Discrete Populations Research Articles

Conformational ensembles explain NMR spectra of frozen intrinsically disordered proteins.

Protein regions which are intrinsically disordered, exist as an ensemble of rapidly interconverting structures. Cooling proteins to cryogenic temperatures for dynamic nuclear polarization (DNP) magic angle spinning (MAS) NMR studies suspends most of the motions, resulting in peaks that are broad but not featureless. To demonstrate that detailed conformational restraints can be retrieved from the peak shapes of frozen proteins alone, we developed and used a simulation framework to assign peak features to conformers in the ensemble. We validated our simulations by comparing them to spectra of α-synuclein acquired under different experimental conditions. Our assignments of peaks to discrete dihedral angle populations suggest that structural constraints are attainable under cryogenic conditions. The ability to infer ensemble populations from peak shapes has important implications for DNP MAS NMR studies of proteins with regions of disorder in living cells because chemical shifts are the most accessible measured parameter.

Integrated systems immunology approach identifies impaired effector T cell memory responses as a feature of progression to severe dengue fever

BackgroundTypical symptoms of uncomplicated dengue fever (DF) include headache, muscle pains, rash, cough, and vomiting. A proportion of cases progress to severe dengue hemorrhagic fever (DHF), associated with increased vascular permeability, thrombocytopenia, and hemorrhages. Progression to severe dengue is difficult to diagnose at the onset of fever, which complicates patient triage, posing a socio-economic burden on health systems.MethodsTo identify parameters associated with protection and susceptibility to DHF, we pursued a systems immunology approach integrating plasma chemokine profiling, high-dimensional mass cytometry and peripheral blood mononuclear cell (PBMC) transcriptomic analysis at the onset of fever in a prospective study conducted in Indonesia.ResultsAfter a secondary infection, progression to uncomplicated dengue featured transcriptional profiles associated with increased cell proliferation and metabolism, and an expansion of ICOS+CD4+ and CD8+ effector memory T cells. These responses were virtually absent in cases progressing to severe DHF, that instead mounted an innate-like response, characterised by inflammatory transcriptional profiles, high circulating levels of inflammatory chemokines and with high frequencies of CD4low non-classical monocytes predicting increased odds of severe disease.ConclusionsOur results suggests that effector memory T cell activation might play an important role ameliorating severe disease symptoms during a secondary dengue infection, and in the absence of that response, a strong innate inflammatory response is required to control viral replication. Our research also identified discrete cell populations predicting increased odds of severe disease, with potential diagnostic value.

Characterisation of NPFF-expressing neurons in the superficial dorsal horn of the mouse spinal cord

Excitatory interneurons in the superficial dorsal horn (SDH) are heterogeneous, and include a class known as vertical cells, which convey information to lamina I projection neurons. We recently used pro-NPFF antibody to reveal a discrete population of excitatory interneurons that express neuropeptide FF (NPFF). Here, we generated a new mouse line (NPFFCre) in which Cre is knocked into the Npff locus, and used Cre-dependent viruses and reporter mice to characterise NPFF cell properties. Both viral and reporter strategies labelled many cells in the SDH, and captured most pro-NPFF-immunoreactive neurons (75–80%). However, the majority of labelled cells lacked pro-NPFF, and we found considerable overlap with a population of neurons that express the gastrin-releasing peptide receptor (GRPR). Morphological reconstruction revealed that most pro-NPFF-containing neurons were vertical cells, but these differed from GRPR neurons (which are also vertical cells) in having a far higher dendritic spine density. Electrophysiological recording showed that NPFF cells also differed from GRPR cells in having a higher frequency of miniature EPSCs, being more electrically excitable and responding to a NPY Y1 receptor agonist. Together, these findings indicate that there are at least two distinct classes of vertical cells, which may have differing roles in somatosensory processing.

Abstract 5811: Epigenetic regulation of chromosomal instability in triple-negative breast cancer

Abstract Metastasis is the leading cause of cancer-related death among women with breast cancer. Chromosomal instability (CIN) has emerged as a hallmark of triple-negative breast cancer (TNBC) as it has recently been shown to promote metastasis. However, the underlying molecular mechanisms by which CIN drives metastasis are not completely understood. We have identified a discrete population of highly metastatic SOX2/OCT4+ cells expressing elevated levels of epigenetic regulator EZH2 associated with increased CIN in both human and mouse TNBC. EZH2 histone methyl transferase (HMT) is the catalytic subunit of the Polycomb repressive complex 2 (PRC2), represses target genes through trimethylation of Histone 3 at lysine 27 (H3K27me3). Importantly, genetic and pharmacologic inhibition of EZH2 lead to reduction of CIN and impaired metastasis. These findings led to the hypothesis that EZH2-mediated CIN constitutes a novel mechanism of metastasis regulation. To directly demonstrate epigenetic regulation of CIN, we used genome wide-Cleavage Under Targets and Release Using Nuclease (CUT&RUN) in parallel with RNA-seq. Gene set enrichment of EZH2-repressed target genes directly implicated the spindle formation pathway network. The central core of this network comprised of tankyrase (TNKS), a multifunctional poly (ADP-ribose) polymerase (PARP) previously implicated in DNA repair, telomere function and centrosome maturation. ChIP-PCR confirmed that EZH2 directly binds to the TNKS promoter, and CRISPR knockout of TNKS abrogated the ability of EZH2 inhibition in suppressing CIN, consistent with pharmacological inhibition of TNKS. More specifically, dysregulation of TNKS by EZH2 in OCT4/SOX2+ cells lead to increased numbers of centrosomes and multipolar mitosis. To directly demonstrate the role of aberrant H3K27me3 in regulating chromosomal segregation during mitosis, we used dCas9-EZH2 or dCas9-EZH2 catalytically dead mutant together with chromosome-specific CRISPR guides to ectopically enhance H3K27 trimethylation at the pericentromeric region of specific chromosomes. Ectopic deposition of EZH2 at pericentromeric regions lead to increased CIN. Conceptually, our work provides an unappreciated link between epigenetic regulation and CIN which have been hitherto studied in isolation. From a clinical perspective, demonstrating epigenetic regulation of CIN has opened the possibility for the development of first CIN suppressive therapeutic strategies targeting TNBC metastasis. Citation Format: Yang Bai, Albert Agustinus, Cem Meydan, Dylan R. McNally, Shira Yomtoubian, Liron Yoffe, Ari M. Melnick, Samuel Bakhoum, Vivek Mittal. Epigenetic regulation of chromosomal instability in triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5811.

Monitoring Temporal Changes in SARS-CoV-2 Spike Antibody Levels and Variant-Specific Risk for Infection, Dominican Republic, March 2021-August 2022.

To assess changes in SARS-CoV-2 spike binding antibody prevalence in the Dominican Republic and implications for immunologic protection against variants of concern, we prospectively enrolled 2,300 patients with undifferentiated febrile illnesses in a study during March 2021-August 2022. We tested serum samples for spike antibodies and tested nasopharyngeal samples for acute SARS-CoV-2 infection using a reverse transcription PCR nucleic acid amplification test. Geometric mean spike antibody titers increased from 6.6 (95% CI 5.1-8.7) binding antibody units (BAU)/mL during March-June 2021 to 1,332 (95% CI 1,055-1,682) BAU/mL during May-August 2022. Multivariable binomial odds ratios for acute infection were 0.55 (95% CI 0.40-0.74), 0.38 (95% CI 0.27-0.55), and 0.27 (95% CI 0.18-0.40) for the second, third, and fourth versus the first anti-spike quartile; findings were similar by viral strain. Combining serologic and virologic screening might enable monitoring of discrete population immunologic markers and their implications for emergent variant transmission.

Comparing discrete Pareto populations under a fixed effects model

The discrete Pareto distribution can be considered as a lifetime distribution and then is widely used in practice. It follows the power law tails property which makes it as a candidate model for natural phenomena. This paper deals with comparison of discrete Pareto populations by proposing a non-linear fixed effects model. Estimators for the factor effects are derived in explicit expressions. Stochastic properties of the estimators are studied in details. A test for assessing the homogeneity of populations is proposed. Illustrative examples are also given. The proposed model is an alternative model for analyzing data sets in which the linear models have poor performance.

Modeling the impacts of temperature during nesting seasons on Loggerhead (Caretta caretta) Sea Turtle populations in South Florida

Loggerhead sea turtles (Caretta caretta) are a threatened sea turtle species that nests on beaches along the northwestern Atlantic Ocean. Loggerhead nesting in Florida accounts for approximately 80% of the loggerhead population in the Atlantic Ocean, yet the underlying ecological mechanisms behind their population dynamics are understudied. C. caretta are largely inaccessible since they spend most of their early life in open ocean habitats. Consequently, their nesting and hatchling production offer quantifiable insight of their population dynamics. Emergence success, the proportion of eggs laid that produce offspring which successfully leave the nest, is the source of all later life stages. Yet the abiotic factors that drive emergence success trends have not been fully described. This study explores the relationship between air temperature and emergence success across multiple nesting seasons to better understand the potential impact of anthropogenic climate change on subsequent loggerhead populations. Here we investigate the effect of changing emergence success on the juvenile and adult life stages. After exploring numerous aspects of temperature and precipitation metrics, we determined that the mean of the maximum daily temperatures for each trimester of the eggs’ incubation periods related most closely to the variation in emergence success (the proportion of hatchlings that make it out of the nest) across nests. A novel feature of our approach to modeling the impact of temperature on the later life stages is through connecting a statistical model into a discrete mechanistic population model. Our population model has two parts, one with eggs and hatchlings on a daily time scale in the nesting season and the other with juveniles and adults on an annual time scale. The statistical model enables us to illustrate the effect of temperature changes across these life stages. The decline in the adult population follows from the decline of the hatchling emergence success. Using predicted increases in temperature due to climate change, we illustrate a corresponding prediction for the population classes.

Distribution of North Pacific right whales (Eubalaena japonica) as shown by 19th and 20th century whaling catch and sighting records

North Pacific right whales (Eubalaena japonica) were extensively exploited in the 19th century, and their recovery was further retarded (severely so in the eastern population) by illegal Soviet catches in the 20th century, primarily in the 1960s. Monthly plots of right whale sightings and catches from both the 19th and 20th centuries are provided, using data summarised by Scarff (1991, from the whale charts of Matthew Fontaine Maury) and Brownell et al. (2001), respectively. Right whales had an extensive offshore distribution in the 19th century, and were common in areas (such as the Gulf of Alaska and Sea of Japan) where few or no right whales occur today. Seasonal movements of right whales are apparent in the data, although to some extent these reflect survey and whaling effort. That said, these seasonal movements indicate a general northward migration in spring from lower latitudes, and major concentrations above 40°N in summer. Sightings diminished and occurred further south in autumn, and few animals were recorded anywhere in winter. These north-south migratory movements support the hypothesis of two largely discrete populations of right whales in the eastern and western North Pacific. Overall, these analyses confirm that the size and range of the right whale population is now considerably diminished in the North Pacific relative to the situation during the peak period of whaling for this species in the 19th century. For management purposes, new surveys are urgently required to establish the present distribution of this species; existing data suggest that the Bering Sea, the Gulf of Alaska, the Okhotsk Sea, the Kuril Islands and the coast of Kamchatka are the areas with the greatest likelihood of finding right whales today.

An iterative neural processing sequence orchestrates feeding

Feeding requires sophisticated orchestration of neural processes to satiate appetite in natural, capricious settings. However, the complementary roles of discrete neural populations in orchestrating distinct behaviors and motivations throughout the feeding process are largely unknown. Here, we delineate the behavioral repertoire of mice by developing a machine-learning-assisted behavior tracking system and show that feeding is fragmented and divergent motivations for food consumption or environment exploration compete throughout the feeding process. An iterative activation sequence of agouti-related peptide (AgRP)-expressing neurons in arcuate (ARC) nucleus, GABAergic neurons in the lateral hypothalamus (LH), and in dorsal raphe (DR) orchestrate the preparation, initiation, and maintenance of feeding segments, respectively, via the resolution of motivational conflicts. The iterative neural processing sequence underlying the competition of divergent motivations further suggests a general rule for optimizing goal-directed behaviors.

Reptiles and Amphibians of the Cape of Good Hope Nature Reserve, Western Cape, South Africa

The status of all the reptile and amphibian species that have been recorded in the Cape of Good Hope Nature Reserve (the southern section of the Table Mountain National Park) is described. A total of 57 species has been recorded, comprising seven tortoises and turtles, 14 lizards, one chamaeleon, 20 snakes, two platannas, and 13 frogs and toads. The Reserve is an important stronghold of the IUCN-classified ‘Endangered’ Cape Platanna Xenopus gilli, and holds the discrete southern population of the range-restricted, ‘Near Threatened’ Cape Peninsula Moss Frog Arthroleptella lightfooti.

A survey of neurophysiological differentiation across mouse visual brain areas and timescales.

Neurophysiological differentiation (ND), a measure of the number of distinct activity states that a neural population visits over a time interval, has been used as a correlate of meaningfulness or subjective perception of visual stimuli. ND has largely been studied in non-invasive human whole-brain recordings where spatial resolution is limited. However, it is likely that perception is supported by discrete neuronal populations rather than the whole brain. Therefore, here we use Neuropixels recordings from the mouse brain to characterize the ND metric across a wide range of temporal scales, within neural populations recorded at single-cell resolution in localized regions. Using the spiking activity of thousands of simultaneously recorded neurons spanning 6 visual cortical areas and the visual thalamus, we show that the ND of stimulus-evoked activity of the entire visual cortex is higher for naturalistic stimuli relative to artificial ones. This finding holds in most individual areas throughout the visual hierarchy. Moreover, for animals performing an image change detection task, ND of the entire visual cortex (though not individual areas) is higher for successful detection compared to failed trials, consistent with the assumed perception of the stimulus. Together, these results suggest that ND computed on cellular-level neural recordings is a useful tool highlighting cell populations that may be involved in subjective perception.

Lightweight lattice Boltzmann.

A regularized version of the lattice Boltzmann method for efficient simulation of soft materials is introduced. Unlike standard approaches, this method reconstructs the distribution functions from available hydrodynamic variables (density, momentum, and pressure tensor) without storing the full set of discrete populations. This scheme shows significantly lower memory requirements and data access costs. A series of benchmark tests of relevance to soft matter, such as collisions of fluid droplets, is discussed to validate the method. The results can be of particular interest for high-performance simulations of soft matter systems on future exascale computers.

Null recurrence and transience for a binomial catastrophe model in random environment

We consider a discrete time population model for which each individual alive at time n survives independently of everybody else at time n + 1 with probability β n . The sequence is i.i.d. and constitutes our random environment. Moreover, at every time n we add Z n individuals to the population. The sequence is also i.i.d. We find sufficient conditions for null recurrence and transience (positive recurrence has been addressed by Neuts 1994 J. Appl. Probab. 31 48–58). We apply our results to a particular distribution and deterministic β. This particular case shows a rather unusual phase transition in β in the sense that the Markov chain goes from transience to null recurrence without ever reaching positive recurrence.

Using the Social Vulnerability Index to Examine Disparities in Surgical Pediatric Trauma Patients

IntroductionThe Social Vulnerability Index (SVI) is a composite measure geocoded at the census tract level that has the potential to identify target populations at risk for postoperative surgical morbidity. We applied the SVI to examine demographics and disparities in surgical outcomes in pediatric trauma patients. MethodsSurgical pediatric trauma patients (≤18-year-old) at our institution from 2010 to 2020 were included. Patients were geocoded to identify their census tract of residence and estimated SVI and were stratified into high (≥70th percentile) and low (<70th percentile) SVI groups. Demographics, clinical data, and outcomes were compared using Kruskal–Wallis and Fisher's exact tests. ResultsOf 355 patients included, 21.4% had high SVI percentiles while 78.6% had low SVI percentiles. Patients with high SVI were more likely to have government insurance (73.7% versus 37.2%, P < 0.001), be of minority race (49.8% versus 19.1%, P < 0.001), present with penetrating injuries (32.9% versus 19.7%, P = 0.007), and develop surgical site infections (3.9% versus 0.4%, P = 0.03) compared to the low SVI group. ConclusionsThe SVI has the potential to examine health care disparities in pediatric trauma patients and identify discrete at-risk target populations for preventative resources allocation and intervention. Future studies are necessary to determine the utility of this tool in additional pediatric cohorts.

A CASE REPORT OF OUTFLOW TRACT VENTRICULAR TACHYCARDIA IN THE PRESENCE OF TRIPLE VESSEL CORONARY ARTERY DISEASE

Non-union fractures have considerable clinical and economic burdens and yet the underlying pathogenesis remains largely undetermined. The fracture healing process involves cellular differentiation, callus formation and remodeling, and implies the recruitment and differentiation of mesenchymal stem cells that are not fully characterized. C-X-C chemokine receptor 4 (CXCR4) and Insulin-like growth factor 1 receptor (IGF-1R) are expressed in the fracture callus, but their interactions still remain elusive. We hypothesized that the regulation of CXCR4 by IGF-1R signaling is essential to maintain the bone homeostasis and to promote fracture repair. By using a combination of in vivo and in vitro approaches, we found that conditional ablation of IGF-1R in osteochondroprogenitors led to defects in bone formation and mineralization that associated with altered expression of CXCR4 by a discrete population of endosteal cells. These defects were corrected by AMD3100 (a CXCR4 antagonist). Furthermore, we found that the inducible ablation of IGF-1R in osteochondroprogenitors led to fracture healing failure, that associated with an altered expression of CXCR4. In vivo AMD3100 treatment improved fracture healing and normalized CXCR4 expression. Moreover, we determined that these effects were mediated through the IGF-1R/Insulin receptor substrate 1 (IRS-1) signaling pathway. Taken together, our studies identified a novel population of endosteal cells that is functionally regulated through the modulation of CXCR4 by IGF-1R signaling, and such control is essential in bone homeostasis and fracture healing. Knowledge gained from these studies has the potential to accelerate the development of novel therapeutic interventions by targeting CXCR4 signaling to treat non-unions.

Where to draw the line? Expanding the delineation of conservation units to highly mobile taxa.

Conservation units (CUs) are an essential tool for maximizing evolutionary potential and prioritizing areas across a species' range for protection when implementing conservation and management measures. However, current workflows for identifying CUs on the basis of neutral and adaptive genomic variation largely ignore information contained in patterns of isolation by distance (IBD), frequently the primary signal of population structure in highly mobile taxa, such as birds, bats, and marine organisms with pelagic larval stages. While individuals located on either end of a species' distribution may exhibit clear genetic, phenotypic, and ecological differences, IBD produces subtle changes in allele frequencies across space, making it difficult to draw clear boundaries for conservation purposes in the absence of discrete population structure. Here, we highlight potential pitfalls that arise when applying common methods for delineating CUs to continuously distributed organisms and review existing methods for detecting subtle breakpoints in patterns of IBD that can indicate barriers to gene flow in highly mobile taxa. In addition, we propose a new framework for identifying CUs in all organisms, including those characterized by continuous genomic differentiation, and suggest several possible ways to harness the information contained in patterns of IBD to guide conservation and management decisions.

Design of agricultural product cold chain transportation monitoring system based on Internet of Things technology

The cold chain transportation monitoring system is mainly responsible for data monitoring and control in the cold chain transportation environment, ensuring the stability of the cold chain compartment environment, and playing an important role in the transportation and storage of fresh agricultural products. The traditional Internet of Things cold chain control system uses manual input of control parameters to realize the monitoring of the cold chain compartment environment, which lacks intelligence. Therefore, the BP (Back propagation, BP) neural network is used to build a cold chain transportation monitoring model to realize the dynamic monitoring of the cold chain compartment environment. Considering that the BP network is easy to fall into the problem of “local fall”, which leads to the decline of the prediction accuracy of the model, the improved discrete artificial bee colony algorithm is used to optimize the parameters of the BP neural network, and the fish swarm algorithm is used to decode the discrete population to obtain the final result. Decimal value to construct the DABC-BP cold chain transportation control model. The experimental simulation results show that in the $$f_{1} (x)$$ function optimization test, the improved DABC-BP (Discrete Artificial Bee Colony-Back Propagation Neural Network, DABC-BP) algorithm has the best optimization accuracy, and the minimum logarithm after 1000 iterations is 10−7. Meanwhile, the DABC algorithm has the best convergence performance, reaching convergence after 821 iterations. Compared with related hybrid algorithms such as mayfly algorithm and extreme learning machine, this research method is suitable for harsher environments and more sensitive to temperature monitoring. The research has important reference value for the transportation and storage of modern agricultural products.

A note on the comparison of humpback whale tail fluke catalogues from the Sultanate of Oman with Madagascar and the East African mainland

The photo-identification catalogue of humpback whale tail flukes from Oman was compared with those from Antongil Bay, Madagascar and study sites in South Africa and Mozambique collectively termed the ‘East African Mainland’. No matches were found, supporting other lines of evidence that the humpback whales studied off the coast of Oman form part of a discrete Arabian Sea population, which adheres to a Northern Hemisphere breeding cycle, and has little or no ongoing exchange with the nearest neighbouring populations in the southern Indian Ocean. While the sample size from Oman is small, and low levels of ongoing exchange might not be detected in this type of catalogue comparison, the study nonetheless emphasises the need to pursue research and conservation efforts in the known and suspected range of the Endangered Arabian Sea humpback whale population.

Lipid-droplet associated mitochondria promote fatty-acid oxidation through a distinct bioenergetic pattern in male Wistar rats

Mitochondria empower the liver to regulate lipid homeostasis by enabling fatty acid oxidation during starvation and lipogenesis during nutrient-rich conditions. It is unknown if mitochondria can seamlessly regulate these two distinct processes or if two discrete populations of mitochondria achieve these two functions in the liver. For the first time in the liver, we report the isolation of two distinct populations of mitochondria from male Wistar rats on an ad-libitum diet: cytoplasmic mitochondria and lipid droplet-associated mitochondria. Our studies show that while lipid droplet mitochondria exhibit higher fatty acid oxidation and are marked by enhanced levels of pACC2, MFN2, and CPT1 activity, cytoplasmic mitochondria are associated with higher respiration capacity. Notably, lipid droplet-associated mitochondria isolated from a non-alcoholic fatty liver disease (NAFLD) rat model are compromised for fatty acid oxidation. We demonstrate the importance of functional segregation of mitochondria as any aberration in lipid droplet-associated mitochondria may lead to NAFLD.

Chaotic enhanced teaching-based differential evolution algorithm applied to discrete truss optimization

In this paper, we develop a discrete chaotic enhanced hybrid teaching-based differential evolution algorithm (CETDE) that can deal with realistic yet challenging constrained discrete truss design problems more efficiently. CETDE adaptively executes multiple mutation operators to quickly search for the solution, but at the same time, premature convergence, a common issue in discrete optimization, is also prevented by embedding the chaotic logistic rule into the mutations. An improved logical strategy that only allows potential mutants to go through structural analysis is introduced to reduce computation. An enhanced chaotic local search strategy and a one-component change technique are also developed for further efficiency. Besides, CETDE simultaneously keeps continuous and discrete population throughout the evolution, which is distinguishable from existing discrete optimizers, to preserve the stochastic nature. Compared to other state-of-the-art performers in the literature, CETDE illustrates both higher efficiency and solution optimality.