bluuebunny/crossref_metadata_2025 huggingface dataset:
Sponges are highly resistant to radiation exposure and cancer
Authors: Fortunato Angelo , Taylor Jake , Scirone Jonathan , Aktipis Athena , Maley Carlo C.
Published: March 2021

There are no reports of cancer in sponges, despite them having somatic cell turnover, long lifespans and no specialized adaptive immune cells. In order to investigate whether sponges are cancer resistant, we exposed a species of sponge,Tethya wilhelma, to X-rays. We found thatT. wilhelmacan withstand 600 Gy of X-ray radiation. That is approximately 100 times the lethal dose for humans. A single high dose of X-rays did not induce cancer in sponges, providing the first experimental evidence of cancer resistance in the phylum, Porifera. Following X-ray exposure, we found an overexpression of genes involved in DNA repair, signaling transduction pathways and epithelial to mesenchymal transition. Sponges have the highest level of radiation resistance that has yet been observed in animals that have sustained somatic cell turnover. This may make them an excellent model system for studying cancer resistance and developing new approaches for cancer prevention and treatment.
The SAGA and NuA4 component Tra1 regulatesCandida albicansdrug resistance and pathogenesis
Authors: Razzaq Iqra , Berg Matthew D. , Jiang Yuwei , Genereaux Julie , Uthayakumar Deeva , Kim Grace H. , Brandl Christopher J. , Lajoie Patrick , Shapiro Rebecca S.
Published: March 2021

Candida albicansis the most common cause of death from fungal infections. Emergence of resistant strains reducing the efficacy of first line therapy with echinocandins such as caspofungin calls for the identification of alternative therapeutic strategies. Tra1 is an essential component of the SAGA and NuA4 transcriptional co-activator complexes. As a PIKK family member, Tra1 is characterized by a C-terminal phosphoinositide 3-kinase domain. InSaccharomyces cerevisiae,the assembly and function of SAGA and NuA4 is compromised by a version of Tra1 (Tra1Q3) with three arginine residues in the putative ATP-binding cleft changed to glutamine, Whole transcriptome analysis of theS. cerevisiae tra1Q3strain highlights Tra1’s role in global transcription, stress response and cell wall integrity. As a result,tra1Q3increases susceptibility to multiple stressors, including caspofungin. Moreover, the sametra1Q3allele in the pathogenic yeastCandida albicanscauses similar phenotypes, suggesting that Tra1 broadly mediates the antifungal response across yeast species. Transcriptional profiling inC. albicansidentified 68 genes that were differentially expressed when thetra1Q3strain was treated with caspofungin, as compared to gene expression changes induced by eithertra1Q3or caspofungin alone. Included in this set were genes involved in cell wall maintenance, adhesion and filamentous growth. Indeed, thetra1Q3allele reduces filamentation and other pathogenesis traits inC. albicans. We identifiedEVP1, which encodes a putative plasma membrane protein, amongst the Tra1-regulated genes, DisruptingEVP1results in reduced filamentation and infection capacity inC. albicans. Thus,Tra1 emerges as a promising therapeutic target for fungal infections.

Importance

Fungal pathogens such asCandida albicansare important agents of infectious disease, with increasing rates of drug resistance, and limited available antifungal therapeutics. In this study, we characterize the role ofC. albicansTra1, a critical component of acetyltransferase complexes, involved in transcriptional regulation and responses to environmental stress. We findC. albicansgenetic mutants with impaired Tra1 function have reduced tolerance to cell-wall targeting stressors, including the clinically-important antifungal caspofungin. We further use RNA-sequencing to profile the global fungal response to thetra1mutation, and identify a previously uncharacterizedC. albicansgene,EVP1. We find that bothTRA1andEVP1play an important role in phenotypes associated with fungal pathogenesis, including cellular morphogenesis, biofilm formation, and toxicity towards host immune cells. Together, this work describes the key role for Tra1 in regulating fungal drug tolerance and pathogenesis, and positions this protein as a promising therapeutic target for fungal infections.
Potential Role of Red Palm Oil Supplemented Diet on Oxidative Stress Enzymes inPlasmodium BergheiInduced Malaria
Authors: Adeleke Temitope Daniel , Adejumobi Olawale Abiodun , Akinola Franklin Folasele , Salau Oluwatosin Abidemi , Uthman-Izobo Oyeronke Suebat
Published: March 2021

Background

Malaria parasites are very vulnerable to oxidative stress during the part of their life cycle when they inhabit the erythrocytes. Studies have shown that dietary intake of antioxidant plays a role in stabilizing oxidative stress.

Methods

The objective of this research work was to examine the antioxidative effect of red palm oil onPlasmodium bergheimalaria induced oxidative stress. Sixty (60) mice were distributed into five groups. Group A served as the negative control (healthy mice with normal feed); group B as positive control (healthy mice fed with red palm oil without malaria parasite.while the other groups (C to E) served as the test groups. Group C served as group of healthy mice fed with red palm oil (pelletized), infected with malaria parasite without antimalaria drug. Group D served as group of healthy mice fed with red palm oil (pelletized), infected with malaria parasite and treated with amodiaquine. Group E served as group of healthy mice fed with normal feed, infected with malaria parasite and treated with amodiaquine. The parasitemia levels were estimated on days 1,4 and 5. The activity of oxidative stress enzymes biomarkers were determined spectrophotometrically.

Result

Group A showed a statistically significant increase in the activity of SOD (1.90 ± 0.16 units/mg protein), GST (1.68 ± 0.086 units/L) compared to group C, SOD (3.54 ± 0.83 units/mg protein), GST (2.12 ± 0.20 units/L). Group B showed a statistical significant decrease in the activities of SOD (3.22 ± 0.33 units/mg protein), Catalase (49.11 ± 2.35 µmol/min), GSH-R (31.50 ± 2.48 units/L) compared to group E, SOD (2.18 ± 0.39 units/mg protein), Catalase (44.07 ± 3.88 µmol/min), GSH-R (27.75 ± 1.64 units/L).

Conclusion

The dietary intake of red palm oil helps to reduce free radical mediated injury to the tissue thus preventing oxidative stress induced by malaria or any other factors.
Comparative genomics reveals evolutionary drivers of sessile life and left-right shell asymmetry in bivalves
Authors: Zhang Yang , Mao Fan , Xiao Shu , Yu Haiyan , Xiang Zhiming , Xu Fei , Li Jun , Wang Lili , Xiong Yuanyan , Chen Mengqiu , Bao Yongbo , Deng Yuewen , Huo Quan , Zhang Lvping , Liu Wenguang , Li Xuming , Ma Haitao , Zhang Yuehuan , Mu Xiyu , Liu Min , Zheng Hongkun , Wong Nai-Kei , Yu Ziniu
Published: March 2021

Bivalves are species-rich mollusks with prominent protective roles in coastal ecosystems. Across these ancient lineages, colony-founding larvae anchor themselves either by byssus production or by cemented attachment. The latter mode of sessile life is strongly molded by left-right shell asymmetry during larval development ofOstreoidaoysters such asCrassostrea hongkongensis. Here, we sequenced the genome ofC. hongkongensisin high resolution and compared it to reference bivalve genomes to unveil genomic determinants driving cemented attachment and shell asymmetry. Importantly, loss of the homeobox geneantennapedia(Antp) and broad expansion of lineage-specific extracellular gene families are implicated in a shift from byssal to cemented attachment in bivalves. Evidence from comparative transcriptomics shows that the left-right asymmetricalC. hongkongensisplausibly diverged from the symmetricalPinctada fucatain expression profiles marked by elevated activities of orthologous transcription factors and lineage-specific shell-related gene families includingtyrosinases, which may cooperatively govern asymmetrical shell formation inOstreoidaoysters.
PI3Kβ inhibition restores ALK inhibitor sensitivity in ALK-rearranged lung cancer
Authors: Talwelkar Sarang S. , Mäyränpää Mikko I. , Schüler Julia , Linnavirta Nora , Hemmes Annabrita , Adinolfi Simone , Kankainen Matti , Sommergruber Wolfgang , Levonen Anna-Liisa , Räsänen Jari , Knuuttila Aija , Verschuren Emmy W. , Wennerberg Krister
Published: March 2021

For non-small cell lung cancer (NSCLC) patients withALK-rearranged tumors, treatment with ALK inhibitors can improve outcomes. However, clinical resistance typically develops over time, and in the majority of cases resistance mechanisms are ALK-independent. We generated tumor cell cultures from multiple regions of anALK-rearranged clinical tumor specimen, and deployed functional drug screens to identify modulators of resistance to ALK inhibitors. This identified a role for PI3Kβ and EGFR in regulating resistance to ALK inhibition. Furthermore, inhibition of ALK elicited activation of EGFR, and inhibition of PI3Kβ rescued EGFR-mediated ALK inhibitor resistance. InALK-rearranged primary cultures, cell lines andin vivoxenograft models, combined inhibition of ALK and PI3Kβ prevented compensatory MAPK and PI3K-AKT pathway reactivation and selectively targeted the cancer cells. The combinatorial effect was seen even in the background ofTP53mutations and in epithelial-mesenchymal transformed cells. In conclusion, combinatorial ALK and PI3Kβ inhibitor treatment carries promise as a treatment forALK-rearranged NSCLC.
Combined epigenetic and metabolic inhibition blocks platinum-induced ovarian cancer stem cell enrichment
Authors: Sood Riddhi , Sriramkumar Shruthi , Muralikrishnan Vaishnavi , Xiao Sikai , Wang Weini , Hassel Christiane , Nephew Kenneth P. , O’Hagan Heather M.
Published: March 2021

High grade serous ovarian cancer (HGSOC) is the most common and aggressive type of ovarian cancer. Platinum resistance is a common occurrence in HGSOC and a main cause of tumor relapse resulting in high patient mortality rates. Recurrent OC is enriched in aldehyde dehydrogenase (ALDH)+ ovarian cancer stem cells (OCSCs), which are resistant to platinum agents. We demonstrated that acute platinum treatment induced a DNA damage-dependent decrease in BRCA1 levels. In a parallel response associated with G2/M arrest, platinum treatment also induced an increase in expression ofNAMPT, the rate limiting regulator of NAD+production from the salvage pathway, and levels of NAD+, the cofactor required for ALDH activity. Concurrent inhibition of DNA methyltransferases (DNMTs) and NAMPT synergistically abrogated the platinum-induced increase in OCSCs. Combining pharmacological inhibitors of DNMT and NAMPT with carboplatin reduced tumorigenesis and OCSC percentagein vivo. We conclude that both epigenetic and metabolic alterations lead to platinum induced OCSC enrichment, providing preclinical evidence that in the neoadjuvant setting, combining DNMT and NAMPT inhibitors with platinum has the potential to reduce OC recurrence and avert the development of platinum resistance.
Cross-platform proteomics to advance genetic prioritisation strategies
Authors: Pietzner Maik , Wheeler Eleanor , Carrasco-Zanini Julia , Kerrison Nicola D. , Oerton Erin , Koprulu Mine , Luan Jian’an , Hingorani Aroon D. , Williams Steve A. , Wareham Nicholas J. , Langenberg Claudia
Published: March 2021

Discovery of protein quantitative trait loci (pQTLs) has been enabled by affinity-based proteomic techniques and is increasingly used to guide genetically informed drug target evaluation. Large-scale proteomic data are now being created, but systematic, bidirectional assessment of platform differences is lacking, restricting clinical translation. We compared genetic, technical, and phenotypic determinants of 871 protein targets measured using both aptamer-(SomaScan® Platform v4) and antibody-based (Olink) assays in up to 10,708 individuals. Correlations coefficients for overlapping protein targets varied widely (median 0.38, IQR: 0.08-0.64). We found that 64% of pQTLs were shared across both platforms among all identified 608cis- and 1,315trans-pQTLs with sufficient power for replication, but with correlations of effect estimates being lower than previously reported (cis: 0.41,trans: 0.34). We identified technical, protein, and variant characteristics that contributed significantly to platform differences and found contradicting phenotypic associations attributable to those. We demonstrate how integrating phenomic and gene expression data improves genetic prioritisation strategies, including platform-specific pQTLs.
Buried but unsafe – defoliation depletes the underground storage organ (USO) of the mesic grassland geophyte,Hypoxis hemerocallidea
Authors: Morris Craig D.
Published: March 2021

Mesic grasslands in South Africa (> 650 mm a-1MAP) are rich in herbaceous forbs, which outnumber grass species by more than 5 to 1. Many of these forbs have underground storage units (USOs), such as thickened rootstocks, rhizomes, bulbs, or corms, that provide resources (non-structural carbohydrates, minerals, and water) enabling them to resprout after dry, frosty winters, and fire. However, despite their extensive biomass and reserves ostensibly protected underground, geophytic mesic grassland forbs can be severely depleted or extirpated by chronic trampling and grazing of their aerial parts by livestock. This study examined a possible explanation for forb demise in overgrazed grassland by investigating, in a pot trial, whether the growth of forbs and the size of their USOs are negatively affected by simulated green leaf loss. In a 2×2 factorial (clipped vs. unclipped x spring regrowth in the dark vs. light), five replicate plants ofHypoxis hemerocallidea, a common mesic grassland forb that resprouts from a corm, were subject to six severe (clipped to 80 mm) defoliations during the growing season and regrown in spring under full or restricted light to measure stored reserve contribution to regrowth. Defoliated plants were resilient to defoliation during the growing season, matching the total biomass production of unclipped plants, though cutting reduced the number of leaves by ¬60% and flowers by almost 85%. Spring regrowth on stored reserves equalled that from reserves plus concurrent photosynthesis, indicating the value of USOs for regrowth. However, there was a marked carry-over effect of previous season defoliation, resulting in a one-third reduction in shoot growth and 40% fewer inflorescence in spring. Crucially, corm mass was more than halved by clipping. Above-ground spring growth was linearly related to corm mass. It was concluded that buried stored reserves are not protected by recurrent disturbance to aerial plant parts and that continued diminishment of USOs under chronic disturbance by overgrazing or frequent mowing would weaken and likely eventually kill plants, reducing forb species richness. Lenient management by infrequent summer mowing or grazing at moderate stocking rates combined with periodic rotational full season resting and dormant-season burning is recommend to maintain the USOs and vigour of forbs in mesic grassland.
An fMRI-based brain marker predicts individual differences in delay discounting
Authors: Koban Leonie , Lee Sangil , Schelski Daniela S. , Simon Marie-Christine , Lerman Caryn , Weber Bernd , Kable Joseph W. , Plassmann Hilke
Published: March 2021

Individual differences in impatience—how much we discount future compared to immediate rewards—are associated with general life outcomes and related to substance use, psychiatric diseases, and obesity. Here, we use machine-learning on fMRI activity during an intertemporal choice task to develop a brain marker of individual differences in delay discounting. Study 1 (N=110) was used as a training and cross-validation set, resulting in significant prediction accuracy (r= 0.49) and suggesting an interplay between brain regions associated with affect, value, and cognitive control. The validity of the brain marker was replicated in an independent data set (Study 2, N=145,r= 0.45). In both studies, responses of the marker significantly differed between overweight and lean individuals. This pattern is a first step towards a generalizable neuromarker of delay discounting and a potentially transdiagnostic phenotype, which can be used as a brain-based target measure in future studies.
Type II alveolar cells with constitutive expression of MHCII and limited antigen presentation capacity contribute to improved respiratory viral disease outcomes
Authors: Toulmin Sushila A. , Bhadiadra Chaitali , Paris Andrew J. , Lin Jeffrey H. , Katzen Jeremy , Basil Maria C. , Morrisey Edward E. , Worthen G. Scott , Eisenlohr Laurence C.
Published: March 2021

Type II alveolar cells (AT2s) are critical for basic respiratory homeostasis and tissue repair after lung injury. Prior studies indicate that AT2s also express major histocompatibility complex II (MHCII) molecules, but how MHCII expression by AT2s is regulated and how it contributes to host defense remain unclear. Here we show that AT2s express high levels of MHCII independent of conventional inflammatory stimuli, and that selective loss of MHCII from AT2s in mice results in the worsening of respiratory virus disease following influenza and Sendai virus infections. We also find that AT2s exhibit MHCII presentation capacity that is substantially limited in comparison to professional antigen presenting cells. The combination of constitutive MHCII expression and restrained presentation may position AT2s to contribute to lung adaptive immune responses in a measured fashion, without over-amplifying damaging inflammation.
Agricultural pressures impair trophic link between aquatic microorganisms and invertebrates
Authors: Blom Rody , Barmentlo S. Henrik , Schrama Maarten J.J. , Hunting Ellard R.
Published: March 2021

Decadal declines in aquatic ecosystem health prompted monitoring efforts and studies on effects of human practices on aquatic biodiversity, yet a consideration of ecological processes and trophic linkages is increasingly required to develop an in-depth understanding of aquatic food webs and its vulnerability to human activities. Here, we test in laboratory incubations using natural organic matter whether agricultural practices have an effect on two interacting ecological processes (i.e., decomposition and invertebrate growth) as the relevant temporal components of the trophic linkage between aquatic microbial communities and aquatic invertebrates. We further assess whether these altered trophic interactions are visible on ecologically relevant scales. We observed clear patterns in agricultural constraints on microbial decomposition, which coincided with reduced invertebrate growth and an unexpected increase in invertebrate consumption of organic matter. Similar differences in invertebrate length depending on land use were observed in our field survey, thereby providing important clues on the relevance and vulnerability of interdependent processes that can serve to improve future forays in monitoring ecosystem health.
Behavioral context shapes vocal sequences in two anuran species with different repertoire sizes
Authors: Bhat Ananda Shikhara , Sane Varun Aniruddha , S Seshadri K , Krishnan Anand
Published: March 2021

Acoustic signals in animals serve to convey context-dependent information to receivers. Birds and mammals combine diverse sounds into complex sequences to communicate, but these sequences largely remain understudied in other taxa. Anuran vocalizations are a prominent feature of their life history, and function in defense of territories and to attract mates. However, despite the spectacular diversity of anurans in tropical regions of the world, vocal diversity and communication strategies remain relatively poorly studied. Specifically, studies of vocal sequences and context-dependent vocal patterns in frogs remain few. Here, we investigated the context-dependent vocal repertoire and the use of vocal sequences by two anuran species belonging to different lineages, both endemic to the hyper-diverse Western Ghats of India. By recording vocal sequences both when frogs were alone and in the presence of a territorial rival, we present evidence that both species modify their vocal repertoire according to context. Specifically, one species appends notes to generate more complex sequences, whereas the other shifts to different note types, resulting in different sequences for different contexts. Thus, despite differences in repertoire size, both frog species are capable of adjusting the temporal sequence of vocalizations to communicate in different contexts. This study highlights the need for further studies of insular frogs, to understand how diversification across these continental islands has influenced the evolution of vocal repertoires, vocal sequence patterns and communication systems.

Lay Summary

Animals employ complex sequences of acoustic signals to communicate in diverse behavioral contexts. Here, we demonstrate that two frog species with different vocal repertoires both modify the sequence of note emissions in the presence of a territorial rival. These patterns demonstrate that anurans are capable of complex shifts in the patterns of their vocalization, to communicate different messages to different receivers. Our findings demonstrate the value of studying behavioral diversity in tropical regions.
Transcriptomic analysis reveals that severity of infectious bursal disease in White Leghorn inbred chicken lines is associated with greater bursal inflammationin vivoand more rapid induction of pro-inflammatory responses in primary bursal cells stimulatedex vivo
Authors: Asfor Amin S. , Nazki Salik , Reddy Vishwanatha RAP , Campbell Elle , Dulwich Katherine L. , Giotis Efstathios S. , Skinner Michael A. , Broadbent Andrew J.
Published: March 2021

In order to better understand differences in the outcome of infectious bursal disease virus (IBDV) infection, we inoculated a very virulent (vv) strain into White Leghorn chickens of inbred line W that was previously reported to experience over 24% flock mortality, and three inbred lines (15I, C.B4 and 0) that were previously reported to display no mortality. Within each experimental group, some individuals experienced more severe disease than others but line 15I birds experienced milder disease based on average clinical scores, percentage of birds with gross pathology, average bursal lesion scores and average peak bursal virus titre. RNA-Seq analysis revealed that more severe disease in line W was associated with significant up-regulation of pathways involved in inflammation, cytoskeletal regulation by Rho GTPases, nicotinic acetylcholine receptor signaling, and Wnt signaling in the bursa compared to line 15I. Primary bursal cell populations isolated from uninfected line W birds contained a significantly greater percentage of KUL01+ macrophages than cells isolated from line 15I birds (p<0.01) and, when stimulatedex vivowith LPS, showed more rapid up-regulation of pro-inflammatory gene expression than those from line 15I birds. We hypothesize that a more rapid induction of pro-inflammatory cytokine responses in bursal cells following IBDV infection leads to more severe disease in line W birds than in line 15I.
Momelotinib is a highly potent inhibitor of FLT3-mutant AML
Authors: Azhar Mohammad , Kincaid Zachary , Kesarwani Meenu , Latif Tahir , Starczynowski Daniel , Azam Mohammad
Published: March 2021

Kinase activating mutation in FLT3 is the most frequent genetic lesion associated with poor prognosis in acute myeloid leukemia (AML). Therapeutic response to FLT3 tyrosine kinase inhibitor (TKI) therapy is dismal, and many patients relapse even after allogenic stem cell transplantation. Despite the introduction of more selective FLT3 inhibitors, remissions are short-lived, and patients show progressive disease after an initial response. Acquisition of resistance-conferring genetic mutations and growth factor signaling are two principal mechanisms that drive relapse. FLT3 inhibitors targeting both escape mechanisms could lead to a more profound and lasting clinical responses. Here we show that the JAK2 inhibitor, momelotinib, is an equipotent type-1 FLT3 inhibitor. Momelotinib showed potent inhibitory activity on both mouse and human cells expressing FLT3-ITD, including clinically relevant resistant mutations within the activation loop at residues, D835, D839, and Y842. Additionally, momelotinib efficiently suppressed the resistance mediated by FLT3 ligand (FL) and hematopoietic cytokine activated JAK2 signaling. Interestingly, unlike gilteritinib, momelotinib inhibits the expression of MYC in leukemic cells. Consequently, concomitant inhibition of FLT3 and downregulation of MYC by momelotinib treatment showed better efficacy in suppressing the leukemia in a preclinical murine model of AML. Altogether, these data provide evidence that momelotinib is an effective type-1 dual JAK2/FLT3 inhibitor and may offer an alternative to gilteritinib. Its ability to impede the resistance conferred by growth factor signaling and activation loop mutants suggests that momelotinib treatment could provide a deeper and durable response; thus, warrants its clinical evaluation.

Key points

Momelotinib shows high efficacy against FLT3 mutated AML cells including quizartinib-resistant activation loop variants.

Momelotinib effectively suppresses intrinsic resistance conferred by FLT3 ligand and hematopoietic cytokines (GM-CSF and IL3).
A Circuit for Secretion-coupled Cellular Autonomy in Multicellular Eukaryotes
Authors: Qiao Lingxia , Sinha Saptarshi , El-Hafeez Amer Ali Abd , Lo I-Chung , Midde Krishna K. , Ngo Tony , Aznar Nicolas , Lopez-Sanchez Inmaculada , Gupta Vijay , Farquhar Marilyn G. , Rangamani Padmini , Ghosh Pradipta
Published: March 2021

Cancers represent complex autonomous systems, displaying self-sufficiency in growth signaling. Autonomous growth is fueled by a cancer cell’s ability to ‘secrete-and-sense’ growth factors: a poorly understood phenomenon. Using an integrated systems and experimental approach, here we dissect the impact of a feedback-coupled GTPase circuit within the secretory pathway that imparts secretion-coupled autonomy. The circuit is assembled when the Ras-superfamily monomeric GTPase Arf1, and the heterotrimeric GTPase Giαβγ and their corresponding GAPs and GEFs are coupled by GIV/Girdin, a protein that is known to fuel aggressive traits in diverse cancers. One forward and two key negative feedback loops within the circuit create closed-loop control (CLC), allow the two GTPases to coregulate each other, and convert the expected switch-like behavior of Arf1-dependent secretion into an unexpected dose response alignment behavior of sensing and secretion. Such behavior translates into cell survival that is self-sustained by stimulus-proportionate secretion. Proteomic studies and protein-protein interaction network analyses pinpoint growth factors (e.g., the epidermal growth factor; EGF) as a key stimuli for such self-sustenance. Findings highlight how enhanced coupling of two biological switches in cancer cells is critical for multiscale feedback control to achieve secretion-coupled autonomy of growth factors.

SYNOPSIS IMAGE

STANDFIRST TEXT

This work defines the inner workings of a Golgi-localized molecular circuitry comprised of coupled GTPases, which empowers cells to achieve self-sufficiency in growth factor signaling by creating a secrete-and-sense autocrine loop.

HIGHLIGHTS/MAIN FINDINGS

Modeling and experimental approaches were used to dissect a coupled GTPase circuit.

Coupling enables closed loop feedback and mutual control of GTPases.

Coupling generates dose response alignment behavior of sensing and secretion of growth factors.

Coupling is critical for multiscale feedback control to achieve secretion-coupled autonomy.
Reverse Transcriptase Real-Time PCR Assay for the Rapid Enumeration of LiveCandida aurisfrom the Healthcare Environment
Authors: Freitas Bryanna Lexus , Leach Lynn , Chaturvedi Vishnu , Chaturvedi Sudha
Published: March 2021

Ongoing healthcare-associated outbreaks of multidrug-resistant yeastCandida aurishave prompted development of several rapid DNA-based molecular diagnostic tests. These tests do not distinguish between live and deadC. auriscells, limiting their use for environmental surveillance and containment efforts. We addressed this critical gap by developing a reverse transcriptase (RT) real-time PCR assay for rapid detection of liveC. aurisin healthcare environments. The assay targets the internal transcribed spacer 2 (ITS2) cDNA ofC. auris, amplified by obtaining pure RNA followed by reverse transcription and real-time PCR assay. The assay was highly sensitive, with the detection limit of ten colony-forming units (CFU) per RT real-time PCR reaction. InC. aurisviability studies, ITS2 cDNA was detectable in heat- and ethanol-killedC. auriscells, but not bleach-killed cells. Validation studies showed no cycle threshold (Ct) values were obtained from samples on a sponge matrix spiked with either deadC. auris(105/ml) or otherCandidaspecies (105/ml), while most environmental samples spiked with 102to 105CFU of liveC. aurisyielded positive Ct values. Finally, 33 environmental samples positive forC. aurisDNA but negative by culture were all negative by RT real-time PCR assay, confirming concordance between culture and the assay. The RT real-time PCR assay appears highly reproducible, robust, and specific for detecting liveC. aurisfrom environmental samples, and could be an invaluable tool in surveillance efforts to control the spread of liveC. aurisin healthcare environments.
Phospholipids stabilize binding of pituitary adenylate cyclase-activating peptide to vasoactive intestinal polypeptide receptor
Authors: Thomas Nidhin , Agrawal Ashutosh
Published: March 2021

Vasoactive intestinal polypeptide receptor (VIP1R) is a class B G-protein coupled receptor (GPCR) that is widely distributed throughout the central nervous system, T-lymphocytes, and peripheral tissues of organs like lungs and liver. Critical functions of these receptors render them potential pharmacological targets for the treatment of a broad spectrum of inflammatory and neurodegenerative diseases. Here we use atomistic studies to show that phospholipids can act as potent regulators of peptide binding on to the receptor. We simulated the binding of neuropeptide pituitary adenylate cyclase-activating peptide (PACAP27) into the transmembrane bundle of the receptor. The simulations reveal two lipid binding sites on the peptidic ligand for the negatively charged phosphodiester of phospholipids in the extracellular leaflet which lower the peptide-receptor binding free energy by ~8kBT. We further simulated the effect of anionic lipids phosphatidylinositol-4,5-bisphosphate (PIP2). These lipids show much stronger interaction, lowering the peptide-receptor binding energy by an additional ~7kBTcompared to POPC lipids. These findings suggest that lipids can play an active role in catalyzing peptide-receptor binding and activating vasoactive intestinal polypeptide receptors.
Does the Zebra Finch Mating Song Circuit Use Spike Times Efficiently?
Authors: Nicola Wilten , Newton Thomas Robert , Clopath Claudia
Published: March 2021

Precise and reliable spike times are thought to subserve multiple possible functions, including improving the accuracy of encoding stimuli or behaviours relative to other coding schemes. Indeed, repeating sequences of spikes with sub-millisecond precision exist in nature, such as the synfire chain of spikes in area HVC of the zebra-finch mating-song circuit. Here, we analyzed what impact precise and reliable spikes have on the encoding accuracy for both the zebra-finch and more generic neural circuits using computational modelling. Our results show that neural circuits can use precisely timed spikes to encode signals with a higher-order accuracy than a conventional rate code. Circuits with precisely timed and reliably emitted spikes increase their encoding accuracy linearly with network size, which is the hallmark signature of an efficient code. This qualitatively differs from circuits that employ a rate code which increase their encoding accuracy with the square-root of network size. However, this improved scaling is dependent on the spikes becoming more accurate and more reliable with larger networks. Finally, we discuss how to test this scaling relationship in the zebra mating song circuit using both neural data and song-spectrogram-based recordings while taking advantage of the natural fluctuation in HVC network size due to neurogenesis. The zebra-finch mating-song circuit may represent the most likely candidate system for the use of spike-timing-based, efficient coding strategies in nature.
Limited effects of m6A modification on mRNA partitioning into stress granules
Authors: Khong Anthony , Matheny Tyler , Huynh Thao Ngoc , Babl Vincent , Parker Roy
Published: March 2021

Recent studies have argued that the m6A modification of mRNAs promotes mRNA recruitment to stress granules through the interaction with YTHDF proteins (Anders et al., 2018; Ries et al., 2019). However, mRNAs that contain multiple m6A modified sites partition similarly into stress granules in both wild-type and m6A-deficient cells by single-molecule FISH suggesting m6A modifications play a minor role in mRNA partitioning into stress granules. Moreover, multiple linear regression analysis suggests m6A modification plays a minimal role in stress granule recruitment. Finally, the artificial tethering of 25 YTHDF proteins on reporter mRNAs leads to only a modest increase in mRNA partitioning to stress granules. These results indicate m6A modification makes a small, but measurable, contribution to recruiting specific mRNAs to stress granules.
Fibrinogen and Complement Factor H are promising CSF protein biomarker(s) for Parkinson’s disease with cognitive impairment- A Proteomics and ELISA based study
Authors: Naskar Aditi , Stezin Albert , Dharmappa Arpitha , Hegde Shantala , Philip Mariamma , Kamble Nitish , Saini Jitender , Sandhya K , Tatu Utpal , Yadav Ravi , Pal Pramod Kumar , Alladi Phalguni Anand
Published: March 2021

Cognitive impairment is a debilitating non-motor symptom of Parkinson’s disease (PD). The diagnosis of PD with cognitive impairment (PDCI) is essentially through clinical and neuropsychological examinations. There is an emerging need to identify biomarker(s) to foresee cognitive decline in PD patients, at an early stage. We performed label-free unbiased nontargeted proteomics (Q-TOF LC/MS-MS) in CSF of non-neurological control (NNC); PDCI; PD and normal pressure hydrocephalus (NPH), followed by targeted ELISA for validation. The diagnosis was confirmed by neuropsychological and MRI assessments prior to CSF collection. Of the 282 proteins identified by mass spectrometry, 42 were differentially altered in PD, PDCI and NPH. Further, 28 proteins were altered in PDCI and 25 in NPH. An interesting overlap of certain proteins was noted both in PDCI and NPH. Five significantly upregulated proteins in PDCI were fibrinogen, gelsolin, complement factor-H, apolipoprotein A-IV and apolipoprotein A-I. Whereas carnosine dipeptidase 1, carboxypeptidase E, dickkpof 3 and secretogranin 3 precursor proteins were down-regulated. NPH also had few uniquely altered proteins viz. insulin-like growth factor-binding protein, ceruloplasmin, α-1 antitrypsin, VGF nerve growth factor, neural cell adhesion molecule L1 like protein. Interestingly, the ELISA-derived protein concentrations correlated well with the neuropsychological scores of certain cognitive domains. Executive function was affected both in PDCI and NPH. In PD, Wisconsin card sorting test (WCST) percentile correlated positively with ApoA-IV and negatively with the ratio of ApoAI: ApoA-IV. Thus assessment of a battery of proteins like fibrinogen-α-chain, CFAH and ApoAI: ApoA-IV ratio alongside neuropsychological could be reliable biomarkers to distinguish PDCI and NPH.
Patterns of brain asymmetry associated with polygenic risks for autism and schizophrenia implicate language and executive functions but not brain masculinization
Authors: Sha Zhiqiang , Schijven Dick , Francks Clyde
Published: March 2021

Autism spectrum disorder (ASD) and schizophrenia have been conceived as partly opposing disorders in terms of systemizing versus empathizing cognitive styles, with resemblances to male versus female average sex differences. Left-right asymmetry of the brain is an important aspect of its organization that shows average differences between the sexes, and can be altered in both ASD and schizophrenia. Here we mapped multivariate associations of polygenic risk scores (PRS) for ASD and schizophrenia with asymmetries of regional cerebral cortical surface area, thickness and subcortical volume measures in 32,256 participants from the UK Biobank. PRS for the two disorders were positively correlated (r=0.08, p=7.13×10−50), and both were higher in females compared to males, consistent with biased participation against higher-risk males. Each PRS was associated with multivariate brain asymmetry after adjusting for sex, ASD PRS r=0.03, p=2.17×10−9, schizophrenia PRS r=0.04, p=2.61×10−11, but the multivariate patterns were mostly distinct for the two PRS, and neither resembled average sex differences. Annotation based on meta-analyzed functional imaging data showed that both PRS were associated with asymmetries of regions important for language and executive functions, consistent with behavioural associations that arose in phenome-wide association analysis. Overall, the results indicate that distinct patterns of subtly altered brain asymmetry may be functionally relevant manifestations of polygenic risk for ASD and schizophrenia, but do not support brain masculinization or feminization in their etiologies.
Ion dynamics at the energy-deprived tripartite synapse
Authors: Kalia Manu , Meijer Hil G.E. , van Gils Stephan A. , van Putten Michel J.A.M. , Rose Christine R.
Published: March 2021

The anatomical and functional organization of neurons and astrocytes at ‘tripartite synapses’ is essential for reliable neurotransmission, which critically depends on ATP. In low energy conditions, synaptic transmission fails, accompanied by a breakdown of ion gradients, changes in membrane potentials and cell swelling. The resulting cellular damage and cell death are causal to the often devastating consequences of an ischemic stroke. The severity of ischemic damage depends on the age and the brain region in which a stroke occurs, but the reasons for this differential vulnerability are far from understood. In the present study, we address this question by developing a comprehensive biophysical model of a glutamatergic synapse to identify key determinants of synaptic failure during energy deprivation. Our model is based on fundamental biophysical principles, includes dynamics of the most relevant ions, i.e., Na+, K+, Ca2+, Cl−and glutamate, and is calibrated with experimental data. It confirms the critical role of the Na+/K+-ATPase in maintaining ion gradients, membrane potentials and cell volumes. Our simulations demonstrate that the system exhibits two stable states, one physiological and one pathological. During energy deprivation, the physiological state may disappear, forcing a transit to the pathological state, which can be reverted when blocking voltage-gated Na+and K+channels. Our model predicts that the transition to the pathological state is favoured if the extracellular space fraction is small. A reduction in the extracellular space volume fraction, as, e.g. observed with ageing, will thus promote the brain’s susceptibility to ischemic damage. Our work provides new insights into the brain’s ability to recover from energy deprivation, with translational relevance for diagnosis and treatment of ischemic strokes.

Author summary

The brain consumes energy to keep ion concentrations at normal working conditions. In the case of energy deprivation (ED), e.g., during a stroke, synaptic communication fails first. Inspired by our recent experimental work on ED, we formulated a novel computational model to explore initial events during ED. Our model reproduces time courses for several ions from different experimental data. In some cases, the system returns to baseline upon restoring energy supply. In others, we observe that neurons and astrocytes cannot recover accompanied by cell swelling. There is a threshold depending on the depth and duration of ATP depletion differentiating these cases. Also, smaller extracellular spaces hamper recovery more. This result may explain clinical observations of increased vulnerability to stroke as the size of the extracellular space shrinks with ageing.
Temperature-gradient analyzers for non-resonant inelastic X-ray scattering
Authors: Ishikawa Daisuke , Baron Alfred Q. R.
Published: March 2021

The detailed fabrication and performance of the temperature-gradient analyzers that were simulated by Ishikawa & Baron [(2010).J. Synchrotron Rad.17, 12–24] are described and extended to include both quadratic and 2D gradients. The application of a temperature gradient compensates for geometric contributions to the energy resolution while allowing collection of a large solid angle, ∼50 mrad × 50 mrad, of scattered radiation. In particular, when operating relatively close to backscattering, π/2 − θB= 1.58 mrad, the application of a gradient of 1.32 K per 80 mm improves the measured total resolution from 60 to 25 meV at the full width at half-maximum, while when operating further from backscattering, π/2 − θB= 6.56 mrad, improvement from 330 to 32 meV is observed using a combination of a gradient of 6.2 K per 80 mm and dispersion compensation with a position-sensitive detector. In both cases, the operating energy was 15.8 keV and the incident bandwidth was 22 meV. Notably, the use of a temperature gradient allows a relatively large clearance at the sample, permitting installation of more complicated sample environments.
High-order derivative fusion estimation of rotorcraft angular rate
Authors: Liu Changwu , Wang Haowen , Jiang Chen
Published: March 2021

Purpose

The paper aims at developing a novel algorithm to estimate high-order derivatives of rotorcraft angular rates to break the contradiction between bandwidth and filtering performance because high-order derivatives of angular rates are crucial to rotorcraft control. Traditional causal estimation algorithms such as digital differential filtering or various tracking differentiators cannot balance phase-lead angle loss and high-frequency attenuation performance of the estimated differentials under the circumstance of strong vibration from the rotor system and the rather low update rate of angular rates.

Design/methodology/approach

The algorithm, capable of estimating angular rate derivatives to maximal second order, fuses multiple attitude signal sources through a first-proposed randomized angular motion maneuvering model independent of platform dynamics with observations generated by cascaded tracking differentiators.

Findings

The maneuvering flight test on 5-kg-level helicopter and the ferry flight test on 230-kg-level helicopter prove such algorithm is feasible to generate higher signal to noise ratio derivative estimation of angular rates than traditional differentiators in regular flight states with enough bandwidth for flight control.

Research limitations/implications

The decrease of update rate of input attitude signals will weaken the bandwidth performance of the algorithm and higher sampling rate setting is recommended.

Practical implications

Rotorcraft flight control researchers and engineers would benefit from the estimation method when implementing flight control laws requiring angular rate derivatives.

Originality/value

A purely kinematic randomized angular motion model for flight vehicle is first established, combining rigid-body Euler kinematics. Such fusion algorithm with observations generated by cascaded tracking differentiators to estimate angular rate derivatives is first proposed, realized and flight tested.
Consumer brand engagement in the US–China trade war
Authors: Lee Yi Hsuan , Wei Chiou-Fong , Lee Bruce C. Y. , Cheng Ya-Yun , Chen Yao
Published: March 2021

Purpose

This study examines whether consumer brand engagement (CBE) can mitigate the negative effects of economic animosity (EA) on purchase intention (PI) and strengthen the positive effect of country-of-origin (COO) on PI.

Design/methodology/approach

Using questionnaires distributed to 372 young Chinese adults, the study collected PI data for US products in the Chinese market. Partial least square structural equation modeling was adopted.

Findings

This study found a positive relationship between COO and CBE and a negative relationship between EA and CBE. CBE exhibits a partial mediating effect in the relationship between COO and PI and a full suppression effect on EA toward PI.

Research limitations/implications

This research is limited to China; future research could extend this framework to the United States.

Practical implications

This study contributes to relationship marketing knowledge. Furthermore, it provides new tools for multinational corporations to deploy their marketing strategies and avoid negative consequences stemming from the EA effect in the Chinese market following the US–China trade war.

Originality/value

This study is the first to extend COO and EA research to CBE discipline.
A COVID-19 contextual study of customers’ mistreatment and counterproductive work behavior at coffee cafés
Authors: Ahmed Ishfaq , Islam Talat , Ahmad Saima , Kaleem Ahmad
Published: March 2021

Purpose

The issue of customer mistreatment in food and retail sectors has come under the spotlight during the COVID-19 crisis. The purpose of this paper is to examine the problem in the COVID-19 pandemic context and study its implications for employee counterproductive behavior in the workplace. Specifically, this study aims to investigate the relationship between customer mistreatment and employee counterproductive behavior by considering the mediating role of cognitive rumination and moderating role of servant leadership at coffee cafés that operated during the COVID-19 smart lockdown period.

Design/methodology/approach

Structured questionnaires were distributed to 479 frontline staff working at cafés and coffee shops located in two large cities of Pakistan. The questionnaire data were analyzed by using bootstrapped regression procedures to determine how the investigated variables influenced counterproductive work behavior during the pandemic.

Findings

The findings revealed a positive influence of customer mistreatment on counterproductive work behavior both directly as well as indirectly in the presence of employee rumination as a mediator. Furthermore, the presence of servant leadership at cafés and coffee shops was found to moderate the impact of customer mistreatment during the pandemic.

Originality/value

The study offers a novel insight into the relationships between mistreatment by customers, counterproductive work behavior, employee rumination and servant leadership in the COVID-19 pandemic context, hitherto unexplored.