bluuebunny/crossref_metadata_2025 huggingface dataset:
Emergency Medicaid programs may be an effective means of providing sustained insurance among trauma patients: A statewide longitudinal analysis
Authors: Knowlton Lisa M. , Tran Linda D. , Arnow Katherine , Trickey Amber W. , Morris Arden M. , Spain David A. , Wagner Todd H.
Published: September 2022

BACKGROUND

Hospital Presumptive Eligibility (HPE) is a temporary Medicaid insurance at hospitalization that offsets costs of care, increases access to postdischarge resources, and provides patients with a path to sustain coverage through Medicaid. Because HPE only lasts up to 60 days, we aimed to determine Medicaid insurance status 6 months after injury among HPE-approved trauma patients and identify factors associated with successful sustainment.

METHODS

Using a customized longitudinal claims data set for HPE-approved patients from the California Department of Health Care Services, we analyzed adults with a primary trauma diagnosis (International Classification of Diseases version 10) who were HPE approved in 2016 and 2017. Our primary outcome was Medicaid sustainment at 6 months. Univariate and multivariate analyses were performed.

RESULTS

A total of 9,749 trauma patients with HPE were analyzed; 6,795 (69.7%) sustained Medicaid at 6 months. Compared with patients who did not sustain, those who sustained had higher Injury Severity Score (ISS > 15: 73.5% vs. 68.7%, p < 0.001), more frequent surgical intervention (74.8% vs. 64.5%, p < 0.001), and were more likely to be discharged to postacute services (23.9% vs. 10.4%, p < 0.001). Medicaid sustainment was high among patients who identified as White (86.7%), Hispanic (86.7%), Black (84.3%), and Asian (83.7%). Medicaid sustainment was low among the 2,505 patients (25.7%) who declined to report race, ethnicity, or preferred language (14.8% sustainment). In adjusted analyses, major injuries (ISS > 16) (vs. ISS < 15: adjusted odds ratio [aOR], 1.51; p = 0.02) and surgery (aOR, 1.85; p < 0.001) were associated with increased likelihood of Medicaid sustainment. Declining to disclose race, ethnicity, or language (aOR, 0.05; p < 0.001) decreased the likelihood of Medicaid sustainment.

CONCLUSION

Hospital Presumptive Eligibility programs are a promising pathway for securing long-term insurance coverage for trauma patients, particularly among the severely injured who likely require ongoing access to health care services. Patient and provider interviews would help to elucidate barriers for patients who do not sustain.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level IV.
Constructional Impairments and Their Neural Correlates in Nondemented Adults With Cerebral Autosomal-dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy
Authors: De Lucia Natascia , Ragno Michele , Paci Cristina , Cacchiò Gabriella , Caiazzo Anna Rita , Tiberi Sara , De Rosa Anna , Navarra Riccardo , Caulo Massimo , De Michele Giuseppe , Trojano Luigi
Published: September 2022

Background:

Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a monogenic small-vessel disease that is characterized by a wide range of neurologic and neuropsychological impairments. Constructional impairments have been reported in some cases but have never been assessed systematically.

Objective:

To evaluate constructional abilities and their cognitive and neural correlates in nondemented individuals with CADASIL.

Method:

Thirty individuals with CADASIL who were not affected by clinically relevant cognitive deterioration and 30 healthy controls (HC) underwent an extensive cognitive assessment and paper-and-pencil visuoconstructional tasks in order to detect constructional impairments. Performance on the visuoconstructional tasks was correlated with the cognitive assessment scores and with quantitative indices of regional gray matter atrophy (obtained via FreeSurfer image analysis) and white matter involvement.

Results:

The individuals with CADASIL achieved significantly lower scores on the cognitive assessment compared with the HC. Poor visuoconstructional abilities were observed in seven (23.3%) of the individuals with CADASIL when performing the copy drawing task and in nine (30%) when performing the Rey Complex Figure Test. Logistic regression revealed that visuoconstructional impairments were significantly associated with scores on the Frontal Assessment Battery and the Attentional Matrices Test. Morphometric results revealed that scores on the visuoconstructional tasks were related to gray matter atrophy of the left frontal lobe and right parietal lobe.

Conclusion:

Impairments on visuoconstructional tasks are quite common in individuals with CADASIL, even in the lack of clinically relevant cognitive deterioration, and are critically related to frontal and parietal atrophy.
Understanding the transmission pathways of Lassa Fever: a mathematical modeling approach
Authors: Madueme Praise-God , Chirove Faraimunashe
Published: September 2022

The spread of Lassa fever infection is increasing in West Africa over the last decade. The impact of this can better be understood when considering the various possible transmission routes. We designed a mathematical model for the epidemiology of Lassa Fever using a system of nonlinear ordinary differential equations to determine the effect of transmission pathways toward the infection progression in humans and rodents including those usually neglected. We analyzed the model and carried out numerical simulations to determine the impact of each of the transmission routes. Our results showed that the burden of Lassa fever infection is increased when all the transmission routes are incorporated and most single transmission routes are less harmful, but when in combination with other transmission routes, they increase the Lassa fever burden. It is therefore important to consider multiple transmission routes to better estimate the Lassa fever burden optimally and in turn determine control strategies targeted at the transmission pathways.
Genomic analysis of early spread of monkeypox virus in Washington State
Authors: Roychoudhury Pavitra , Sereewit Jaydee , Xie Hong , Nunley Ethan , Lieberman Nicole A.P. , Greninger Alexander L.
Published: September 2022

Genomic analysis of the monkeypox virus outbreak in Washington State using 109 viral genome sequences collected from July-August 2022 shows low overall genetic diversity, multiple introductions into the state with ongoing community transmission, and potential for coinfection of an individual by multiple strains.

Biography

Dr. Roychoudhury is Acting Instructor and Director of COVID-19 NGS in the Department of Laboratory Medicine and Pathology at the University of Washington and Associate in the Vaccine and Infectious Disease Division at the Fred Hutchinson Cancer Research Center. Her primary research interests are pathogen genomics and mathematical models of viral evolution and host-pathogen interactions.
Evidence-based intrapartum care practice and its associated factors among obstetric care providers working in hospitals of the four Wollega Zones, Oromia Region, West Ethiopia, 2022
Authors: Wodajo Seid , Olani Adugna , Mosisa Alemnesh , Misganaw Dawit , Minayehu Ambaye , Teklay Berhane , Desalew Yaregal , Gashaw Yegoraw , Dagnaw Yilkal
Published: September 2022

Background

Even though Evidence-Based Practice (EBP) is a key component of quality of Intrapartum care and links to improved health care outcomes, consistent application of EBP in patient care remains a challenge for health care providers. In the study area, there are no previous studies conducted on evidence-based Intrapartum care practice among obstetric care providers. Therefore, this study was aimed to assess the magnitude of evidence based intra-partum care practice and its associated factors among obstetric care providers working in hospitals of Wollega zones, Oromia, Western Ethiopia, 2022.

Method

An institution-based cross-sectional study design using quantitative method was conducted from January to April/2022 in 11 hospitals of the four Wollega zones. All obstetric care providers (278) who were practicing Intrapartum care in the selected hospitals were included. The data was collected using structured self-administered questionnaire and paper-based observational checklist. Data was entered via Epi-Data version 3.1 and analyzed by SPSS version 25 statistical software. To see the association between the independent variables and evidence based Intrapartum care practice, multivariable logistic regression analysis was done. Adjusted odds ratios (OR) with their 95% Confidence interval were reported. The statistical significance of association was declared at p-value ≤ 0.05. Tables, figures and charts were also used in descriptive statistics.

Result

The overall magnitude of evidence-based Intrapartum care practice was found to be 63.7% [95% CI (59.7, 67.7)]. There was a statistically significant association between evidence-based Intrapartum care practice and having good knowledge about Intrapartum care practice [AOR=2.95; 95% CI (1.52,5.73)], positive attitude towards Intrapartum care practice [AOR=3.13; 95% CI (1.59,6.16)], availability of updated Intrapartum care guideline [AOR=2.88; 95% CI (1.46,5.70)], number of obstetric care providers per a shift (≥5 care providers) [AOR=2.31; 95% CI (1.01,5.29)], number of deliveries within a day (<10 deliveries) [AOR=4.61; 95% CI (2.28,9.31)], educational level (MSc and above) [AOR=5.75; 95% CI (2.23,14.84)] at p-value ≤ 0.05.

Conclusion and recommendations

Our study revealed that, magnitude of evidence-based Intrapartum care practice was found to be low according to the WHO recommendation. These findings indicate that additional attention and monitoring is required to implement current Intrapartum care practices with the WHO guidelines.
Inactivation of DRG1, encoding a translation factor GTPase, causes a Recessive Neurodevelopmental Disorder
Authors: Westrip Christian A. E. , Paul Franziska , Al-Murshedi Fathiya , Qaitoon Hashim , Cham Breana , Fletcher Sally C. , Hendrix Eline , Boora Uncaar , Ng Alvin Yu Jin , Bonnard Carine , Najafi Maryam , Alawbathani Salem , Lambert Imelda , Fox Gabriel , Venkatesh Byrappa , Bertoli-Avella Aida , Tan Ee Shien , Al-Maawali Almundher , Reversade Bruno , Coleman Mathew L.
Published: September 2022

DRG1 is a highly conserved member of a class of GTPases implicated in ribosome biogenesis and translation. The expression of mammalian DRG1 is elevated in the central nervous system during development, and its function has been implicated in fundamental cellular processes including protein synthesis and cellular proliferation. Using exome sequencing, we identified rare and likely pathogenic germlineDRG1variants including three stop-gained p.Gly54*, p.Arg140*, p.Lys263* and a p.Asn248Phe missense variant. These alleles segregate recessively in four affected individuals from three unrelated families and cause a neurodevelopmental disorder with global developmental delay, microcephaly, short stature and craniofacial anomalies. Using functional assays, we show that these loss-of-function variants: 1) severely disrupt DRG1 mRNA/protein stability in patient-derived fibroblasts, 2) impair it’s GTPase activityin vitroand 3) compromise it’s binding to partner protein ZC3H15. Consistent with the importance of DRG1 in humans, targeted inactivation ofDrg1in mice resulted in pre-weaning lethality. Our work highlights the importance of DRG1 GTPase activity for normal development and underscores the significance of translation factor GTPases in human physiology and homeostasis.
Predictive Biomarkers for the Responsiveness of Recurrent Glioblastomas to Activated Killer Cell Immunotherapy
Authors: Hwang Sohyun , Lim Jaejoon , Kang Haeyoun , Jeong Ju-Yeon , Joung Je-Gun , Heo Jinhyung , Jung Daun , Cho Kyunggi , An Hee Jung
Published: September 2022

Background

Recurrent glioblastoma multiforme (GBM) is a highly aggressive primary malignant brain tumor that is resistant to existing treatments. Recently, we reported that activated autologous natural killer (NK) cell therapeutics induced a marked increase in survival of some patients with recurrent GBM.

Methods

To identify biomarkers that predict responsiveness to NK therapeutics, we examined immune profiles in tumor tissues using NanoString nCounter analysis and compared the profiles between 5 responders and 7 non-responders. Through a three-step data analysis, we identified three candidate biomarkers (TNFRSF18, TNFSF4, and IL12RB2) and performed validation with qRT-PCR. We also performed immunohistochemistry and an NK cell migration assay to assess the function of these genes.

Results

Responders had higher expression of many immune-signaling genes compared with non-responders, which suggests an immune-active tumor microenvironment in responders. The random forest model that identified TNFRSF18, TNFSF4, and IL12RB2 showed a 100% accuracy (95% CI: 73.5%–100%) for predicting the response to NK therapeutics. The expression levels of these three genes by qRT-PCR were highly correlated with the NanoString levels, with high Pearson’s correlation coefficients (0.419 (TNFRSF18), 0.700 (TNFSF4), and 0.502 (IL12RB2)); their prediction performance also showed 100% accuracy (95% CI: 73.54%–100%) by logistic regression modeling. We also demonstrated that these genes were related to cytotoxic T cell infiltration and NK cell migration in the tumor microenvironment.

Conclusions

We identified TNFRSF18, TNFSF4, and IL12RB2 as biomarkers that predict response to NK cell therapeutics in recurrent GBM, which might provide a new treatment strategy for this highly aggressive tumor.
Screening and Development of Constitutively Synergistic Combination Drug Formulations for T Cell Acute Lymphoblastic Leukemia
Authors: Kelvin James M , Zhang Dan Y , Williams Evelyn K , Moore Samuel G , Birnbaum Lacey A , Zecca Henry , Wang Xiaodong , Jain Juhi , Qui Min , Jui Nathan T , Fu Haian , Du Yuhong , Kemp Melissa L , Lam Wilbur A , DeRyckere Deborah , Graham Douglas K , Dreaden Erik C
Published: September 2022

Advances in multiagent chemotherapy have led to recent improvements in overall survival for patients with acute lymphoblastic leukemia (ALL); however, a significant fraction do not respond to frontline chemotherapy or later relapse with recurrent disease, after which long-term survival rates remain low. To address the challenge of developing new, effective treatment options for these patients, we conducted a series of high-throughput combination drug screens to identify chemotherapies that synergize in a lineage-specific manner with MRX-2843, a small molecule dual MERTK and FLT3 kinase inhibitor currently in clinical testing for treatment of relapsed/refractory leukemias and solid tumors. Using experimental and computational approaches, we found that MRX-2843 synergized strongly – and in a ratio-dependent manner – with vincristine chemotherapy to inhibit T-ALL cell expansion and, based on these findings, we developed multiagent lipid nanoparticle formulations of these drugs that not only constitutively maintained ratiometric drug synergy following T-ALL cell delivery, but also improved anti-leukemic activity following drug encapsulation. To determine the clinical relevance of these combination drug formulations and the therapeutic impact of ratiometric drug synergy, we compared the efficacy of lipid nanoparticles comprising synergistic, additive, and antagonistic ratios of MRX-2843 and vincristine, and observed that trends in in vitro synergy were directly recapitulated in primary T-ALL patient samples. Together, these findings present a systematic approach to high-throughput combination drug screening and multiagent drug delivery that maximizes the therapeutic potential of combined MRX-2843 and vincristine in T-ALL. This broadly generalizable approach could lead to the development of constitutively synergistic combination products for the treatment of cancer and other diseases.
MalariaSED: a deep learning framework to decipher the regulatory contributions of noncoding variants in malaria parasites
Authors: Wang Chengqi , Dong Yibo , Li Chang , Oberstaller Jenna , Zhang Min , Gibbons Justin , Pires Camilla Valente , Xiao Mianli , Zhu Lei , Jiang Rays H.Y. , Kim Kami , Miao Jun , Otto Thomas D. , Cui Liwang , Adams John H. , Liu Xiaoming
Published: September 2022

Malaria remains one of the deadliest infectious diseases. Transcriptional regulation effects of noncoding variants in this unusual genome of malaria parasites remain elusive. We developed a sequence-based,ab initiodeep learning framework, MalariaSED, for predicting chromatin profiles in malaria parasites. The MalariaSED performance was validated by published ChIP-qPCR and TF motifs results. Applying MalariaSED to ∼1.3 million variants shows that geographically differentiated noncoding variants are associated with parasite invasion and drug resistance. Further analysis reveals chromatin accessibility changes atPlasmodium falciparumrings are partly associated with artemisinin resistance. MalariaSED illuminates the potential functional roles of noncoding variants in malaria parasites.
Deep proteomics identifies shared molecular pathway alterations in synapses of schizophrenia and bipolar disorder patients and mouse model
Authors: Aryal Sameer , Bonanno Kevin , Song Bryan , Mani D.R. , Keshishian Hasmik , Carr Steven A. , Sheng Morgan , Dejanovic Borislav
Published: September 2022

Synaptic dysfunction is implicated in the pathophysiology of schizophrenia (SCZ) and bipolar disorder (BP). We used quantitative mass-spectrometry to carry out deep and unbiased profiling of the proteome of synapses purified from the dorsolateral prefrontal cortex of 35 cases of SCZ, 35 cases of BP, and 35 controls. Compared to controls, SCZ and BP synapses showed substantial and similar proteomic alterations. Network and gene set enrichment analyses revealed upregulation of proteins associated with autophagy and certain vesicle transport pathways, and downregulation of proteins related to synaptic, mitochondrial, and ribosomal function in the synapses of individuals with SCZ or BP. Some of the same pathways (e.g., upregulation of vesicle transport, downregulation of mitochondrial and ribosomal proteins) were similarly dysregulated in the synaptic proteome of mutant mice deficient in Akap11, a recently discovered shared risk gene for SCZ and BP. Our work provides novel biological insights into molecular dysfunction at the synapse in SCZ and BP and serves as a resource for understanding the pathophysiology of these debilitating neuropsychiatric disorders.
Contribution of private game ranching and captive bred operations in South Africa to White rhinoCeratotherium simumspecies survival conservation
Authors: Furstenburg Deon , Otto Michelle , Van Niekerk Pieter , Lewitton Derek
Published: September 2022

The southern white rhinoceros (SWR)Ceratotherium simum simum,like all extant rhinoceros’ species, is under global threat of extinction, due to their dwindling wild population numbers in protected areas and state-owned parks as a result of poaching. The Kruger National Park (KNP), the renowned state-owned stronghold for SWR, has suffered an estimated decline of over 75.0% of its population since 2011, with the highest annual poaching rates over the past decade and a remaining population estimated at only 2,607 animals by the end of 2020, which is an average annual population decline of −10.2% from 2008 to 2020, and 2,458 animals left by the end of June 2022. On the contrary, SWR under private custodianship and management on rewilded agro-sustainable biodiversity game ranches in South Africa (estimated currently at >8,000 animals, some of which are registered Captive Breeding Operations [CBO]; assessed CBOs contained 2,882 rhinos at the time of this study (Sep 2021), have increased in population numbers and survival rates, sustaining average annual population growth performances of 9.0%. This increase has been attributed to effective security, provision of additional habitat, dispersal, and frequent genetic exchange of rhinos between breeding subpopulations by the private sector. The conservation success of the private sector has largely been overlooked and disregarded by world conservation bodies and organizations, mostly due to misguided and prejudiced media publicity and the lack of scientific analytical assessment. Private rhino custodians and their biological/ conservation breeding practices, with private agro-sustainable biodiversity wildlife management and/ or captive breeding, generally being perceived and branded as either “canned” or equated to “captive zoological-gardens”. Since the commencement of the International Convention on Biodiversity, global controversy exists whereby most of mankind today perceive bio-conservation of a species to be assigned in principle solely to protected areas and state-owned parks. The unique and advantageous roles of rewilded bio-conservation and sustainable-use conservation CBOs, being a key to green-economy and natural capital in a post-Covid-19 struggle, are mostly ignored. This study serves to assess and quantify the impact of private wildlife ranching in South Africa with specific focus on its potential contribution to rhino conservation specifically for that of the SWRC.s. simum.

Data Availability Statement

The data belong to third parties, six different private owners respectively, and cannot be shared publicly. Interested, qualified researchers can request the data by contacting the author, subject to owner’s permission. The authors confirm that they did not have any special access privileges to the data and data will be made available to other researchers in the same manner that the authors accessed it.
New estimates of genome size in Orthoptera and their evolutionary implications
Authors: Hawlitschek Oliver , Sadílek David , Dey Lara-Sophie , Buchholz Katharina , Noori Sajad , Baez Inci Livia , Wehrt Timo , Brozio Jason , Trávníček Pavel , Seidel Matthias , Husemann Martin
Published: September 2022

Animal genomes vary widely in size, and much of their architecture and content remains poorly understood. Even among related groups, such as orders of insects, genomes may vary in size by orders of magnitude – for reasons unknown. The largest known insect genomes were repeatedly found in Orthoptera, e.g.,Podisma pedestris(1C = 16.93 pg),Stethophyma grossum(1C = 18.48 pg) andBryodemella holdereri(1C = 18.64 pg). While all these species belong to the suborder of Caelifera, the ensiferanDeracantha onos(1C = 19.60 pg) was recently found to have the largest genome. Here, we present new genome size estimates of 50 further species of Ensifera (superfamilies Gryllidea, Tettigoniidea) and Caelifera (Acrididae, Tetrigidae) based on flow cytometric measurements. We found thatBryodemella tuberculata(Caelifera: Acrididae) has the so far largest measured genome of all insects with 1C = 21.96 pg (21.48 gBp). Species with 2n = 16 and 2n = 22 chromosomes have significantly larger genomes than species with other chromosome counts. Gryllidea genomes vary between 1C = 0.95 and 2.88 pg, and Tetrigidae between 1C = 2.18 and 2.41, while the genomes of all other studied Orthoptera range in size from 1C = 1.37 to 21.96 pg. Reconstructing ancestral genome sizes based on a phylogenetic tree of mitochondrial genomic data, we found genome size values of >15.84 pg only for the nodes ofBryodemella holdereri/B. tuberculataandChrysochraon dispar/Euthystira brachyptera. The predicted values of ancestral genome sizes are 6.19 pg for Orthoptera, 5.37 pg for Ensifera, and 7.28 pg for Caelifera. The reasons for the large genomes in Orthoptera remain largely unknown, but a duplication seems unlikely as chromosome numbers do not differ. Sequence-based genomic studies may shed light on the underlying evolutionary mechanisms.
Using occipital ⍺-bursts to modulate behaviour in real-time
Authors: Vigué-Guix Irene , Soto-Faraco Salvador
Published: September 2022

Spontaneous oscillatory neural activity can influence the processing of incoming sensory input and subsequent behavioural reactions. Spontaneous oscillatory activity mostly appears in stochastic bursts, but typical trial-averaged approaches fail to capture this. We aimed at relating oscillatory bursts in the alpha band (8-13 Hz) to behaviour directly, via an EEG-based brain-computer interface (BCI) that allowed for burst-triggered stimulus presentation in real-time in a visual detection task. According to alpha theories, we hypothesised that targets presented during alpha-bursts should lead to slower responses and higher miss rates, whereas targets presented in the absence of bursts should lead to faster responses and higher false alarm rates. Our findings support the role of bursts in alpha-oscillations in visual perception and exemplify how real-time BCI systems can be used as a test bench for brain-behavioural theories.
Syndecan-4 Proteoliposomes Enhance Revascularization in a Rabbit Hind Limb Ischemia Model of Peripheral Ischemia
Authors: Sligar Andrew D , Howe Gretchen , Goldman Julia , Felli Patricia , Gómez-Hernández Almudena , Takematsu Eri , Veith Austin , Desai Shubh , Riley William J. , Singeetham Rohan , Mei Lei , Callahan Gregory , Ashirov David , Smalling Richard , Baker Aaron B.
Published: September 2022

Regenerative therapeutics for treating peripheral arterial disease are an appealing strategy for creating more durable solutions for limb ischemia. In this work, we performed preclinical testing of an injectable formulation of syndecan-4 proteoliposomes combined with growth factors as treatment for peripheral ischemia delivered in an alginate hydrogel. We tested this therapy in an advanced model of hindlimb ischemia in rabbits with diabetes and hyperlipidemia. Our studies demonstrate enhancement in vascularity and new blood vessel growth with treatment with syndecan-4 proteoliposomes in combination with FGF-2 or FGF-2/PDGF-BB. The effects of the treatments were particularly effective in enhancing vascularity in the lower limb with a 2-4 increase in blood vessels in the treatment group in comparison to the control group. In addition, we demonstrate that the syndecan-4 proteoliposomes have stability for at least 28 days when stored at 4°C to allow transport and use in the hospital environment. In addition, we performed toxicity studies in the mice and found no toxic effects even when injected at high concentration. Overall, our studies support that syndecan-4 proteoliposomes markedly enhance the therapeutic potential of growth factors in the context of disease and may be promising therapeutics for inducing vascular regeneration in peripheral ischemia.
Magnitude and kinetics of the human immune cell response associated with severe dengue progression by single-cell proteomics
Authors: Robinson Makeda L. , Glass David R. , Duran Veronica , Rojas Olga Lucia Agudelo , Sanz Ana Maria , Consuegra Monika , Sahoo Malaya Kumar , Hartmann Felix J. , Bosse Marc , Gelvez Rosa Margarita , Bueno Nathalia , Pinsky Benjamin A. , Montoya Jose G. , Maecker Holden , Cardenas Maria Isabel Estupiñan , Villar Centeno Luis Angel , Garrido Elsa Marina Rojas , Rosso Fernando , Bendall Sean C. , Einav Shirit
Published: September 2022

Approximately five million dengue virus-infected patients, particularly children, progress to a potentially life-threatening severe dengue (SD) infection annually. To identify the immune features and temporal dynamics underlying SD progression, we performed deep immune profiling by mass cytometry of PBMCs collected longitudinally from SD progressors (SDp) and uncomplicated dengue (D) patients. While D is characterized by early activation of innate immune responses, in SDp there is rapid expansion and activation of IgG-secreting plasma cells and memory and regulatory T cells. Concurrently, SDp, particularly children, demonstrate increased proinflammatory NK cells, inadequate expansion of CD16+ monocytes, and high expression of the FcγR, CD64 on myeloid cells, yet diminished antigen presentation. Syndrome-specific determinants include suppressed dendritic cell abundance in shock/hemorrhage vs. enriched plasma cell expansion in organ impairment. This study reveals uncoordinated immune responses in SDp and provides insights into SD pathogenesis in humans with potential implications for prediction and treatment.
Predicting phenotype transition probabilities via conditional algorithmic probability approximations
Authors: Dingle Kamaludin , Novev Javor K , Ahnert Sebastian E , Louis Ard A
Published: September 2022

Unravelling the structure of genotype-phenotype (GP) maps is an important problem in biology. Recently, arguments inspired by algorithmic information theory (AIT) and Kolmogorov complexity have been invoked to uncover simplicity bias in GP maps, an exponentially decaying upper bound in phenotype probability with increasing phenotype descriptional complexity. This means that phenotypes with very many genotypes assigned via the GP map must be simple, while complex phenotypes must have few genotypes assigned. Here we use similar arguments to bound the probability P(x → y) that phenotype x, upon random genetic mutation, transitions to phenotype y. The bound is P(x → y)≲ 2−aK˜(y|x)−b, where K˜(y|x) is the estimated conditional complexity of y given x, quantifying how much extra information is required to make y given access to x. This upper bound is related to the conditional form of algorithmic probability from AIT. We demonstrate the practical applicability of our derived bound by predicting phenotype transition probabilities (and other related quantities) in simulations of RNA and protein secondary structures. Our work contributes to a general mathematical understanding of GP maps, and may also facilitate the prediction of transition probabilities directly from examining phenotype themselves, without utilising detailed knowledge of the GP map.
Topological Gelation of Reconnecting Polymers
Authors: Bonato Andrea , Marenduzzo Davide , Michieletto Davide , Orlandini Enzo
Published: September 2022

DNA recombination is a ubiquitous process that ensures genetic diversity. Contrary to textbook pictures, DNA recombination, as well as generic DNA translocations, occur in a confined and highly entangled environment. Inspired by this observation, here we investigate a solution of semiflexible polymer rings undergoing generic cutting and reconnection operations under spherical confinement. Our setup may be realised using engineered DNA in presence of recombinase proteins or by considering micelle-like components able to form living (or reversibly breakable) polymer rings. We find that in such systems there is a topological gelation transition, which can be triggered by increasing either the stiffness or concentration of the rings. Flexible or dilute polymers break into an ensemble of short, unlinked and segregated rings, whereas sufficiently stiff or dense polymers self-assemble into a network of long, linked and mixed loops, many of which are knotted. We predict the two phases should behave qualitatively differently in elution experiments monitoring the escape dynamics from a permeabilised container. Besides shedding some light on the biophysics and topology of genomes undergoing DNA reconnection in vivo, our findings could be leveraged in vitro to design polymeric complex fluids, e.g., DNA-based complex fluids or living polymer networks, with desired topologies.
Development of muti-agent-simulation models for intercellular communication via cytokines and extracellular matrices
Authors: Inoue Ken-ichi , Kishimoto Satoko , Mogami Tomoki , Toyoda Shigeru , Hariyama Masanori
Published: September 2022

Background

Intercellular communication is a critical innovation during multicellular organismal evolution. Cells release / receive cytokines and utilize them as intercellular signal entities. How a well-orchestrated communication emerges from individual cell behavior remains largely unknown. Here we abstracted the biological phenomenon and developed multi-agent-simulation to investigate the intracellular communication.

Methods

Two dimensional MAS platform was developed using Artisoc 4.2.1 standard software. We focused on intercellular communication via cytokines and extracellular matrices. Three agents, “cells”, “cytokines” and “extracellular matrices” were defined and the interaction rules among the agents were designed. Two different mathematical models of cytokine-gradient determination were tested: spatial derivative and temporal derivative models. As a case study, neutrophil swarming was modeled and the cell swarming was defined as an evaluation criterion. Moreover, a surgically injured mouse model and a fluorescent time-lapse imaging were used to observe neutrophil swarming.

Results

We performed multiple simulations with six different virtual conditions, changing multiple parameters simultaneously and randomly. After 400 simulations for each condition, we counted the number of successful trials (i.e. neutrophil swarming within 10000 steps). Spatial derivative model showed more successes compared to temporal derivative model. Among eight parameters randomly assigned, cell’s exploration speed by random walk most remarkably influenced on success rate of neutrophil swarming. In in vivo model, bone marrow derived neutrophils gather towards the clumps with various migration speed. The mode of approaching resembles to spatial derivative model, rather than temporal derivative model.

Conclusions

MAS could be a useful approach to investigate the emergence of intercellular communication during multicellular evolution. Neutrophil could adopt the spatial derivative model as a sensing mechanism of cytokine gradient.
A systems immunology study comparing innate and adaptive immune responses in adults to COVID-19 mRNA (BNT162b2/mRNA-1273) and adenovirus vectored vaccines (ChAdOx1-S) after the first, second and third doses
Authors: Ryan Feargal J. , Norton Todd S. , McCafferty Conor , Blake Stephen J. , Stevens Natalie E. , James Jane , Eden Georgina L. , Tee Yee C. , Benson Saoirse C. , Masavuli Makutiro G. , Yeow Arthur EL , Abayasingam Arunasingam , Agapiou David , Stevens Hannah , Zecha Jana , Messina Nicole L. , Curtis Nigel , Ignjatovic Vera , Monagle Paul , Tran Huyen , McFadyen James D. , Bull Rowena A. , Grubor-Bauk Branka , Lynn Miriam A. , Botten Rochelle , Barry Simone E. , Lynn David J.
Published: September 2022

We longitudinally profiled immune responses in 102 adults who received BNT162b2 (Pfizer-BioNTech) or ChAdOx1-S (Oxford-AstraZeneca) as their primary vaccinations. Bloods were collected pre-vaccination, 1-7 days after the 1st, 2ndand 3rddoses (BNT162b2 or mRNA-1273) to assess innate and early adaptive responses, and ∼28 days after the 2ndand 3rddoses to assess immunogenicity. Using a multi-omics approach including RNAseq, cytokine multiplex assay, proteomics, lipidomics, and flow cytometry we identified key differences in the immune responses induced by the ChAdOx1-S and BNT162b2 vaccines that were correlated with subsequent antigen-specific antibody and T cell responses or vaccine reactogenicity. We observed that vaccination with ChAdOx1-S but not BNT162b2 induced a memory-like response after the first dose, which was correlated with the expression of several proteins involved in complement and coagulation. The COVID-19 Vaccine Immune Responses Study (COVIRS) thus represents a major resource to understand the immunogenicity and reactogenicity of these COVID-19 vaccines.
Glutamatergic Supramammillary Nucleus Neurons Respond to Threatening Stressors and Promote Active Coping
Authors: Escobedo Abraham , Holloway Salli-Ann , Votoupal Megan , Cone Aaron L , Skelton Hannah E , Legaria Alex A. , Ndiokho Imeh , Floyd Tasheia , Kravitz Alexxai V. , Bruchas Michael R. , Norris Aaron J.
Published: September 2022

Threat-response neural circuits are conserved across species and play roles in normal behavior and psychiatric diseases. Maladaptive changes in these neural circuits contribute to stress, mood, and anxiety disorders. Active coping in response to stressors is a psychosocial factor associated with resilience against stress-induced mood and anxiety disorders. The neural circuitry underlying active coping is poorly understood, but the functioning of these circuits could be key for overcoming anxiety and related disorders. The supramammillary nucleus (SuM) has been suggested to be engaged by threat. SuM has many projections and contains a poorly understood diversity of populations. We identified a unique population of glutamatergic SuM neurons (SuMVGLUT2+::POA) based on projection to the preoptic area of the hypothalamus (POA) and found SuMVGLUT2+::POA neurons have extensive arborizations. SuMVGLUT2+::POA neurons project to brain areas that mediate various features of the stress and threat responses including the paraventricular nucleus thalamus (PVT), periaqueductal gray (PAG), and the habenula (Hb). Thus, SuMVGLUT2+::POA neurons are positioned as a hub, connecting to areas implicated in regulating stress responses. Here we report SuMVGLUT2+::POA neurons are recruited by diverse threatening stressors, and recruitment of SuMVGLUT2+::POA neurons correlated with active coping behaviors. We found that selective photoactivation of the SuMVGLUT2+::POA population drove aversion but not anxiety like behaviors. Activation of SuMVGLUT2+::POA neurons in the absence of acute stressors evoked active coping like behaviors and drove instrumental behavior (selective port activations) (Figure 6). Also, activation of SuMVGLUT2+::POA neurons was sufficient to convert passive coping strategies to active behaviors during acute stress. In contrast, we found activation of GABAergic (VGAT+) SuM neurons (SuMVGAT+) neurons did not alter drive aversion or active coping, but termination of photostimulation was followed by increased mobility in the forced swim test. These findings establish a new node in stress response circuitry that has projections to many brain areas, evokes flexible active coping behaviors, and offers new opportunities for furthering our neurobiological understanding of stress.
Phytohormones enhance heavy metal responses inEuglena gracilis: evidence from uptake of Ni, Pb and Cd and linkages to hormonomic and metabolomic dynamics
Authors: Nguyen Hai Ngoc , Nguyen Quoc Thien , Dang Duc Huy , R. J. Neil Emery
Published: September 2022

Over the last decade, significant effort has been made to understand phytohormonal functions (e.g. cytokinins (CKs) and abscisic acid (ABA)) in metal stress responses of higher plants and algae. Despite the potential for these phytohormones to improve industrial remediation byEuglena gracilis(Euglenophyceae), no such roles have been elucidated for this highly adaptive species and its response to heavy metals. This study demonstrates that toxic metals (nickel, lead, cadmium) modify hormonal activity profiles (i.e., CK forms and their concentrations) inE. gracilis. Furthermore, exogenous ABA or CK (tZ) enabled higher metal uptake efficiency and alleviated metal toxicity through the regulation of endogenous CKs and gibberellins (GAs) levels. These responses suggest thatE. gracilisregulates multiple phytohormone signals during metal stress acclimation. A deeper approach, using untargeted metabolomic analyses, gave more detailed insight into phytohormone-controlled pathways and associated modified metabolites, which were frequently related to metal accumulation and the physiological acclimation to metal presence. Significant changes in the levels of cellular metabolites, especially those involved in acclimation to metal stress, were under the influence of phytohormones in algal cells. When grown under metal stress conditions, the presence of exogenous ABA or CKs, caused changes in cellular metabolites which included those from: lipid pathways, riboflavin metabolism, the biosynthesis of cofactors/vitamins, and carbohydrate metabolism. Also, bioactive secondary metabolites (e.g., terpenoids, alkaloids, flavonoids, carotenoids) were modified in algal cells treated with phytohormones. Thus, the study gives a detailed view on the regulatory functions of ABA and CKs in algal metal bioremediation strategies, which are attributed to enhanced metal uptake and in the fine-tuning of plant hormone levels during metal stress response. The results can guide efforts to develop efficient, low-cost and environmentally friendly methods for bioremediation.

Highlights

Metal stress produces phytohormone-specific responses inEuglena gracilis.

Phytohormones (ABA and CK) enhance metal accumulation rates.

Phytohormone-controlled metal uptake reflects enhanced CK activity profiles.

Modified hormonal crosstalk is involved in phytohormone-induced metal uptake.

Metabolomic responses to phytohormones-involve metal stress mitigation compounds.
Altered MAM function shifts mitochondrial metabolism in SOD1-mutant models of ALS
Authors: Larrea Delfina , Tamucci Kirstin A. , Kabra Khushbu , Velasco Kevin R. , Yun Taekyung D. , Pera Marta , Montesinos Jorge , Agrawal Rishi R. , Smerdon John W. , Lowry Emily R. , Stepanova Anna , Yoval-Sanchez Belem , Galkin Alexander , Wichterle Hynek , Area-Gomez Estela
Published: September 2022

Mitochondrial defects are a common hallmark of familial and sporadic forms of amyotrophic lateral sclerosis (ALS). However, the origin of these defects, including reduced pyruvate metabolism and reduced oxygen consumption, is poorly understood. These metabolic functions are regulated in specialized endoplasmic reticulum (ER) domains in close contact with mitochondria, called mitochondrial-associated ER membranes (MAM). Recently it has been shown that MAM domains are disrupted in ALS, but the connection between MAM dysregulation and mitochondrial defects in ALS cells remains unclear. Using human embryonic stem cell (ESC)-derived motor neurons (hMNs) and mouse models with ALS-pathogenic mutations in superoxide dismutase 1 (SOD1), we found that the glycolytic deficiency in ALS is a direct consequence of the progressive disruption of MAM structure and function that hinders the use of glucose-derived pyruvate as a mitochondrial fuel and triggers a shift in mitochondrial substrates from pyruvate to fatty acids. This glycolytic deficiency, over time, induces significant alterations in mitochondrial electron flow and in the active/dormant (A/D) status of complex I in spinal cord, but not in brain. These data agree with a role for MAM in the maintenance and regulation of cellular glucose metabolism and suggest that MAM disruption in ALS could be the underlying cause of the bioenergetic deficits observed in the disease.
Environmental, social, and morphological drivers of fission-fusion dynamics in a social ungulate
Authors: Goff Morgane Le , Hendrix Jack G. , Webber Quinn M. R. , Robitaille Alec L. , Wal Eric Vander
Published: September 2022

Social groups exist because individuals within the group accrue a net benefit from sharing space. The profitability of sociality, however, varies with ecological context. As ecological context varies, tension emerges among the costs and benefits of social grouping. Fission-fusion societies are fluid in their group dynamics across spatial and temporal contexts, permitting insights into how context affects whether animals choose to join or depart a group. We tested four non-mutually exclusive hypotheses driving variation in fission and fusion in caribou: the risky places, environment heterogeneity, activity budget, and social familiarity hypotheses. The risky places hypothesis predicts animals are unlikely to diffuse when habitats are open and risk of predation is elevated. The habitat heterogeneity hypothesis predicts that fission is more likely in a heterogeneous landscape due to the rising conflicts of interest between group members. The activity budget hypothesis predicts dyads associate by body size due to similar food passage rates. The social cohesion hypothesis predicts that familiar individuals are less likely to fission. We tested the hypotheses using time-to-event (time before fission) analyses and a linear model that assesses spatial, social, and body size relationships among female caribou (n = 22) on Fogo Island, Newfoundland, Canada. Contrary to our prediction for risky places, probability of fission was not influenced by habitat openness. The hypothesis of environmental heterogeneity was partially supported, as caribou remained less cohesive in environments with a higher richness of habitats. No direct evidence emerged to support the activity budget hypothesis. However, it appears that caribou maintain the strongest social bonds among variably sized individuals and these social bonds do decrease the propensity to split. Collectively, our findings showed that social interactions may depend not only on individual identity and characteristics, but also the spatial context in which these interactions occur.
Tumoroscope: a probabilistic model for mapping cancer clones in tumor tissues
Authors: Shafighi Shadi Darvish , Geras Agnieszka , Jurzysta Barbara , Naeini Alireza Sahaf , Filipiuk Igor , Rączkowski Łukasz , Toosi Hosein , Koperski Łukasz , Thrane Kim , Engblom Camilla , Mold Jeff , Chen Xinsong , Hartman Johan , Nowis Dominika , Carbone Alessandra , Lagergren Jens , Szczurek Ewa
Published: September 2022

Spatial and genomic heterogeneity of tumors is the key for cancer progression, treatment, and survival. However, a technology for direct mapping the clones in the tumor tissue based on point mutations is lacking. Here, we propose Tumoroscope, the first probabilistic model that accurately infers cancer clones and their high-resolution localization by integrating pathological images, whole exome sequencing, and spatial transcriptomics data. In contrast to previous methods, Tumoroscope explicitly addresses the problem of deconvoluting the proportions of clones in spatial transcriptomics spots. Applied to a reference prostate cancer dataset and a newly generated breast cancer dataset, Tumoroscope reveals spatial patterns of clone colocalization and mutual exclusion in sub-areas of the tumor tissue. We further infer clone-specific gene expression levels and the most highly expressed genes for each clone. In summary, Tumoroscope enables an integrated study of the spatial, genomic, and phenotypic organization of tumors.
Dopaminergic innervation at the central nucleus of the amygdala reveals distinct topographically and functionally segregated regions
Authors: Casey Eric , Avale María Elena , Kravitz Alexxai , Rubinstein Marcelo
Published: September 2022

The central nucleus of the amygdala (CeA) is involved in the expression of fear and has been implicated in several anxiety disorders. Anatomically, it is divided in a medial (CeM), a lateral (CeL) and a capsular division (CeC). The CeA is densely innervated by dopaminergic projections that originate in the ventral periaqueductal gray/dorsal raphe (vPAG/DR) and the ventral tegmental area/substantia nigra compacta (VTA/SNc). However, it is unknown if DA exerts a homogenous control over the CeA or, conversely, if different parts of the CeA are regulated in a distinct manner. Here, we performed a neuroanatomical and functional analysis of the mouse CeA and revealed that dopaminergic innervations arriving from the PAG/DR and the VTA/SNc constitute distinct, non-overlapping pathways that differ in their expression of dopamine transporter. By quantifying the distribution of DAergic fibers and the origin of the innervation, we identified two regions in the CeL: a frontal region innervated by both the VTA/SNc and the vPAG/DR, and a caudal region innervated only by the vPAG/DR; and three regions in the CeC: a fronto-dorsal region innervated only by the VTA/SNc, a fronto-ventral region with sparse DAergic innervation, and a caudal region with low innervation from the vPAG/DR. In addition, we found that each region displays a unique pattern of cFos activation after the administration of cocaine, SKF 38393, quinpirole or haloperidol, demonstrating that the regions identified here are functionally distinct from each other. In summary, this analysis reveals unique properties of the DAergic pathways innervating the CeA, and distinguishes six topographically segregated and functionally distinct regions in the CeA. This unanticipated level of functional heterogeneity calls for more precise anatomical specificity in future functional studies of the CeA.