bluuebunny/crossref_metadata_2025 huggingface dataset:
Proapoptotic RHG genes and mitochondria play a key non-apoptotic role in remodelling theDrosophilasensory system
Authors: Mukherjee Amrita , Pop Sinziana , Kondo Shu , Williams Darren W
Published: January 2021

Caspases are best known for their role in programmed cell death but have also been found to be important in several non-apoptotic phenomena such as cell fate specification, cell migration and terminal differentiation. The dynamics of such sub-lethal caspase events and the molecular mechanisms regulating them are still largely unknown. As more tools for visualizing and manipulating caspase activationin vivobecome available, greater insights into this biology are being made. Using a new and sensitivein vivoeffector caspase probe, called SR4VH, we demonstrate that effector caspases are activated in pruning sensory neurons earlier than previously thought and that the level of caspase activation in these neurons is consistently lower than in neurons undergoing cell death. We reveal that Grim and Reaper, two of the four pro-apoptotic RHG proteins, are required for sensory neuron pruning and that disrupting the dynamics of the mitochondrial network prevents effector caspase activation in both pruning and dying sensory neurons. Overall, our findings demonstrate that a sublethal deployment of the ‘apoptotic machinery’ is critical for remodelling dendrites and also reveal a direct link between mitochondria and sensory neuron cell deathin vivo.
Social boldness correlates with brain gene expression in male green anoles
Authors: Kabelik David , Julien Allison R. , Ramirez Dave , O’Connell Lauren A.
Published: January 2021

Within populations, some individuals tend to exhibit a bold or shy social behavior phenotype relative to the mean. The neural underpinnings of these differing phenotypes – also described as syndromes, personalities, and coping styles – is an area of ongoing investigation. Although a social decision-making network has been described across vertebrate taxa, most studies examining activity within this network do so in relation to exhibited differences in behavioral expression. Our study instead focuses on constitutive gene expression in bold and shy individuals by isolating baseline gene expression profiles that influence social boldness predisposition, rather than those reflecting the results of social interaction and behavioral execution. We performed this study on male green anole lizards (Anolis carolinensis), an established model organism for behavioral research, which provides a crucial comparison group to investigations of birds and mammals. After identifying subjects as bold or shy through repeated reproductive and agonistic behavior testing, we used RNA sequencing to compare gene expression profiles between these groups within various forebrain, midbrain, and hindbrain regions. The ventromedial hypothalamus had the largest group differences in gene expression, with bold males having increased expression of neuroendocrine and neurotransmitter receptor and calcium channel genes compared to shy males. Conversely, shy males express more integrin alpha-10 in the majority of examined regions. There were no significant group differences in physiology or hormone levels. Our results highlight the ventromedial hypothalamus as an important center of behavioral differences across individuals and provide novel candidates for investigations into the regulation of individual variation in social behavior phenotype.
Genetic control of pluripotency epigenome determines differentiation bias in mouse embryonic stem cells
Authors: Byers Candice , Spruce Catrina , Fortin Haley J. , Czechanski Anne , Munger Steven C. , Reinholdt Laura G. , Skelly Daniel A. , Baker Christopher L.
Published: January 2021

Genetically diverse pluripotent stem cells (PSCs) display varied, heritable responses to differentiation cues in the culture environment. By harnessing these disparities through derivation of embryonic stem cells (ESCs) from the BXD mouse genetic reference panel, along with C57BL/6J (B6) and DBA/2J (D2) parental strains, we demonstrate genetically determined biases in lineage commitment and identify major regulators of the pluripotency epigenome. Upon transition to formative pluripotency using epiblast-like cells (EpiLCs), B6 quickly dissolves naïve networks adopting gene expression modules indicative of neuroectoderm lineages; whereas D2 retains aspects of naïve pluripotency with little bias in differentiation. Genetic mapping identifies 6 majortrans-acting loci co-regulating chromatin accessibility and gene expression in ESCs and EpiLCs, indicating a common regulatory system impacting cell state transition. These loci distally modulate occupancy of pluripotency factors, including TRIM28, P300, and POU5F1, at hundreds of regulatory elements. Onetrans-acting locus on Chr 12 primarily impacts chromatin accessibility in ESCs; while in EpiLCs the same locus subsequently influences gene expression, suggesting early chromatin priming. Consequently, the distal gene targets of this locus are enriched for neurogenesis genes and were more highly expressed when cells carried B6 haplotypes at this Chr 12 locus, supporting genetic regulation of biases in cell fate. Spontaneous formation of embryoid bodies validated this with B6 showing a propensity towards neuroectoderm differentiation and D2 towards definitive endoderm, confirming the fundamental importance of genetic variation influencing cell fate decisions.
Ubx orchestrates tissue identity through regional and bidirectional changes to chromatin accessibility
Authors: Loker Ryan , Sanner Jordyn E. , Mann Richard S.
Published: January 2021

Hox proteins are homeodomain transcription factors that diversify serially homologous segments along the animal body axis, as revealed by the classic bithorax phenotype ofDrosophila melanogasterwhere mutations inUltrabithorax(Ubx) transform the third thoracic segment into the likeness of the second thoracic segment. To specify segment identity we show that Ubx both increases and decreases chromatin accessibility, coinciding with its role as both an activator and repressor of transcription. Surprisingly, whether Ubx functions as an activator or repressor differs depending on the proximal-distal position in the segment and the availability of Hox cofactors. Ubx-mediated changes to chromatin accessibility positively and negatively impact the binding of Scalloped (Sd), a transcription factor that is required for appendage development in both segments. These findings reveal how a single Hox protein can modify complex gene regulatory networks to transform the identity of an entire tissue.
Multiple RNA regulatory pathways coordinate the activity and expression pattern of a conserved germline RNA-binding protein
Authors: Albarqi Mennatallah M.Y. , Ryder Sean P.
Published: January 2021

RNA regulation is essential to successful reproduction. Messenger RNAs delivered from parent to progeny govern early embryonic development. RNA-binding proteins (RBPs) are the key effectors of this process, controlling the translation and stability of parental transcripts to control cell fate specification events prior to zygotic gene activation. The KH-domain RBP MEX-3 is conserved from nematode to human. It was first discovered inCaenorhabditis elegans, where it is essential for anterior cell fate and embryo viability. Here, we show thatmex-3mRNA is itself regulated by several RBPs to define its unique germline spatiotemporal expression pattern. We also show that both poly(A) tail length control and translational regulation contribute to this expression pattern. Though the 3’UTR is sufficient to establish the germline expression pattern, we show that it is not essential for reproduction. An allelic series of 3’UTR deletion variants identifies repressing regions of the UTR and show that the expression pattern is not precisely coupled to reproductive health. Together, our results define the pathways that govern the spatiotemporal regulation of this highly conserved germline RBP and suggest that redundant mechanisms control MEX-3 function when RNA regulation is compromised.
The Cardiolipin Transacylase Tafazzin Regulates Basal Insulin Secretion and Mitochondrial Function in Pancreatic Islets from Mice
Authors: Cole Laura K. , Agarwal Prasoon , Doucette Christine , Fonseca Mario , Xiang Bo , Sparagna Genevieve C. , Seshadri Nivedita , Vandel Marilyne , Dolinsky Vernon W. , Hatch Grant M.
Published: January 2021

Objective

Tafazzin (TAZ) is a cardiolipin (CL) biosynthetic enzyme important for maintaining mitochondrial function. TAZ impacts both the species and content of CL in the inner mitochondrial membrane which are essential for normal cellular respiration. In pancreatic β-cells, mitochondrial function is closely associated with insulin secretion. However, the role of TAZ and CL in the secretion of insulin from pancreatic islets remains unknown.

Methods

Male 4-month-old doxycycline-inducible TAZ knock-down (TAZ KD) mice and wild-type littermate controls were utilized. Immunohistochemistry was used to assess β-cell morphology in whole pancreas sections, whileex vivoinsulin secretion, CL content, RNA-Seq analysis and mitochondrial oxygen consumption were measured from isolated islet preparations.

Results

Ex vivoinsulin secretion under non-stimulatory low-glucose concentrations was reduced ∼52% from islets isolated from TAZ KD mice. Mitochondrial oxygen consumption under low-glucose conditions was also reduced ∼58% in islets from TAZ KD animals. TAZ-deficiency in pancreatic islets was associated with significant alteration in CL molecular species and reduced oxidized CL content. In addition, RNA-Seq of isolated islets showed that TAZ KD increased expression of extracellular matrix genes which are linked to pancreatic fibrosis, activated stellate cells and impaired β-cell function.

Conclusion

These data indicate a novel role for TAZ in regulating normal β-cell function, particularly under low-glucose conditions.
Protein Phosphatase 1 regulates atypical mitotic and meiotic division inPlasmodiumsexual stages
Authors: Zeeshan Mohammad , Pandey Rajan , Subudhi Amit Kumar , Ferguson David J. P. , Kaur Gursimran , Rashpa Ravish , Nugmanova Raushan , Brady Declan , Bottrill Andrew R. , Vaughan Sue , Brochet Mathieu , Bollen Mathieu , Pain Arnab , Holder Anthony A. , Guttery David S. , Tewari Rita
Published: January 2021

PP1 is a conserved eukaryotic serine/threonine phosphatase that regulates many aspects of mitosis and meiosis, often working in concert with other phosphatases, such as CDC14 and CDC25. The proliferative stages of the malaria parasite life cycle include sexual development within the mosquito vector, with male gamete formation characterized by an atypical rapid mitosis, consisting of three rounds of DNA synthesis, successive spindle formation with clustered kinetochores, and a meiotic stage during zygote to ookinete development following fertilization. It is unclear how PP1 is involved in these unusual processes. Using real-time live-cell and ultrastructural imaging, conditional gene knockdown, RNA-seq and proteomic approaches, we show thatPlasmodiumPP1 is implicated in both mitotic exit and, potentially, establishing cell polarity during zygote development in the mosquito midgut, suggesting that small molecule inhibitors of PP1 should be explored for blocking parasite transmission.
Phospholipids Uniquely Modify Secondary Structure of α-Synuclein Oligomers
Authors: Dou Tianyi , Zhou Lei , Kurouski Dmitry
Published: January 2021

Parkinson disease (PD) is a severe neurological disorder that affects more than a million people in the U.S. alone. A hallmark of PD is the formation of intracellular α-synuclein (α-Syn) protein aggregates called Lewy bodies (LBs). Although this protein does not have a particular localization in the central neural system, α-Syn aggregates are primarily found in certain areas of midbrain, hypothalamus and thalamus. Microscopic analysis of LBs revealed fragments of lipid-rich membranes, organelles and vesicles. These and other pieces of experimental evidence suggest α-Syn aggregation can be triggered by lipids. In this study, we used atomic force microscope Infrared (AFM-IR) spectroscopy to investigate structural organization of individual α-Syn oligomers grown in the presence of two different phospholipids vesicles. AFM-IR is a modern optical nanoscopy technique that has single-molecule sensitivity and sub-diffraction spatial resolution. Our results show that α-Syn oligomers grown in the presence of phosphatidylcholine have distinctly different structure than oligomers grown in the presence on phosphatidylserine. We infer that this occurs because of specific charges adopted by lipids, which in turn governs protein aggregation. We also found that protein to phospholipid ratio makes a substantial impact on the structure of α-Syn oligomers. These findings demonstrate that α-Syn is far more complex than expected from the perspective of structural organization of oligomeric species.
Actin dependent membrane polarization reveals the mechanical nature of the neuroblast polarity cycle
Authors: LaFoya Bryce , Prehoda Kenneth E.
Published: January 2021

The Par complex directs fate determinant segregation from the apical membrane of asymmetrically dividingDrosophilaneuroblasts. While the physical interactions that recruit the Par complex have been extensively studied, little is known about how the membrane itself behaves during polarization. We examined the membrane dynamics of neuroblasts and surrounding cells using a combination of super-resolution and time lapse imaging, revealing cellular-scale movements of diverse membrane features during asymmetric division cycles. Membrane domains that are distributed across the neuroblast membrane in interphase become polarized in early mitosis, where they mediate formation of cortical patches of the Par protein aPKC. Membrane and protein polarity cycles are precisely synchronized and are generated by extensive actin dependent forces that deform the surrounding tissue. In addition to suggesting a role for the membrane in asymmetric division, our results reveal the mechanical nature of the neuroblast polarity cycle.
Tonic activity in lateral habenula neurons promotes disengagement from reward-seeking behavior
Authors: Sleezer Brianna J. , Post Ryan J. , Bulkin David A. , Ebitz R. Becket , Lee Vladlena , Han Kasey , Warden Melissa R.
Published: January 2021

Survival requires both the ability to persistently pursue goals and the ability to determine when it is time to stop, an adaptive balance of perseverance and disengagement. Neural activity in the lateral habenula (LHb) has been linked to aversion and negative valence, but its role in regulating the balance between reward-seeking and disengaged behavioral states remains unclear. Here, we show that LHb neural activity is tonically elevated during minutes-long disengagements from reward-seeking behavior, whether due to repeated reward omission or following sufficient consumption of reward. Further, we show that LHb inhibition extends ongoing reward-seeking behavioral states but does not prompt re-engagement. We find no evidence for similar tonic activity fluctuations in ventral tegmental area (VTA) dopamine neurons. Our findings implicate the LHb as a key mediator of disengagement from reward-seeking behavior in multiple contexts and argue against the idea that the LHb contributes to decisions solely by signaling aversion.
Lifecycle dominates the volatilome character of the dimorphic fungusCoccidioidesspp
Authors: Keppler Emily A. Higgins , Mead Heather L. , Barker Bridget M. , Bean Heather D.
Published: January 2021

Valley fever (coccidioidomycosis) is an endemic fungal pneumonia of the North and South American deserts. The causative agents of Valley fever are the dimorphic fungiCoccidioides immitisandC. posadasii, which grow as mycelia in the environment and spherules within the lungs of vulnerable hosts. The current diagnostics for Valley fever are severely lacking due to poor sensitivity and invasiveness, contributing to a 23-day median time-to-diagnosis, and therefore new diagnostic tools are needed. We are working toward the development of a breath-based diagnostic for coccidioidomycosis, and in this initial study we characterized the volatile metabolomes (or volatilomes) ofin vitrocultures ofCoccidioides. Using solid-phase microextraction and comprehensive two-dimensional gas chromatography coupled to time-of-flight mass spectrometry (GC×GC–TOFMS), we characterized the VOCs produced by six strains of each species during mycelial or spherule growth. We detected a total of 353 VOCs that were at least two-fold more abundant in aCoccidioidesculture versus medium controls and found the volatile metabolome ofCoccidioidesis more dependent on growth phase (spherule versus mycelia) than on the species. The volatile profiles ofC. immitisandC. posadasiihave strong similarities, indicating that a single suite of Valley fever breath biomarkers can be developed to detect both species.

IMPORTANCE

Coccidioidomycosis, or Valley fever, causes up to 30% of community-acquired pneumonias in endemic and highly populated areas of the US desert southwest. The infection is difficult to diagnose by standard serological and histopathological methods, which delays an appropriate treatment. Therefore, we are working toward the development of breath-based diagnostics for Valley fever. In this study, we characterized the volatile metabolomes of six strains each ofCoccidioides immitisandC. posadasii, the dimorphic fungal species that cause Valley fever. By analyzing the volatilomes during the two modes of growth for the fungus—mycelia and spherules—we observed that the lifecycle plays a significant role in the volatiles produced byCoccidioides. In contrast, we observed no significant differences in theC. immitisversusC. posadasiivolatilomes. These data suggest that lifecycle, rather than species, should guide the selection of putative biomarkers for a Valley fever breath test.
Compound FC-10696 Inhibits Egress and Spread of Marburg Virus
Authors: Han Ziying , Ye Hong , Liang Jingjing , Shepley-McTaggart Ariel , Wrobel Jay E. , Reitz Allen B. , Whigham Alison , Kavelish Katrina N. , Saporito Michael S. , Freedman Bruce D. , Shtanko Olena , Harty Ronald N.
Published: January 2021

Marburg virus (MARV) VP40 protein (mVP40) directs egress and spread of MARV, in part, by recruiting specific host WW-domain containing proteins via its conserved PPxY Late (L) domain motif to facilitate efficient virus-cell separation. We reported previously that small molecule compounds targeting the viral PPxY/host WW-domain interaction inhibited VP40-mediated egress and spread. Here, we report on the antiviral potency of novel compound FC-10696, which emerged from extensive structure activity relationship (SAR) of a previously described series of PPxY inhibitors. We show that FC-10696 inhibits egress of both mVP40 VLPs and egress and spread of authentic MARV from HeLa cells and primary human macrophages. Moreover, FC-10696 treated mice displayed delayed onset of weight loss, clinical signs, and significantly lower viral loads compared to controls, with 14% of animals surviving 21 days following a lethal MARV challenge. Thus, FC-10696 represents a first-in-class, host-oriented inhibitor effectively targeting late stages of the MARV lifecycle.
Cognitive boundary signals in the human medial temporal lobe shape episodic memory representation
Authors: Zheng Jie , Gómez Palacio Schjetnan Andrea , Yebra Mar , Mosher Clayton , Kalia Suneil , Valiante Taufik A. , Mamelak Adam N. , Kreiman Gabriel , Rutishauser Ueli
Published: January 2021

While experience unfolds continuously, memories are organized as a set of discrete events that bind together the “where”, “when”, and “what” of episodic memory. This segmentation of continuous experience is thought to be facilitated by the detection of salient environmental or cognitive events. However, the underlying neural mechanisms and how such segmentation shapes episodic memory representations remain unclear. We recorded from single neurons in the human medial temporal lobe while subjects watched videos with different types of embedded boundaries and were subsequently evaluated for memories of the video contents. Here we show neurons that signal the presence of cognitive boundaries between subevents from the same episode and neurons that detect the abstract separation between different episodes. The firing rate and spike timing of these boundary-responsive neurons were predictive of later memory retrieval accuracy. At the population level, abrupt neural state changes following boundaries predicted enhanced memory strength but impaired order memory, capturing the behavioral tradeoff subjects exhibited when recalling episodic content versus temporal order. Successful retrieval was associated with reinstatement of the neural state present following boundaries, indicating that boundaries structure memory search. These findings reveal a neuronal substrate for detecting cognitive boundaries and show that cognitive boundary signals facilitate the mnemonic organization of continuous experience as a set of discrete episodic events.
Salt Inducible Kinase activation and IRE1-dependent intracellular ATP depletion to form Sec bodies in Drosophila cells
Authors: Zhang Chujun , van Leeuwen Wessel , Blotenburg Marloes , Aguilera-Gomez Angelica , Brussee Sem , Grond Rianne , Kampinga Harm H. , Rabouille Catherine
Published: January 2021

The phase separation of the non-membrane bound Sec bodies occurs in Drosophila S2 cells by coalescence of components of the ER exit sites under the stress of amino-acid starvation. Here we address which signaling pathways cause Sec body formation. We find that two pathways are critical. The first is a SIK dependent pathway induced by salt (NaCl) stress in a necessary and sufficient manner. The second is the activation of IRE1 (one of the key kinases mediating the Unfolded Protein Response) by absence of amino- acids, which partly leads to the depletion of intracellular ATP. However, IRE1 activation is not sufficient to induce Sec body formation and needs to be combined to salt stress. This works pioneers the role of SIK in phase transition and re-enforces the role of IRE1 as a metabolic sensor for the level of circulating amino-acids.
An early-morning flowering trait in rice helps retain grain yield under heat stress field conditions at flowering stage
Authors: Ishimaru Tsutomu , Hlaing Khin Thandar , Oo Ye Min , Lwin Tin Mg , Sasaki Kazuhiro , Lumanglas Patrick D. , Simon Eliza-Vie M. , Myint Tin Tin , Hairmansis Aris , Susanto Untung , Ayyenar Bharathi , Muthurajan Raveendran , Hirabayashi Hideyuki , Fukuta Yoshimichi , Kobayasi Kazuhiro , Matsui Tsutomu , Yoshimoto Mayumi , Htun Than Myint
Published: January 2021

Early-morning flowering (EMF) trait is supposed to be effective in retaining grain yield due to mitigation of heat-induced spikelet sterility at flowering in rice. This study evaluated (i) phenotypic differences between a near-isogenic line carrying a QTL for EMF trait, designated as IR64+qEMF3, and a recurrent parent, IR64, under wide variation in climates and (ii) whether an EMF trait can retain grain yield under heat stress at flowering. IR64+qEMF3had significant earlier flower opening time (FOT) in diverse environmental conditions including temperate, subtropical, and tropical regions. Under normal temperatures at flowering, IR64+qEMF3had similar grain yield to IR64 with some significant changes in agronomic traits and yield components. Field trials in heat-vulnerable regions of central Myanmar for seven crop seasons showed that higher percentage of filled grains contributed to the significantly higher grain yield in IR64+qEMF3among yield components when plants were exposed to daily maximum air temperatures around 36.5 °C or higher. Lower spikelet sterility in IR64+qEMF3was attributed to the earlier FOT during cooler early morning hours. This is the first field study that clearly demonstrates the advantage of the EMF trait for retaining grain yield by stabilizing percentage of fertile grains under heat stress at flowering.
A conserved role of Parkinson-associated DJ-1 metabolites in sperm motility, mitosis, and embryonic development
Authors: Bour Susanne , Dening Yanina , Balbach Melanie , Poser Ina , Álvarez Inés Ramírez , den Haan Helena , Kluge Christoph , Naumann Ronald , Oertel Reinhard , Alba-Alejandre Irene , Accardi Davide , Stief Christian G. , Dieterich Marianne , Falkai Peter , Böckmann Rainer A. , Pérez-Sánchez Horacio , Hyman Anthony A. , Trottmann Matthias , Pan-Montojo Francisco
Published: January 2021

Fertility rates in the developing world have dramatically dropped in the last decades. This drop is likely due to a decline in sperm quality and women having children at older ages. Loss of function mutations inDJ-1, a Parkinson’s associated gene, are linked to alterations in multiple cellular processes such as mitochondrial activity, ROS production or sperm motility and lead to an early onset of Parkinson’s disease and male infertility in humans and other species. Glycolate (GA) and D-lactate (DL), products ofDJ-1glyoxalase activity, sustain mitochondrial function and protect against environmental aggressions. We, therefore, tested whether these substances could also have a rescue effect on these phenotypes. Here, we show thatDJ-1loss of function not only affects sperm motility but also leads to defects in mitosis and an age-dependent increase in the abortion rate. Remarkably, whereas DL was only able to rescue embryonic lethality inC. elegans, GA rescued these phenotypes in all model systems tested and even increased sperm motility in wild-type sperm. These positive effects seem to be mediated through an increase in NAD(P)H production and the regulation of intracellular calcium. These findings not only strongly suggest GA as a new therapeutic candidate to improve male and female fertility but also show its potential to treat diseases associated with a decline in mitochondrial function or to improve mitochondrial function in aging.
Conditional deletion of HIF-1α provides new insight regarding the murine response to gastrointestinal infection withSalmonellaTyphimurium
Authors: Robrahn Laura , Dupont Aline , Jumpertz Sandra , Zhang Kaiyi , Holland Christian H. , Guillaume Joël , Rappold Sabrina , Cerovic Vuk , Saez-Rodriguez Julio , Hornef Mathias W. , Cramer Thorsten
Published: January 2021

The hypoxia-inducible transcription factor 1 (HIF-1) has been shown to ameliorate different bacterial infections through enhancement of microbial killing. While the impact of HIF-1 on inflammatory diseases of the gut has been studied intensively, its function in bacterial infections of the intestine remains largely elusive. With the help of a publicly available gene expression data set, we could infer significant activation of the HIF-1 transcription factor after oral infection of mice withSalmonellaTyphimurium. This prompted us to apply lineage-restricted deletion of theHif1alocus in mice to examine cell type-specific functions of HIF-1 in this model. We show hypoxia-independent induction of HIF-1 activity uponSalmonellainfection in the intestinal epithelium as well as in macrophages. Surprisingly,Hif1adeletion in intestinal epithelial cells impacted neither disease outcome nor inflammatory activity. The conditional knockout ofHif1ain myeloid cells enhanced the mRNA expression of the largely pro-inflammatory chemokineCxcl2, revealing a potentially inflammatory effect of HIF-1 deficiency in myeloid cells in the gutin vivo. Again, the disease outcome was not affected.In vitroHIF-1-deficient macrophages showed an overall impaired transcription of pro-inflammatory factors, however,Salmonellabypassed direct intracellular, bactericidal HIF-1-dependent mechanisms in aSalmonellapathogenicity island (SPI)-2 independent manner. Taken together, our data suggest that HIF-1 in intestinal epithelial and myeloid cells is either dispensable or compensable in the immune defense againstSalmonellaTyphimurium.
Conditions under which distributions of edge length ratios on phylogenetic trees can be used to order evolutionary events
Authors: Susko Edward , Steel Mike , Roger Andrew J.
Published: January 2021

Two recent high profile studies have attempted to use edge (branch) length ratios from large sets of phylogenetic trees to determine the relative ages of genes of different origins in the evolution of eukaryotic cells. This approach can be straightforwardly justified if substitution rates are constant over the tree for a given protein. However, such strict molecular clock assumptions are not expected to hold on the billion-year timescale. Here we propose an alternative set of conditions under which comparisons of edge length distributions from multiple sets of phylogenies of proteins with different origins can be validly used to discern the order of their origins. We also point out scenarios where these conditions are not expected to hold and caution is warranted.
Nucleus-accumbens dopamine tracks aversive-stimulus duration and prediction but not value or prediction error
Authors: Goedhoop J.N. , van den Boom B.J.G. , Fellinger L. , Arbab T. , Willuhn I.
Published: January 2021

There is active debate on the role of dopamine in processing aversive stimuli, where inferred roles range from no involvement at all, to signaling an aversive-prediction error (APE). Here, we systematically investigate dopamine release in the nucleus-accumbens core (NAC), which is closely linked to reward-prediction errors, in rats exposed to white noise (WN, a versatile, underutilized, aversive stimulus) and its predictive cues. Both induced a negative dopamine ramp, followed by slow signal recovery upon stimulus cessation. In contrast to reward conditioning, this dopamine signal was unaffected by WN value, context valence, or probabilistic contingencies, and the WN dopamine-response shifted only partially towards its predictive cue. However, unpredicted WN provoked slower post-stimulus signal recovery than predicted WN. Despite differing signal qualities, dopamine responses to simultaneous presentation of rewarding and aversive stimuli were additive. Together, our findings demonstrate that instead of an APE, NAC dopamine primarily tracks prediction and duration of aversive events.
Random sub-diffusion and capture of genes by the nuclear pore reduces dynamics and coordinates interchromosomal movement
Authors: Sumner Michael Chas , Torrisi Steven B. , Brickner Donna Garvey , Brickner Jason H.
Published: January 2021

Hundreds of genes interact with the yeast nuclear pore complex (NPC), localizing at the nuclear periphery and clustering with co-regulated genes. Dynamic tracking of peripheral genes shows that they cycle on and off the NPC and that interaction with the NPC slows their sub-diffusive movement. Furthermore, NPC-dependent inter-chromosomal clustering leads to coordinated movement of pairs of loci separated by hundreds of nanometers. We developed Fractional Brownian Motion simulations for chromosomal loci in the nucleoplasm and interacting with NPCs. These simulations predict the rate and nature of random sub-diffusion during repositioning from nucleoplasm to periphery and match measurements from two different experimental models, arguing that recruitment to the nuclear periphery is due to random subdiffusion, collision, and capture by NPCs. Finally, the simulations do not lead to inter-chromosomal clustering or coordinated movement, suggesting that interaction with the NPC is necessary, but not sufficient, to cause clustering.
A sexual dimorphic role of themiR-465cluster in placental development
Authors: Wang Zhuqing , Meng Nan , Wang Yue , Zhou Tong , Li Musheng , Wang Shawn , Chen Sheng , Zheng Huili , Kong Shuangbo , Wang Haibin , Yan Wei
Published: January 2021

A sexually dimorphic role of miRNAs in placental development has never been reported. Here, we show that ablation of themiR-465cluster caused selective degeneration of female conceptuses as early as embryonic day (E)8.5, leading to a male-biased sex ratio (60% males) amongmiR-465KO mice. Given that themiR-465cluster miRNAs were predominantly expressed in the extraembryonic tissue and ablation of these miRNAs led to dysregulation of numerous critical placental genes, our data strongly suggest themiR-465cluster is required for full developmental potential of the female, but not the male, extraembryonic tissue/placenta.
T cell self-reactivity during thymic development dictates the timing of positive selection
Authors: Lutes Lydia K. , Steier Zoë , McIntyre Laura L. , Pandey Shraddha , Kaminski James , Hoover Ashley R. , Ariotti Silvia , Streets Aaron , Yosef Nir , Robey Ellen A.
Published: January 2021

Functional tuning of T cells based on their degree of self-reactivity is established during positive selection in the thymus, although how positive selection differs for thymocytes with relatively low versus high self-reactivity is unclear. In addition, preselection thymocytes are highly sensitive to low-affinity ligands, but the mechanism underlying their enhanced TCR sensitivity is not fully understood. Here we show that murine thymocytes with low self-reactivity experience briefer TCR signals and complete positive selection more slowly than those with high self-reactivity. Additionally, we provide evidence that cells with low self-reactivity retain a preselection gene expression signature as they mature, including genes previously implicated in modulating TCR sensitivity and a novel group of ion channel genes. Our results imply that thymocytes with low self-reactivity down-regulate TCR sensitivity more slowly during positive selection, and suggest that modulation of membrane ion channel function may play a role in regulating TCR tuning throughout development.

Impact Statement

Developing T cells whose TCRs have relatively low reactivity experience very brief TCR signaling events, delayed positive selection, and do not fully down regulate their TCR sensitivity as they mature.
Impact of Immediate and Preferential Relaxation of Social and Travel Restrictions for Vaccinated People on the Spreading Dynamics of COVID-19 : a Model-Based Analysis
Authors: Shayak B , Sharma Mohit M , Mishra Anand K
Published: January 2021

Background

Four COVID-19 vaccine candidates developed by Pfizer, Moderna, University of Oxford/ Astra Zeneca (also Oxford/ Serum Institute of India) and ICMR/ Bharat Biotech have been granted emergency use authorization in the democratic world following established clinical trial procedures in their respective countries. Vaccination of the general public is expected to begin in several weeks. We consider the question of whether people who have received the vaccine can be selectively and immediately cleared to return to normal activities, including hassle-free travel.

Methods

We use a delay differential equation model developed previously by our group to calculate the effects of vaccinee “immunity passports” on the spreading trajectories of the disease. We consider default virus strains as well as high-transmissibility variants such as B1.1.7 in our analysis.

Results

We find that with high vaccine efficacy of 80 percent or greater, vaccinees may be immediately cleared for normal life with no significant increase in case counts. Free travel of such vaccinees between two regions should not jeopardize the infection control performance of either. At current vaccine administration rates, it may be eight months or more before COVID-19 transmission is significantly reduced or eliminated. With lower vaccine efficacy of approximately 60 percent however, social as well as travel restrictions for vaccinees may need to remain in place until transmission of the disease is eliminated.

Conclusions

Designing high-efficacy vaccines with easily scalable manufacturing and distribution capacity should remain on the priority list in academic as well as industrial circles. Performance of all vaccines should continue to be monitored in real time during vaccination drive with a view to analysing socio-demographic determinants if any of efficacy, and optimizing distribution accordingly. A speedy and efficacious vaccination drive will provide the smoothest path out of the pandemic with the least additional caseloads, death toll and socioeconomic cost.
Changes in healthcare workers’ knowledge, attitudes, practices, and stress during the COVID-19 pandemic
Authors: Temsah Mohamad-Hani , Al Huzaimi Abdullah , Alrabiaah Abdulkarim , Alamro Nurah , Al-Sohime Fahad , Al-Eyadhy Ayman , Alhasan Khalid , Kari Jameela A , Alhaboob Ali , Salmi Amro Al , AlMuhanna Wejdan , Almaghlouth Ibrahim , Aljamaan Fadi , Halwani Rabih , Barry Mazin , Al-Zamil Fahad , Al-Hadi Ahmad , Al-Subaie Sarah , Jamal Amr , Somily Ali Mohammed
Published: January 2021

Introduction

Coronavirus disease 2019 (COVID-19) has caused an unprecedented health crisis around the world, not least because of its heterogeneous clinical presentation and course. The new information on the pandemic emerging daily has made it challenging for healthcare workers (HCWs) to stay current with the latest knowledge, which could influence their attitudes and practices during patient care.

Methods

This study is a follow-up evaluation of changes in HCWs’ knowledge, attitudes, and practices as well as anxiety levels regarding COVID-19 since the beginning of the pandemic. Data were collected through an anonymous, predesigned, self-administered questionnaire that was sent online to HCWs in Saudi Arabia.

Results

The questionnaire was sent to 1500 HCWs, with a 63.8% response rate (N=957). The majority of respondents were female (83%), and the most common age group was 31–40 years (52.2%). Nurses constituted 86.3% of the respondents. HCWs reported higher anxiety during the COVID-19 pandemic which increased from 4.91±2.84 to 8.6±2.27 on an 11-point Likert scale compared to other viral outbreaks. HCWs believed that their own preparedness as well as that of their hospital’s intensive care unit (ICU) or emergency room (ER) was higher during the COVID-19 pandemic than during the Middle East respiratory syndrome coronavirus pandemic (2012–2015). About 58% of HCWs attended one or more simulations concerning the management of COVID-19 patients in their ICU/ER, and nearly all had undergone N95 mask fit testing. The mean score of HCWs’ knowledge of COVID-19 was 9.89/12. For most respondents (94.6%), the perception of being at increased risk of infection was the main cause of anxiety related to COVID-19; the mean score of anxiety over COVID-19 increased from 4.91±2.84 before to 8.6±2.27 during the pandemic in Saudi Arabia.

Conclusions

HCWs’ anxiety levels regarding COVID-19 have increased since a pandemic was declared. It is vital that healthcare facilities provide more emotional and psychological support for all HCWs.
Clear cell injury associated with reduced expression of carbonic anhydrase II in eccrine glands consistently occurs in patients with acquired idiopathic generalized anhidrosis
Authors: Sano Kenji , Asahina Masato , Uehara Takeshi , Araki Nobuyuki , Yamanaka Yoshitaka , Matsumoto Kazuhiko , Okuyama Ryuhei
Published: January 2021

Acquired idiopathic generalized anhidrosis (AIGA) is characterized by anhidrosis/hypohidrosis without other autonomic and neurological dysfunctions. It has been believed that AIGA patients usually present no significant morphological alterations in the secretory portion of eccrine glands consisting of clear, dark and myoepithelial cells. However, we have recently revealed morphological damage of eccrine glands in AIGA patients by immunohistochemistry. Moreover, inhibitory side‐effects against carbonic anhydrase II (CA II) by the antiepileptic reagent topiramate have been reported to cause heat intolerance mimicking AIGA. To determine the precise morphological changes and CA II expression in eccrine glands of AIGA patients, electron microscopic observation and immunohistochemistry were applied to skin of both anhidrotic (non‐sweating) and normohidrotic (sweating‐preserved) sites, taken from each patient clinically diagnosed with AIGA. We found consistent clear cell injury in eccrine glands in anhidrotic skin samples of AIGA patients. Electron micrographs demonstrated edematous, swollen and destructive damage in clear cells of eccrine glands from non‐sweating areas of almost all AIGA patients. Immunohistochemically, clear cells showed reduced CA II expression that was heterogeneously distributed in non‐sweating skin. Some areas showed almost complete loss of CA II expression in spite of preserved dark cells, and others showed mild or moderate loss of it. Selective destruction of clear cells resulting in heterogenous atrophy in AIGA patients may be important to elucidate its etiology.
Pralatrexate for refractory mycosis fungoides in two Japanese patients
Authors: Teraishi Mika , Oguro Tokuko , Kusume Ema , Kobashi Haruka , Sano Hozumi , Fujioka Ai , Yamamoto Mayuko , Nakajima Hideki , Sano Shigetoshi
Published: January 2021

Pralatrexate has been approved for the treatment of relapsed/refractory peripheral T cell lymphomas. Studies in the U.S. also support the clinical efficacy of pralatrexate to treat advanced‐stage cutaneous T‐cell lymphomas, but outcomes in Japanese patients have not yet been reported. We herein describe two Japanese patients with heavily‐pretreated relapsed/refractory mycosis fungoides that were successfully controlled by pralatrexate.
Overlooked Husbands: The Paradox of Unfree Marriage in the Carolingian World
Authors: Stone Rachel
Published: January 2021

Unfree people in the Roman world could not legally marry, while they could in the Middle Ages. This paper explores the marriage of the unfree in the Carolingian empire (750–900 CE), a society with an intense moral concern about marriage. Carolingian churchmen wrote extensively about marriage, using a strongly gendered discourse focusing on how men should approach marriage and behave as husbands. However, these moral and legal texts rarely discussed unfree marriage, even though the practice was common. It is argued that this silence reflects the persistence of late antique class‐based gender models, in which masculinity was reserved for married property holders. Although legal prohibitions on unfree marriages had ended, Carolingian moralists continued to be influenced by patristic assumptions that these were not valid relationships. These assumptions, combined with Frankish social practices that largely excluded unfree men from other key male roles, such as arms‐bearing, meant that unfree husbands were not conceptualised as sufficiently ‘manly’ to have their marriages discussed. It is only from the tenth century onwards, when images of masculinity began to fragment more along lines of social status, that authors began explicitly to state that the Christian ideas of marriage applied to all, free and unfree.
Supraclavicular ultrasonographic real‐time guidance of peripherally inserted central catheters – A feasibility study
Authors: Kirkegaard Ellen , Lind Peter C. , Dolmer Henrik , Juhl‐Olsen Peter
Published: January 2021

Background

Mispositioning is common during insertion of peripherally inserted central catheters. Ultrasonographic visualization of anatomical structures may enable continuous guidance during insertion. The aim was to investigate the feasibility of ultrasonographic real‐time guidance of peripherally inserted central catheter placement using the supraclavicular fossa view.

Methods

An observational quality control study was performed including 20 patients. Ultrasonography was performed via the right supraclavicular fossa using a microconvex probe identifying the junction between the right internal jugular‐ and the subclavian vein forming the right brachiocephalic vein. The wire guide tip was identified at the junction allowing estimation of catheter length. The catheter stiffening wire was followed in real‐time into the right brachiocephalic vein towards the superior vena cava. Mispositions and the ability to redirect in real‐time were detected. Final catheter tip positions were evaluated by either fluoroscopy or a chest radiograph.

Results

Catheters were successfully placed in 19/20 patients. In all patients the junction and the right brachiocephalic vein was identified. Two thrombi were identified in the right brachiocephalic vein and left‐sided insertions were performed. In 16 of 17 right‐sided insertions, wire guide and catheter stiffening wire were visible. Of the 16 visual catheters, 15 could be followed into the right brachiocephalic vein. Real‐time mispositioning was identified in eight cases and optimal redirection was successful in seven. All ultrasound‐guided catheter length estimations were adequate.

Conclusions

Supraclavicular ultrasonographic real‐time guidance for peripherally inserted central catheter placement was feasible and enabled successful placement together with detection and redirection of mispositioned catheters without delay.
Lycorine hydrochloride suppresses stress‐induced premature cellular senescence by stabilizing the genome of human cells
Authors: Zhang Weina , Yang Jiaqing , Chen Yu , Xue Renhao , Mao Zhiyong , Lu Wen , Jiang Ying
Published: January 2021

Lycorine, a natural compound isolated from the traditional Chinese medicinal herb Lycoris radiata, exhibits multiple pharmacological effects, such as anti‐inflammatory, antiviral, and anticancer effects. Accumulating evidence also indicates that lycorine might hold the potential to treat age‐associated Alzheimer's disease. However, whether lycorine is involved in delaying the onset of cellular senescence and its underlying mechanisms has not been determined. Here, we demonstrate that the salt of lycorine, lycorine hydrochloride, significantly suppressed stress‐induced premature cellular senescence (SIPS) by ~2‐fold, as determined by senescence‐associated beta‐galactosidase (SA‐β‐gal) staining and the expression of p16 and p21. In addition, pretreating cells with lycorine hydrochloride significantly inhibited the expression of CXCL1 and IL1α, two factors of the senescence‐associated secreted phenotype (SASP) in SIPS cells. Further experiments revealed that lycorine hydrochloride promoted both the homologous recombination (HR) and nonhomologous end joining (NHEJ) pathways of DNA double‐strand break (DSB) repair. Mechanistic studies suggested that lycorine hydrochloride treatment promoted the transcription of SIRT1 and SIRT6, critical longevity genes positively regulating both HR and NHEJ repair pathways, thereby stimulating DSB repair and stabilizing genomes. Inhibiting SIRT1 enzymatic activity abrogated the protective effect of lycorine hydrochloride on delaying the onset of SIPS, repairing DSBs, and restoring genome integrity. In summary, our work indicates that lycorine hydrochloride might hold therapeutic potential for treating age‐associated diseases or promoting healthy aging by stabilizing genomes.