Quantifying cell cycle regulation by tissue crowding.

The spatiotemporal coordination and regulation of cell proliferation is fundamental in many aspects of development and tissue maintenance. Cells have the ability to adapt their division rates in response to mechanical constraints, yet we do not fully understand how cell proliferation regulation impacts cell migration phenomena. Here, we present a minimal continuum model of cell migration with cell cycle dynamics, which includes density-dependent effects and hence can account for cell proliferation regulation. By combining minimal mathematical modeling, Bayesian inference, and recent experimental data, we quantify the impact of tissue crowding across different cell cycle stages in epithelial tissue expansion experiments. Our model suggests that cells sense local density and adapt cell cycle progression in response, during G1 and the combined S/G2/M phases, providing an explicit relationship between each cell-cycle-stage duration and local tissue density, which is consistent with several experimental observations. Finally, we compare our mathematical model's predictions to different experiments studying cell cycle regulation and present a quantitative analysis on the impact of density-dependent regulation on cell migration patterns. Our work presents a systematic approach for investigating and analyzing cell cycle data, providing mechanistic insights into how individual cells regulate proliferation, based on population-based experimental measurements.

A phase I dose-escalation study of pulsatile afatinib in patients with recurrent or progressive brain cancer.

Background: Afatinib (BIBW2992; Gilotrif®) is a selective and irreversible inhibitor of the epidermal growth factor receptor (ErbB; EGFR) family. It inhibits EGFR, HER2, and HER4 phosphorylation, resulting in tumor growth inhibition and regression. This phase I dose-escalation trial of pulsatile afatinib examined the safety, drug penetration into the central nervous system, preliminary antitumor activity, and recommended phase II dose in patients with progressive or recurrent brain cancers. Methods: Afatinib was taken orally once every 4 days or once every 7 days depending on dose cohort, until disease progression or unacceptable toxicity. Results: A total of 24 patients received the investigational agent and were evaluable for safety analyses, and 21 patients were evaluable for efficacy. Dosing was administered at 80 mg every 4 days, 120 mg every 4 days, 180 mg every 4 days, or 280 mg every 7 days. A recommended phase II dose of pulsatile afatinib was established at 280 mg every 7 days as there were no dose-limiting toxicities in any of the dosing cohorts and all toxicities were deemed manageable. The most common drug-related toxicities were diarrhea, rash, nausea, vomiting, fatigue, stomatitis, pruritus, and limb edema. Out of the 21 patients evaluable for efficacy, 2 patients (9.5%) exhibited partial response based on Response Assessment in Neuro-Oncology criteria and disease stabilization was seen in 3 patients (14.3%). Conclusions: Afatinib taken orally was safe and well-tolerated up to 280 mg every 7 days in brain cancer patients.

Pilot Study of High-Dose Pemetrexed in Patients with Progressive Chordoma.

PURPOSE: Chordomas are ultrarare tumors of the axial spine and skull-base without approved systemic therapy. Most chordomas have negative expression of thymidylate synthase (TS), suggesting a potential for responding to the antifolate agent pemetrexed, which inhibits TS and other enzymes involved in nucleotide biosynthesis. We evaluated the therapeutic activity and safety of high-dose pemetrexed in progressive chordoma. PATIENTS AND METHODS: Adult patients with previously treated, progressive chordoma participated in an open-label, single-institution, single-arm, pilot clinical trial of intravenous pemetrexed 900 mg/m2 every 3 weeks and supportive medications of folic acid, vitamin B12, and dexamethasone. The primary endpoint was objective response rate according to RECIST v1.1. Secondary endpoints included adverse events, progression-free survival (PFS), tumor molecular profiles, and alterations in tissue and blood-based biomarkers. RESULTS: Fifteen patients were enrolled and the median number of doses administered was 15 (range, 4-31). One patient discontinued treatment due to psychosocial issues after four cycles and one contracted COVID-19 after 13 cycles. Of the 14 response-evaluable patients, 2 (14%) achieved a partial response and 10 (71%) demonstrated stable disease. Median PFS was 10.5 months (95% confidence interval: 9 months-undetermined) and 6-month PFS was 67%. Adverse events were expected and relatively mild, with one grade 3 creatinine increased, and one each of grade 3 and 4 lymphopenia. No grade 5 adverse events, unexpected toxicities, or dose-limiting toxicities were observed. Several patients reported clinical improvement in disease-related symptoms. CONCLUSIONS: High-dose pemetrexed appears tolerable and shows objective antitumor activity in patients with chordoma. Phase II studies of high-dose pemetrexed are warranted.

Aneurisma del seno de Valsalva roto a la aurícula derecha resuelto con intervencionismo / Rupture of sinus of Valsalva aneurysm to the right atrium resolved with interventionism

Resumen Se presenta un caso de aneurisma del seno de Valsalva derecho roto a la aurícula derecha, que en el transcurso de tres meses desarrolló insuficiencia cardiaca global y fue resuelto del todo por medio de intervencionismo, colocando un dispositivo oclusor en el sitio de la fístula. Se discute su etología, así como las pautas para el diagnóstico clínico y el tratamiento.

Abstract We present a case of a ruptured right sinus of Valsalva aneurysm to the right atrium that developed global heart failure over the course of three months, and which was completely resolved through cardiac catheterism, placing an occlusive device at the site of the fistula. Its ethology is discussed, as well as the guidelines for clinical diagnosis and treatment.

Existence of Radial Global Smooth Solutions to the Pressureless Euler-Poisson Equations with Quadratic Confinement.

We consider the pressureless Euler-Poisson equations with quadratic confinement. For spatial dimension d≥2,d≠4, we give a necessary and sufficient condition for the existence of radial global smooth solutions, which is formulated explicitly in terms of the initial data. This condition appears to be much more restrictive than the critical-threshold conditions commonly seen in the study of Euler-type equations. To obtain our results, the key observation is that every characteristic satisfies a periodic ODE system, and the existence of a global smooth solution requires the period of every characteristic to be identical.

Rupture of sinus of Valsalva aneurysm to the right atrium resolved with interventionism.

We present a case of a ruptured right sinus of Valsalva aneurysm to the right atrium that developed global heart failure over the course of three months, and which was completely resolved through cardiac catheterism, placing an occlusive device at the site of the fistula. Its ethology is discussed, as well as the guidelines for clinical diagnosis and treatment.

Se presenta un caso de aneurisma del seno de Valsalva derecho roto a la aurícula derecha, que en el transcurso de tres meses desarrolló insuficiencia cardiaca global y fue resuelto del todo por medio de intervencionismo, colocando un dispositivo oclusor en el sitio de la fístula. Se discute su etología, así como las pautas para el diagnóstico clínico y el tratamiento.

Quantifying tissue growth, shape and collision via continuum models and Bayesian inference.

Although tissues are usually studied in isolation, this situation rarely occurs in biology, as cells, tissues and organs coexist and interact across scales to determine both shape and function. Here, we take a quantitative approach combining data from recent experiments, mathematical modelling and Bayesian parameter inference, to describe the self-assembly of multiple epithelial sheets by growth and collision. We use two simple and well-studied continuum models, where cells move either randomly or following population pressure gradients. After suitable calibration, both models prove to be practically identifiable, and can reproduce the main features of single tissue expansions. However, our findings reveal that whenever tissue-tissue interactions become relevant, the random motion assumption can lead to unrealistic behaviour. Under this setting, a model accounting for population pressure from different cell populations is more appropriate and shows a better agreement with experimental measurements. Finally, we discuss how tissue shape and pressure affect multi-tissue collisions. Our work thus provides a systematic approach to quantify and predict complex tissue configurations with applications in the design of tissue composites and more generally in tissue engineering.

Phase 2 study of AV-GBM-1 (a tumor-initiating cell targeted dendritic cell vaccine) in newly diagnosed Glioblastoma patients: safety and efficacy assessment.

BACKGROUND: Vaccine immunotherapy may improve survival in Glioblastoma (GBM). A multicenter phase II trial was designed to determine: (1) the success rate of manufacturing the Aivita GBM vaccine (AV-GBM-1), (2) Adverse Events (AE) associated with AV-GBM-1 administration, and (3) survival. METHODS: Fresh suspected glioblastoma tissue was collected during surgery, and patients with pathology-confirmed GBM enrolled before starting concurrent Radiation Therapy and Temozolomide (RT/TMZ) with Intent to Treat (ITT) after recovery from RT/TMZ. AV-GBM-1 was made by incubating autologous dendritic cells with a lysate of irradiated autologous Tumor-Initiating Cells (TICs). Eligible patients were adults (18 to 70 years old) with a Karnofsky Performance Score (KPS) of 70 or greater, a successful TIC culture, and sufficient monocytes collected. A cryopreserved AV-GBM-1 dose was thawed and admixed with 500 µg of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) before every subcutaneous (s.c.) administration. RESULTS: Success rates were 97% for both TIC production and monocyte collection. AV-GBM-1 was manufactured for 63/63 patients; 60 enrolled per ITT; 57 started AV-GBM-1. The most common AEs attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). Treatment-emergent AEs included seizures (33%), headache (37%), and focal neurologic symptoms (28%). One patient discontinued AV-GBM-1 because of seizures. Median Progression-Free Survival (mPFS) and median Overall Survival (mOS) from ITT enrollment were 10.4 and 16.0 months, respectively. 2-year Overall Survival (OS) is 27%. CONCLUSIONS: AV-GBM-1 was reliably manufactured. Treatment was well-tolerated, but there were numerous treatment-emergent central nervous system AEs. mPFS was longer than historical benchmarks, though no mOS improvement was noted. TRIAL REGISTRATION: NCT, NCT03400917 , Registered 10 January 2018.

Noise-driven bifurcations in a neural field system modelling networks of grid cells.

The activity generated by an ensemble of neurons is affected by various noise sources. It is a well-recognised challenge to understand the effects of noise on the stability of such networks. We demonstrate that the patterns of activity generated by networks of grid cells emerge from the instability of homogeneous activity for small levels of noise. This is carried out by analysing the robustness of network activity patterns with respect to noise in an upscaled noisy grid cell model in the form of a system of partial differential equations. Inhomogeneous network patterns are numerically understood as branches bifurcating from unstable homogeneous states for small noise levels. We show that there is a phase transition occurring as the level of noise decreases. Our numerical study also indicates the presence of hysteresis phenomena close to the precise critical noise value.

Genomic selection in United States dairy cattle.

The genomic selection program for dairy cattle in the United States has doubled the rate of genetic gain. Since 2010, the average annual increase in net merit has been $85 compared to $40 during the previous 5 years. The number of genotypes has been rapidly increasing both domestically and internationally and reached over 6.5 million in 2022 with 1,134,593 submitted in 2021. Evaluations are calculated for over 50 traits. Feed efficiency (residual feed intake), heifer and cow livability, age at first calving, six health traits, and gestation length have been added in recent years to represent the economic value of selection candidates more accurately; work is underway to develop evaluations for hoof health. Evaluations of animals with newly submitted genotypes are calculated weekly. In April 2019, evaluations were extended to crossbreds; to support that effort, evaluations are initially calculated on an all-breed base and then blended by an estimated breed composition. For animals that are less than 90% of one breed, the evaluation is calculated by weighting contributions of each of the five major dairy breeds evaluated (Ayrshire, Brown Swiss, Guernsey, Holstein, and Jersey) by the breed proportion. Nearly 200,000 animals received blended evaluations in July 2022. Pedigree is augmented by using haplotype matching to discover maternal grandsires and great-grandsires. Haplotype analysis is also used to discover undesirable recessive conditions. In many cases, the causative variant has been identified, and results from a gene test or inclusion on a genotyping chip improves the accuracy of those determinations for the current 27 conditions reported. Recently discovered recessive conditions include neuropathy with splayed forelimbs in Jerseys, early embryonic death in Holsteins, and curly calves in Ayrshires. Techniques have been developed to support rapid searches for parent-progeny relationships and identical genotypes among all likely genotypes, which substantially reduces processing time. Work continues on using sequence data to discover additional informative single nucleotide polymorphisms and to incorporate those previously discovered. Adoption of genotyping by sequencing is expected to improve flexibility of marker selection. The success of the Council on Dairy Cattle Breeding in conducting the genetic evaluation program is the result of close cooperation with industry and research groups, including the United States Department of Agriculture, breed associations, genotyping laboratories, and artificial-insemination organizations.

Genetic Evaluations of Stillbirth for Five United States Dairy Breeds: A Data-Resource Feasibility Study.

Genetic selection has been an effective strategy to improve calving traits including stillbirth in dairy cattle. The primary objectives of the present study were to characterize stillbirth data and determine the feasibility of implementing routine genetic evaluations of stillbirth in five non-Holstein dairy breeds, namely Ayrshire, Guernsey, Milking Shorthorn, Brown Swiss, and Jersey. An updated sire-maternal grandsire threshold model was used to estimate genetic parameters and genetic values for stillbirth. Stillbirth data with the birth years of dams from 1995 to 2018 were extracted from the United States national calving ease database maintained by the Council on Dairy Cattle Breeding. The extracted stillbirth records varied drastically among the five dairy breeds. There were approximately 486K stillbirth records for Jersey and more than 80K stillbirth records for Brown Swiss. The direct and maternal heritability estimates of stillbirth were 6.0% (4.5-7.6%) and 4.7% (3.3-6.1%) in Jersey and 6.8% (3.2-10.5%) and 1.1% (0.6-2.9%) in Brown Swiss. The estimated genetic correlations between direct and maternal genetic effects for stillbirth were -0.15 (-0.38 to -0.08) in Jersey and -0.35 (-0.47 to -0.12) in Brown Swiss. The estimated genetic parameters for stillbirth in these two breeds were within close ranges of previous studies. The reliabilities of predicted transmitting abilities in Jersey and Brown Swiss increased substantially, thanks to the substantial increase in available stillbirth data in the past 10 years. The stillbirth records for Ayrshire, Guernsey, and Milking Shorthorn, which ranged approximately between 3K and 12K, are insufficient to implement reliable routine genetic evaluations of stillbirth in these three dairy breeds. Estimated genetic (co)variances and genetic values deviated considerably from the reported ranges of previous studies, and the reliabilities of predicted transmitting abilities were low in these three breeds. In conclusion, routine genetic evaluations of stillbirth are feasible in Brown Swiss and Jersey. However, reliable genetic evaluations of stillbirth in Ayrshire, Guernsey, and Milking Shorthorn require further data collection on stillbirth.

Mean-Field Limits: From Particle Descriptions to Macroscopic Equations.

We rigorously derive pressureless Euler-type equations with nonlocal dissipative terms in velocity and aggregation equations with nonlocal velocity fields from Newton-type particle descriptions of swarming models with alignment interactions. Crucially, we make use of a discrete version of a modulated kinetic energy together with the bounded Lipschitz distance for measures in order to control terms in its time derivative due to the nonlocal interactions.

Enhancement of damaged-image prediction through Cahn-Hilliard image inpainting.

We assess the benefit of including an image inpainting filter before passing damaged images into a classification neural network. We employ an appropriately modified Cahn-Hilliard equation as an image inpainting filter which is solved numerically with a finite-volume scheme exhibiting reduced computational cost and the properties of energy stability and boundedness. The benchmark dataset employed is Modified National Institute of Standards and Technology (MNIST) dataset, which consists of binary images of handwritten digits and is a standard dataset to validate image-processing methodologies. We train a neural network based on dense layers with MNIST, and subsequently we contaminate the test set with damages of different types and intensities. We then compare the prediction accuracy of the neural network with and without applying the Cahn-Hilliard filter to the damaged images test. Our results quantify the significant improvement of damaged-image prediction by applying the Cahn-Hilliard filter, which for specific damages can increase up to 50% and is advantageous for low to moderate damage.

Phase Transitions for Nonlinear Nonlocal Aggregation-Diffusion Equations.

We are interested in studying the stationary solutions and phase transitions of aggregation equations with degenerate diffusion of porous medium-type, with exponent 1 < m < ∞ . We first prove the existence of possibly infinitely many bifurcations from the spatially homogeneous steady state. We then focus our attention on the associated free energy, proving existence of minimisers and even uniqueness for sufficiently weak interactions. In the absence of uniqueness, we show that the system exhibits phase transitions: we classify values of m and interaction potentials W for which these phase transitions are continuous or discontinuous. Finally, we comment on the limit m → ∞ and the influence that the presence of a phase transition has on this limit.

Identification of a novel differentially methylated region adjacent to ATG16L2 in lung cancer cells using methyl-CpG binding domain protein-enriched genome sequencing.

Lung cancer is the most common cancer worldwide. Epigenetic modifications like DNA methylation play fundamental roles in the dynamic process of lung cancer. The objective of this study was to use methyl-CpG binding domain protein-enriched genome sequencing (MBD-Seq) to identify novel and high-confidence DNA methylation in lung tumor. We first compared the whole-genome DNA methylation of three lung cancer cell lines, including A549, H1299, and SK-MES-1, against BEAS-2B, a lung/bronchial normal epithelial cell line. We then used pyrosequencing and OneStep qMethyl kit methods to verify the results in the cell line specimens. MBD-Seq identified 279, 8046, and 22 887 differentially methylated regions (DMRs), respectively, with 120 common DMRs among three comparison groups. Three DMRs were consistent with the MBD-Seq results by both pyrosequencing and OneStep qMethyl validations. Furthermore, OneStep qMethyl kit was also performed for functional validation of these three potential DMRs in sputum DNA from clinical participants. We successfully identified one new DMR adjacent to ATG16L2. The novel DMR might have an important function in lung carcinogenesis. Further validation of the finding in clinical specimens of lung cancer patients and functional analysis of this novel DMR in the development of lung cancer through transcriptional silencing of ATG16L2 are warranted.

The Profiling of DNA Methylation and Its Regulation on Divergent Tenderness in Angus Beef Cattle.

Beef is an essential food source in the world. Beef quality, especially tenderness, has a significant impact on consumer satisfaction and industry profit. Many types of research to date have focused on the exploration of physiological and developmental mechanisms of beef tenderness. Still, the role and impact of DNA methylation status on beef tenderness have yet to be elucidated. In this study, we exhaustively analyzed the DNA methylation status in divergent tenderness observed in Angus beef. We characterized the methylation profiles related to beef tenderness and explored methylation distributions on the whole genome. As a result, differentially methylated regions (DMRs) associated with tenderness and toughness of beef were identified. Importantly, we annotated these DMRs on the bovine genome and explored bio-pathways of underlying genes and methylation biomarkers in beef quality. Specifically, we observed that the ATP binding cassette subfamily and myosin-related genes were highly methylated gene sets, and generation of neurons, regulation of GTPase activity, ion transport and anion transport, etc., were the significant pathways related with beef tenderness. Moreover, we explored the relationship between DNA methylation and gene expression in DMRs. Some methylated genes were identified as candidate biomarkers for beef tenderness. These results provide not only novel epigenetic information associated with beef quality but offer more significant insights into meat science, which will further help us explore the mechanism of muscle biology.

Traveling bands, clouds, and vortices of chiral active matter.

We consider stochastic dynamics of self-propelled particles with nonlocal normalized alignment interactions subject to phase lag. The role of the lag is to indirectly generate chirality into particle motion. To understand large-scale behavior, we derive a continuum description of an active Brownian particle flow with macroscopic scaling in the form of a partial differential equation for a one-particle probability density function. Due to indirect chirality, we find a spatially homogeneous nonstationary analytic solution for this class of equations. Our development of kinetic and hydrodynamic theories towards such a solution reveals the existence of a wide variety of spatially nonhomogeneous patterns reminiscent of traveling bands, clouds, and vortical structures of linear active matter. Our model may thereby serve as the basis for understanding the nature of chiral active media and designing multiagent swarms with designated behavior.

Correction to: Diet induced the change of mtDNA copy number and metabolism in Angus cattle.

[This corrects the article DOI: 10.1186/s40104-020-00482-x.].

Diet induced the change of mtDNA copy number and metabolism in Angus cattle.

BACKGROUND: Grass-fed and grain-fed Angus cattle differ in the diet regimes. However, the intricate mechanisms of different beef quality and other phenotypes induced by diet differences are still unclear. Diet affects mitochondrial function and dynamic behavior in response to changes in energy demand and supply. In this study, we examined the mtDNA copy number, mitochondria-related genes expression, and metabolic biomarkers in grass-fed and grain-fed Angus cattle. RESULTS: We found that the grass-fed group had a higher mtDNA copy number than the grain-fed group. Among different tissues, the mtDNA copy number was the highest in the liver than muscle, rumen, and spleen. Based on the transcriptome of the four tissues, a lower expression of mtDNA-encoded genes in the grass-fed group compared to the grain-fed group was discovered. For the mitochondria-related nuclear genes, however, most of them were significantly down-regulated in the muscle of the grass-fed group and up-regulated in the other three tissues. In which, COX6A2, POLG2, PPIF, DCN, and NDUFA12, involving in ATP synthesis, mitochondrial replication, transcription, and maintenance, might contribute to the alterations of mtDNA copy number and gene expression. Meanwhile, 40 and 23 metabolic biomarkers were identified in the blood and muscle of the grain-fed group compared to a grass-fed group, respectively. Integrated analysis of the altered metabolites and gene expression revealed the high expression level of MDH1 in the grain-fed group might contribute to the mitochondrial NADH oxidation and spermidine metabolism for adapting the deletion mtDNA copy number. CONCLUSIONS: Overall, the study may provide further deep insight into the adaptive and regulatory modulations of the mitochondrial function in response to different feeding systems in Angus cattle.