Atrial and Sinoatrial Node Development in the Zebrafish Heart

Proper development and function of the vertebrate heart is vital for embryonic and postnatal life. Many congenital heart defects in humans are associated with disruption of genes that direct the formation or maintenance of atrial and pacemaker cardiomyocytes at the venous pole of the heart. Zebrafish are an outstanding model for studying vertebrate cardiogenesis, due to the conservation of molecular mechanisms underlying early heart development, external development, and ease of genetic manipulation. Here, we discuss early developmental mechanisms that instruct appropriate formation of the venous pole in zebrafish embryos. We primarily focus on signals that determine atrial chamber size and the specialized pacemaker cells of the sinoatrial node through directing proper specification and differentiation, as well as contemporary insights into the plasticity and maintenance of cardiomyocyte identity in embryonic zebrafish hearts. Finally, we integrate how these insights into zebrafish cardiogenesis can serve as models for human atrial defects and arrhythmias.

Two distinct types of nodes of Ranvier support auditory nerve function in the mouse cochlea

Glial cells of the auditory nerve regulate formation of the nodes of Ranvier that are needed for regeneration of action potentials and proper hearing function. Here we identify and describe the distinct features of two novel types of Ranvier nodes—the axonal node and the ganglion node—in the mouse auditory nerve that change across the lifespan, including during myelination and postnatal development, and degenerate during aging. Cellular, molecular, and structure-function correlation evaluations revealed that nodal types are critical for different aspects of auditory nerve function. Specifically, the length of the axonal node is associated with neural processing speed and neural synchrony, whereas ganglion node development is associated with amplitude growth of the action potential. Moreover, our data indicate that dysregulation of glial cells and associated degeneration of the ganglion node structure are an important and new mechanism of auditory nerve dysfunction in age-related hearing loss.

GATA6 is a regulator of sinus node development and heart rhythm

The sinus node (SAN) is the primary pacemaker of the human heart, and abnormalities in its structure or function cause sick sinus syndrome, the most common reason for electronic pacemaker implantation. Here we report that transcription factor GATA6, whose mutations in humans are linked to arrhythmia, is highly expressed in the SAN and its haploinsufficiency in mice results in hypoplastic SANs and rhythm abnormalities. Cell-specific deletion reveals a requirement for GATA6 in various SAN lineages. Mechanistically, GATA6 directly activates key regulators of the SAN genetic program in conduction and nonconduction cells, such as TBX3 and EDN1, respectively. The data identify GATA6 as an important regulator of the SAN and provide a molecular basis for understanding the conduction abnormalities associated with GATA6 mutations in humans. They also suggest that GATA6 may be a potential modifier of the cardiac pacemaker.

Control of sinus venous valve and sinoatrial node development by endocardial NOTCH1

Aims Sinus venous valve (SVV) and sinoatrial node (SAN) develop together at the sinoatrial junction during embryogenesis. SVV ensures unidirectional cardiac input and SAN generates sinus rhythmic contraction, respectively; both functions are essential for embryonic survival. We aim to reveal the potential role of endocardial NOTCH signalling in SVV and SAN formation. Methods and results We specifically deleted Notch1 in the endocardium using an Nfatc1Cre line. This deletion resulted in underdeveloped SVV and SAN, associated with reduced expression of T-box transcription factors, Tbx5 andTbx18, which are essential for the formation of SVV and SAN. The deletion also led to decreased expression of Wnt2 in myocardium of SVV and SAN. WNT2 treatment was able to rescue the growth defect of SVV and SAN resulted from the Notch1 deletion in whole embryo cultures. Furthermore, the Notch1 deletion reduced the expression of Nrg1 in the SVV myocardium and supplement of NRG1 restored the growth of SVV in cultured Notch1 knockout embryos. Conclusion Our findings support that endocardial NOTCH1 controls the development of SVV and SAN by coordinating myocardial WNT and NRG1 signalling functions.

Strengthening Rural and Regional Economic Competitiveness Triggering Purworejo Regency Economic Growth through Tourism-Based Kutoarjo Transit Node Development

The railway transport node in Kutoarjo, serving the southern route of Java, is an excellent opportunity for Kutoarjo's economic growth. Kutoarjo, located in the administrative area of Purworejo Regency in RTRW of Central Java Province belongs to Purwomanggung regional system covering Purworejo Regency, Wonosobo Regency, Magelang Regency, Magelang City, and Temanggung Regency. An international airport is also being built in Kulonprogo Regency, Special Region of Jogjakarta Province, which will be integrated with the existing stations in Purworejo Regency, explicitly located in Kutoarjo sub-district, Kutoarjo Station. The construction of NYIA (New Yogyakarta International Airport) in Kulon Progo is an excellent opportunity for the rise and trigger for Kutoarjo. However, the current condition of the existing Kutoharjo station is not optimal and does not significantly give added value to the economy either in Kutoarjo or Purworejo. Kutoharjo Station is only a temporary transit point, and there is no other object which can make visitors want to stop longer in Kutoharjo. This study aims to formulate a management development of Kutoarjo as a transit city that can contribute to mobilizing the economy in Purworejo Regency and its surrounding areas. The analysis is conducted by considering movement patterns, development of transit areas, supporting sectors and policies. Based on the analysis results, it can be seen that the development of transit area using seamless tourism concept requires ± 1.4 ha of land around Kutoarjo station, which is still included in 200 meters (walkable) radius. Result of study reveals that the development of node transit is supported by a potential tourism sector. The implication of this transit area development is the absorption of labor force in 2038 as many as 12,213 people. Besides, there is an economic increase of PAD (LGR) of 55.7% which eventually leads the LGR (PAD) reach IDR. 2.328.129.852.138 in 2039.

Multiple roles of lymphatic vessels in peripheral lymph node development

The mammalian lymphatic system consists of strategically located lymph nodes (LNs) embedded into a lymphatic vascular network. Mechanisms underlying development of this highly organized system are not fully understood. Using high-resolution imaging, we show that lymphoid tissue inducer (LTi) cells initially transmigrate from veins at LN development sites using gaps in venous mural coverage. This process is independent of lymphatic vasculature, but lymphatic vessels are indispensable for the transport of LTi cells that egress from blood capillaries elsewhere and serve as an essential LN expansion reservoir. At later stages, lymphatic collecting vessels ensure efficient LTi cell transport and formation of the LN capsule and subcapsular sinus. Perinodal lymphatics also promote local interstitial flow, which cooperates with lymphotoxin-β signaling to amplify stromal CXCL13 production and thereby promote LTi cell retention. Our data unify previous models of LN development by showing that lymphatics intervene at multiple points to assist LN expansion and identify a new role for mechanical forces in LN development.

Developing Integrated Solutions and Wet Cleans to Eliminate Tungsten Contact Attack in Sub 0x nm Nodes

Having successfully developed high volume manufacturing (HVM) processes for the 0x nm node, the semiconductor industry is now engaged in developing the next advanced node. This 0xnm node development is being accomplished by a combination of shrinking 0x nm dimensions, introducing new materials and films and consequently new lithography, dry etch and wet clean processes for the new node. One of the major challenges is developing processes, including BEOL Cleans Steps, to successfully and reliably expose the MOL metal contact during the first metal line formation without degrading the contact itself. One such compatible method/clean is discussed in this study.