bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid gene evolution in an ancient post-transcriptional and translational regulatory system compensates for meiotic X chromosomal inactivation
Authors: Xia Shengqian , Ventura Iuri M. , Blaha Andreas , Sgromo Annamaria , Han Shuaibo , Izaurralde Elisa , Long Manyuan 
Published: August 2021

SUMMARYIt is conventionally assumed that conserved pathways evolve slowly with little participation of gene evolution. Nevertheless, it has been recently observed that young genes can take over fundamental functions in essential biological processes, for example, development and reproduction. It is unclear how newly duplicated genes are integrated into ancestral networks and reshape the conserved pathways of important functions. Here, we investigated origination and function of two autosomal genes that evolved recently in Drosophila: Poseidon and Zeus, which were created by RNA-based duplications from the X-linked CAF40, a subunit of the conserved CCR4-NOT deadenylase complex involved in post-transcriptional and translational regulation. Knockdown and knockout assays show that the two genes quickly evolved critically important functions in viability and male fertility. Moreover, our transcriptome analysis demonstrates that the three genes have a broad and distinct effect in the expression of hundreds of genes, with almost half of the differentially expressed genes being perturbed exclusively by one paralog, but not the others. Co-immunoprecipitation and tethering assays show that the CAF40 paralog Poseidon maintains the ability to interact with the CCR4-NOT deadenylase complex and might act in post-transcriptional mRNA regulation. The rapid gene evolution in the ancient post-transcriptional and translational regulatory system may be driven by evolution of sex chromosomes to compensate for the meiotic X chromosomal inactivation (MXCI) in Drosophila.
Expression variations in Ectodysplasin-A gene (eda) may contribute to morphological divergence of scales in Haplochromine cichlids
Authors: Wagner Maximilian , Bračun Sandra , Duenser Anna , Sturmbauer Christian , Gessl Wolfgang , Ahi Ehsan Pashay 
Published: August 2021

AbstractBackgroundElasmoid scales are one of the most common dermal appendages and can be found in almost all species of bony fish differing greatly in their shape. Whilst the genetic underpinnings behind elasmoid scale development have been investigated, not much is known about the mechanisms involved in the shaping of scales. To investigate the links between gene expression differences and morphological divergence, we inferred shape variation of scales from two different areas of the body (anterior and posterior) stemming from ten haplochromine cichlid species from different origins (Lake Tanganyika, Lake Malawi, Lake Victoria and riverine). Additionally, we investigated transcriptional differences of a set of genes known to be involved in scale development and morphogenesis in fish.ResultsWe found that scales from the anterior and posterior part of the body strongly differ in their overall shape, and a separate look on scales from each body part revealed similar trajectories of shape differences considering the lake origin of single investigated species. Above all, nine as well as 11 out of 16 target genes showed expression differences between the lakes for the anterior and posterior dataset, respectively. Whereas in posterior scales four genes (dlx5, eda, rankl and shh) revealed significant correlations between expression and morphological differentiation, in anterior scales only one gene (eda) showed such a correlation. Furthermore, eda displayed the most significant expression difference between species of Lake Tanganyika and species of the other two younger lakes. Finally, we found genetic differences in downstream regions of eda gene (e.g. in the eda-tnfsf13b inter-genic region) that are associated with observed expression differences. This is reminiscent of a genetic difference in the eda-tnfsf13b inter-genic region which leads to gain or loss of armour plates in stickleback.ConclusionThese findings provide evidence for cross-species transcriptional differences of an important morphogenetic factor, eda, which is involved in formation of ectodermal appendages. These expression differences appeared to be associated with morphological differences observed in the scales of haplochromine cichlids indicating potential role of eda mediated signal in divergent scale morphogenesis in fish.
C. elegansenteric motor neurons fire synchronized action potentials underlying the defecation motor program
Authors: Jiang Jingyuan , Su Yifan , Zhang Ruilin , Li Haiwen , Tao Louis , Liu Qiang 
Published: August 2021

AbstractTheC. elegansnervous system was thought to be strictly analog, constituted solely by graded neurons. We recently discovered neuronal action potentials in the sensory neuron AWA; however, the extent to which theC. elegansnervous system relies on analog or digital neural signaling and coding is unclear. Here we report that the enteric motor neurons AVL and DVB fire all-or-none calcium-mediated action potentials that play essential roles in the rhythmic defecation behavior inC. elegans. Both AVL and DVB synchronously fire giant action potentials to faithfully execute all-or-none expulsion following the intestinal pacemaker. AVL fires unusual compound action potentials with each positive calcium-mediated spike followed by a potassium-mediated negative spike. The depolarizing calcium spikes in AVL are mediated by a CaV2 calcium channel UNC-2, while the negative potassium spikes are mediated by a repolarization-activated potassium channel EXP-2. Whole-body behavior tracking and simultaneous neural imaging in free-moving animals suggest that action potentials initiated in AVL in the head propagate along its axon to the tail and activate DVB through the INX-1 gap junction. Synchronized action potential spikes between AVL and DVB, as well as the negative spike and long-lasting afterhyperpolarization in AVL, play an important function in executing expulsion behavior. This work provides the first evidence that in addition to sensory coding,C. elegansmotor neurons also use digital coding scheme to perform specific functions including long-distance communication and temporal synchronization, suggesting further, unforeseen electrophysiological diversity remains to be discovered in theC. elegansnervous system.
The Lambda variant of SARS-CoV-2 has a better chance than the Delta variant to escape vaccines
Authors: Liu Haolin , Wei Pengcheng , Zhang Qianqian , Aviszus Katja , Linderberger Jared , Yang John , Liu Junfeng , Chen Zhongzhou , Waheed Hassan , Reynoso Lyndon , Downey Gregory P. , Frankel Stephen K. , Kappler John , Marrack Philippa , Zhang Gongyi 
Published: August 2021

SummaryThe newly emerging variants of SARS-CoV-2 from India (Delta variant) and South America (Lambda variant) have led to a higher infection rate of either vaccinated or unvaccinated people. We found that sera from Pfizer-BioNTech vaccine remain high reactivity toward the receptor binding domain (RBD) of Delta variant while it drops dramatically toward that of Lambda variant. Interestingly, the overall titer of antibodies of Pfizer-BioNTech vaccinated individuals drops 3-fold after 6 months, which could be one of major reasons for breakthrough infections, emphasizing the importance of potential third boost shot. While a therapeutic antibody, Bamlanivimab, decreases binding affinity to Delta variant by ~20 fold, it fully lost binding to Lambda variant. Structural modeling of complexes of RBD with human receptor, Angiotensin Converting Enzyme 2 (ACE2), and Bamlanivimab suggest the potential basis of the change of binding. The data suggest possible danger and a potential surge of Lambda variant in near future.
The Specious Art of Single-Cell Genomics
Authors: Chari Tara , Pachter Lior 
Published: August 2021

AbstractDimensionality reduction is standard practice for filtering noise and identifying relevant features in large-scale data analyses. In biology, single-cell genomics studies typically begin with reduction to two or three dimensions to produce ‘all-in-one’ visuals of the data that are amenable to the human eye, and these are subsequently used for qualitative and quantitative exploratory analysis. However, there is little theoretical support for this practice, and we show that extreme dimension reduction, from hundreds or thousands of dimensions to two, inevitably induces significant distortion of high-dimensional datasets. We therefore examine the practical implications of low-dimensional embedding of single-cell data, and find that extensive distortions and inconsistent practices make such embeddings counter-productive for exploratory, biological analyses. In lieu of this, we discuss alternative approaches for conducting targeted embedding and feature exploration, to enable hypothesis-driven biological discovery.
The PH/MyTH4/FERM molecule MAX-1 inhibits UNC-5 activity in regulation of VD growth cone protrusion in Caenorhabditis elegans
Authors: Mahadik Snehal S. , Lundquist Erik A. 
Published: August 2021

AbstractUNC-6/Netrin is a secreted conserved guidance cue that regulates dorsal-ventral axon guidance of C. elegans and in the vertebral spinal cord. In the polarity/protrusion model of VD growth cone guidance away from ventrally-expressed UNC-6 (repulsion), UNC-6 first polarizes the growth cone via the UNC-5 receptor such that filopodial protrusions are biased dorsally. UNC-6 then regulates a balance of protrusion in the growth cone based upon this polarity. UNC-5 inhibits protrusion ventrally, and the UNC-6 receptor UNC-40/DCC stimulates protrusion dorsally, resulting in net dorsal growth cone outgrowth. UNC-5 inhibits protrusion through the flavin monooxygenases FMO-1, 4, and 5 and possible actin destabilization, and inhibits pro-protrusive microtubule entry into the growth cone utilizing UNC-33/CRMP. The PH/MyTH4/FERM myosin-like protein was previously shown to act with UNC-5 in VD axon guidance utilizing axon guidance endpoint analysis. Here, we analyzed the effects of MAX-1 on VD growth cone morphology during outgrowth. We found that max-1 mutant growth cones were smaller and less protrusive than wild-type, the opposite of the unc-5 mutant phenotype. Furthermore, genetic interactions suggest that MAX-1 might normally inhibit UNC-5 activity, such that in a max-1 mutant growth cone, UNC-5 is overactive. Our results, combined with previous studies suggesting that MAX-1 might regulate UNC-5 levels in the cell or plasma membrane localization, suggest that MAX-1 attenuates UNC-5 signaling by regulating UNC-5 stability or trafficking. In summary, in the context of growth cone protrusion, MAX-1 inhibits UNC-5, demonstrating the mechanistic insight that can be gained by analyzing growth cones during outgrowth in addition to axon guidance endpoint analysis.
Nontypeable Haemophilus influenzae redox recycling of protein thiols promotes resistance to oxidative killing and bacterial survival in biofilms in a smoke related infection model
Authors: Hunt Benjamin C. , Xu Xin , Gaggar Amit , Swords W. Edward 
Published: August 2021

AbstractSmoke exposure is a risk factor for community acquired pneumonia, which is typically caused by host adapted opportunists like nontypeable Haemophilus influenzae (NTHi). Genomic analyses of NTHi revealed homologs of enzymes involved in thiol metabolism, which can have key roles in oxidant resistance. Using a clinical NTHi isolate (NTHi 7P49H1), we generated isogenic mutant bacterial strains in which homologs of glutathione reductase (NTHI 0251), thiol peroxidase (NTHI 0361), thiol peroxidase (NTHI 0907), thioredoxin reductase (NTHI 1327) and glutaredoxin/peroxiredoxin (NTHI 0705) were inactivated. Bacterial protein analyses revealed significant increases in protein oxidation after oxidative stress for all the mutant strains. Similarly, each of these mutants were less resistant to oxidative killing compared with the parental strain; these phenotypes were reversed by genetic complementation. Quantitative confocal analysis of biofilms showed reducted biofilm thickness and density, and significant sensitization of bacteria within the biofilm structure to oxidative killing for thiol mutant strains. Smoke-exposed mice infected with NTHi 7P49H1 showed significantly increased lung bacterial load, as compared to control mice. Immunofluorescent staining of lung tissues showed NTHi communities on the lung mucosa, interspersed with host neutrophil extracellular traps; these bacteria had surface moieties associated with the Hi biofilm matrix, and transcript profiles consistent with NTHi biofilms. In contrast, infection with the panel of NTHi mutants showed significant decrease in lung bacterial load. Comparable results were observed in bactericidal assays with neutrophil extracellular traps in vitro. Thus, we conclude that thiol mediated redox homeostasis promotes persistence of NTHi within biofilm communities.ImportanceChronic bacterial respiratory infections are a significant problem for smoke exposed individuals, especially those with chronic obstructive pulmonary disease (COPD). These infections often persist despite antibiotic use. Thus, the bacteria remain and contribute to the development of inflammation and other respiratory problems. Respiratory bacteria often form biofilms within the lungs, while growing in a biofilm their antibiotic and oxidative stress resistance is incredibly heightened. It is well documented that redox homeostasis genes are upregulated during this phase of growth. Many common respiratory pathogens such as NTHi and Streptococcus pneumoniae are reliant on scavenging from the host the necessary components they need to maintain these redox systems. This work here begins to lay down the foundation for exploiting this requirement and thiol redox homeostasis pathways of these bacteria as a therapeutic target for managing chronic respiratory bacterial infections, which are resistant to traditional antibiotic treatments alone.
Long-term immunogenicity of BNT162b2 vaccination in the elderly and in younger health care workers
Authors: Tober-Lau Pinkus , Schwarz Tatjana , Vanshylla Kanika , Hillus David , Gruell Henning ,   EICOV/COVIM Study Group, Suttorp Norbert , Landgraf Irmgard , Kappert Kai , Seybold Joachim , Drosten Christian , Klein Florian , Kurth Florian , Corman Victor Max , Sander Leif Erik 
Published: August 2021

AbstractCOVID-19 mRNA vaccine BNT162b2 is highly immunogenic and effective, but recent studies have indicated waning anti-SARS-CoV-2 immune responses over time. Increasing infection rates has led authorities in several countries to initiate booster campaigns for vulnerable populations, including the elderly. However, the durability of vaccine-induced immunity in the elderly is currently unknown. Here, we describe interim results of a prospective cohort study comparing immune responses in a cohort of vaccinated elderly persons to those in healthcare workers (HCW), measured six months after first immunisation with BNT162b2. Anti-SARS-CoV-2 S1-, full Spike- and RBD-IgG seropositivity rates and IgG levels at six months were significantly lower in the elderly compared to HCW. Serum neutralization of Delta VOC measured by pseudovirus neutralisation test was detectable in 43/71 (60.6%, 95%CI: 48.9-71.1) in the elderly cohort compared to 79/83 in the HCW cohort (95.2%, 95%CI: 88.3-98.1) at six months post vaccination. Consistent with the overall lower antibody levels, SARS-CoV-2-S1 T cell reactivity was reduced in the elderly compared to HCW (261.6 mIU/ml, IQR:141.5-828.6 vs 1198.0 mIU/ml, IQR: 593.9-2533.6, p<0.0001).Collectively, these findings suggest that the established two-dose vaccination regimen elicits less durable immune responses in the elderly compared to young adults. Given the recent surge in hospitalisations, even in countries with high vaccination rates such as Israel, the current data may support booster vaccinations of the elderly. Further studies to determine long-term effectiveness of COVID-19 vaccines in high-risk populations and the safety and effectiveness of additional boosters are needed.
Hydroxylation of Actin Impairs Cell Motility Through Blocking its’ Histidine Methylation
Authors: Zi Zhenzhen , Yuan Lin , Ding Qing , Kim Chiho , Wang Xu-dong , Zhang Xiaoyu , Yu Yonghao 
Published: August 2021

AbstractProtein hydroxylation is a post translational modification happens on various amino acids, which is catalyzed by the oxoglutarate and oxygen dependent dioxygenases. The best characterized hydroxylated protein is the hypoxia inducible factor (HIF), which is degraded by VHL/elongin C/elongin B/cullin 2/RBX1 (VCB/CR) E3 complex under normal oxygen conditions. Hypoxia or inhibitors (including FG4592 and MK8617) of PHDs stabilize HIF1a and regulate its downstream targets. Prolyl hydroxylase, including PHD2 and PHD3 has been reported in regulating actin polymerization and cell motility. Here, we found MK8617 regulated cell motility in Von Hippel Lindau (VHL) dependent manner. Through the protein hydroxylation proteome experiment upon MK8617 treatment, we identified Pro70 in actin could be hydroxylated and near to His73, which has been reported be methylated and stabilize actin polymerization. Using biochemical assay, we found that binding of VHL with hydroxylated actin (Pro70) decrease the His73 methylation by blocking the interaction of actin with SETD3, the His73 methyltransferase, and further regulated actin polymerization and cell motility. In summary, our study revealed that hypoxia and deficiencies in the VHL, in a HIF independent and prolyl hydroxylation dependent manner, regulate actin polymerization and cell motility through the PTM (Post Translational Modifications) crosstalk.
Health assessment of the pink land iguana,Conolophus marthae
Authors: Gentile Gabriele , Colosimo Giuliano , Vera Carlos A. , Gerber Glenn P. , Westermeyer Hans , Sevilla Christian , Lewbart Gregory A. 
Published: August 2021

AbstractThe pink land iguana,Conolophus marthae, is one of four species of iguanas (three terrestrial and one marine) in the Galápagos Islands, and the only one listed as critically endangered by the IUCN. The species can only be found on the north-west slopes of the highest volcano on the island of Isabela and was first described to science in 2009. As part of a population telemetry study, a health assessment was authorized by the Galápagos National Park. Wild adult iguanas were captured on Wolf Volcano in September 2019 and April 2021 to record morphological and physiological parameters including body temperature, heart rate, body measurements, intraocular pressures, tear formation, and infrared iris images. Blood samples were also collected and analyzed. An i-STAT portable blood analyzer was used to obtain values for base excess in the extracellular fluid compartment (BEECF), glucose, hematocrit, hemoglobin, ionized calcium (iCa), partial pressure of carbon dioxide (pCO2), partial pressure of oxygen (pO2), percent oxygen saturation (sO2%), pH, potassium (K), and sodium (Na). Standard laboratory hematology techniques were employed for packed-cell-volume (PCV) determination. When possible, data were compared to previously published and available data for the other Galápagos iguanas. The results reported here provide baseline values that may be useful in detecting changes in health status among pink land iguanas affected by climate change, invasive species, anthropogenic threats, or natural disturbances.
Relationship between bacterial phylotype and specialized metabolite production in the culturable microbiome of two freshwater sponges
Authors: Clark Chase M. , Hernandez Antonio , Mullowney Michael W. , Fitz-Henley Jhewelle , Li Emma , Romanowski Sean B. , Pronzato Roberto , Manconi Renata , Murphy Brian T. 
Published: August 2021

AbstractMicrobial drug discovery programs rely heavily on accessing bacterial diversity from the environment to acquire new specialized metabolite (SM) lead compounds for the therapeutic pipeline. Therefore, knowledge of how certain bacterial taxa are distributed in nature, in addition to the degree of variation of SM production within those taxa, is critical to informing these front-end discovery efforts and making the overall sample collection and bacterial library creation process more efficient. In the current study we employed MALDI-TOF mass spectrometry and the bioinformatics pipeline IDBac to analyze diversity within phylotype groupings and SM profiles of hundreds of bacterial isolates from two Eunapius fragilis freshwater sponges, collected 1.5 km apart. We demonstrated that within two sponge samples of the same species, the culturable bacterial populations contained significant overlap in approximate genus-level phylotypes but mostly non-overlapping populations of isolates when grouped lower than the level of genus. Further, correlations between bacterial phylotype and SM production varied at the species level and below, suggesting SM distribution within bacterial taxa must be analyzed on a case-by-case basis. Our results suggest that two E. fragilis freshwater sponges collected in similar environments can exhibit large culturable diversity on a species-level scale, thus researchers should scrutinize the isolates with analyses that take both phylogeny and SM production into account in order to optimize the chemical space entering into a downstream bacterial library.
Pseudomonas aeruginosa differentiates substrate rigidity using retraction of type IV pili
Authors: Koch Matthias D. , Han Endao , Shaevitz Joshua W. , Gitai Zemer 
Published: August 2021

AbstractThe ability of eukaryotic cells to differentiate substrate stiffness is fundamental for many processes such as the development of stem cells into mature tissue. Here, we establish that bacteria feel their microenvironment in a similar manner. We show that Pseudomonas aeruginosa actively probes and measures substrate stiffness using type IV pili (TFP). The activity of the major virulence factor regulator Vfr is peaked with stiffness in a physiologically important range between 0.1 kPa (mucus) and 1000 kPa (cartilage). The local concentration of PilA at the base of dynamic TFP changes during extension and retraction in a surface dependent manner due to slow PilA diffusion in the cell membrane. Traction force measurements reveal that TFP retraction deforms even stiff substrates. Modeling of the measured substrate deformation and optical tweezers experiments suggest that TFP adhere at the tip only. Informed by these experimental results, we developed a model that describes substrate stiffness dependent dynamics of the polar PilA concentration which are quantitatively consistent with the transcriptional response to stiffness. Manipulating the ATPase activity of the TFP motors changes the TFP extension and retraction velocities and consequently the PilA concentration dynamics in a manner that is predictive of the experimental stiffness response. This work points to the use of a competition between PilA diffusion and TFP extension-retraction as a molecular shear rheometer. Our results highlight that stiffness sensing is a conserved property between the kingdoms of life.