Spatiotemporal control of pattern formation during somitogenesis.

Spatiotemporal patterns widely occur in biological, chemical, and physical systems. Particularly, embryonic development displays a diverse gamut of repetitive patterns established in many tissues and organs. Branching treelike structures in lungs, kidneys, livers, pancreases, and mammary glands as well as digits and bones in appendages, teeth, and palates are just a few examples. A fascinating instance of repetitive patterning is the sequential segmentation of the primary body axis, which is conserved in all vertebrates and many arthropods and annelids. In these species, the body axis elongates at the posterior end of the embryo containing an unsegmented tissue. Meanwhile, segments sequentially bud off from the anterior end of the unsegmented tissue, laying down an exquisite repetitive pattern and creating a segmented body plan. In vertebrates, the paraxial mesoderm is sequentially divided into somites. In this review, we will discuss the most prominent models, the most puzzling experimental data, and outstanding questions in vertebrate somite segmentation.

Comparison of peripapillary vascular density as measured by optical coherence tomography angiography between various types of open-angle glaucoma.

PURPOSE: The purpose of this study is to compare the peripapillary vascular density in patients with various types of open-angle glaucoma (primary open-angle glaucoma, pseudoexfoliative glaucoma and pigmentary glaucoma) with healthy subjects by optic coherence tomography angiography (OCTA). METHODS: Twenty-seven eyes with diagnosed POAG, thirty-four eyes with diagnosed PXG, twenty eyes with diagnosed PG and thirty eyes of healthy individuals were included in our study. Peripapillary vessel density measurements were performed with all images; (AI-DD), intra-disc (ID-DD) and peripapillary (PP-DD); measurement of vascular density in the radial peripapillary capillary network was performed by OCTA. The Kruskal-Wallis test and post-hoc test were performed for statistical analysis. RESULTS: AI-DD was 50.76±2.07% in the healthy group, 47.12±2.57% in POAG, 39.71±6.64% in PXG, and 43.37±1.55% in PG. ID-DD was 50.49±3.74% in the healthy group, 49.51±6.83% in POAG, 38.42±13.46% in PXG, and 40.9±4.45% in PG. PP-DD was 51.26±3.12% in the healthy group, 50.13±3.04% in POAG, 42.31±7.31% in PXG, and 47.6±1.40% in PG. While it was found that all image and intra-disc vascular density measurements were statistically significantly lower in the PG and PXG group compared to the healthy group and the POAG (P<0.001), there was no significant difference between PXG and PG or between the control group and POAG. CONCLUSIONS: The lower radial peripapillary capillary density in PXG and PG compared to the POAG and healthy groups suggests that the blood flow around the optic disc is negatively affected in these patients.

Evaluation of the association between the optic nerve sheath diameter and extracorporeal life support time during cardiac surgery in newborns.

OBJECTIVE: Congenital heart disease (CHD), a birth defect, is a major cause of neonatal mortality; however, improvements in surgical procedures and medical treatments have resulted in decreased mortality rates. Nonetheless, postoperative morbidity, particularly cerebral dysfunction, remains an issue in patients receiving extracorporeal life support (ECLS) for cardiac surgeries. Herein, we aimed to assess the association between optic nerve sheath diameter (ONSD) and ECLS time in newborns receiving ECLS for cardiac surgery. PATIENTS AND METHODS: We enrolled 25 newborn patients who received ECLS for cardiac surgery at our hospital. ONSD was measured at four different time points during the surgery: baseline (T1), 15 min after cross-clamping (T2), after displacement of cross-clamping (T3) and at the end of the surgery (T4). Furthermore, the ECLS time, aortic cross-clamp time, and surgery time were recorded. RESULTS: The regression analysis revealed a significant association between ONSD and ECLS time, cross-clamp time and surgery time. The correlation analysis showed strong associations between baseline ONSD and ONSD at T2, T3, and T4. Moreover, ONSDs significantly increased at T2 compared with those at baseline during cardiac surgery. CONCLUSIONS: Our findings suggest an association between ONSD and ECLS time in newborns receiving ECLS for cardiac surgery. Monitoring ONSD may provide valuable information about intracranial pressure changes in these patients.

A design logic for sequential segmentation across organisms.

Multitudes of organisms display metameric compartmentalization of their body plan. Segmentation of these compartments happens sequentially in diverse phyla. In several sequentially segmenting species, periodically active molecular clocks and signaling gradients have been found. The clocks are proposed to control the timing of segmentation, while the gradients are proposed to instruct the positions of segment boundaries. However, the identity of the clock and gradient molecules differs across species. Furthermore, sequential segmentation of a basal chordate, Amphioxus, continues at late stages when the small tail bud cell population cannot establish long-range signaling gradients. Thus, it remains to be explained how a conserved morphological trait (i.e., sequential segmentation) is achieved by using different molecules or molecules with different spatial profiles. Here, we first focus on sequential segmentation of somites in vertebrate embryos and then draw parallels with other species. Thereafter, we propose a candidate design principle that has the potential to answer this puzzling question.

Human stem cell models unravel mechanisms of somite segmentation.

In vitro models to study human somitogenesis, the formation of the segmented body plan, have so far been limited.1 Two papers in Nature now report the creation of pluripotent stem cell (PSC)-derived 3D culture systems that recapitulate the formation of somite-like structures and help gain insights into this developmental process.2,3.

Periodic inhibition of Erk activity drives sequential somite segmentation.

Sequential segmentation creates modular body plans of diverse metazoan embryos1-4. Somitogenesis establishes the segmental pattern of the vertebrate body axis. A molecular segmentation clock in the presomitic mesoderm sets the pace of somite formation4. However, how cells are primed to form a segment boundary at a specific location remains unclear. Here we developed precise reporters for the clock and double-phosphorylated Erk (ppErk) gradient in zebrafish. We show that the Her1-Her7 oscillator drives segmental commitment by periodically lowering ppErk, therefore projecting its oscillation onto the ppErk gradient. Pulsatile inhibition of the ppErk gradient can fully substitute for the role of the clock, and kinematic clock waves are dispensable for sequential segmentation. The clock functions upstream of ppErk, which in turn enables neighbouring cells to discretely establish somite boundaries in zebrafish5. Molecularly divergent clocks and morphogen gradients were identified in sequentially segmenting species3,4,6-8. Our findings imply that versatile clocks may establish sequential segmentation in diverse species provided that they inhibit gradients.

COMPARISON OF C-PEPTIDE LEVELS IN MONOGENIC FORMS OF DIABETES WITH OTHER TYPES OF DIABETES: A SINGLE-CENTER STUDY.

Objective: This study aimed to evaluate the utility of C-peptide levels in the differentiation of monogenic forms of diabetes from type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) in clinical practice. Subjects and Methods: A total of 104 patients aged >16 who visited the Dicle University's Faculty of Medicine between April 2011 and December 2020 and were diagnosed with monogenic diabetes by genetic analysis or with T1DM and T2DM were randomly selected for retrospective evaluation. The C-peptide levels of these patients at the time of diagnosis of diabetes were compared. Results: Of the 104 patients, 24 (23%) were diagnosed with maturity-onset diabetes of the young (MODY), 40 (38.5%) with T1DM, and 40 (38.5%) with T2DM. Median C-peptide levels (ng/mL) (interquartile range) were 1.78 (1.24-2.88) in MODY group, 0.86 (0.34-1.22) in T1DM group, and 2.38 (1.58-4.27) in T2DM group. Conclusions: There was a difference in C-peptide levels between MODY and T1DM groups but not between MODY and T2DM groups. As per clinical evaluations, although C-peptide levels of patients with MODY are similar to those of patients with T2DM patients, the possibility of C-peptide levels being similar to those required for T1DM diagnosis should also be considered.

Patterning principles of morphogen gradients.

Metazoan embryos develop from a single cell into three-dimensional structured organisms while groups of genetically identical cells attain specialized identities. Cells of the developing embryo both create and accurately interpret morphogen gradients to determine their positions and make specific decisions in response. Here, we first cover intellectual roots of morphogen and positional information concepts. Focusing on animal embryos, we then provide a review of current understanding on how morphogen gradients are established and how their spans are controlled. Lastly, we cover how gradients evolve in time and space during development, and how they encode information to control patterning. In sum, we provide a list of patterning principles for morphogen gradients and review recent advances in quantitative methodologies elucidating information provided by morphogens.

Muscle strength but not balance improves after arthroscopic biodegradable polyurethane meniscus scaffold application.

PURPOSE: This study aimed to assess the impact of biodegradable polyurethane meniscus scaffold implantation (BPMSI) on muscle strength and balance in comparison with the healthy contralateral knee in patients with irreparable medial meniscus defect. METHODS: This observational and prospective case-cohort study was conducted with patients who had irreparable meniscal defects and underwent arthroscopic meniscus scaffold implantation. Surgeries were carried out on the medial meniscus of 16 right and 4 left knees. Visual analog scale (VAS) was used to assess the degree of pain relief. Knee Injury and Osteoarthritis Outcome Score (KOOS) and Lysholm (LYS) score were used to evaluate the functional improvement at weeks 12, 24 and 36. Concentric and eccentric quadriceps and hamstring peak torque (PT) as well as the peak torque-to-body weight (PTB) ratio, anterior-posterior, mediolateral and overall stability indexes were assessed at the same time points. RESULTS: Twenty male patients with a mean age and body mass index of 32.2 ± 8.8 years and 26.2 ± 4.2 kg/m2, respectively, were included in the study. The amount of pain decreased from 7.6 ± 1.5% to 2.9 ± 1.5% at postoperative week 36. Range of motion, Lysholm score and KOOS increased from 87.0ο ± 9.5ο to 115.0ο ± 15.1ο, 30.8 ± 4.3 to 81.5 ± 5.3 and 37.4 ± 5.3 to 74.1 ± 7.2, respectively. Concentric quadriceps and hamstring peak torque values and peak torque/body weight ratios were improved in the knees that received a meniscus scaffold implant. Anterior/posterior, medial/lateral, and overall stability indexes with or without biofeedback exhibited a slight improvement, which was not statistically significant. CONCLUSION: BPMSI led to decreased pain and improved function at postoperative week 36. Although muscle strength almost returned to normal, balance parameters did not recover within 36 weeks after the procedure.

A 3-D Tail Explant Culture to Study Vertebrate Segmentation in Zebrafish.

Vertebrate embryos pattern their major body axis as repetitive somites, the precursors of vertebrae, muscle, and skin. Somites progressively segment from the presomitic mesoderm (PSM) as the tail end of the embryo elongates posteriorly. Somites form with regular periodicity and scale in size. Zebrafish is a popular model organism as it is genetically tractable and has transparent embryos that allow for live imaging. Nevertheless, during somitogenesis, fish embryos are wrapped around a large, rounding yolk. This geometry limits live imaging of PSM tissue in zebrafish embryos, particularly at higher resolutions that require a close objective working distance. Here, we present a flattened 3-D tissue culture method for live imaging of zebrafish tail explants. Tail explants mimic intact embryos by displaying a proportional slowdown of axis elongation and shortening of rostrocaudal somite lengths. We are further able to stall axis elongation speed through explant culture. This, for the first time, enables us to untangle the chemical input of signaling gradients from the mechanistic input of axial elongation. In future studies, this method can be combined with a microfluidic setup to allow time-controlled pharmaceutical perturbations or screening of vertebrate segmentation without any drug penetration concerns.

Prevalence of odontogenic cysts and tumors on turkish sample according to latest classification of world health organization: A 10-year retrospective study.

AIM: The aims of this study are to investigate the prevalence of odontogenic cysts and tumors occurred in a sample of Turkish population in the last 10 years and to compare the data with latest reports. METHODS AND MATERIAL: The present retrospective study was carried out at Gazi University, School of Dentistry (GUSD) in Ankara, Turkey. All the data was retrieved from the GUSD archive on patients treated for various oral and maxillofacial lesions between 2008 and 2018. Patients' demographical data, main clinical features of the lesions along with histopathological findings were retrieved from the dental files of the patients. The type of lesions was evaluated according to the latest Head and Neck Tumor (HNT) classification published by the World Health Organization (WHO) in 2017. Data was analyzed by descriptive statistics and Chi-square test using SPSS version 21.0 software. RESULTS: Among a total of 739 biopsy-conducted lesions, 467 (63.19%) were odontogenic cysts, 43 (5.82%) were benign odontogenic tumors, and 7 (0.95%) were malignant tumors. The rest of 222 cases were defined as others. CONCLUSIONS: The present study assessed the demographic and clinico-pathological characteristics of odontogenic cysts/tumors in a group of Turkish people, who visited GUSD for therapeutic purpose in the past 10 years. Results showed that male patients in their 5th-6th decades have the highest risk of odontogenic cyst/tumor, especially in the mandibular posterior region.

mFOLFOX-based Chemotherapy Can Augment Survival in Advanced Gastric Cancer Patient with Disseminated Intravascular Coagulation

ABSTRACT Although gastric cancer is a frequent cancer type, disseminated intravascular coagulation is a very rare but serious complication of this disease. We report a 65-year-old man who complained of weight loss, nausea and vomiting, fatigue and dyspnoea for three days. He was diagnosed as having advanced gastric cancer complicated with disseminated intravascular coagulation, which was successfully treated with mFOLFOX chemotherapy regimen. After one cycle of mFOLFOX therapy, thrombocytopenia was improved and serum lactate dehydrogenase levels decreased. Remarkable remission was seen. After 12 cycles of chemotherapy, remarkable remission was seen in the primary tumour and multiple metastatic bone lesions.

The effect of adenosine triphosphate on sunitinib-induced cardiac injury in rats.

In this study, we aimed to show the effect of adenosine 5'-triphosphate (ATP) on sunitinib-induced cardiac injury in rats. The rats (n = 30) were divided equally into three groups as sunitinib group (SG), sunitinib plus ATP group (SAG), and healthy group (HG); 2 mg/kg ATP was injected intraperitoneally (ip) to the SAG group. Same volume normal saline as solvent was administered ip to the other two groups. After 1 h, 25 mg/kg sunitinib was applied orally via catheter to stomach in the SAG and SG groups. This procedure was repeated once daily for 5 weeks. At the end of this period, all animals were sacrificed and their cardiac tissue was removed. Malondialdehyde (MDA), total glutathione (tGSH), tumor necrosis factor α (TNF-α), and nuclear factor κB (NF-κB) levels in rats' cardiac tissues and troponin I (Tp-I) levels in rats' blood samples were evaluated. Histopathological analysis was also performed in cardiac tissues of the animals. MDA, TNF-α, NF-κB, and Tp-I levels were higher in the SG group compared to the SAG and HG groups (p < 0.001). tGSH levels of the SG group were lower than the SAG and HG groups (p < 0.001). The structure and morphology of cardiac muscle fibers and blood vessels were normal in the control group. In the SG group, obvious cardiac muscle tissue damage with dilated myofibers, locally atrophic myofibers, and congested blood vessels were observed. In the SAG group, marked amelioration in these findings was observed. We showed this for the first time that ATP administration exerts a protective effect against cardiac effects of sunitinib.

Regulatory Network of the Scoliosis-Associated Genes Establishes Rostrocaudal Patterning of Somites in Zebrafish.

Gene regulatory networks govern pattern formation and differentiation during embryonic development. Segmentation of somites, precursors of the vertebral column among other tissues, is jointly controlled by temporal signals from the segmentation clock and spatial signals from morphogen gradients. To explore how these temporal and spatial signals are integrated, we combined time-controlled genetic perturbation experiments with computational modeling to reconstruct the core segmentation network in zebrafish. We found that Mesp family transcription factors link the temporal information of the segmentation clock with the spatial action of the fibroblast growth factor signaling gradient to establish rostrocaudal (head to tail) polarity of segmented somites. We further showed that cells gradually commit to patterning by the action of different genes at different spatiotemporal positions. Our study provides a blueprint of the zebrafish segmentation network, which includes evolutionarily conserved genes that are associated with the birth defect congenital scoliosis in humans.

Determination of the antibiotic resistance rates of Serratia marcescens isolates obtained from various clinical specimens.

AIM: Serratia marcescens clinical isolates are increasingly resistant to antibiotics. Therefore, the treatment of infections caused by S. marcescens becomes difficult. The aim of this study was to examine the antimicrobial resistance profiles of S. marcescens bacteria isolated from various clinical specimens according to body regions and clinics and to evaluate for enzyme production rates associated with antibiotic resistance of these isolates. MATERIALS AND METHODS: Blood culture samples were incubated in a fully automated BACTEC-FX system. Identification and antibiogram processing was carried out by fully automated VITEK 2 identification and antibiogram system. The obtained results were retrospectively screened. RESULTS: S. marcescens was identified in a total of 158 clinical specimens. The departments where S. marcescens was most commonly identified were the Anesthesia Intensive Care Unit (25.9%), followed by Chest Diseases (19.6%). Serratia isolates were most commonly determined in blood culture (35.4%) and sputum culture (24.6%). Resistance rates to ceftriaxone and ceftazidime were 22.7% and 19.6%, respectively. However, the rate of resistance detected to cefotaxime and gentamicin (0.6%) was very low. CONCLUSION: Clinical isolates of Serratia exhibited highest resistance to ceftriaxone, ceftazidime, and piperacillin/tazobactam. However, it was found that the tested Serratia strains did not exhibit high resistance to other antibiotics. Our results suggest that cefotaxime and gentamicin are the most suitable antibiotics for treatment. The extended-spectrum ß-lactamase and inducible ß-lactamase ratios were found to be decreased by 6%-7%. Although different results may be obtained from different hospitals and regions, it should not be forgotten that Serratia strains may be resistant to many antibiotics and that the results of antibiotic susceptibility testing may help plan antibiotic treatment.

Spatial Fold Change of FGF Signaling Encodes Positional Information for Segmental Determination in Zebrafish.

Signal gradients encode instructive information for numerous decision-making processes during embryonic development. A striking example of precise, scalable tissue-level patterning is the segmentation of somites-the precursors of the vertebral column-during which the fibroblast growth factor (FGF), Wnt, and retinoic acid (RA) pathways establish spatial gradients. Despite decades of studies proposing roles for all three pathways, the dynamic feature of these gradients that encodes instructive information determining segment sizes remained elusive. We developed a non-elongating tail explant system, integrated quantitative measurements with computational modeling, and tested alternative models to show that positional information is encoded solely by spatial fold change (SFC) in FGF signal output. Neighboring cells measure SFC to accurately position the determination front and thus determine segment size. The SFC model successfully recapitulates results of spatiotemporal perturbation experiments on both explants and intact embryos, and it shows that Wnt signaling acts permissively upstream of FGF signaling and that RA gradient is dispensable.

Quantifying spatial and temporal variations of the cell membrane ultra-structure by bimFCS.

It has been long recognized that the cell membrane is heterogeneous on scales ranging from a couple of molecules to micrometers in size and hence diffusion of receptors is length scale dependent. This heterogeneity modulates many cell-membrane-associated processes requiring transient spatiotemporal separation of components. The transient increase in local concentration of interacting signal components enables robust signaling in an otherwise thermally noisy system. Understanding how lipids and proteins self-organize and interact with the cell cortex requires quantifying the motion of the components. Multi-length scale diffusion measurements by single particle tracking, fluorescence correlation spectroscopy (FCS) or related techniques are able to identify components being transiently trapped in nanodomains, from freely moving one and from ones with reduced long-scale diffusion due to interaction with the cell cortex. One particular implementation of multi-length scale diffusion measurements is the combination of FCS with a spatially resolved detector, such as a camera and two-dimensional extended excitation profile. The main advantages of this approach are that all length scales are interrogated simultaneously, uniquely permits quantifying changes to the membrane structure caused by extrenal or internal perturbations. Here, we review how combining total internal reflection microscopy (TIRF) with FC resolves the membrane organization in living cells. We show how to implement the method, which requires only a few seconds of data acquisition to quantify membrane nanodomains, or the spacing of membrane fences caused by the actin cortex. The choice of diffusing fluorescent probe determines which membrane heterogeneity is detected. We review the instrument, sample preparation, experimental and computational requirements to perform such measurements, and discuss the potential and limitations. The discussion includes examples of spatial and temporal comparisons of the membrane structure in response to perturbations demonstrating the complex cell physiology.

[Continued development of drugs: the path of thioguanine]. / Van doorontwikkeling van een geneesmiddel tot registratie-uitbreiding.

Continued development of existing drugs ('drug rediscovery') may offer new therapeutic options and be cost-effective. Rediscovered drugs are commonly prescribed off-label, although licensing can be important to allow safe and controlled prescription of the drugs to patients. Licensing of a new indication for a generic drug, however, is a complicated process since there is no blueprint for this and there is little interest from the pharmaceutical industry due to an unattractive cost-recovery model. In this article, we illustrate the successful license-extension for thioguanine - initially developed in 1950 for leukaemia - as a new treatment for patients with inflammatory bowel disease.

Comparison of sedation method in pediatrics cardiac catheterization.

OBJECTIVE: Purpose of this study is to compare the effects of various anaesthetic combinations on hemodynamics, sedation level, recovery period and complications in the patients which undergo pediatric cardiac catheterization. PATIENTS AND METHODS: Four groups of anaesthetic combinations was created. The groups are classified as propofol-ketamine (group 1), propofol-dexmedetomidine (group 2), dexmedetomidine-ketamine (group 3), midazolam-ketamine (group 4) (for each group n=20). Baseline heart rate (HR), mean arterial blood pressure (MAP), respiratory rate (RR), peripheral oxygen saturation (SpO2) were recorded. This parameters values were recorded at 0., 5., 10., 15., 20., 25., 30. minutes; and the groups were compared according to these measurements data. RESULTS: For heart rate, Group 2 and 3 reduce the HR more than the drugs of Group 1 and 4 (p < 0.05). The SpO2 values of Group 1 were measured to have 5% further reduction compared to the Group 2 and 3; and Group 4 has the same SpO2 recordings compared to the Group 3 (p < 0.05). Comparing the recovery times; Group 4 was found to have the highest recovery time compared to the other drug groups. It is found that additional doses are needed for recovery in Group 4 (p < 0.008). Side effects were lowest for Group 3 and highest for Group 4. CONCLUSIONS: Considering the complication rates, it is concluded that Group 3 is spotted as the better sedation method among the other groups. In terms of additional propofol dose, Group 1 would be the better choice. Thus, the clinician should choose the suitable methods for the patient.