Bismuth drugs, despite being clinically used for decades, surprisingly remain in use and effective for the treatment of Helicobacter pylori infection, even for resistant strains when co-administrated with antibiotics. However, the molecular mechanisms underlying the clinically sustained susceptibility of H. pylori to bismuth drugs remain elusive. Herein, we report that integration of in-house metalloproteomics and quantitative proteomics allows comprehensive uncovering of the bismuth-associated proteomes, including 63 bismuth-binding and 119 bismuth-regulated proteins from Helicobacter pylori, with over 60% being annotated with catalytic functions. Through bioinformatics analysis in combination with bioassays, we demonstrated that bismuth drugs disrupted multiple essential pathways in the pathogen, including ROS defence and pH buffering, by binding and functional perturbation of a number of key enzymes. Moreover, we discovered that HpDnaK may serve as a new target of bismuth drugs to inhibit bacterium-host cell adhesion. The integrative approach we report, herein, provides a novel strategy to unveil the molecular mechanisms of antimicrobial metals against pathogens in general. This study sheds light on the design of new types of antimicrobial agents with multiple targets to tackle the current crisis of antimicrobial resistance.

Competing endogenous RNAs (ceRNAs) are RNA molecules that sequester shared microRNAs (miRNAs) thereby affecting the expression of other targets of the miRNAs. Whether genetic variants in ceRNA can affect its biological function and disease development is still an open question. Here we identified a large number of genetic variants that are associated with ceRNA's function using Geuvaids RNA-seq data for 462 individuals from the 1000 Genomes Project. We call these loci competing endogenous RNA expression quantitative trait loci or ‘cerQTL’, and found that a large number of them were unexplored in conventional eQTL mapping. We identified many cerQTLs that have undergone recent positive selection in different human populations, and showed that single nucleotide polymorphisms in gene 3΄UTRs at the miRNA seed binding regions can simultaneously regulate gene expression changes in both cis and trans by the ceRNA mechanism. We also discovered that cerQTLs are significantly enriched in traits/diseases associated variants reported from genome-wide association studies in the miRNA binding sites, suggesting that disease susceptibilities could be attributed to ceRNA regulation. Further in vitro functional experiments demonstrated that a cerQTL rs11540855 can regulate ceRNA function. These results provide a comprehensive catalog of functional non-coding regulatory variants that may be responsible for ceRNA crosstalk at the post-transcriptional level.

Infection after renal transplantation remains a major cause of morbidity and death, especially infection from the extensively drug-resistant bacteria, A. baumannii. A total of fourteen A. baumannii isolates were isolated from the donors’ preserved fluid from DCD (donation after cardiac death) renal transplantation and four isolates in the recipients’ draining liquid at the Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, from March 2013 to November 2014. An outbreak of A. baumannii emerging after DCD renal transplantation was tracked to understand the transmission of the pathogen. PFGE displayed similar DNA patterns between isolates from the same hospital. Antimicrobial susceptibility tests against thirteen antimicrobial agents were determined using the K-B diffusion method and eTest. Whole-genome sequencing was applied to investigate the genetic relationship of the isolates. With the clinical data and research results, we concluded that the A. baumannii isolates 3R1 and 3R2 was probably transmitted from the donor who acquired the bacteria during his stay in the ICU, while isolate 4R1 was transmitted from 3R1 and 3R2 via medical manipulation. This study demonstrated the value of integration of clinical profiles with molecular methods in outbreak investigation and their importance in controlling infection and preventing serious complications after DCD transplantation.

Of particular interest to the neuroscience and robotics communities is the understanding of how two humans could physically collaborate to perform motor tasks such as holding a tool or moving it across locations. When two humans physically interact with each other, sensory consequences and motor outcomes are not entirely predictable as they also depend on the other agent’s actions. The sensory mechanisms involved in physical interactions are not well understood. The present study was designed (1) to quantify human–human physical interactions where one agent (“follower”) has to infer the intended or imagined—but not executed—direction of motion of another agent (“leader”) and (2) to reveal the underlying strategies used by the dyad. This study also aimed at verifying the extent to which visual feedback (VF) is necessary for communicating intended movement direction. We found that the control of leader on the relationship between force and motion was a critical factor in conveying his/her intended movement direction to the follower regardless of VF of the grasped handle or the arms. Interestingly, the dyad’s ability to communicate and infer movement direction with significant accuracy improved (>83%) after a relatively short amount of practice. These results indicate that the relationship between force and motion (interpreting as arm impedance modulation) may represent an important means for communicating intended movement direction between biological agents, as indicated by the modulation of this relationship to intended direction. Ongoing work is investigating the application of the present findings to optimize communication of high-level movement goals during physical interactions between biological and non-biological agents.

Whole genome sequencing (WGS) is a promising strategy to unravel variants or genes responsible for human diseases and traits. However, there is a lack of robust platforms for a comprehensive downstream analysis. In the present study, we first proposed three novel algorithms, sequence gap-filled gene feature annotation, bit-block encoded genotypes and sectional fast access to text lines to address three fundamental problems. The three algorithms then formed the infrastructure of a robust parallel computing framework, KGGSeq, for integrating downstream analysis functions for whole genome sequencing data. KGGSeq has been equipped with a comprehensive set of analysis functions for quality control, filtration, annotation, pathogenic prediction and statistical tests. In the tests with whole genome sequencing data from 1000 Genomes Project, KGGSeq annotated several thousand more reliable non-synonymous variants than other widely used tools (e.g. ANNOVAR and SNPEff). It took only around half an hour on a small server with 10 CPUs to access genotypes of ∼60 million variants of 2504 subjects, while a popular alternative tool required around one day. KGGSeq's bit-block genotype format used 1.5% or less space to flexibly represent phased or unphased genotypes with multiple alleles and achieved a speed of over 1000 times faster to calculate genotypic correlation.

Humans are able to intuitively exploit the shape of an object and environmental constraints to achieve stable grasps and perform dexterous manipulations. In doing that, a vast range of kinematic strategies can be observed. However, in this work we formulate the hypothesis that such ability can be described in terms of a synergistic behavior in the generation of hand postures, i.e., using a reduced set of commonly used kinematic patterns. This is in analogy with previous studies showing the presence of such behavior in different tasks, such as grasping. We investigated this hypothesis in experiments performed by six subjects, who were asked to grasp objects from a flat surface. We quantitatively characterized hand posture behavior from a kinematic perspective, i.e., the hand joint angles, in both pre-shaping and during the interaction with the environment. To determine the role of tactile feedback, we repeated the same experiments but with subjects wearing a rigid shell on the fingertips to reduce cutaneous afferent inputs. Results show the persistence of at least two postural synergies in all the considered experimental conditions and phases. Tactile impairment does not alter significantly the first two synergies, and contact with the environment generates a change only for higher order Principal Components. A good match also arises between the first synergy found in our analysis and the first synergy of grasping as quantified by previous work. The present study is motivated by the interest of learning from the human example, extracting lessons that can be applied in robot design and control. Thus, we conclude with a discussion on implications for robotics of our findings.

Modeling of transcriptional regulatory networks (TRNs) has been increasingly used to dissect the nature of gene regulation. Inference of regulatory relationships among transcription factors (TFs) and genes, especially among multiple TFs, is still challenging. In this study, we introduced an integrative method, LogicTRN, to decode TF–TF interactions that form TF logics in regulating target genes. By combining cis-regulatory logics and transcriptional kinetics into one single model framework, LogicTRN can naturally integrate dynamic gene expression data and TF-DNA-binding signals in order to identify the TF logics and to reconstruct the underlying TRNs. We evaluated the newly developed methodology using simulation, comparison and application studies, and the results not only show their consistence with existing knowledge, but also demonstrate its ability to accurately reconstruct TRNs in biological complex systems.

The concept of postural synergies of the human hand has been shown to potentially reduce complexity in the neuromuscular control of grasping. By merging this concept with soft robotics approaches, a multi degrees of freedom soft-synergy prosthetic hand [SoftHand-Pro (SHP)] was created. The mechanical innovation of the SHP enables adaptive and robust functional grasps with simple and intuitive myoelectric control from only two surface electromyogram (sEMG) channels. However, the current myoelectric controller has very limited capability for fine control of grasp forces. We addressed this challenge by designing a hybrid-gain myoelectric controller that switches control gains based on the sensorimotor state of the SHP. This controller was tested against a conventional single-gain (SG) controller, as well as against native hand in able-bodied subjects. We used the following tasks to evaluate the performance of grasp force control: (1) pick and place objects with different size, weight, and fragility levels using power or precision grasp and (2) squeezing objects with different stiffness. Sensory feedback of the grasp forces was provided to the user through a non-invasive, mechanotactile haptic feedback device mounted on the upper arm. We demonstrated that the novel hybrid controller enabled superior task completion speed and fine force control over SG controller in object pick-and-place tasks. We also found that the performance of the hybrid controller qualitatively agrees with the performance of native human hands.

Human physical interactions can be intrapersonal, e.g., manipulating an object bimanually, or interpersonal, e.g., transporting an object with another person. In both cases, one or two agents are required to coordinate their limbs to attain the task goal. We investigated the physical coordination of two hands during an object-balancing task performed either bimanually by one agent or jointly by two agents. The task consisted of a series of static (holding) and dynamic (moving) phases, initiated by auditory cues. We found that task performance of dyads was not affected by different pairings of dominant and non-dominant hands. However, the spatial configuration of the two agents (side-by-side vs. face-to-face) appears to play an important role, such that dyads performed better side-by-side than face-to-face. Furthermore, we demonstrated that only individuals with worse solo performance can benefit from interpersonal coordination through physical couplings, whereas the better individuals do not. The present work extends ongoing investigations on human-human physical interactions by providing new insights about factors that influence dyadic performance. Our findings could potentially impact several areas, including robotic-assisted therapies, sensorimotor learning and human performance augmentation.

Biological and robotic grasp and manipulation are undeniably similar at the level of mechanical task performance. However, their underlying fundamental biological vs. engineering mechanisms are, by definition, dramatically different and can even be antithetical. Even our approach to each is diametrically opposite: inductive science for the study of biological systems vs. engineering synthesis for the design and construction of robotic systems. The past 20 years have seen several conceptual advances in both fields and the quest to unify them. Chief among them is the reluctant recognition that their underlying fundamental mechanisms may actually share limited common ground, while exhibiting many fundamental differences. This recognition is particularly liberating because it allows us to resolve and move beyond multiple paradoxes and contradictions that arose from the initial reasonable assumption of a large common ground. Here, we begin by introducing the perspective of neuromechanics, which emphasizes that real-world behavior emerges from the intimate interactions among the physical structure of the system, the mechanical requirements of a task, the feasible neural control actions to produce it, and the ability of the neuromuscular system to adapt through interactions with the environment. This allows us to articulate a succinct overview of a few salient conceptual paradoxes and contradictions regarding under-determined vs. over-determined mechanics, under- vs. over-actuated control, prescribed vs. emergent function, learning vs. implementation vs. adaptation, prescriptive vs. descriptive synergies, and optimal vs. habitual performance. We conclude by presenting open questions and suggesting directions for future research. We hope this frank and open-minded assessment of the state-of-the-art will encourage and guide these communities to continue to interact and make progress in these important areas at the interface of neuromechanics, neuroscience, rehabilitation and robotics.