooled 5‐year overall survival was significantly higher in the CME group (relative risk 0.82, P < 0.001).

Conclusion

Based on the available evidence, CME is associated with improved oncologic outcomes at the expense of higher complication rates, including vascular injury. The oncological benefits need to weighed up against a multitude of factors including the level of hospital support, surgeon experience, patient age, and associated comorbidities.
Transperineal systematic biopsies in addition to targeted biopsies are important in the detection of clinically significant prostate cancer
Authors: Lahoud John , Doan Paul , Kim Lawrence H , Patel Manish I.
Published: January 2021

Background

This study aimed to determine whether the addition of transperineal systematic biopsies (SB) to targeted biopsies (TB) improved clinically significant prostate cancer (csPC) detection rates without high increase in insignificant prostate cancer detection rates in an Australian population.

Methods

In this retrospective review, a total of 254 patients who had a Prostate Imaging‐Reporting and Data System score between 3 and 5, and a transperineal TB and SB between 2014 and 2019 from two centres were included in this study. The primary outcome of this study was to determine csPC rates on TB and SB. The secondary outcome was a comparison of the Gleason Grade Group between TB and SB. csPC was defined as an International Society of Urological Pathology Gleason Grade Group of 2 or greater.

Results

SB alone detected more csPC overall compared to TB (152/254 (60%) versus 128/254 (51%), respectively). An additional 40 of 254 (16%) csPC cases were diagnosed with the addition of SB. Furthermore, the cost of diagnosing insignificant prostate cancer by SB when TB were negative was an additional 13/254 (5.1%).

Conclusion

A combination of TB and SB provides the best outcomes for detecting csPC and is especially warranted for patients with a higher Prostate Imaging‐Reporting and Data System score on multiparametric magnetic resonance imaging.
Deconstructing Cumulative Risk: Poverty and Aspects of Instability Relate Uniquely to Young Children’s Basal Cortisol
Authors: Brown Eleanor D. , Holochwost Steven J. , Laurenceau Jean‐Philippe , Garnett Mallory L. , Anderson Kate E.
Published: January 2021

This study deconstructs cumulative risk to probe unique relations to basal cortisol for family income and four distinct aspects of poverty‐related instability. Participants were 288 children aged 3–5 years who attended Head Start preschool. Parents reported on poverty risks. Children provided samples of salivary cortisol at four times of day on 6 days. Results of hierarchical linear modeling with piecewise latent growth curves representing basal cortisol indicated unique relations for family income, household chaos, neighborhood risk, attachment‐disruptive residential changes, and non‐attachment changes. The findings support an equifinality implied by cumulative risk models in demonstrating that multiple risks relate to cortisol dysregulation yet also suggest the utility of considering unique effects of different risks for neurophysiological stress response functioning.
Using Cusco’s speculum to endoscopically remove a large colonic endoscopic submucosal dissection specimen
Authors: Suzuki Sho , Kawakami Hiroshi , Miike Tadashi
Published: January 2021

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