Tessellation of artificial touch via microstimulation of human somatosensory cortex.

When we interact with objects, we rely on signals from the hand that convey information about the object and our interaction with it. A basic feature of these interactions, the locations of contacts between the hand and object, is often only available via the sense of touch. Information about locations of contact between a brain-controlled bionic hand and an object can be signaled via intracortical microstimulation (ICMS) of somatosensory cortex (S1), which evokes touch sensations that are localized to a specific patch of skin. To provide intuitive location information, tactile sensors on the robotic hand drive ICMS through electrodes that evoke sensations at skin locations matching sensor locations. This approach requires that ICMS-evoked sensations be focal, stable, and distributed over the hand. To systematically investigate the localization of ICMS-evoked sensations, we analyzed the projected fields (PFs) of ICMS-evoked sensations - their location and spatial extent - from reports obtained over multiple years from three participants implanted with microelectrode arrays in S1. First, we found that PFs vary widely in their size across electrodes, are highly stable within electrode, are distributed over large swaths of each participant's hand, and increase in size as the amplitude or frequency of ICMS increases. Second, while PF locations match the locations of the receptive fields (RFs) of the neurons near the stimulating electrode, PFs tend to be subsumed by the corresponding RFs. Third, multi-channel stimulation gives rise to a PF that reflects the conjunction of the PFs of the component channels. By stimulating through electrodes with largely overlapping PFs, then, we can evoke a sensation that is experienced primarily at the intersection of the component PFs. To assess the functional consequence of this phenomenon, we implemented multichannel ICMS-based feedback in a bionic hand and demonstrated that the resulting sensations are more localizable than are those evoked via single-channel ICMS.

Biomimetic multi-channel microstimulation of somatosensory cortex conveys high resolution force feedback for bionic hands.

Manual interactions with objects are supported by tactile signals from the hand. This tactile feedback can be restored in brain-controlled bionic hands via intracortical microstimulation (ICMS) of somatosensory cortex (S1). In ICMS-based tactile feedback, contact force can be signaled by modulating the stimulation intensity based on the output of force sensors on the bionic hand, which in turn modulates the perceived magnitude of the sensation. In the present study, we gauged the dynamic range and precision of ICMS-based force feedback in three human participants implanted with arrays of microelectrodes in S1. To this end, we measured the increases in sensation magnitude resulting from increases in ICMS amplitude and participant's ability to distinguish between different intensity levels. We then assessed whether we could improve the fidelity of this feedback by implementing "biomimetic" ICMS-trains, designed to evoke patterns of neuronal activity that more closely mimic those in natural touch, and by delivering ICMS through multiple channels at once. We found that multi-channel biomimetic ICMS gives rise to stronger and more distinguishable sensations than does its single-channel counterpart. Finally, we implemented biomimetic multi-channel feedback in a bionic hand and had the participant perform a compliance discrimination task. We found that biomimetic multi-channel tactile feedback yielded improved discrimination over its single-channel linear counterpart. We conclude that multi-channel biomimetic ICMS conveys finely graded force feedback that more closely approximates the sensitivity conferred by natural touch.

Axin1: A novel scaffold protein joins the antiviral network of interferon.

Acute respiratory infection by influenza virus is a persistent and pervasive public health problem. Antiviral innate immunity initiated by type I interferon (IFN) is the first responder to pathogen invasion and provides the first line of defense. We discovered that Axin1, a scaffold protein, was reduced during influenza virus infection. We also found that overexpression of Axin1 and the chemical stabilizer of Axin1, XAV939, reduced influenza virus replication in lung epithelial cells. This effect was also observed with respiratory syncytial virus and vesicular stomatitis virus. Axin1 boosted type I IFN response to influenza virus infection and activated JNK/c-Jun and Smad3 signaling. XAV939 protected mice from influenza virus infection. Thus, our studies provide new mechanistic insights into the regulation of the type I IFN response and present a new potential therapeutic of targeting Axin1 against influenza virus infection.

Induction of Trained Immunity Protects Neonatal Mice Against Microbial Sepsis by Boosting Both the Inflammatory Response and Antimicrobial Activity.

Background: Neonates are susceptible to a wide range of microbial infection and at a high risk to develop severe sepsis and septic shock. Emerged evidence has shown that induction of trained immunity triggers a much stronger inflammatory response in adult monocytes/macrophages, thereby conferring protection against microbial infection. Methods: This study was carried out to examine whether trained immunity is inducible and exerts its protection against microbial sepsis in neonates. Results: Induction of trained immunity by Bacillus Calmette-Guerin (BCG) plus bacterial lipoprotein (BLP) protected neonatal mice against cecal slurry peritonitis-induced polymicrobial sepsis, and this protection is associated with elevated circulating inflammatory cytokines, increased neutrophil recruitment, and accelerated bacterial clearance. In vitro stimulation of neonatal murine macrophages with BCG+BLP augmented both inflammatory response and antimicrobial activity. Notably, BCG+BLP stimulation resulted in epigenetic remodeling characterized by histone modifications with enhanced H3K4me3, H3K27Ac, and suppressed H3K9me3 at the promoters of the targeted inflammatory and antimicrobial genes. Critically, BCG+BLP stimulation led to a shift in cellular metabolism with increased glycolysis, which is the prerequisite for subsequent BCG+BLP-triggered epigenetic reprogramming and augmented inflammatory response and antimicrobial capacity. Conclusion: These results illustrate that BCG+BLP induces trained immunity in neonates, thereby protecting against microbial infection by boosting both inflammatory and antimicrobial responses.

Perioperative cell-free DNA trends predict recurrence of non-metastatic colorectal cancer significantly earlier than CEA trends over the first 2 years post-operatively in stage II and stage III colon cancer.

PURPOSE: We aimed to compare the diagnostic accuracy of perioperative ΔcfDNA to ΔCEA (over the first 2 years post-operatively) for identifying disease recurrence in colon cancer. METHODS: Patients presenting for elective resection for colon cancer with curative intent were screened for inclusion. Perioperative cfDNA levels were measured at seven different times points(pre-operative and post-operative at 3 h, 6 h, 24 h, 48 h, POD3 and POD5). CEA levels were measured on the same patients up to 2 years post-operatively. Change in trend (Δ) was defined as the ß coefficient using a logistic regression model. Statistical analysis was performed using SPSS, version 23. RESULTS: Longitudinal data on twenty-two patients were analysed (n = 16 male, n = 6 female) for a median of 29 months (IQR 23 months) during which time three patients developed (distant) recurrence. Perioperative ΔcfDNA at 48Hrs, POD3 and POD5 were significantly associated with early recurrence. ΔCEA was significantly associated with early recurrence at 6 months, 1 year and 2 years post-operatively, only when disease recurrence was macroscopically established. ΔcfDNA was associated with an area under the curve (AUC) of 0.947 (95% CI 0.88-1.0, p < 0.001) and ΔCEA was associated with an AUC of 0.9382 (95%CI 0.88-0.99, p < 0.0001). This translated into a specificity of 97% (95%CI 86.51-99.87%) for ΔcfDNA and 77.5% sensitivity (95%CI 62.5-87.7%) in the immediate perioperative period and an 88.9% specificity (95%CI 56.5-99.4%) and 76.5% sensitivity (95%CI 63.24-86%) for ΔCEA over the first 2 years post-operatively. CONCLUSIONS: In this pilot study, following curative resection for colon cancer changing trends in perioperative cfDNA (ΔcfDNA) identify those at risk of recurrent disease before recurrence develops which is at least 6 months earlier than CEA changes (ΔCEA) which are only observed when recurrence is established.

The relevance of liquid biopsy in surgical oncology: The application of perioperative circulating nucleic acid dynamics in improving patient outcomes.

BACKGROUND: Liquid biopsy is gaining increasing clinical utility in the management of cancer patients. The main components of a liquid biopsy are circulating nucleic acids, circulating tumour cells and extracellular vesicles such as exosomes. Circulating nucleic acids including cell free DNA (cfDNA) and circulating tumour DNA (ctDNA) in particular have been the focus of recent attention as they have demonstrated excellent potential in cancer screening, provision of prognostic information and in genomic profiling of a tumour without the need for repeated tissue biopsies. The aim of this review was to explore the current evidence in relation to the use of liquid biopsy in the perioperative setting and identify ways in which liquid biopsy may be applied in the future. METHODS: This narrative review is based on a comprehensive literature search up to the 1st of June 2020 for papers relevant to the application of liquid biopsy in surgical oncology, focusing particularly on the perioperative period. RESULTS: Recent evidence has demonstrated that perioperative liquid biopsy can accurately stratify patients' risk of recurrence compared to conventional biomarkers. Attention to the perioperative dynamics of liquid biopsy components can potentially provide new understanding of the complex relationship between surgery and cancer outcome. In addition, careful evaluation of liquid biopsy components in the perioperative window may provide important diagnostic and therapeutic information for cancer patients. CONCLUSION: The rapidly evolving concept of the liquid biopsy has the potential to become the cornerstone for decision making around surveillance and adjuvant therapies the era of personalised medicine.

Investigating the Prevalence of Reactive Online Searching in the COVID-19 Pandemic: Infoveillance Study.

BACKGROUND: The ongoing pandemic has placed an unprecedented strain on global society, health care, governments, and mass media. Public dissemination of government policies, medical interventions, and misinformation has been remarkably rapid and largely unregulated during the COVID-19 pandemic, resulting in increased misinterpretations, miscommunication, and public panic. Being the first full-scale global pandemic of the digital age, COVID-19 has presented novel challenges pertinent to government advice, the spread of news and misinformation, and the trade-off between the accessibility of science and the premature public use of unproven medical interventions. OBJECTIVE: This study aims to assess the use of internet search terms relating to COVID-19 information and misinformation during the global pandemic, identify which were most used in six affected countries, investigate any temporal trends and the likely propagators of key search terms, and determine any correlation between the per capita cases and deaths with the adoption of these search terms in each of the six countries. METHODS: This study uses relative search volume data extracted from Google Trends for search terms linked to the COVID-19 pandemic alongside per capita case and mortality data extracted from the European Open Data Portal to identify the temporal dynamics of the spread of news and misinformation during the global pandemic in six affected countries (Australia, Germany, Italy, Spain, the United Kingdom, and the United States). A correlation analysis was carried out to ascertain any correlation between the temporal trends of search term use and the rise of per capita mortality and disease cases. RESULTS: Of the selected search terms, most were searched immediately following promotion by governments, public figures, or viral circulation of information, but also in relation to the publication of scientific resources, which were sometimes misinterpreted before further dissemination. Strong correlations were identified between the volume of these COVID-19-related search terms (overall mean Spearman rho 0.753, SD 0.158), and per capita mortality (mean per capita deaths Spearman rho 0.690, SD 0.168) and cases (mean per capita cases Spearman rho 0.800, SD 0.112). CONCLUSIONS: These findings illustrate the increased rate and volume of the public consumption of novel information during a global health care crisis. The positive correlation between mortality and online searching, particularly in countries with lower COVID-19 testing rates, may demonstrate the imperative to safeguard official communications and dispel misinformation in these countries. Online news, government briefings, and social media provide a powerful tool for the dissemination of important information to the public during pandemics, but their misuse and the presentation of misrepresented medical information should be monitored, minimized, and addressed to safeguard public safety. Ultimately, governments, public health authorities, and scientists have a moral imperative to safeguard the truth and maintain an accessible discourse with the public to limit fear.

Polypropylene mesh and systemic side effects in inguinal hernia repair: current evidence.

INTRODUCTION: Increasing awareness and regulatory body attention is directed towards the insertion of synthetic material for a variety of surgical procedures. This review aims to assess current evidence regarding systemic and auto-immune effects of polypropylene mesh insertion in hernia repair. METHODS: The electronic literature on systemic and auto-immune effects associated with mesh insertion was examined. RESULTS: Foreign body reaction following mesh implantation initiates an acute inflammatory cellular response. Involved markers such as IL-1, IL-6, IL-10 and fibrinogen are increased in circulation in the presence of mesh but return to normal at 7 days post operatively. Oxidative degradation of implanted mesh is likely, but no evidence exists to support systemic absorption or resulting disease effects. Variable cytokine production in healthy hosts leading to unpredictable or overwhelming response to implanted biomaterial warrants further investigation. Clinical studies show no associated long-term systemic effects with mesh. CONCLUSION: To date, there remains no evidence to link polypropylene mesh and systemic or auto-immune symptoms. Based on current evidence, the use of polypropylene mesh is supported.

Using technology to enhance medication regimen education after solid organ transplantation.

PURPOSE: The design and implementation of a tool that combines clinical teaching with cutting-edge, simplified technology for providing medication education to solid organ transplant (SOT) recipients are described. METHODS: In a retrospective study of adults who received kidney transplants from February 2015 through May 2017, patients were educated about their medications using a tablet computer application, Medication Regimen Education (MRxEd), that presented concise videos describing the name, indication, dose, adverse effects, and associated interactions of all medications received, as well as special considerations applicable to each agent. Assessment questions were used to reinforce key concepts and identify knowledge gaps. RESULTS: The digital educational intervention was provided to 282 kidney transplant recipients. Patients were predominantly white (48%) and/or male (63%), with a median age of 51 years (interquartile range, 37-61 years). Patients came from a variety of education backgrounds. Most patients (81%) were educated on dual maintenance immunosuppression (with tacrolimus and mycophenolate) and 3 infection prophylaxis agents (nystatin, sulfamethoxazole-trimethoprim, and valganciclovir). Most patients (90%) correctly answered questions related to medication indications, dosing, and special rules, but many (61%) had difficulty correctly answering questions about adverse effects. CONCLUSION: An innovative approach for interactive and engaging medication teaching with the MRxEd application enhanced the education process for SOT recipients.

Airway Macrophage and Dendritic Cell Subsets in the Resting Human Lung.

Dendritic cells (DCs) and macrophages (MΦs) are antigen-presenting phagocytic cells found in many peripheral tissues of the human body, including the blood, lymph nodes, skin, and lung. They are vital to maintaining steady-state respiration in the human lung based on their ability to clear airways while also directing tolerogenic or inflammatory responses based on specific stimuli. Over the past three decades, studies have determined that there are multiple subsets of these two general cell types that exist in the airways and interstitium. Identifying these numerous subsets has proven challenging, especially with the unique microenvironments present in the lung. Cells found in the vasculature are not the same subsets found in the skin or the lung, as demonstrated by surface marker expression. By transcriptional profiling, these subsets show similarities but also major differences. Primary human lung cells and/ or tissues are difficult to acquire, particularly in a healthy condition. Additionally, surface marker screening and transcriptional profiling are continually identifying new DC and MΦ subsets. While the overall field is moving forward, we emphasize that more attention needs to focus on replicating the steady-state microenvironment of the lung to reveal the physiological functions of these subsets.

Identification and characterization of human dendritic cell subsets in the steady state: a review of our current knowledge.

Dendritic cells (DC) are generally categorized as a group of rare antigen presenting cells that are to the crucial development of immune responses to pathogens and also of tolerance to self-antigens. Therefore, having the ability to identify DC in specific tissues and to test their functional abilities in the steady state are scientific gaps needing attention. Research on primary human DC is lacking due to their rarity and the difficulty of obtaining tissue samples. However, recent findings have shown that several different DC subsets exist, and that these subsets vary both by markers expressed and functions depending on their specific microenvironment. After discriminating from other cell types, DC can be split into myeloid and plasmacytoid fractions. While plasmacytoid DC express definite markers, CD123 and BDCA-2, myeloid DC encompass several different subsets with overlapping markers expressed. Such markers include the blood DC antigens BDCA-1 and BDCA-3, along with Langerin, CD1a and CD14. Marker specificity is further reduced when accounting for microenvironmental differences, as observed in the blood, primary lymphoid tissues, skin and lungs. The mixed leukocyte reaction (MLR) has been used to measure the strength of antigen presentation by specific DC subsets. Surface markers and MLR require standardization to enable consistent identification of and comparisons between DC subsets. To alleviate these issues, researchers have begun comparing DC subsets at the transcriptional level. This has allowed degrees of relatedness to be determined between DC in different microenvironments, and should be a continued area of focus in years to come.

Bacillus anthracis lethal toxin reduces human alveolar epithelial barrier function.

The lung is the site of entry for Bacillus anthracis in inhalation anthrax, the deadliest form of the disease. Bacillus anthracis produces virulence toxins required for disease. Alveolar macrophages were considered the primary target of the Bacillus anthracis virulence factor lethal toxin because lethal toxin inhibits mouse macrophages through cleavage of MEK signaling pathway components, but we have reported that human alveolar macrophages are not a target of lethal toxin. Our current results suggest that, unlike human alveolar macrophages, the cells lining the respiratory units of the lung, alveolar epithelial cells, are a target of lethal toxin in humans. Alveolar epithelial cells expressed lethal toxin receptor protein, bound the protective antigen component of lethal toxin, and were subject to lethal-toxin-induced cleavage of multiple MEKs. These findings suggest that human alveolar epithelial cells are a target of Bacillus anthracis lethal toxin. Further, no reduction in alveolar epithelial cell viability was observed, but lethal toxin caused actin rearrangement and impaired desmosome formation, consistent with impaired barrier function as well as reduced surfactant production. Therefore, by compromising epithelial barrier function, lethal toxin may play a role in the pathogenesis of inhalation anthrax by facilitating the dissemination of Bacillus anthracis from the lung in early disease and promoting edema in late stages of the illness.

Compensatory load redistribution of horses with induced weight-bearing forelimb lameness trotting on a treadmill.

The study was performed to obtain a detailed insight into the load and time shifting mechanisms of horses with unilateral weight-bearing forelimb lameness. Reversible lameness was induced in 11 clinically sound horses by applying a solar pressure model. Three degrees of lameness (subtle, mild and moderate) were induced and compared with sound control measurements. Vertical ground reaction force-time histories of all four limbs were recorded simultaneously on an instrumented treadmill. Four compensatory mechanisms could be identified that served to reduce structural stress, i.e. peak vertical force on the affected limb: (1) with increasing lameness, horses reduced the total vertical impulse per stride; (2) the diagonal impulse decreased selectively in the lame diagonal; (3) the impulse was shifted within the lame diagonal to the hindlimb and in the sound diagonal to the forelimb; (4) the rate of loading and the peak forces were reduced by prolonging the stance duration. Except in the diagonal hindlimb, where peak vertical forces increased slightly in the moderate lameness condition, no equivalent compensatory overload situation was observed in the other limbs. Specific force and time information of all four limbs allow the unequivocal identification of the affected limb.

Vertical ground reaction force-time histories of sound Warmblood horses trotting on a treadmill.

The objective of this study was to establish representative treadmill ground reaction force (GRF) and interlimb co-ordination time data of clinically sound horses at the trot. It was anticipated that these normative standards would provide a reference data base against which lame horses could be compared. GRF-time histories were collected from 30 Warmblood riding horses with easy, wide natural gaits. Data were recorded of all four limbs simultaneously by the use of an instrumented treadmill. A total of 912 stride cycles per limb were analysed for force, time and spatial parameters and were averaged. The shape and amplitude of the treadmill force curves were very similar to force traces recorded with a stationary force plate. The horses showed a high degree of symmetry in all investigated parameters (95% reference interval of left-right asymmetry +/-1.8-6.8%). No significant differences were found between left and right mean values. Intra-individual coefficients of variance of the various parameters did not exceed 2.7%. Inter-individual coefficients of variance were 2.5-3.5 times larger than the respective intra-individual coefficients. An instrumented treadmill provides a number of decisive advantages, such as time-efficient data acquisition of all four feet simultaneously over successive strides, or the high regularity of the horse's gait pattern at controlled velocities, which allow the clinical assessment of locomotor performance of horses.

Structure and function of photosystem I: interaction with its soluble electron carriers and external antenna systems.

Photosystem I (PS I) is a large membrane protein complex that catalyzes the first step of solar conversion, the light-induced transmembrane electron transfer, and generates reductants for CO2 assimilation. It consists of 12 different proteins and 127 cofactors that perform light capturing and electron transfer. The function of PS I includes inter-protein electron transfer between PS I and smaller soluble electron transfer proteins. The structure of PS I is discussed with respect to the potential docking sites for the soluble electron acceptors, ferredoxin/flavodoxin, at the stromal side and the soluble electron donors, cytochrome c6/plastocyanin, at the luminal side of the PS I complex. Furthermore, the potential interaction sites with the peripheral antenna proteins are discussed.

Assembly of protein subunits within the stromal ridge of photosystem I. Structural changes between unbound and sequentially PS I-bound polypeptides and correlated changes of the magnetic properties of the terminal iron sulfur clusters.

The X-ray structure of Photosystem I (PS I) from Synechococcus elongatus was recently solved at 2.5A resolution (PDB entry 1JB0). It provides a structural model for the stromal subunits PsaC, PsaD and PsaE, which comprise the "stromal ridge" of PS I. In a separate set of studies the three-dimensional solution structures of the unbound, recombinant PsaC (PDB entry 1K0T) and PsaE (PDB entries 1PSF, 1QP2 and 1GXI) subunits were solved by NMR. The PsaC subunit of PS I is a small (9.3 kDa) protein that harbors binding sites for two [4Fe-4S] clusters F(A) and F(B), which are the terminal electron acceptors in PS I. Comparison of the PsaC structure in solution with that in the X-ray structure of PS I reveals significant differences between them which are summarized and evaluated here. Changes in the magnetic properties of [4Fe-4S] centers F(A) and F(B) are related to changes in the protein structure of PsaC, and they are further influenced by the presence of PsaD. Based on experimental evidence, three assembly stages are analyzed: PsaC(free), PsaC(only), PsaC(PS I). Unbound, recombinant PsaD, studied by NMR, has only a few elements of secondary structure and no stable three-dimensional structure in solution. When PsaD is bound in PS I, it has a well-defined three-dimensional structure. For PsaE the three-dimensional structure is very similar in solution and in the PS I-bound form, with the exception of two loop regions. We suggest that the changes in the structures of PsaC and PsaD are caused by the sequential formation of multiple networks of contacts between the polypeptides of the stromal ridge and between those polypeptides and the PsaA/PsaB core polypeptides. The three-dimensional structure of the C(2)-symmetric F(X)-binding loops on PsaA and PsaB were also analyzed and found to be significantly different from the binding sites of other proteins that contain interpolypeptide [4Fe-4S] clusters. The aim of this work is to relate contact information to structural changes in the proteins and to propose a model for the assembly of the stromal ridge of PS I based on this analysis.

Light harvesting in photosystem I: modeling based on the 2.5-A structure of photosystem I from Synechococcus elongatus.

The structure of photosystem I from the thermophilic cyanobacterium Synechococcus elongatus has been recently resolved by x-ray crystallography to 2.5-A resolution. Besides the reaction center, photosystem I consists also of a core antenna containing 90 chlorophyll and 22 carotenoid molecules. It is their function to harvest solar energy and to transfer this energy to the reaction center (RC) where the excitation energy is converted into a charge separated state. Methods of steady-state optical spectroscopy such as absorption, linear, and circular dichroism have been applied to obtain information on the spectral properties of the complex, whereas transient absorption and fluorescence studies reported in the literature provide information on the dynamics of the excitation energy transfer. On the basis of the structure, the spectral properties and the energy transfer kinetics are simultaneously modeled by application of excitonic coupling theory to reveal relationships between structure and function. A spectral assignment of the 96 chlorophylls is suggested that allows us to reproduce both optical spectra and transfer and emission spectra and lifetimes of the photosystem I complex from S. elongatus. The model calculation allowed to study the influence of the following parameters on the excited state dynamics: the orientation factor, the heterogeneous site energies, the modifications arising from excitonic coupling (redistribution of oscillator strength, energetic splitting, reorientation of transition dipoles), and presence or absence of the linker cluster chlorophylls between antenna and reaction center. For the Förster radius and the intrinsic primary charge separation rate, the following values have been obtained: R(0) = 7.8 nm and k(CS) = 0.9 ps(-1). Variations of these parameters indicate that the excited state dynamics is neither pure trap limited, nor pure transfer (to-the-trap) limited but seems to be rather balanced.

The assembly of protein subunits and cofactors in photosystem I.

The recently determined crystal structures of photosystems I and II at 2.5 A and 3.8 A resolution, respectively, have improved the structural basis for understanding the processes of light trapping, exciton transfer and electron transfer occurring in the primary steps of oxygenic photosynthesis. Understanding the assembly of the 12 protein subunits and 128 cofactors in photosystem I allows us to study the possible functions of the individual players in this protein-cofactor complex.