High Contact Density Research Articles

Perspectives for the reconstruction of 3D chromatin conformation using single cell Hi-C data.

Construction of chromosomes 3D models based on single cell Hi-C data constitute an important challenge. We present a reconstruction approach, DPDchrom, that incorporates basic knowledge whether the reconstructed conformation should be coil-like or globular and spring relaxation at contact sites. In contrast to previously published protocols, DPDchrom can naturally form globular conformation due to the presence of explicit solvent. Benchmarking of this and several other methods on artificial polymer models reveals similar reconstruction accuracy at high contact density and DPDchrom advantage at low contact density. To compare 3D structures insensitively to spatial orientation and scale, we propose the Modified Jaccard Index. We analyzed two sources of the contact dropout: contact radius change and random contact sampling. We found that the reconstruction accuracy exponentially depends on the number of contacts per genomic bin allowing to estimate the reconstruction accuracy in advance. We applied DPDchrom to model chromosome configurations based on single-cell Hi-C data of mouse oocytes and found that these configurations differ significantly from a random one, that is consistent with other studies.

Spatiotemporal contact density explains the disparity of COVID-19 spread in urban neighborhoods

The rapid early spread of COVID-19 in the US was experienced very differently by different socioeconomic groups and business industries. In this study, we study aggregate mobility patterns of New York City and Chicago to identify the relationship between the amount of interpersonal contact between people in urban neighborhoods and the disparity in the growth of positive cases among these groups. We introduce an aggregate spatiotemporal contact density index (CDI) to measure the strength of this interpersonal contact using mobility data collected from mobile phones, and combine it with social distancing metrics to show its effect on positive case growth. With the help of structural equations modeling, we find that the effect of CDI on case growth was consistently positive and that it remained consistently higher in lower-income neighborhoods, suggesting a causal path of income on case growth via CDI. Using the CDI, schools and restaurants are identified as high contact density industries, and the estimation suggests that implementing specific mobility restrictions on these point-of-interest categories is most effective. This analysis can be useful in providing insights for government officials targeting specific population groups and businesses to reduce infection spread as reopening efforts continue to expand across the nation.

Community structure of domesticated pigs in livestock facilities

The social structure of animal groups is considered to have an impact on their health and welfare. This could also be true for animals under commercial conditions, but research in this area has been limited. Pigs for example are known to be very social animals, but information about their grouping behavior is mostly derived from wild boars and a limited number of studies in seminatural and commercial conditions. Specifically under commercial conditions it is still unclear to what extent pig herds organize themselves in subgroups and how such group patterns emerge. To answer these questions, we tracked the positions of about 200 sows inside a barn during ongoing production over a period of five weeks and used these data to construct and analyze the animal contact networks. Our analysis showed a very high contact density and only little variation in the number of other animals that a specific animal is in contact with. Nevertheless, in each week we consistently detected three subgroups inside the barn, which also showed a clear spatial separation. Our results show that even in the high density environment of a commercial pig farm, the behavior of pigs to form differentiated groups is consistent with their behavior under seminatural conditions. Furthermore, our findings also imply that the barn layout could play an important role in the formation of the grouping pattern. These insights could be used to monitor and understand the spread of infectious diseases inside the barn better. In addition, our insights could potentially be used to improve the welfare of pigs.

Intraoperative Responses May Predict Chronic Performance of Composite Flat Interface Nerve Electrodes on Human Femoral Nerves.

Peripheral nerve cuff electrodes (NCEs) in motor system neuroprostheses can generate strong muscle contractions and enhance surgical efficiency by accessing multiple muscles from a single proximal location. Predicting chronic performance of high contact density NCEs based on intraoperative observations would facilitate implantation at locations that maximize selective recruitment, immediate connection of optimal contacts to implanted pulse generators (IPGs) with limited output channels, and initiation of postoperative rehabilitation as soon as possible after surgery. However, the stability of NCE intraoperative recruitment to predict chronic performance has not been documented. Here we report the first-in-human application of a specific NCE, the composite flat interface nerve electrode (C-FINE), at a new and anatomically challenging location on the femoral nerve close to the inguinal ligaments. EMG and moment recruitment curves were recorded for each of the 8 contacts in 2 C-FINE intraoperatively, perioperatively, and chronically for 6 months. Intraoperative measurements predicted chronic outcomes for 87.5% of contacts with 14/16 recruiting the same muscles at 6 months as intraoperatively. In both 8-contact C-FINEs, 3 contacts elicited hip flexion and 5 selectively generated knee extension, 3 of which activated independent motor unit populations each sufficient to support standing. Recruitment order stabilized in less than 3 weeks and did not change thereafter. While confirmation of these results will be required with future studies and implant locations, this suggests that remobilization and stimulated exercise may be initiated 3 weeks after surgery with little risk of altering performance.

Analytical gate fringe capacitance model for nanoscale MOSFET with layout dependent effect and process variations

In this paper, we present an analytical closed model for the gate to source/drain fringing capacitance (Cf) of nanoscale metal oxide semiconductor field effect transistors (MOSFETs), with the consideration of layout dependent effects and process fluctuations. A kind of field-poly structure on shallow trench isolation (STI) is used to separate Cf from other gate-around parasitic capacitances. A significant layout-dependent-effect is found in Cf for the case with high contact density. Based on the device structure, Cf is divided and analytically modeled by three dual-k perpendicular-plate capacitances. The effects of gate to contact space (CPS), contact to contact space (CCS) and the process variations, such as the over-etching of source/drain contact, are taken into account. The proposed model is validated on 40 nm MOSFETs, with a series of layout parameters, and good agreement is obtained between the modeled and measured data over a large range of CPS and CCS. The proposed model can improve the precision for digital and RF circuit simulation in sub-nanometer technology generation.

Discrete Element Method Investigation of Bulk Density and Electrical Resistivity of Calcined Coke Mixes

Packing density and electrical resistivity of particles assemblies are important factors for a variety of applications of granular materials. In the present work, a three-dimensional imaging technique is coupled with the discrete element method (DEM) to model anode grade calcined coke particles. Three-dimensional DEM models of samples with different size distribution of particles were studied to obtain the inter-particle contact information. As the content of fine particles increased, a higher inter-particle contact density and smaller average contact radius was observed in the samples. Confronting the DEM data and experimental measurements of electrical resistivity showed the simultaneous effects of packing density and contact density. Samples with higher contact density and smaller contact radius in general held high electrical resistivities. However, if increasing the contact density does not modify contacts between large particles, this will have a positive effect on packing density, so a lower electrical resistivity was obtained.

3D High Density: technology, roadmap and applications

After many years of packaging evolution as main industrial driver for 3D integration, even denser integration scheme have gained recently more interest. Slowdown of Moore's law while maintaining the need of high performance and/or low power from one hand, and a combination of performance / form factor from the other, lead research to innovation and alternative solutions. Additionally, difficulty of associating in a same 2D wafer heterogeneous processes (ie: combining Cmos device with “exotic” material, with low temperature dielectric) also gives an opportunity for a high density 3D approach rather than a 2D one. As an example, back-side illuminated imagers (BSI Imagers) players have recently released such 3D density (pitch in the range of 5 to 10 micron) [1] � From now, thinking about a 3D industrial integration within the range of few microns pitch is not anymore a dream. This specific application may raise some interest for other products such as memory denser stacking, partitioning of a large SoC � The objective of the paper is to describe 2 complementary technologies developed at CEA-Leti which address such high density of 3D integration: Hybrid Bonding in the range of few �ms; Coolcube in the range of few 100e of nms. We will first take some time to describe both technologies and recent CEA-Leti's results. The positioning of each technologies in terms of pitch and performance will be given. 1 - 3D parallel integration: hybrid bonding Hybrid bonding integration scheme has been first developed on a wafer scale approach. A test vehicle, with several BEOL layers and connected by the implementation of hybrid bonding, has been designed. Morphological and electrical data will be given leading to the conclusion that the process is very reliable and robust [1], [2]. Contact resistance per contact pads has been measured at few mOhms, which is relatively low compared to tens or even hundreds of mOhms for more classical interconnection technologies (copper pillar, bump, Cu-Cu thermos-compression). Nevertheless, for cost reason, as well as for multi dies stacking, the need for Die-To-Wafer approach remains true, while keeping a high density of interconnect [3]. The process flow as well as test vehicle designed for this approach will be described. Major challenges including handling of the dies after sawing and till the bonding itself will be addressed in the paper: wafer handler, wafer preparation and pick & place. Deep characterization is proposed. 2 - 3D sequential integration: CoolCube An alternative approach to conventional planar integration for future nodes is the monolithic 3D integration (3DVLSI). Monolithic offers the possibility to stack devices with a lithographic alignment precision enabling 3D contacts introduction at the device level (up to 100 million vias per mm� with 14nm ground rules). 3DVLSI can by routed either at gate or transistor levels. The partitioning at the gate level allows IC performance gain without resorting to scaling thanks to wire length reduction. Partitioning at the transistor level by stacking n-FET over p-FET (or the opposite) enables the independent optimization of both types of transistors (customized implementation of performance boosters: channel material / substrate orientation / channel and Raised Sources and Drains strain, etc. [4–5]) with reduced process complexity compared to a planar co-integration. The ultimate example of high performance CMOS at low process cost is the stacking of III–V nFETs above SiGe pFETs [6–7]. These high mobility transistors are well suited for 3DVLSI because their process temperatures are intrinsically low. 3DVLSI, with its high contact density, can also be seen as a powerful solution for heterogeneous co-integrations requiring high 3D vias densities such as NEMS with CMOS for gas sensing applications [8–9] or highly miniaturized imagers [10]. 3- Comparison and roadmap This paper will also provide features that give some applications' meaning for the development of both technologies in parallel. Particularly, both technologies will be compared in terms of possible pitch reachable. Main comparison features rely on advanced interconnection: dimension & pitch resistance, parasite. A thermal simulation comparison study will also be included.

Novell Plating Processes for Silicon Based Pixel Detectors

New generation silicon detectors produced in Thuringia (Germany) will play an important role in the future, during the upgrade phase of the Large Hadron Collider (LHC) at the CERN nuclear research center. Such detectors are used for monitoring radioactive reactions during the collision of highly accelerated positron radiations produced in large scale experiments like ATLAS (A Toroidal LHC ApparatuS) or CMS (Compact-Muon-Solenoid). The development of the new detectors aims at a functional improvement that will bring an enhanced resistance against radiation damage. At the same time, the surface reengineering for an increased active surface should address also important cost related aspects. This paper will discuss recent results from the authors' labs on the development of such novel sensors. The aim is a full understanding and coverage of the complete production process for the sensor modules. An important challenge to be addressed is the development of low cost metallisation procedures for the silicon detectors that do not require lithographic steps. Especially promising are extreme small and round surfaces of about 10 µm diameter distributed over the entire detector surface with a contact pitch of 50 µm that would add up to several thousand contacts and a high contact density. Given the special structure of the detector surface, electric current can be generated by incoming electromagnetic radiation, e.g. light. This current can be used in a light-induced metallization process of the front side contacts. We will present results from a light-induced plating process involving nickel and tin. The suitability of this layer system for subsequent bonding processes will also be discussed.

Mobile and Hard-to-Reach Voters

By taking into account mobile device samples to not exclude Mobile-Only respondents, a better representation of the general population can be obtained. This leads to more accu-rate analyses and findings that closely reflect reality. Data are collected that provides more representative and dynamic analyses by using the Rolling Cross-Section Design (see Johnston/Brady 2002), which takes a cross-section and distributes interviewing in a controlled way over time. A strict contact scheme with a high contact density allows even Hard-to-Reach populations to be taken into account appropriately in the random sample. Minimal deviations from the sample and general population will be corrected at the conclusion by a dual frame assessment system developed by the Association of German Market and Social Researchers. This paper investigates how the inclusion of Mobile-Only, Mostly-Mobile and Hard-to-Reach voters affects the estimates of voting behavior within the context of Germany. It be-gins by showing that these groups differ from the general population in terms of age, sex, employment, school graduation and income. Furthermore, there are significant differences in their political issues priorities and participation. Especially Hard-to-Reach voters have a higher voting intention and should be conducted.

Context-Dependent Folding: Sequence-Encoded Strategies for Stabilizing a Protein Subdomain in Isolation

Many proteins are made up of smaller structural units called subdomains. Dissecting proteins into these small units is important for protein engineering and design. In part, the ability to create novel fusion proteins relies on a subdomain's ability to fold autonomously. Subdomains are usually identified as regions that have high contact density, in other words, they have more residue-residue contacts within a specified region than they do with other areas of the protein. Due to their high contact density, subdomains are often assumed to be able to fold in isolation. We evaluate this hypothesis, by examining the foldability of a subdomain from T4 Lysozyme (T4L). In full-length T4L, the N-terminal subdomain has high contact density yet its sequence does not fold in isolation. This suggests that high contact density is not always enough for subdomain folding. To explore this, we have extended the boundary to the complete the sequence of a helix found in the full-length protein that has no contacts with the rest of the subdomain. We find that even without increasing predicted contacts, the sequence is able to fold autonomously. To determine if the sequence of the helix is important, we created a fusion protein that appends an alanine-based helix, which is able to fold in isolation, to the original N-terminal subdomain sequence. Surprisingly, we find that this structural mimicry allows the sequence to fold. In total, our findings point to the importance of considering not just considering the contact density when choosing boundaries of subdomains. We also demonstrate strategies to stabilize the folding of otherwise unfolded subdomain sequences.

Comparative Dynamics of NMDA- and AMPA-Glutamate Receptor N-Terminal Domains

SummaryIonotropic glutamate receptors (iGluRs) harbor two extracellular domains: the membrane-proximal ligand-binding domain (LBD) and the distal N-terminal domain (NTD). These are involved in signal sensing: the LBD binds L-glutamate, which activates the receptor channel. Ligand binding to the NTD modulates channel function in the NMDA receptor subfamily of iGluRs, which has not been observed for the AMPAR subfamily to date. Structural data suggest that AMPAR NTDs are packed into tight dimers and have lost their signaling potential. Here, we assess NTD dynamics from both subfamilies, using a variety of computational tools. We describe the conformational motions that underly NMDAR NTD allosteric signaling. Unexpectedly, AMPAR NTDs are capable of undergoing similar dynamics; although dimerization imposes restrictions, the two subfamilies sample similar, interconvertible conformational subspaces. Finally, we solve the crystal structure of AMPAR GluA4 NTD, and combined with molecular dynamics simulations, we characterize regions pivotal for an as-yet-unexplored dynamic spectrum of AMPAR NTDs.

Importance of a single disulfide bond for the PsbO protein of photosystem II: protein structure stability and soluble overexpression in Escherichia coli

PsbO protein is an important constituent of the water-oxidizing complex, located on the lumenal side of photosystem II. We report here the efficient expression of the spinach PsbO in E. coli where the solubility depends entirely on the formation of the disulfide bond. The PsbO protein purified from a pET32 system that includes thioredoxin fusion is properly folded and functionally active. Urea unfolding experiments imply that the reduction of the single disulfide bridge decreases stability of the protein. Analysis of inter-residue contact density through the PsbO molecule shows that Cys51 is located in a cluster with high contact density. Reduction of the Cys28-Cys51 bond is proposed to perturb the packing interactions in this cluster and destabilize the protein as a whole. Taken together, our results give evidence that PsbO exists in solution as a compact highly ordered structure, provided that the disulfide bridge is not reduced.

Contact Density Affects Protein Evolutionary Rate from Bacteria to Animals

The density of contacts or the fraction of buried sites in a protein structure is thought to be related to a protein's designability, and genes encoding more designable proteins should evolve faster than other genes. Several recent studies have tested this hypothesis but have found conflicting results. Here, we investigate how a gene's evolutionary rate is affected by its protein's contact density, considering the four species Escherichia coli, Saccharomyces cerevisiae, Drosophila melanogaster, and Homo sapiens. We find for all four species that contact density correlates positively with evolutionary rate, and that these correlations do not seem to be confounded by gene expression level. The strength of this signal, however, varies widely among species. We also study the effect of contact density on domain evolution in multidomain proteins and find that a domain's contact density influences the domain's evolutionary rate. Within the same protein, a domain with higher contact density tends to evolve faster than a domain with lower contact density. Our study provides evidence that contact density can increase evolutionary rates, and that it acts similarly on the level of entire proteins and of individual protein domains.

Structural Determinants of the Rate of Protein Evolution in Yeast

We investigate how a protein's structure influences the rate at which its sequence evolves. Our basic hypothesis is that proteins with highly designable structures (structures that are encoded by many sequences) will evolve more rapidly. Recent theoretical advances argue that structures with a higher density of interresidue contacts are more designable, and we show that high contact density is correlated with an increased rate of sequence evolution in yeast. In addition, we investigate the correlations between the rate of sequence evolution and several other structural descriptors, carefully controlling for the strong effect of expression level on evolutionary rate. Overall, we find that the structural descriptors that we consider appear to explain roughly 10% of the variation in rates of protein evolution in yeast. We also show that despite the well-known trend for buried residues to be more conserved, proteins with a higher fraction of buried residues, nonetheless, tend to evolve their sequences more rapidly. We suggest that this effect is due to the increased designability of structures with more buried residues. Our results provide evidence that protein structure plays an important role in shaping the rate of sequence evolution and provide evidence to support recent theoretical advances linking structural designability to contact density.

Solder connections for high frequency applications between flexible and rigid printed circuit boards

This article examines the backplane connector technology for high frequency use and presents a novel concept for shielded enclosures without air vents. The experimental soldering of connections between a flexible printed circuit (flex, for short) and a FR4-board as part of a backplane connector is presented. A very high contact density is reached by soldering vias on the flex to pads on the FR4; this soldering was performed both with ordinary Sn/Pb solder material and as well with lead-free solder alloy. The solder joints were examined using a scanning electron microscope (SEM) and the electrical properties of the flex/solder joint structure were measured.