bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling the metabolic evolution of mixotrophic phytoplankton in response to rising ocean surface temperatures
Authors: Gonzalez Logan M. , Proulx Stephen R. , Moeller Holly V.
Published: July 2022

Background

Climate change is expected to lead to warming in ocean surface temperatures which will have unequal effects on the rates of photosynthesis and heterotrophy. As a result of this changing metabolic landscape, directional phenotypic evolution will occur, with implications that cascade up to the ecosystem level. While mixotrophic phytoplankton, organisms that combine photosynthesis and heterotrophy to meet their energetic and nutritional needs, are expected to become more heterotrophic with warmer temperatures due to heterotrophy increasing at a faster rate than photosynthesis, it is unclear how evolution will influence how these organisms respond to warmer temperatures. In this study, we used adaptive dynamics to model the consequences of temperature-mediated increases in metabolic rates for the evolution of mixotrophic phytoplankton, focusing specifically on phagotrophic mixotrophs.

Results

We find that mixotrophs tend to evolve to become more reliant on phagotrophy as temperatures rise, leading to reduced prey abundance through higher grazing rates. However, if prey abundance becomes too low, evolution favors greater reliance on photosynthesis. These responses depend upon the trade-off that mixotrophs experience between investing in photosynthesis and phagotrophy. Mixotrophs with a convex trade-off maintain mixotrophy over the greatest range of temperatures; evolution in these “generalist” mixotrophs was found to exacerbate carbon cycle impacts, with evolving mixotrophs exhibiting increased sensitivity to rising temperature.

Conclusions

Our results show that mixotrophs may respond more strongly to climate change than predicted by phenotypic plasticity alone due to evolutionary shifts in metabolic investment. However, the type of metabolic trade-off experienced by mixotrophs as well as ecological feedback on prey abundance may ultimately limit the extent of evolutionary change along the heterotrophy-phototrophy spectrum.
Suppression of systemic T cell immunity to viral infection during liver injury is prevented by inhibition of interferon and IL-10 signaling
Authors: Hackstein Carl-Philipp , Spitzer Jasper , Symeonidis Konstantinos , Horvatic Helena , Bedke Tanja , Steglich Babett , Assmus Lisa M. , Odainic Alexandru , Kessler Nina , Klein Sabine , Beyer Marc , Schmithausen Ricarda , Latz Eicke , Kurts Christian , Trebicka Jonel , Flavell Richard A. , Garbi Natalio , Roers Axel , Huber Samuel , Schmidt Susanne V. , Knolle Percy A. , Abdullah Zeinab
Published: July 2022

Patients with liver injury such as cirrhosis are at increased risk of intractable viral infections and are hyporesponsive to vaccination. Here, we report that liver injury leads to inhibition of systemic T cell immunity (LIST), which abrogated anti-viral immunity and caused persistent infection in preclinical liver injury models. Enhanced gut microbial-translocation but not dysbiosis induced tonic type-I-interferon (IFN) signaling in hepatic myeloid cells, which was responsible for their excessive production of IL-10 after viral infection. Antibiotic treatment reducing intestinal microbial burden or inhibition of IFN- and IL-10-signaling all restored anti-viral immunity without immune pathology. Importantly, inhibition of IL-10 restored virus-specific immune responses to vaccination in cirrhotic patients. Thus, LIST results from sequential events involving intestinal microbial translocation, hepatic myeloid cell-derived IFN-/IL-10 expression, and finally inhibitory IL-10 receptor-signaling in T cells, of which IL-10Rα-signaling may serve as target to reconstitute anti-viral T cell immunity in cirrhotic patients.
Selection of an Ideal Machine Learning Framework for Predicting Perturbation Effects on Network Topology of Bacterial KEGG Pathways
Authors: Robben Michael , Nasr Mohammad Sadegh , Das Avishek , Huber Manfred , Jaworski Justyn , Weidanz Jon , Luber Jacob
Published: July 2022

Biological networks for bacterial species are used to assign functional information to newly sequenced organisms but network quality can be largely affected by poor gene annotations. Current methods of gene annotation use homologous alignment to determine orthology, and have been shown to degrade network accuracy in non-model bacterial species. To address these issues in the KEGG pathway database, we investigated the ability for machine learning (ML) algorithms to re-annotate bacterial genes based on motif or homology information. The majority of the ensemble, clustering, and deep learning algorithms that we explored showed higher prediction accuracy than CD-hit in predicting EC ID, Map ID, and partial Map ID. Motif-based, machine-learning methods of annotation in new species were more accurate, faster, and had higher precisionrecall than methods of homologous alignment or orthologous gene clustering. Gradient boosted ensemble methods and neural networks also predicted higher connectivity of networks, finding twice as many new pathway interactions than blast alignment. The use of motif-based, machine-learning algorithms in annotation software will allow researchers to develop powerful network tools to interact with bacterial microbiomes in ways previously unachievable through homologous sequence alignment.

CCS CONCEPTS

• Applied computing → Computational biology; Life and medical sciences; Bioinformatics; • Computing methodologies → Machine learning algorithms; Machine learning approaches.

ACM Reference Format

Michael Robben, Mohammad Sadegh Nasr, Avishek Das, Manfred Huber, Justyn Jaworski, Jon Weidanz, and Jacob Luber. 2022. Selection of an Ideal Machine Learning Framework for Predicting Perturbation Effects on Network Topology of Bacterial KEGG Pathways. In The 13th ACM Conference on Bioinformatics, Computational Biology, and Health Informatics, August 07–10, 2022, Chicago, IL. ACM, New York, NY, USA, 11 pages. https://doi.org/XXXXXXX.XXXXXXX
Temporal dynamics of metabolic acquisition in grafted engineered human liver tissue
Authors: Fortin Chelsea L. , McCray Tara N. , Saxton Sarah H. , Johansson Fredrik , Andino Christian B. , Mene Jonathan , Wang Yuliang , Stevens Kelly R.
Published: July 2022

Liver disease affects millions globally and end-stage liver failure is only cured by organ transplant. Unfortunately, there is a growing shortage of donor organs and disparities in equitable access to transplants among different populations. Less than 10% of global transplantation needs are currently met, highlighting the demand for alternative therapies. Engineered liver tissue grafts that supplement organ function could address these demands. While engineered liver tissues built from human hepatocytes, endothelial cells, and fibroblasts encased in hydrogel have been successfully engrafted in rodent models previously, the extent to which these tissues express human liver metabolic genes and proteins remains unknown. Here, we built engineered human liver tissues and characterized their engraftment, expansion, and metabolic phenotype at sequential stages post-implantation by RNA sequencing, histology, and host serology. Expression of metabolic genes was observed at weeks 1-2, followed by cellular organization into hepatic cords by weeks 4-9.5. Furthermore, grafted engineered tissues exhibited progressive spatially restricted expression of critical functional proteins known to be zonated in the native human liver. To our knowledge, this is the first report of engineered human liver tissue zonation after implantation in vivo, which could have important translational implications for this field.
Single-cell profiling identifies ACE+granuloma macrophages as a non-permissive niche for intracellular bacteria during persistentSalmonellainfection
Authors: Pham Trung H. M. , Xue Yuan , Brewer Susan M. , Bernstein KE , Quake Stephen R. , Monack Denise M.
Published: July 2022

Macrophages mediate key antimicrobial responses against intracellular bacterial pathogens, such asSalmonella enterica. Yet, they can also act as a permissive niche for these pathogens to persist in infected tissues within granulomas, which are immunological structures comprised of macrophages and other immune cells. We apply single-cell transcriptomics to investigate macrophage functional diversity during persistentSalmonella entericaserovar Typhimurium (STm) infection in mice. We identify determinants of macrophage heterogeneity in infected spleens and describe populations of distinct phenotypes, functional programming, and spatial localization. Using aSTm mutant with impaired ability to polarize macrophage phenotypes, we find that angiotensin converting enzyme (ACE) defines a granuloma macrophage population that is non-permissive for intracellular bacteria and their abundance anticorrelates with tissue bacterial burden. Disruption of pathogen control by neutralizing TNF preferentially depletes ACE+macrophages in infected tissues. Thus ACE+macrophages have differential capacity to serve as cellular niche for intracellular bacteria to establish persistent infection.

Teaser

This study shows that ACE+granuloma macrophages have restricted capacity to act as a cellular niche that enables intracellular bacterial persistence.
Allelic diversity of the pharmacogene CYP2D6 in New Zealand Māori and Pacific peoples
Authors: Hitchman Leonie M. , Faatoese Allamanda , Merriman Tony R. , Miller Allison L. , Liau Yusmiati , Graham Oscar E.E. , Kee Ping Siu , Pearson John F. , Fakahau Tony , Cameron Vicky A. , Kennedy Martin A. , Maggo Simran D.S.
Published: July 2022

The enzyme cytochrome P450 2D6 (CYP2D6) metabolises approximately 25% of commonly prescribed drugs, including analgesics, anti-hypertensives, and anti-depressants, among many others. Genetic variation in drug metabolising genes can alter how an individual responds to prescribed drugs, including predisposing to adverse drug reactions. The majority of research on the CYP2D6 gene has been carried out in European and East Asian populations, with Indigenous and minority populations greatly underrepresented. However, genetic variation is often population specific and analysis of diverse ethnic groups can reveal differences in alleles that may be of clinical significance. For this reason, we set out to examine the range and frequency of CYP2D6 variants in a sample of 202 Māori and Pacific people living in Aotearoa (New Zealand). We carried out a long PCR to isolate the CYP2D6 region before performing nanopore sequencing to identify all variants and alleles in these samples. We identified eleven novel variants, three of which were exonic missense variations. Six of these occurred in single samples and one was found in 19 samples (9.4% of the cohort). The remaining four novel variants were identified in two samples each. In addition, five new suballeles of CYP2D6 were identified. One striking finding was that CYP2D6*71, an allele of unknown functional status which has been rarely observed in previous studies, occurs at a relatively high frequency (9.2%) within this cohort. These data will help to ensure that CYP2D6 genetic analysis for pharmacogenetic purposes can be carried out accurately and effectively in this population group.
AIFS: A novel perspective, Artificial Intelligence infused wrapper based Feature Selection Algorithm on High Dimensional data analysis
Authors: Jain Rahi , Xu Wei
Published: July 2022

Background

Feature selection is important in high dimensional data analysis. The wrapper approach is one of the ways to perform feature selection, but it is computationally intensive as it builds and evaluates models of multiple subsets of features. The existing wrapper approaches primarily focus on shortening the path to find an optimal feature set. However, these approaches underutilize the capability of feature subset models, which impacts feature selection and its predictive performance.

Method and Results

This study proposes a novel Artificial Intelligence infused wrapper based Feature Selection (AIFS), a new feature selection method that integrates artificial intelligence with wrapper based feature selection. The approach creates a Performance Prediction Model (PPM) using artificial intelligence (AI) which predicts the performance of any feature set and allows wrapper based methods to predict and evaluate the feature subset model performance without building actual model. The algorithm can make wrapper based method more relevant for high-dimensional data and is flexible to be applicable in any wrapper based method. We evaluate the performance of this algorithm using simulated studies and real research studies. AIFS shows better or at par feature selection and model prediction performance than standard penalized feature selection algorithms like LASSO and sparse partial least squares.

Conclusion

AIFS approach provides an alternative method to the existing approaches for feature selection. The current study focuses on AIFS application in continuous cross-sectional data. However, it could be applied to other datasets like longitudinal, categorical and time-to-event biological data.
Stimulus duration encoding occurs early in the moth olfactory pathway
Authors: Barta Tomas , Monsempès Christelle , Demondion Elodie , Chatterjee Abhishek , Kostal Lubomir , Lucas Philippe
Published: July 2022

Pheromones convey rich ethological information and guide insects’ search behavior. Insects navigating in turbulent environments are tasked with the challenge of coding the temporal structure of an odor plume, obliging recognition of the onset and offset of whiffs of odor. The coding mechanisms that shape odor offset recognition remain elusive. We designed a device to deliver sharp pheromone pulses and simultaneously measured the response dynamics from pheromone-tuned olfactory receptor neurons (ORNs) in male moths andDrosophila. We show that concentration-invariant stimulus duration encoding is implemented in moth ORNs by spike frequency adaptation at two time scales. A linear-nonlinear model fully captures the underlying neural computations and offers an insight into their biophysical mechanisms.Drosophilause pheromonecis-vaccenyl acetate (cVA) only for very short distance communication and are not faced with the need to encode the statistics of the cVA plume. Their cVA-sensitive ORNs are indeed unable to encode odor-off events. Expression of moth pheromone receptors inDrosophilacVA-sensitive ORNs indicates that stimulus-offset coding is receptor independent. In moth ORNs, stimulus-offset coding breaks down for short (<200 ms) whiffs. This physiological constraint matches the behavioral latency of switching from the upwind surge to crosswind cast flight upon losing contact with the pheromone.
Climate and Morphology Drive Breeding Periods in Frogs
Authors: Juarez Bryan H , O’Connell Lauren A
Published: July 2022

Aim

Climate can have profound effects on reproductive behavior and physiology, especially in ectothermic animals. Breeding periods in amphibians have received little attention despite amphibian reliance on climate and water due to their reproductive biology and ecological diversity. The aim of this study is to determine how global climate impacts breeding periods in ectothermic animals through physiology, body size, and microhabitat.

Location

All continents, except Antarctica.

Time period

Breeding periods and climate both dating as far back as 1970.

Major taxa studied

497 (7%) anuran species of 41 (76%) families.

Methods

We used phylogenetic comparative methods to analyze a global dataset of frog breeding periods, climate, body size, and microhabitat for 497 species.

Results

We found support for a global latitudinal gradient of breeding periods which are longer in the warmer, wetter tropics while shorter in the colder, dryer temperate zone. Latitudinal and non-latitudinal global patterns of breeding period were composites of the same patterns in the temperate and tropical zones. However, the effect of climate and body size in each zone is unique. Breeding periods displayed weak phylogenetic signal and were similar across microhabitats.

Main conclusions

Breeding periods show a global latitudinal gradient but this concept breaks down within the tropical zone. Our results are consistent with the importance of physiology in driving breeding periods and we describe how breeding period and body size may exhibit trade-offs which make latitudinal gradients context-dependent. Our results set within an ecophysiological framework have broad implications for understanding reproductive diversity in other ectothermic organisms.
Independent evolution of influenza A virus H1N1 in pigs in Guatemala
Authors: Ortiz Lucia , Geiger Ginger , Ferreri Lucas , Moran David , Alvarez Danilo , Gonzalez-Reiche Ana Silvia , Mendez Dione , Rajao Daniela , Cordon-Rosales Celia , Perez Daniel R.
Published: July 2022

Commercial swine farms provide unique systems for interspecies transmission of influenza A viruses (FLUAVs) at the animal-human interface. Bidirectional transmission of FLUAVs between pigs and humans plays a significant role in the generation of novel strains that become established in the new host population. Active FLUAV surveillance was conducted for two years on a commercial pig farm in Southern Guatemala with no history of FLUAV vaccination. Nasal swabs (n=2,094) from fattening pigs (6 to 24 weeks old) with respiratory signs were collected from May 2016 to February 2018. Swabs were screened for FLUAV by RRT-PCR and full virus genomes of FLUAV-positive swabs were sequenced by next-generation sequencing (NGS). FLUAV prevalence was 12.0% (95% CI: 10.6% – 13.4%) with two distinct periods of high infection. All samples were identified as FLUAVs of the H1N1 subtype within the H1 swine clade 1A.3.3.2 and whose ancestors are the human origin 2009 H1N1 influenza pandemic virus (H1N1 pdm09). Compared to the prototypic reference segment sequence, 10 amino acid signatures were observed on relevant antigenic sites on the hemagglutinin. We also found that Guatemalan swine-origin FLUAVs show independent evolution from other H1N1 pdm09 FLUAVs circulating in Central America. The zoonotic risk of these viruses remains unknown, but strongly calls for continued FLUAV surveillance in pigs in Guatemala.

Importance

Despite increased surveillance efforts, the epidemiology of FLUAVs circulating in swine in Latin America remains understudied. For instance, the 2009 H1N1 influenza pandemic strain (H1N1 pdm09) emerged in Mexico, but its circulation remained undetected in pigs. In Central America, Guatemala is the country with the largest swine industry. We found a unique group of H1N1 pdm09 sequences that suggests independent evolution from similar viruses circulating in Central America. These viruses may represent the establishment of a novel genetic lineage with the potential to reassort with other co-circulating viruses, and whose zoonotic risk remains to be determined.
Highly pathogenic avian influenza H5N1 virus infections in wild red foxes (Vulpes vulpes) show neurotropism and adaptive virus mutations
Authors: Bordes Luca , Vreman Sandra , Heutink Rene , Roose Marit , Venema Sandra , Pritz-Verschuren Sylvia B E , Rijks Jolianne M , Gonzales José L , Germeraad Evelien A , Engelsma Marc , Beerens Nancy
Published: July 2022

During the 2020-2022 epizootic of highly pathogenic avian influenza virus (HPAI) several infections of mammalian species were reported in Europe. In the Netherlands, HPAI H5N1 virus infections were detected in three wild red foxes (Vulpes vulpes) that were submitted with neurological symptoms between December 2021 and February 2022. Histopathological analysis demonstrated the virus was mainly present in the brain, with limited or no detection in the respiratory tract and other organs. Phylogenetic analysis showed the three fox viruses were not closely related, but were related to HPAI H5N1 clade 2.3.4.4b viruses found in wild birds. In addition, limited virus shedding was detected suggesting the virus was not transmitted between the foxes. Genetic analysis demonstrated the presence of mammalian adaptation E627K in the polymerase basic two (PB2) protein of the two fox viruses. In both foxes the avian (PB2-627E) and the mammalian (PB2-627K) variant were present as a mixture in the virus population, which suggests the mutation emerged in these specific animals. The two variant viruses were isolated and virus replication and passaging experiments were performed. These experiments showed mutation PB2-627K increases replication of the virus in mammalian cell lines compared to the chicken cell line, and at the lower temperatures of the mammalian upper respiratory tract. This study showed the HPAI H5N1 virus is capable of adaptation to mammals, however more adaptive mutations are required to allow efficient transmission between mammals. Therefore, surveillance in mammals should be expanded to closely monitor the emergence of zoonotic mutations for pandemic preparedness.

IMPORTANCE

Highly pathogenic avian influenza (HPAI) viruses caused high mortality amongst wild birds in 2021-2022 in the Netherlands. Recently three wild foxes were found to be infected with HPAI H5N1 viruses, likely by feeding on infected birds. Although HPAI is a respiratory virus, in these foxes the viruses were mostly detected in the brain. Two viruses isolated from the foxes contained a mutation that is associated with adaptation to mammals. We show the mutant virus replicates better in mammalian cells than in avian cells, and at the lower body temperature of mammals. More mutations are required before viruses can transmit between mammals, or can be transmitted to humans. However, the infections in mammalian species should be closely monitored to swiftly detect mutations that may increase the zoonotic potential of the HPAI H5N1 viruses as these may threaten public health.
Cysteine dependent conformation heterogeneity of Shigella flexneri autotransporter IcsA and implications in its function
Authors: Qin Jilong , Hong Yaoqin , Morona Renato , Totsika Makrina
Published: July 2022

Shigella IcsA is a versatile surface virulence factor required for both early and late pathogenesis stages, extracellularly to intracellularly. Despite IcsA serving as a model Type V secretion system (T5SS) autotransporter to study host pathogen interactions, its detailed molecular architecture is poorly understood. Recently, IcsA was found to switch to a different conformation for its adhesin activity upon sensing of the host stimuli by Shigella Type III secretion system (T3SS). Here, we report that the single cysteine residue (C130) near the N-terminus of IcsA passenger has a role in IcsA adhesin activity. We also show that the IcsA passenger (IcsAp) exists in multiple conformations, and the conformation populations are influenced by a central pair of cysteine residues (C375 and C379), which is not previously reported for any Type V autotransporter passengers. Disruption of either or both central cysteine residues alters the exposure of IcsA epitopes to polyclonal anti-IcsA antibodies previously shown to block Shigella adherence, yet without loss of IcsA intracellular functions in actin-based motility (ABM). Anti-IcsA antibody reactivity was restored when the IcsA paired cysteine substitution mutants were expressed in a ∆ipaD background with a constitutively active T3SS, highlighting an interplay between T3SS and T5SS. The work here uncovers a novel molecular switch empowered by a centrally localised, short-spaced cysteine pair in the Type V autotransporter IcsA that ensures conformational heterogeneity to aid IcsA evasion of host immunity.

Importance

Shigella species are the leading cause of diarrheal related death globally by causing bacillary dysentery. The surface virulence factor IcsA which is essential for Shigella pathogenesis is a unique multi-functional autotransporter that is responsible for cell adhesion, and actin-based motility, yet detailed mechanistic understanding is lacking. Here, we show that the three cysteine residues in IcsA contribute to the protein’s distinct functions. The N terminus cysteine residue within the IcsA passenger domain plays a role in adhesin function, while a centrally localised cysteine pair provides conformational heterogeneity resulting in IcsA molecules with different reactivity to adhesion-blocking anti-IcsA antibodies. In synergy with the Type III secretion system, this molecular switch preserves biological function in distinct IcsA conformations for cell adhesion, actin-based motility and autophagy escape, providing a potential strategy by which Shigella evade host immunity targeting of this essential virulence factor.
Morphology of proximal and distal human semitendinosus compartments and the effects of distal tendon harvesting for anterior cruciate ligament reconstruction
Authors: Kositsky Adam , Maas Huub , Barrett Rod S. , Kennedy Ben , Stenroth Lauri , Korhonen Rami K. , Vertullo Chris J. , Diamond Laura E. , Saxby David J.
Published: July 2022

The human semitendinosus muscle is characterized by a tendinous inscription separating proximal (STprox) and distal (STdist) neuromuscular compartments. As each compartment is innervated by separate nerve branches, potential exists for the compartments to operate and be controlled independently. However, the morphology and function of each compartment have not been thoroughly examined in a human adult population. Further, the distal semitendinosus tendon is typically harvested for use in anterior cruciate ligament reconstruction (ACLR) surgery, which induces long-term morphological changes to the semitendinosus muscle-tendon unit. It remains unknown if muscle morphological alterations following ACLR are uniform between STproxand STdist. Here, we performed magnetic resonance imaging on ten individuals who had undergone ACLR involving an ipsilateral distal semitendinosus tendon graft 14 ± 6 months prior, extracting morphological parameters of the whole ST muscle and each individual muscle compartment from both the (non-injured) contralateral and surgical legs. In the contralateral non-surgical leg, volume and length of STproxwere lower than STdist. No between-compartment differences in volume or length were found for ACLR legs, likely due to greater shortening of STdistcompared to STproxafter ACLR. The maximal anatomical cross-sectional area of both compartments was substantially smaller on the ACLR leg, but did not differ between STproxand STdiston either leg. The absolute and relative differences in STproxmorphology on the ACLR leg were strongly correlated with the corresponding between-leg differences in STdistmorphological parameters. Specifically, greater morphological differences in one compartment were highly correlated with large differences in the other compartment, and vice versa for smaller differences. These relationships indicate that despite the heterogeneity in compartment length and volume, compartment atrophy is not independent or random. Further, the tendinous inscription endpoints were generally positioned at the same proximodistal level as the compartment maximal anatomical cross-sectional areas, providing a wide area over which the tendinous inscription could mechanically interact with compartments. Overall, results suggest the two human semitendinosus compartments are not mechanically independent.
Pin-pointing the key hubs in the IFN-γ pathway responding to SARS-CoV-2 infection
Authors: Toro Ayelen , Lage-Vickers Sofia , Bizzotto Juan , Vilicich Felipe , Sabater Agustina , Pascual Gaston , Ledesma-Bazan Sabrina , Sanchis Pablo , Ruiz Maria S. , Arevalo Ana P. , Porfido Jorge L. , Seniuk Rocio , Labanca Estefania , Anselmino Nicolas , Navone Nora , Alonso Daniel F. , Vazquez Elba , Crispo Martina , Cotignola Javier , Gueron Geraldine
Published: July 2022

Interferon gamma may be a potential adjuvant immunotherapy for COVID-19 patients. In this work, we assessed gene expression profiles associated with the IFN-γ pathway in response to SARS-CoV-2 infection. Employing a case-control study from SARS-CoV-2 positive and negative patients, we identified IFN-γ-associated pathways to be enriched in positive patients. Bioinformatics analyses showed upregulation ofMAP2K6, CBL, RUNX3, STAT1andJAK2in COVID-19 positive vs. negative patients. A positive correlation was observed betweenSTAT1/JAK2, which varied alongside the patient’s viral load. Expression ofMX1, MX2, ISG15andOAS1(4 well-known IFN-stimulated genes (ISGs)) displayed upregulation in COVID-19 positive vs. negative patients. Integrative analyses showcased higher levels of ISGs which were associated with increased viral load andSTAT1/JAK2expression. Confirmation of ISGs up-regulation was performedin vitrousing the A549 lung cell line treated with Poly(I:C), a synthetic analog of viral double-stranded RNA; and in different pulmonary human cell lines and ferret tracheal biopsies infected with SARS-CoV-2. A pre-clinical murine model of coronavirus infection confirmed findings displaying increased ISGs in the liver and lungs from infected mice. Altogether, these results demonstrate the role of IFN-γ and ISGs in response to SARS-CoV-2 infection, highlighting alternative druggable targets that can boost the host response.
Predictive Modelling of Service Pathways to Admission in Psychiatric Residential Treatment Facilities
Authors: Vsevolozhskaya Olga A. , Turner Brian W. , Shimshock Stephen M. , Harp Kathi L.H. , Tong Xiaoran , Lyons John S.
Published: July 2022

Objective

To develop and test predictive models of admissions to a psychiatric residential treatment facility (PRTF) in transitional age youth using routinely collected health insurance claims and enrollment data.

Data Sources

We used outpatient service and pharmaceutical claims from Medicaid beneficiaries aged 6-to 21-years old in Kentucky for the years 2010-2017.

Study Design

We assessed over 1,250 predictors (derived from Medicaid claims data) prior to the first PRTF admission. An ensemble machine learning (ML) algorithm based on logistic regression models fitted to a random subsample of the original data was used to predict pathways to the first PRTF admission. Discrimination performance of the ML ensemble was evaluated by comparing predictions to actual outcomes and calculating area under the curve (AUC), accuracy, sensitivity, and specificity. Additionally, a multivariate logistic regression model was fit to investigate the contribution of the continuity of mental health care after the initial PRTF admission on the risk of readmission.

Data Collection/Extraction Methods

We identified N = 519,011 unique children and youth with at least one outpatient service or pharmaceutical claim during our study period (January 1, 2010 through December 31, 2017).

Principal Findings

Fewer than 0.5% of children and youth in Kentucky had an episode of PRTF admission. Despite a very low prevalence of PRTF admission, classification accuracy of the ML ensemble for identifying PRTF youth achieved over 90% accuracy (AUC = 0.96). Factors associated with the initial PRTF admission were having been prescribed anti-psychotic and anti-manic medications, and receiving outpatient psychiatric care. Within six months after the initial PRTF discharge, there was a surprising drop in service utilization with a large proportion of youth not appearing to receive any follow-up care.

Conclusions

Despite the fact that admission into a PRTF was a relatively rare event, our findings suggest that it is a predictable event among youth with identified mental health conditions who are receiving care in the community.

What is known on this topic

After psychiatric hospitalization, PRTF treatment is the most expensive and restrictive intervention available to serve children and youth.

Previous research examining predictors of PRTF entry using Medicaid reimbursement data showed that clinical factors were strong predictors of hospitalization.

What this study adds

We provide a comprehensive analysis of the factors beyond clinical diagnoses that lead to PRTF entry.

We also seek to identify whether any specific patterns of service and/or pharmacy claims utilization are associated with reducing the likelihood of readmission.
Autonomous Remotely Controlled Closed System Transgenic Cell Technologies Robot: CRISPR.BOT
Authors: Erkek Fatmanur , Gulden Gamze , Sert Berranur , Yilmaz Menekse Cagla , Odabas Sibel Pinar , Bal Enes , Yelgen Gamze , Teymur Tarik , Ay Yasin , Dogdu Solen , Tiryaki Nulifer Neslihan , Baran Buse , Gelsin Beste , Araz Hasret , Cavrar Ilayda , Tastan Cihan
Published: July 2022

In manually advancing experimental processes, the stages may be long-term and need to be repeated. Human errors with the repetition of the steps turn into a time-consuming and high-cost for the experiment processes. For this reason, autonomous liquid processing systems are promising technologies. However, in addition to the high cost of fully automatic systems, their maintenance is also quite expensive. Furthermore, conventional systems usually require system-specific protocols and laboratory equipment. Here, we aimed to show that the autonomous robotic systems may provide a closed and error-free molecular biology bench to perform genetic engineering automatically, quickly, and practically 7-24. In this way, researchers can save time from repetitive experiment processes and perform BSL3 experiments including pathogens without human contact. In this study, we built CRISPR.BOT robotic systems to perform Green Fluorescent Protein (GFP) encoding plasmid DNA transfer into bacteria, lentiviral transduction of the gene-of-interests including GFP encoding gene and CRISPR-Cas9 with gRNAs genetic editing system to a human cell line. Furthermore, we showed that CRISPR.BOT system achieved to accomplish single-cell subcloning of GFP+ CRISPR-gRNA+ cells with 90-100% purity. This study suggests that CRISPR.BOT-like approaches may reduce manpower in a safely closed bench in which molecular biology and genetic engineering can be done by robots in a closed system without touching pathogenic microorganisms (virus or bacteria, for example, SARS CoV-2 virus). Furthermore, LEGO Mindstorms robots showed to have the potential to be used in daily laboratory routines with their cost-effectiveness reduced by up to 50 times compared to normal commercial robots.
Measuring the threat from a distance: insight into the complexity and perspectives for implementing sentinel plantation to test host range ofXylella fastidiosa
Authors: Casarin Noemi , Hasbroucq Séverine , López-Mercadal Júlia , Miranda Miguel Ángel , Bragard Claude , Grégoire Jean-Claude
Published: July 2022

The sentinel plantation concept consists of assessing the impact of exotic factors, such as pests and pathogens, on plants of interest by planting them out of their native range. This tool is a way to enhance knowledge for pest risk analysis (PRA) by guiding decisions on how quarantine organisms should be regulated and where to focus prevention and surveillance efforts for an early detection. In this study, the sentinel method was used in the case of research onXylella fastidiosa, a plant pathogenic bacterium that has recently been found established in southern Europe, but whose potential impact and possible host range are still poorly documented in northern areas where the bacterium is not known to occur. To improve knowledge on the susceptibility of potential hosts ofX. fastidiosain northern Europe, a sentinel plantation ofPrunus domesticacv. Opal,Quercus petraeaandSalix albawas established in theX. fastidiosa-infected area of Majorca. In order to assess the circulation of the bacterium in the sentinel plot and around it, surveys of the local flora and insect vectors were carried out, as well as the planting of a network of rosemary “spy plants”. Symptomatic monitoring and molecular analyses were performed on the sentinel plants for four years. During these years,X. fastidiosawas never detected in our sentinel plants most likely because of the low infectivity pressure recorded in the surroundings. This study underlines the complexity of conducting sentinel plantation assays combined withX. fastidiosaresearch, highlighting the need for long-term investigation and questioning the efficiency of the sentinel tool. However, this study is placed in perspective with other valuable sentinel plantations. It also highlights the complementarity of the tool and proposes elements to improve or reorient the implementation of future sentinel projects.
Age-associated DNA methylation changes in Xenopus frogs
Authors: Morselli Marco , Bennett Ronan , Shaidani Nikko-Ideen , Horb Marko , Peshkin Leonid , Pellegrini Matteo
Published: July 2022

Age-associated changes in DNA methylation have been widely established and characterized in mammals but not yet extended to other species. We present clear evidence that the aquatic vertebrate species Xenopus tropicalis displays clear patterns of age-associated changes in DNA methylation. This observation allows us to leverage the unique resources available for Xenopus to study how DNA methylation relates to other hallmarks of aging. We have generated whole genome bisulfite sequencing (WGBS) profiles in nine samples representing young, mature and old adults and characterize the gene- and chromosome-scale changes. Moreover, we selected a few thousands CpG sites to expand the findings in a larger cohort of individuals through targeted DNA methylation analysis to produce a cost effective epigenetic clock assay.
Obesity promotes Fumonisin B1 toxicity and induces hepatitis
Authors: Dopavogui Léonie , Régnier Marion , Polizzi Arnaud , Ponchon Quentin , Smati Sarra , Klement Wendy , Lasserre Frédéric , Lukowicz Céline , Lippi Yannick , Fougerat Anne , Bertrand-Michel Justine , Naylies Claire , Canlet Cécile , Debrauwer Laurent , Gamet-Payrastre Laurence , Dauriat Charlène , Casas Josefina , Croubels Siska , De Baere Siegrid , Burger Hester M. , Chassaing Benoit , Ellero-Simatos Sandrine , Guillou Hervé , Oswald Isabelle P. , Loiseau Nicolas
Published: July 2022

Background and aim

Obesity is a major public health issue worldwide. Obesity is associated with chronic inflammation that contribute to long-term complications, including insulin resistance, type 2 diabetes and non-alcoholic fatty liver disease. We hypothesized that obesity may also influence the sensitivity to food contaminants, such as fumonisin B1 (FB1), a mycotoxin produced mainly by theFusarium verticillioides. FB1, a common contaminant of corn, is the most abundant and best characterized member of the fumonisins family. This toxin provokes severe mycotoxicosis in animals, which leads to hepatotoxicity and alterations in the immune response and intestinal barrier permeability. We investigated here whether diet-induced obesity could modulate the sensitivity to oral FB1 exposure, with emphasis on gut health and hepatotoxicity.

Methods

The metabolic effects of FB1 were assessed in obese and non-obese male C57BL/6J mice. For 15 weeks, mice received a high-fat diet (HFD) or normal chow diet (CHOW). During the last three weeks, mice were exposed or not to FB1 (10 mg/kg body weight/day) through drinking water.

Results

As expected, HFD feeding induced significant body weight gain, glucose intolerance, and hepatic steatosis. FB1-exposed mice displayed a higher sphinganine/sphingosine ratio, a well-known FB1 biomarker of exposure, due to inhibition of ceramide synthases activity by FB1. Combined exposure to HFD and FB1 resulted in body weight loss and a decrease in fasting blood glucose level. This co-exposition also induces gut dysbiosis, an increase in plasma FB1 level, a decrease in liver weight and hepatic steatosis. Moreover, plasma transaminase levels were significantly increased and associated with liver inflammation in HFD/FB1-treated mice. Liver gene expression analysis revealed that the combined exposure to HFD and FB1 was associated with reduced expression of genes involved in lipogenesis and increased expression of immune response and cell cycle-associated genes.

Conclusion

These results suggest that, in the context of obesity, FB1 exposure promotes gut dysbiosis and severe liver inflammation. To our knowledge, this study provides the first example of obesity-induced hepatitis in response to a food contaminant.
Deep self-supervised learning for biosynthetic gene cluster detection and product classification
Authors: Rios-Martinez Carolina , Bhattacharya Nicholas , Amini Ava P. , Crawford Lorin , Yang Kevin K.
Published: July 2022

Natural products are chemical compounds that form the basis of many therapeutics used in the pharmaceutical industry. In microbes, natural products are synthesized by groups of colocalized genes called biosynthetic gene clusters (BGCs). With advances in high-throughput sequencing, there has been an increase of complete microbial isolate genomes and metagenomes, from which a vast number of BGCs are undiscovered. Here, we introduce a self-supervised learning approach designed to identify and characterize BGCs from such data. To do this, we represent BGCs as chains of functional protein domains and train a masked language model on these domains. We assess the ability of our approach to detect BGCs and characterize BGC properties in bacterial genomes. We also demonstrate that our model can learn meaningful representations of BGCs and their constituent domains, detect BGCs in microbial genomes, and predict BGC product classes. These results highlight self-supervised neural networks as a promising framework for improving BGC prediction and classification.

Author summary

Biosynthetic gene clusters (BGCs) encode for natural products of diverse chemical structures and function, but they are often difficult to discover and characterize. Many bioinformatic and deep learning approaches have leveraged the abundance of genomic data to recognize BGCs in bacterial genomes. However, the characterization of BGC properties remains the main bottleneck in identifying novel BGCs and their natural products. In this paper, we present a self-supervised masked language model that learns meaningful representations of BGCs with improved downstream detection and classification.
Thermal cycling-hyperthermia ameliorates cognitive impairment of intracerebroventricular Aβ25-35-induced Alzheimer’s disease in C57BL/6 mice
Authors: Kuo Yu-Yi , Chen Wei-Ting , Lin Guan-Bo , Chen You-Ming , Liu Hsu-Hsiang , Chao Chih-Yu
Published: July 2022

Despite continuation of some controversies, Alzheimer’s disease (AD), the most common cause of dementia nowadays, has been widely believed to derive mainly from excessive β-amyloid (Aβ) aggregation, that would increase reactive oxygen species (ROS) and induce neuroinflammation, leading to neuron loss and cognitive impairment. Existing drugs on Aβ have been ineffective or offer only temporary relief at best, due to blood-brain barrier or severe side effects. The study employed thermal cycling-hyperthermia (TC-HT) as an alternative AD therapy and compared its effect with continuous hyperthermia (HT)in vivo. It established an AD mice model via intracerebroventricular (i.c.v.) injection of Aβ25-35, proving that TC-HT is much more effective in alleviating its performance decline in Y-maze and NOR test, in comparison with HT. In addition, TC-HT also exhibits a better performance in decreasing the hippocampal Aβ and BACE1 expressions as well as the neuroinflammation markers Iba-1 and GFAP levels. Furthermore, the study finds that TC-HT can elevate more protein expressions of IDE and antioxidative enzyme SOD2 than HT. Besides, after establishment of neuroprotective mechanism, removal of TC-HT-induced ROS can further augment protection of neural cells against Aβ. In sum, the study proves the potential of TC-HT in AD treatment, which can be put into clinical application with the use of focused ultrasound (FUS).
Engineering cellular communication between light-activated synthetic cells and bacteria
Authors: Smith Jefferson M. , Hartmann Denis , Booth Michael J.
Published: July 2022

Gene-expressing compartments assembled from simple, modular parts, are a versatile platform for creating minimal synthetic cells. In a manner synonymous with natural cells, these life-like assemblies utilise information encoded in DNA within the compartment’s interior to dictate which proteins are expressed and consequently the overall function of the synthetic cell. Hence, by incorporating gene regulatory motifs into the DNA templates, in situ gene expression can be controlled according to specific stimuli. In this work, cell-free protein synthesis within synthetic cells was controlled using light by encoding genes of interest on light-activated DNA templates. Light-activated DNA contained a photocleavable blockade within the T7 promoter region that tightly repressed transcription until the blocking groups were removed with UV light. In this way, synthetic cells were activated remotely, in a spatiotemporally controlled manner. By applying this strategy to the expression of an acyl homo-serine lactone synthetase, BjaI, quorum-sensing based communication between synthetic cells and bacteria was controlled with light. This work provides a framework for the remote-controlled production and delivery of small molecules from non-living matter to living matter, with applications in biology and medicine.
Fenretinide inhibits obesity and fatty liver disease but induces Smpd3 to increase serum ceramides and worsen atherosclerosis in LDLR-/- mice
Authors: Thompson Dawn , Mahmood Shehroz , Morrice Nicola , Kamli-Salino Sarah , Dekeryte Ruta , Hoffmann Philip , Doherty Mary K. , Whitfield Philip D. , Delibegović Mirela , Mody Nimesh
Published: July 2022

Fenretinide is a synthetic retinoid that can prevent obesity and improve insulin sensitivity in mice by directly altering retinol/retinoic acid homeostasis and inhibiting excess ceramide biosynthesis. We determined the effects of Fenretinide on LDLR-/- mice fed high-fat/high-cholesterol diet +/- Fenretinide, a model of atherosclerosis and non-alcoholic fatty liver disease (NAFLD). Fenretinide prevented obesity, improved insulin sensitivity and completely inhibited hepatic triglyceride accumulation, ballooning and steatosis. Moreover, Fenretinide decreased the expression of hepatic genes driving NAFLD, inflammation and fibrosis e.g. Hsd17b13, Cd68 and Col1a1. The mechanisms of Fenretinide’s beneficial effects in association with decreased adiposity were mediated by inhibition of ceramide synthesis, via hepatic DES1 protein, leading to increased dihydroceramide precursors. However, Fenretinide treatment in LDLR-/- mice enhanced circulating triglycerides and worsened aortic plaque formation. Interestingly, Fenretinide led to a 4-fold increase in hepatic sphingomyelinase Smpd3 expression, via a retinoic acid-mediated mechanism and a further increase in circulating ceramide levels, linking induction of ceramide generation via sphingomyelin hydrolysis to a novel mechanism of increased atherosclerosis. Thus, despite beneficial metabolic effects, Fenretinide treatment may under certain circumstances enhance the development of atherosclerosis. However, targeting both DES1 and Smpd3 may be a novel, more potent therapeutic approach for the treatment of metabolic syndrome.
REGENERATION VIA SOMATIC EMBRYOGENESIS FROM SEED EXPLANT OF MEDICINAL PLANT SOLANUM VIRGINIANUM (L.)
Authors: Patil Dhanashree S. , Patil Swaroopa A.
Published: July 2022

Solanum virginianum (L.) belonging to family Solanaceae is an important medicinal plant, used in traditional ayurvedic medicines. It is one of the ten constituents of “Dashmoola”. Present work deals with the development of efficient procedure for inducing somatic embryogenesis followed by regeneration of Solanum virginianum (L.). Initially, seeds of S. virginianum were used as explant and inoculated on ½ MS basal medium. The stem explant from in vitro germinated seeds was used for callus induction. MS medium supplemented with BAP (1mg/L) was used for callus induction. Callus proliferation started when initiated callus was subcultured on different concentrations and combination of BAP, IAA, IBA, 2,4-D and NAA. Where highest embryogenesis took place in BAP (2mg/l)+IAA(5mg/l) combination. The somatic embryos were transferred onto MS basal medium for maturation. These embryos matured and were converted into complete plantlets with well developed shoot and root system.