bluuebunny/crossref_metadata_2025 huggingface dataset:
SARS-CoV-2 variants of concern dominate in Lahore, Pakistan in April 2021
Authors: Sarwar Muhammad Bilal , Yasir Muhammad , Alikhan Nabil-Fareed , Afzal Nadeem , de Oliveira Martins Leonardo , Le Viet Thanh , Trotter Alexander J. , Prosolek Sophie J. , Kay Gemma L. , Foster-Nyarko Ebenezer , Rudder Steven , Baker David J. , Muntaha Sidra Tul , Roman Muhammad , Webber Mark A. , Shafiq Almina , Shabbir Bilquis , Akram Javed , Page Andrew J. , Jahan Shah
Published: November 2021

The SARS-CoV-2 pandemic continues to expand globally, with case numbers rising in many areas of the world, including the Indian sub-continent. Pakistan has one of the world’s largest populations, of over 200 million people and is experiencing a severe third wave of infections caused by SARS-CoV-2 that began in March 2021. In Pakistan, during the third wave until now only 12 SARS-CoV-2 genomes have been collected and among these nine are from Islamabad. This highlights the need for more genome sequencing to allow surveillance of variants in circulation. In fact, more genomes are available among travellers with a travel history from Pakistan, than from within the country itself. We thus aimed to provide a snapshot assessment of circulating lineages in Lahore and surrounding areas with a combined population of 11.1 million. Within a week of April 2021, 102 samples were sequenced. The samples were randomly collected from two hospitals with a diagnostic PCR cutoff value of less than 25 cycles. Analysis of the lineages shows that the Alpha variant of concern (first identified in the UK) dominates, accounting for 97.9 % (97/99) of cases, with the Beta variant of concern (first identified in South Africa) accounting for 2.0 % (2/99) of cases. No other lineages were observed. In depth analysis of the Alpha lineages indicated multiple separate introductions and subsequent establishment within the region. Eight samples were identical to genomes observed in Europe (seven UK, one Switzerland), indicating recent transmission. Genomes of other samples show evidence that these have evolved, indicating sustained transmission over a period of time either within Pakistan or other countries with low-density genome sequencing. Vaccines remain effective against Alpha, however, the low level of Beta against which some vaccines are less effective demonstrates the requirement for continued prospective genomic surveillance.
Predatory bacteria in the haemolymph of the cultured spiny lobster Panulirus ornatus
Authors: Ooi Mei C. , Goulden Evan F. , Smith Gregory G. , Bridle Andrew R.
Published: November 2021

Bdellovibrio

and like organisms (BALOs) are Gram-negative obligate predators of other bacteria in a range of environments. The recent discovery of BALOs in the circulatory system of cultured spiny lobster P. ornatus warrants more investigation. We used a combination of co-culture agar and broth assays and transmission electron microscopy to show a

Halobacteriovorax

sp. strain Hbv preyed upon the model prey bacterium

Vibrio

sp. strain Vib. The haemolymph microbiome of juvenile P. ornatus was characterised following injection of phosphate buffered saline (control) or prey and/or predator bacteria for 3 d. The predator Hbv had no effect on survival compared to the control after 3 d. However, when compared to the prey only treatment group, lobsters injected with both prey and predator showed significantly lower abundance of genus

Vibrio

in the haemolymph bacterial community composition. This study indicates that predatory bacteria are not pathogenic and may assist in controlling microbial population growth in the haemolymph of lobsters.
Anticipating future SARS-CoV-2 variants of concern through ab initio quantum mechanical modeling
Authors: Zaccaria Marco , Genovese Luigi , Farzan Michael , Dawson William , Nakajima Takahito , Johnson Welkin , Momeni Babak
Published: November 2021

Evolved SARS-CoV-2 variants are currently challenging the efficacy of first-generation vaccines, largely through the emergence of spike protein mutants. Among these variants, Delta is presently the most concerning. We employ an ab initio quantum mechanical model based on Density Functional Theory to characterize the spike protein Receptor Binding Domain (RBD) interaction with host cells and gain mechanistic insight into SARS-CoV-2 evolution. The approach is illustrated via a detailed investigation of the role of the E484K RBD mutation, a signature mutation of the Beta and Gamma variants. The simulation is employed to: predict the depleting effect of the E484K mutation on binding the RBD with select antibodies; identify residue E484 as a weak link in the original interaction with the human receptor hACE2; and describe SARS-CoV-2 Wuhan strand binding to the bat Rhinolophus macrotis ACE2 as more optimized than the human counterpart. Finally, we predict the hACE2 binding efficacy of a hypothetical E484K mutation added to the Delta variant RBD, identifying a potential future variant of concern. Results can be generalized to other mutations, and provide useful information to complement existing experimental datasets of the interaction between randomly generated libraries of hACE2 and viral spike mutants. We argue that ab initio modeling is at the point of being aptly employed to inform and predict events pertinent to viral and general evolution.
MTSviewer: a database to visualize mitochondrial targeting sequences, cleavage sites, and mutations on protein structures
Authors: Bayne Andrew N. , Dong Jing , Amiri Saeid , Farhan Sali M.K. , Trempe Jean-François
Published: November 2021

Mitochondrial dysfunction is implicated in a wide array of human diseases ranging from neurodegenerative disorders to cardiovascular defects. The coordinated localization and import of proteins into mitochondria are essential processes that ensure mitochondrial homeostasis and consequently cell survival. The localization and import of most mitochondrial proteins are driven by N-terminal mitochondrial targeting sequences (MTS’s), which interact with import machinery and are removed by the mitochondrial processing peptidase (MPP). The recent discovery of internal MTS’s - those which are distributed throughout a protein and act as import regulators or secondary MPP cleavage sites – has expanded the role of both MTS’s and MPP beyond conventional N-terminal regulatory pathways. Still, the global mutational landscape of MTS’s remains poorly characterized, both from genetic and structural perspectives. To this end, we have integrated a variety of tools into one harmonized R/Shiny database called MTSviewer (https://neurobioinfo.github.io/MTSvieweR/) which combines MTS predictions, cleavage sites, genetic variants, pathogenicity predictions, and N-terminomics data with structural visualization using AlphaFold models of human and yeast mitochondrial proteomes.

Availability and Implementation

MTSviewer is freely available on the web athttps://neurobioinfo.github.io/MTSvieweR/.

Source code is available athttps://github.com/neurobioinfo/MTSvieweR.

Contact

eanfrancois.trempe@mcgill.ca;sali.farhan@mcgill.ca
A recombinant SARS-CoV-2 RBD antigen expressed in insect cells elicits immunogenicity and confirms safety in animal models
Authors: Choque-Guevara Ricardo , Poma-Acevedo Astrid , Montesinos-Millán Ricardo , Rios-Matos Dora , Gutiérrez-Manchay Kristel , Montalvan Angela , Quiñones-Garcia Stefany , de Grecia Cauti-Mendoza Maria , Agurto-Arteaga Andres , Ramirez-Ortiz Ingrid , Criollo-Orozco Manuel , Huaccachi-Gonzales Edison , Lázaro Yomara K. Romero , Perez-Martinez Norma , Isasi-Rivas Gisela , Sernaque-Aguilar Yacory , Villanueva-Pérez Doris , Vallejos-Sánchez Katherine , Fernández-Sánchez Manolo , Guevara Luis , Fernández-Díaz Manolo , Zimic Mirko ,   for the COVID-19 Working Group in Perú
Published: November 2021

COVID-19 pandemic has accelerated the development of vaccines against its etiologic agent, SARS-CoV-2. However, the emergence of new variants of the virus requires new immunization strategies in addition to the current vaccines approved for human administration. In the present report, the immunological and safety evaluation in mice and hamsters of a subunit vaccine based on the RBD sub-domain with two adjuvants of oil origin is described.

The RBD protein was expressed in insect cells and purified by chromatography until >95% purity. The protein was shown to have the appropriate folding as determined by ELISA and flow cytometry binding assays to its receptor, as well as by its detection by hamster immune anti-S1 sera under non-reducing conditions.

In immunization assays in mice and hamsters, the purified RBD formulated with adjuvants based on oil-water emulsifications and squalene was able to stimulate specific neutralizing antibodies and confirm the secretion of IFN-γ after stimulating spleen cells with the purified RBD. The vaccine candidate was shown to be safe, as demonstrated by the histopathological analysis in lungs, liver and kidney. These results demonstrate the potential of the purified RBD administered with adjuvants through an intramuscular route, to be evaluated in a challenge against SARS-CoV-2 and determine its ability to confer protection against infection.
Incorporating the mutational landscape of SARS-COV-2 variants and case-dependent vaccination rates into epidemic models
Authors: Chowdhury Mohammad Mihrab , Islam Md Rafiul , Hossain Md Sakhawat , Tabassum Nusrat , Peace Angela
Published: November 2021

Coronavirus Disease (COVID-19), which began as a small outbreak in Wuhan, China in December 2019, became a global pandemic within months due to its high transmissibility. In the absence of pharmaceutical treatment, various non-pharmaceutical interventions (NPIs) to contain the spread of COVID-19 brought the entire world to a halt. After almost a year of seemingly returning to normalcy with the world’s quickest vaccine development, the emergence of more infectious and vaccine resistant coronavirus variants is bringing the situation back to where it was a year ago. In the light of this new situation, we conducted a study to portray the possible scenarios based on the three key factors : impact of interventions (pharmaceutical and NPIs), vaccination rate, and vaccine efficacy. In our study, we assessed two of the most crucial factors, transmissibility and vaccination rate, in order to reduce the spreading of COVID-19 in a simple but effective manner. In order to incorporate the time-varying mutational landscape of COVID-19 variants, we estimated a weighted transmissibility composed of the proportion of existing strains that naturally vary over time. Additionally, we consider time varying vaccination rates based on the number of daily new cases. Our method for calculating the vaccination rate from past active cases is an effective approach in forecasting probable future scenarios as it actively tracks people’s attitudes toward immunization as active cases change. Our simulations show that if a large number of individuals cannot be vaccinated by ensuring high efficacy in a short period of time, adopting NPIs is the best approach to manage disease transmission with the emergence of new vaccine breakthrough and more infectious variants.
Neurocognition and its association with adverse childhood experiences and familial risk of mental illness
Authors: Lakkireddy Sai Priya , Balachander Srinivas , Dayal Pavithra , Bhattacharya Mahashweta , Joseph Mino Susan , Kumar Pramod , Kannampuzha Anand Jose , Mallappagari Sreenivasulu , Shruthi Suvarna , Chandy Alen Alexander , Kumaran Muthu , Sheth Sweta , Ramesh Vinutha , Puzhakkal Joan C , Selvaraj S Sowmya , Ithal Dhruva , Sreeraj Vanteemar S , Mahadevan Jayant , Holla Bharath , Venkatasubramanian Ganesan , John John P. , Murthy Pratima , Benegal Vivek , Janardhan Reddy YC , Jain Sanjeev ,   ADBS Consortium, Viswanath Biju
Published: November 2021

Background

Neurocognitive deficits are considered an endophenotype for several psychiatric disorders, typically studied in unaffected first-degree relatives (FDRs). Environmental factors such as adverse childhood experiences (ACEs) may also affect neurocognition. This study examines the effect of ACEs on neurocognitive performance in FDRs of patients with severe mental illness in order to determine whether familial risk has a moderating effect on the relationship between ACEs and neurocognition.

Methods

The sample consists of a total of 512 individuals composed of unaffected FDRs from multiplex families with severe mental illnesses (schizophrenia, bipolar disorder, obsessive-compulsive disorder or alcohol use disorder) and healthy controls (with no familial risk). Neurocognitive tests included processing speed (Color Trails), new learning (Auditory Verbal Learning Test), working memory (N-Back), and Theory of Mind (SOCRATIS). ACEs were measured using the WHO ACE-International Questionnaire (ACE-IQ). Regression models adjusted for age, gender and education were done to predict each neurocognitive domain by the effect of familial risk, ACE-IQ Total Score and the interaction (familial risk x ACE-IQ Total score).

Results

When all FDRs were examined as a group, the main effect of familial risk predicted poor performance in all domains of neurocognition (p <0.01), and the ACEs x familial risk interaction had a significant negative association with global neurocognition, processing speed & working memory. This interaction effect was driven predominantly by the familial risk of AUD. In FDRs of schizophrenia & bipolar disorder, only the main effects of familial risk were significant (working memory, theory of mind & global neurocognition), with no impact of ACEs or its interaction in both these sub-groups.

Conclusions

The impact of childhood adversity on neurocognition is moderated by familial risk of psychiatric disorders. Genetic or familial vulnerability may play a greater role in disorders such as schizophrenia and bipolar disorder, while the interaction between ACEs and family history may be more relevant in the case of disorders with greater environmental risk, such as substance use.
A microbial mutualist within host individuals increases parasite transmission between host individuals: Evidence from a field mesocosm experiment
Authors: O’Keeffe Kayleigh R. , Wheeler Brandon T. , Mitchell Charles E.
Published: November 2021

The interactions among host-associated microbes and parasites can have clear consequences for disease susceptibility and progression within host individuals. Yet, empirical evidence for how these interactions impact parasite transmission between host individuals remains scarce. We address this scarcity by using a field mesocosm experiment to investigate the interaction between a systemic fungal endophyte,Epichloë coenophiala, and a fungal parasite,Rhizoctonia solani, in leaves of a grass host, tall fescue. Specifically, we investigated how this interaction impacted parasite transmission under field conditions in replicated experimental host populations.Epichloë-inoculated populations tended to have greater disease prevalence over time, though this difference had weak statistical support. More clearly,Epichloë-inoculated populations experienced higher peak parasite prevalences thanEpichloë-free populations.Epichloëconferred a benefit in growth;Epichloë-inoculated populations had greater aboveground biomass thanEpichloë-free populations. Using biomass as a proxy, host density was correlated with peak parasite prevalence, butEpichloëstill increased peak parasite prevalence after controlling for the effect of biomass. Together, these results suggest that within-host microbial interactions can impact disease at the population level. Further, whileEpichloëis clearly a mutualist of tall fescue, it may not be a defensive mutualist in relation toR. solani.
Transient adverse events after REGN-CoV2 administration for mild COVID-19 patients and their potential predictive factors: a single center analysis
Authors: Kano Gen , Taniguchi Kyoko , Oue Yukiko
Published: November 2021

Background

REGN-COV2, a monoclonal antibody cocktail drug against the SARS-COV-2 virus, has proven to be effective in preventing the development of severe COVID-19 and is increasingly being administered in outpatient and home settings. Adverse events such as fever and decreased oxygen saturation may occur after administration of REGN-COV2, and although these symptoms are generally mild and transient, predicting the occurrence of these adverse events is useful in developing a monitoring plan for patients.

Methods

We performed a retrospective analysis of 76 patients who received REGN-CoV2 between August and September 2021. We collected information on fever, decreased oxygen saturation requiring oxygen supplementation, and other adverse events from medical records. Patients were divided into two subgroups: those who presented with fever or oxygen desaturation and those who did not, and underlying medical conditions and laboratory data were compared between each group. The parameters that exhibited significant differences were further tested using Fisher’s exact test to evaluate whether appropriate thresholds could be set to distinguish the incidence group from the non-incidence group.

Findings

Of the 76 patients, 47 had fever of 38.5°C or higher within 24 hours after administration, and 27 of these patients had a body temperature of 37.5°C or lower before administration. Oxygen was required in 17 cases, 7 of which required oxygen more than 24 hours after administration of REGN-COV2, and additional treatment such as dexamethasone was given as the disease progressed to moderate. Among the parameters analyzed, lymphocyte count and IFNλ3 showed significant differences between the fever and non-fever groups. This was also the case in the comparison excluding patients who had fever before administration. There was also a significant difference in ferritin and CRP between the oxygen required and non-required groups. In addition to IFNλ3, ferritin, and CRP, there was a significant difference in LDH between the group that required additional treatment and the group that did not. When lymphocytes count <950/µL was used to predict fever, the sensitivity and specificity were 55% and 79%, respectively, with odds ratio 4.746 (95% CI: 1.666 to 14.12, p=0.004) in contingency table analysis. Similarly, when IFNλ3 >5.0 was used as the cutoff, sensitivity 72%, specificity 76%, odds ratio 8.220 (2.857 to 22.22; p<0.0001).

Interpretations

Transient fever and decreased oxygen saturation are common adverse events after REGN-CoV2 administration, and their occurrence correlated with the severity factor of COVID-19 itself. Evaluation of these items at the time of administration is useful not only for predicting the severity of COVID-19 but also for the development of adverse events in patients receiving REGN-CoV2.
Mitochondrial DNA copy number, metabolic syndrome, and insulin sensitivity: Insights from the Sugar, Hypertension, and Physical Exercise Studies
Authors: Yang Stephanie Y. , Mirabal Caleb S. , Newcomb Charles E. , Stewart Kerry J. , Arking Dan E.
Published: November 2021

Mitochondrial DNA copy number (mtDNA-CN) measured in blood has been associated with many aging-related diseases, with higher mtDNA-CN typically associated with lower disease risk. Exercise training is an excellent preventative tool against aging-related disorders and has been shown to increase mitochondrial function in muscle. Using the Sugar, Hypertension, and Physical Exercise cohorts (N = 105), we evaluated the effect of 6-months of exercise intervention on mtDNA-CN measured in blood. Although there was no significant relationship between exercise intervention and mtDNA-CN change (P = 0.29), there was a nominally significant association between mtDNA-CN and metabolic syndrome (P = 0.04), which has been seen in previous literature. We also identified a nominally significant association between higher mtDNA-CN and higher insulin sensitivity (P = 0.02).
Phase Shift Between Age-Specific COVID-19 Incidence Curves Points to a Potential Epidemic Driver Function of Kids and Juveniles in Germany
Authors: Diebner Hans H.
Published: November 2021

Mutual phase shifts between three German COVID-19 incidence curves corresponding to the age classes of children, juveniles and adults, respectively, are calculated by means of delay-cross-correlations. At the country level, a phase shift of −5 weeks during the first half of the epidemic between the incidence curves corresponding to the juvenile age class and the curve corresponding to the adult class is observed. The children’s incidence curve is shifted by −3 weeks with respect to the adults’ curve. On the regional level of the 411 German districts (Landkreise) the distributions of observed time lags are inclined towards negative values. Regarding the incidence time series of the juvenile sub-population, 20% of the German districts exhibit negative phase shifts and only 3% show positive shifts versus the incidence curves of the adult sub-population. Similarly for the children with 6% positive shifts. Thus, children’s and juveniles’ epidemic activity is ahead of the adults’ activity. The correlation coefficients of shifted curves are large (> 0.9 for juveniles versus adults on the country level) which indicates that aside from the phase shift the sub-populations follow a similar epidemic dynamics. Negative phase shifts of the children’s incidence curves during the first and second epidemic waves are predictors for high incidences during the current fourth wave with respect to the corresponding districts.
An amino residue that guides the correct photoassembly of the water-oxidation complex but is not required for high affinity Mn2+ binding
Authors: Avramov Anton P. , Zhang Minquan , Burnap Robert L.
Published: November 2021

The assembly of the Mn4O5Ca cluster of the photosystem II (PSII) starts from the initial binding and photooxidation of the first Mn2+ at a high affinity site (HAS). Recent cryo-EM apo-PSII structures reveal an altered geometry of amino ligands in this region and suggest the involvement of D1-Glu189 ligand in the formation of the HAS. We now find that Gln and Lys substitution mutants photoactivate with reduced quantum efficiency compared to the wild-type. However, the affinity of Mn2+ at the HAS in D1-E189K was very similar to the wild-type (~2.2 μM). Thus, we conclude that D1-E189 does not form the HAS (~2.9 μM) and that the reduced quantum efficiency of photoactivation in D1-E189K cannot be ascribed to the initial photooxidation of Mn2+ at the HAS. Besides reduced quantum efficiency, the D1-E189K mutant exhibits a large fraction of centers that fail to recover activity during photoactivation starting early in the assembly phase, becoming recalcitrant to further assembly. Fluorescence relaxation kinetics indicate on the presence of an alternative route for the charge recombination in Mn-depleted samples in all studied mutants and exclude damage to the photochemical reaction center as the cause for the recalcitrant centers failing to assemble and show that dark incubation of cells reverses some of the inactivation. This reversibility would explain the ability of these mutants to accumulate a significant fraction of active PSII during extended periods of cell growth. The failed recovery in the fraction of inactive centers appears to a reversible mis-assembly involving the accumulation of photooxidized, but non-catalytic high valence Mn at the donor side of photosystem II, and that a reductive mechanism exists for restoration of assembly capacity at sites incurring mis-assembly. Given the established role of Ca2+ in preventing misassembled Mn, we conclude that D1-E189K mutant impairs the ligation of Ca2+ at its effector site in all PSII centers that consequently leads to the mis-assembly resulting in accumulation of non-catalytic Mn at the donor side of PSII. Our data indicate that D1-E189 is not functionally involved in Mn2+ oxidation\binding at the HAS but rather involved in Ca2+ ligation and steps following the initial Mn2+ photooxidation.
Orthoformimycin inhibits translation elongation by displacing the A-site tRNA and preventing peptide bond formation
Authors: Schedlbauer Andreas , Kaminishi Tatsuya , Fabbretti Attilio , Milón Pohl , Han Xu , Ochoa-Lizarralde Borja , Çapuni Retina , Gualerzi Claudio O. , Connell Sean R. , Fucini Paola
Published: November 2021

The ribosome is a major target for antibiotics owing to its essential cellular role in protein synthesis. Structural analysis of ribosome-antibiotic complexes provides insight into the molecular basis for their inhibitory action and highlights possible avenues to improve their potential or overcome existing resistance mechanisms. Here we use X-ray crystallography and pre-steady state kinetics to detail the inhibitory mechanism of the antimicrobial on the large ribosomal subunit.
A Conformational Transition of Von Willebrand Factor’s D’D3 Domain Primes It For Multimerization
Authors: Gruber Sophia , Löf Achim , Hausch Adina , Jöhr Res , Obser Tobias , König Gesa , Schneppenheim Reinhard , Brehm Maria A. , Benoit Martin , Lipfert Jan
Published: November 2021

Von Willebrand factor (VWF) is a multimeric plasma glycoprotein that is critically involved in hemostasis. Biosynthesis of long VWF concatemers in the endoplasmic reticulum and the (trans-)Golgi is still not fully understood. We use the single-molecule force spectroscopy technique magnetic tweezers to analyze a previously hypothesized conformational change in the D’D3 domain crucial for VWF multimerization. We find that the interface formed by submodules C8-3, TIL3, and E3 wrapping around VWD3 can open and expose two previously buried cysteines that are known to be vital for multimerization. By characterizing the conformational change at varying levels of force, we are able to quantify the kinetics of the transition and the stability of the interface. We find a pronounced destabilization of the interface upon lowering the pH from 7.4 to 6.2 and 5.5. This is consistent with initiation of the conformational change that enables VWF multimerization at the D’D3 domain by a decrease in pH in the trans-Golgi network and Weibel-Palade bodies. Furthermore, we find a stabilization of the interface in the presence of coagulation factor VIII (FVIII), providing evidence for a previously hypothesized binding site in submodule C8-3. Our findings highlight the critical role of the D’D3 domain in VWF biosynthesis and function and we anticipate our methodology to be applicable to study other, similar conformational changes in VWF and beyond.
A positive feedback loop mediates crosstalk between calcium, cyclic nucleotide and lipid signalling in Toxoplasma gondii
Authors: Dominicus Caia , Nofal Stephanie D. , Broncel Malgorzata , Katris Nicholas J. , Flynn Helen R. , Arrizabalaga Gustavo , Botté Cyrille Y. , Invergo Brandon M. , Treeck Moritz
Published: November 2021

Fundamental processes of obligate intracellular parasites, such as Toxoplasma gondii and Plasmodium falciparum, are controlled by a set of plant-like calcium dependent kinases (CDPKs), the conserved cAMP- and cGMP-dependent protein kinases (PKA and PKG), secondary messengers and lipid signalling. While some major components of the signalling networks have been identified, how these are connected remains largely unknown. Here, we compare the phospho-signalling networks during Toxoplasma egress from its host cell by artificially raising cGMP or calcium levels to activate PKG or CDPKs, respectively. We show that both these inducers trigger near identical signalling pathways and provide evidence for a positive feedback loop involving CDPK3. We measure phospho- and lipid signalling in parasites treated with the Ca2+ ionophore A23187 in a sub-minute timecourse and show CDPK3-dependent regulation of diacylglycerol levels and increased phosphorylation of four phosphodiesterases (PDEs), suggesting their function in the feedback loop. Disruption of CDPK3 leads to elevated cAMP levels and inhibition of PKA signalling rescues the egress defect of ΔCDPK3 parasites treated with A23187. Biochemical analysis of the four PDEs identifies PDE2 as the only cAMP-specific PDE among these candidates, while the other PDEs are cGMP specific, two of which are inhibited by the predicted PDE inhibitor BIPPO. Conditional deletion of the four PDEs supports an important, but non-essential role for PDE1 and PDE2 in growth, with PDE2 controlling A23187-mediated egress. In summary we uncover a positive feedback loop that enhances signalling during egress and links several signalling pathways together.
Effect of gastrointestinal alterations mimicking elderly conditions on in vitro digestion of meat and soy proteins
Authors: Wang Chong , Zhao Fan , Bai Yun , Li Chunbao , Xu Xinglian , Kristiansen Karsten , Zhou Guanghong
Published: November 2021

We evaluated the digestion of meat (chicken, beef, and pork) and soy proteins under in vitro conditions mimicking gastrointestinal (GI) conditions of adults (control, C) and elderly with achlorhydria (EA). The changes in degree of hydrolysis (DH), SDS-PAGE profiles, peptide concentration, and proteomics profiles during the digestion process were investigated. Digestion under the EA condition markedly decreased the DH of all protein sources, especially for soy protein. SDS-PAGE profiling and proteomics showed that myofibrillar/sarcoplasmic protein from meat and glycinin/beta-conglycinin from soy were the proteins most affected by the different digestive conditions. Our results indicated that the difference in the digestibility of meat protein between EA and control conditions gradually narrowed from the gastric to the intestinal phase, while a pronounced difference between control and EA conditions was maintained also in the intestinal phase. This work provides new insights of value for future dietary recommendations for elderly individuals.
Non-random interactions within and across guilds shape the potential to coexist in multi-trophic ecological communities
Authors: García-Callejas David , Godoy Oscar , Buche Lisa , Hurtado María , Lanuza Jose B. , Allen-Perkins Alfonso , Bartomeus Ignasi
Published: November 2021

Theory posits that the persistence of species in ecological communities is shaped by their interactions within and across trophic guilds. However, we lack empirical evaluations of how the structure, strength, and sign of biotic interactions drive the potential to coexist in diverse multi-trophic communities. Here we model community feasibility domains, a theoretically-informed measure of multi-species coexistence probability, from grassland communities comprising more than 45 species on average from three trophic guilds (plants, pollinators, and herbivores). Contrary to our hypothesis, increasing community complexity, measured either as the number of guilds or community richness, did not decrease community feasibility. Rather, we observed that high degrees of species self-regulation and niche partitioning allow maintaining larger levels of community feasibility and higher species persistence in more diverse communities. Our results show that biotic interactions within and across guilds are not random in nature and both structures significantly contribute to maintaining multi-trophic diversity.
Habitat Suitability modeling of Urial (Ovis orientalis arkal) in the Samelghan plain by using Maximum Entropy Method
Authors: Naqibzadeh Abbas , Sarhangzadeh Jalil , Sotoudeh Ahad , Mashkur Marjan , Thomalsky Judith
Published: November 2021

Habitat suitability models are useful tools for a variety of wildlife management objectives. Distributions of wildlife species can be predicted for geographical areas that have not been extensively surveyed. The basis of these models’ work is to minimize the relationship between species distribution and biotic and abiotic environments. For some species, there is information about presence and absence that allows the use of a variety of standard statistical methods, however, the absence data is not available for most species. Nowadays, the methods that need presence-only data are expanded. One of these methods is the Maximum Entropy (MaxEnt) modeling. The purpose of this study is to model the habitat of Urial (Ovis orientalis arkal) in the Samelghan plain in the North East of Iran with the MaxEnt method. This algorithm uses the Jackknife plot and percent contribution values to determine the significance of the variables. The results showed that variables such as southern aspects, Juniperus-Acer, Artemisia-Perennial plants, slope 0-5%, and asphalt road were the most important factors affecting the species’ habitat selection. The area under curve (AUC) Receiver Operating Characteristic (ROC) showed an excellent model performance. Suitable habitat was classified based on the threshold value (0.0513) and the ROC, which based on the results 28% of the area was a suitable habitat for Urial.
Endocytic Trafficking Promotes Vacuolar Enlargements for Fast Cell Expansion Rates in Plants
Authors: Dünser Kai , Schöller Maria , Löfke Christian , Xiao Nannan , Pařízková Barbora , Melnik Stanislav , Stöger Eva , Novák Ondřej , Kleine-Vehn Jürgen
Published: November 2021

The vacuole has a space-filling function, allowing a particularly rapid plant cell expansion with very little increase in cytosolic content (Löfke et al., 2015; Scheuring et al., 2016; Dünser et al., 2019). Despite its importance for cell size determination in plants, very little is known about the mechanisms that define vacuolar size. Here we show that the cellular and vacuolar size expansions are coordinated. By developing a pharmacological tool, we enabled the investigation of membrane delivery to the vacuole during cellular expansion. Counterintuitively, our data reveal that endocytic trafficking from the plasma membrane to the vacuole is enhanced in the course of rapid root cell expansion. While this “compromise” mechanism may theoretically at first decelerate cell surface enlargements, it fuels vacuolar expansion and, thereby, ensures the coordinated augmentation of vacuolar occupancy in dynamically expanding plant cells.
Mapping trait versus species turnover reveals spatiotemporal variation in functional redundancy in a plant-pollinator network
Authors: Cantwell-Jones Aoife , Larson Keith , Ward Alan , Bates Olivia K. , Cox Tara , Brannlund Frida , Gibbons Charlotte , Richardson Ryan , Tylianakis Jason M. , Johansson Jacob , Gill Richard J.
Published: November 2021

Functional overlap between species (redundancy) shapes competitive and mutualistic interactions, determining community responses to perturbations. Most studies view functional redundancy as static, even though individuals within species vary in traits over seasonal or spatial gradients. Consequently, we lack knowledge on trait turnover within species, how functional redundancy spatiotemporally varies, and when and where interaction networks are vulnerable to functional loss. Studying an Arctic bumblebee community, we investigated how body-size turnover over elevation and season shapes their host-plant interactions, and test how sensitive networks are to sequentially losing body-size groups. With trait turnover being larger than species, we found: i) late-season networks were less specialised when nodes comprised functionally similar bumblebees; ii) removal of bumblebee-body-size groups over species accelerated coextinction of host plants, with the magnitude varying in space and time. We demonstrate functional redundancy can vary spatiotemporally, and functional loss impacts interaction partners more than expected from species loss alone.
DeepSNEM: Deep Signaling Network Embeddings for compound mechanism of action identification
Authors: Fotis C. , Alevizos G. , Meimetis N. , Koleri C. , Gkekas T. , Alexopoulos LG.
Published: November 2021

Motivation

The analysis and comparison of compounds’ transcriptomic signatures can help elucidate a compound’s Mechanism of Action (MoA) in a biological system. In order to take into account the complexity of the biological system, several computational methods have been developed that utilize prior knowledge of molecular interactions to create a signaling network representation that best explains the compound’s effect. However, due to their complex structure, large scale datasets of compound-induced signaling networks and methods specifically tailored to their analysis and comparison are very limited. Our goal is to develop graph deep learning models that are optimized to transform compound-induced signaling networks into high-dimensional representations and investigate their relationship with their respective MoAs.

Results

We created a new dataset of compound-induced signaling networks by applying the CARNIVAL network creation pipeline on the gene expression profiles of the CMap dataset. Furthermore, we developed a novel unsupervised graph deep learning pipeline, called deepSNEM, to encode the information in the compound-induced signaling networks in fixed-length high-dimensional representations. The core of deepSNEM is a graph transformer network, trained to maximize the mutual information between whole-graph and sub-graph representations that belong to similar perturbations. By clustering the deepSNEM embeddings, using the k-means algorithm, we were able to identify distinct clusters that are significantly enriched for mTOR, topoisomerase, HDAC and protein synthesis inhibitors respectively. Additionally, we developed a subgraph importance pipeline and identified important nodes and subgraphs that were found to be directly related to the most prevalent MoA of the assigned cluster. As a use case, deepSNEM was applied on compounds’ gene expression profiles from various experimental platforms (MicroArrays and RNA sequencing) and the results indicate that correct hypotheses can be generated regarding their MoA.

Availability and Implementation

The source code and pre-trained deepSNEM models are available at https://github.com/BioSysLab/deepSNEM.

Contact

Email for correspondence: leo@mail.ntua.gr.

Supplementary information

Accompanying supplementary material are available online.
Several different sequences are implicated in bloodstream-form-specific gene expression in Trypanosoma brucei
Authors: Tshitenge Tania Bishola , Reichert Lena , Liu Bin , Clayton Christine
Published: November 2021

The parasite Trypanosoma brucei grows as bloodstream forms in mammalian hosts, and as procyclic forms in tsetse flies. In trypanosomes, gene expression regulation depends heavily on post-transcriptional mechanisms. Both the RNA-binding protein RBP10 and glycosomal phosphoglycerate kinase PGKC are expressed only in mammalian-infective forms. RBP10 targets procyclic-specific mRNAs for destruction, while PGKC is required for bloodstream-form glycolysis. Developmental regulation of both is essential: expression of either RBP10 or PGKC in procyclic forms inhibits their proliferation. We show that the 3′-untranslated region of the RBP10 mRNA is extraordinarily long - 7.3kb - and were able to identify six different sequences, scattered across the untranslated region, which can independently cause bloodstream-form-specific expression. The 3′-untranslated region of the PGKC mRNA, although much shorter, still contains two different regions, of 125 and 153nt, that independently gave developmental regulation. No short consensus sequences were identified that were enriched either within these regulatory regions, or when compared with other mRNAs with similar regulation, suggesting that more than one regulatory RNA-binding protein is important for repression of mRNAs in procyclic forms. We also identified regions, including an AT repeat, that increased expression in bloodstream forms, or suppressed it in both forms. Trypanosome mRNAs that encode RNA-binding proteins often have extremely extended 3′-untranslated regions. We suggest that one function of this might be to act as a fail-safe mechanism to ensure correct regulation even if mRNA processing or expression of trans regulators is defective.
Dual-modal metabolic analysis reveals hypothermia-reversible uncoupling of oxidative phosphorylation in neonatal brain hypoxia-ischemia
Authors: Sun Naidi , Sun Yu-Yo , Cao Rui , Chen Hong-Ru , Wang Yiming , Fugate Elizabeth , Smucker Marchelle R. , Kuo Yi-Min , Grant P. Ellen , Lindquist Diana M. , Kuan Chia-Yi , Hu Song
Published: November 2021

Hypoxia-ischemia (HI), which disrupts the oxygen supply-demand balance in the brain by impairing blood oxygen supply and the cerebral metabolic rate of oxygen (CMRO2), is a leading cause of neonatal brain injury. However, it is unclear how post-HI hypothermia helps to restore the balance, as cooling reduces CMRO2. Also, how transient HI leads to secondary energy failure (SEF) in neonatal brains remains elusive. Using photoacoustic microscopy, we examined the effects of HI on CMRO2in awake 10-day-old mice, supplemented by bioenergetic analysis of purified cortical mitochondria. Our results show that while HI suppresses ipsilateral CMRO2, it sparks a prolonged CMRO2-surge post-HI, associated with increased mitochondrial oxygen consumption, superoxide emission, and reduced mitochondrial membrane potential necessary for ATP synthesis—indicating oxidative phosphorylation (OXPHOS) uncoupling. Post-HI hypothermia prevents the CMRO2-surge by constraining oxygen extraction fraction, reduces mitochondrial oxidative stress, and maintains ATP and N-acetylaspartate levels, resulting in attenuated infarction at 24 hours post-HI. Our findings suggest that OXPHOS-uncoupling induced by the post-HI CMRO2-surge underlies SEF and blocking the surge is a key mechanism of hypothermia protection. Also, our study highlights the potential of optical CMRO2-measurements for detecting neonatal HI brain injury and guiding the titration of therapeutic hypothermia at the bedside.
The evolutionary history of human spindle genes includes back-and-forth gene flow with Neandertals
Authors: Peyrégne Stéphane , Kelso Janet , Peter Benjamin M. , Pääbo Svante
Published: November 2021

Proteins associated with the spindle apparatus, a cytoskeletal structure that ensures the proper segregation of chromosomes during cell division, experienced an unusual number of amino acid substitutions in modern humans after the split from the ancestors of Neandertals and Denisovans. Here, we analyze the history of these substitutions and show that some of the genes in which they occur may have been targets of positive selection. We also find that the two changes in the kinetochore scaffold 1 (KNL1) protein, previously believed to be specific to modern humans, were present in some Neandertals. We show that the KNL1 gene of these Neandertals shared a common ancestor with present-day Africans about 200,000 years ago due to gene flow from the ancestors (or relatives) of modern humans into Neandertals. Subsequently, some non-Africans inherited this modern human-like gene variant from Neandertals, but none inherited the ancestral gene variants. These results add to the growing evidence of early contacts between modern humans and archaic groups in Eurasia and illustrate the intricate relationships among these groups.
Synaptotagmin-1 C2B domains cooperatively stabilize the fusion stalk via a master-servant mechanism
Authors: Di Bartolo Ary Lautaro , Masone Diego
Published: November 2021

Synaptotagmin-1 is a low-affinity Ca2+ sensor that triggers synchronous vesicle fusion. It contains two similar C2 domains (C2A and C2B) that cooperate in membrane binding, being the C2B domain the main responsible for the membrane fusion process due to its polybasic patch KRLKKKKTTIKK (321-332). In this work, a master-servant mechanism between two identical C2B domains is shown to control the formation of the fusion stalk. Two regions in C2B are essential for the process, the well-known polybasic patch and a recently described pair of arginines (398,399). The master domain shows strong PIP2 interactions with its polybasic patch and its pair of arginines. At the same time, the servant analogously cooperates with the master to reduce the total work to form the fusion stalk. The strategic mutation (T328E,T329E) in both master and servant domains disrupts the cooperative mechanism, drastically increasing the free energy needed to induce the fusion stalk, however with negligible effects on the master domain interactions with PIP2. These data point to a difference in the behavior of the servant domain, which is unable to sustain its PIP2 interactions neither through its polybasic patch nor through its pair of arginines, in the end losing its ability to assist the master in the formation of the fusion stalk.
Multi-task representations in human cortex transform along a sensory-to-motor hierarchy
Authors: Ito Takuya , Murray John D.
Published: November 2021

Human cognition recruits diverse neural processes, yet the organizing computational and functional architectures remain unclear. Here, we characterized the geometry and topography of multi-task representations across human cortex using functional MRI during 26 cognitive tasks in the same subjects. We measured the representational similarity across tasks within a region, and the alignment of representations between regions. We found a cortical topography of representational alignment following a hierarchical sensory-association-motor gradient, revealing compression-then-expansion of multi-task dimensionality along this gradient. To investigate computational principles of multi-task representations, we trained multi-layer neural network models to transform empirical visual to motor representations. Compression-then-expansion organization in models emerged exclusively in a training regime where internal representations are highly optimized for sensory-to-motor transformation, and not under generic signal propagation. This regime produces hierarchically structured representations similar to empirical cortical patterns. Together, these results reveal computational principles that organize multi-task representations across human cortex to support flexible cognition.
The FORCE panel: An all-in-one SNP marker set for confirming investigative genetic genealogy leads and for general forensic applications
Authors: Tillmar Andreas , Sturk-Andreaggi Kimberly , Daniels-Higginbotham Jennifer , Thomas Jacqueline Tyler , Marshall Charla
Published: December 2021

The FORensic Capture Enrichment (FORCE) panel is an all-in-one SNP panel for forensic applications. This panel of 5,422 markers encompasses common, forensically relevant SNPs (identity, ancestry, phenotype, X- and Y-chromosomal SNPs), a novel set of 3,931 autosomal SNPs for extended kinship analysis, and no clinically relevant/disease markers. The FORCE panel was developed as a custom hybridization capture assay utilizing ∼20,000 baits to target the selected SNPs. Five non-probative, previously identified World War II (WWII) cases were used to assess the kinship panel. Each case included one bone sample and associated family reference DNA samples. Additionally, seven reference quality samples, two 200-year-old bone samples, and four control DNAs were processed for kit performance and concordance assessments. SNP recovery after capture resulted in a mean of ∼99% SNPs exceeding 10X coverage for reference and control samples, and 44.4% SNPs for bone samples. The WWII case results showed that the FORCE panel could predict 1st to 5th degree relationships with strong statistical support (likelihood ratios over 10,000 and posterior probabilities over 99.99%). To conclude, SNPs will be important for further advances in forensic DNA analysis. The FORCE panel shows promising results and demonstrates the utility of a 5,000 SNP panel for forensic applications.