Modal Frequencies Associations with Musculoskeletal Components of Human Legs for Extracorporeal Bone Healing Assessment Based on a Vibration Analysis Approach

Reliable and quantitative assessments of bone quality and fracture healing prompt well-optimised patient healthcare management and earlier surgical intervention prior to complications of nonunion and malunion. This study presents a clinical investigation on modal frequencies associations with musculoskeletal components of human legs by using a prototype device based on a vibration analysis method. The findings indicated that the first out-of-plane and coupled modes in the frequency range from 60 to 110 Hz are associated with the femur length, suggesting these modes are suitable quantitative measures for bone evaluation. Furthermore, higher-order modes are shown to be associated with the muscle and fat mass of the leg. In addition, mathematical models are formulated via a stepwise regression approach to determine the modal frequencies using the measured leg components as variables. The optimal models of the first modes consist of only femur length as the independent variable and explain approximately 43% of the variation of the modal frequencies. The subsequent findings provide insights for further development on utilising vibration-based methods for practical bone and fracture healing monitoring.

Nanocages engineered from Bacillus Calmette-Guerin facilitate protective Vγ2Vδ2 T cell immunity against Mycobacterium tuberculosis infection

Tuberculosis (TB), induced by Mycobacterium tuberculosis (Mtb) infection, remains a top killer among infectious diseases. While Bacillus Calmette-Guerin (BCG) is the sole TB vaccine, the clumped-clustered features of BCG in intradermal immunization appear to limit both the BCG protection efficacy and the BCG vaccination safety. We hypothesize that engineering of clumped-clustered BCG into nanoscale particles would improve safety and also facilitate the antigen-presenting-cell (APC)’s uptake and the following processing/presentation for better anti-TB protective immunity. Here, we engineered BCG protoplasts into nanoscale membraned BCG particles, termed as “BCG-Nanocage” to enhance the anti-TB vaccination efficiency and safety. BCG-Nanocage could readily be ingested/taken by APC macrophages selectively; BCG-Nanocage-ingested macrophages exhibited better viability and developed similar antimicrobial responses with BCG-infected macrophages. BCG-Nanocage, like live BCG bacilli, exhibited the robust capability to activate and expand innate-like T effector cell populations of Vγ2+ T, CD4+ T and CD8+ T cells of rhesus macaques in the ex vivo PBMC culture. BCG-Nanocage immunization of rhesus macaques elicited similar or stronger memory-like immune responses of Vγ2Vδ2 T cells, as well as Vγ2Vδ2 T and CD4+/CD8+ T effectors compared to live BCG vaccination. BCG-Nanocage- immunized macaques developed rapidly-sustained pulmonary responses of Vγ2Vδ2 T cells upon Mtb challenge. Furthermore, BCG- and BCG-Nanocage- immunized macaques, but not saline controls, exhibited undetectable Mtb infection loads or TB lesions in the Mtb-challenged lung lobe and hilar lymph node at endpoint after challenge. Thus, the current study well justifies a large pre-clinical investigation to assess BCG-Nanocage for safe and efficacious anti-TB vaccination, which is expected to further develop novel vaccines or adjuvants. Graphical Abstract

The impact of calcitriol and estradiol on the SARS-CoV-2 biological activity: a molecular modeling approach

The novel coronavirus disease (COVID-19) is currently a big concern around the world. Recent reports show that the disease severity and mortality of COVID-19 infected patients may vary from gender to gender with a very high risk of death for seniors. In addition, some steroid structures have been reported to affect coronavirus, SARS-CoV-2, function and activity. The entry of SARS-CoV-2 into host cells depends on the binding of coronavirus spike protein to angiotensin converting enzyme-2 (ACE2). Viral main protease is essential for the replication of SARS-CoV-2. It was hypothesized that steroid molecules (e.g., estradiol, progesterone, testosterone, dexamethasone, hydrocortisone, prednisone and calcitriol) could occupy the active site of the protease and could alter the interaction of spike protein with ACE2. Computational data showed that estradiol interacted more strongly with the main protease active site. In the presence of calcitriol, the binding energy of the spike protein to ACE2 was increased, and transferring Apo to Locked S conformer of spike trimer was facilitated. Together, the interaction between spike protein and ACE2 can be disrupted by calcitriol. Potential use of estradiol and calcitriol to reduce virus invasion and replication needs clinical investigation.

Host-Adapted Gene Families Involved in Murine Cytomegalovirus Immune Evasion

Cytomegaloviruses (CMVs) are host species-specific and have adapted to their respective mammalian hosts during co-evolution. Host-adaptation is reflected by “private genes” that have specialized in mediating virus-host interplay and have no sequence homologs in other CMV species, although biological convergence has led to analogous protein functions. They are mostly organized in gene families evolved by gene duplications and subsequent mutations. The host immune response to infection, both the innate and the adaptive immune response, is a driver of viral evolution, resulting in the acquisition of viral immune evasion proteins encoded by private gene families. As the analysis of the medically relevant human cytomegalovirus by clinical investigation in the infected human host cannot make use of designed virus and host mutagenesis, the mouse model based on murine cytomegalovirus (mCMV) has become a versatile animal model to study basic principles of in vivo virus-host interplay. Focusing on the immune evasion of the adaptive immune response by CD8+ T cells, we review here what is known about proteins of two private gene families of mCMV, the m02 and the m145 families, specifically the role of m04, m06, and m152 in viral antigen presentation during acute and latent infection.

LncRNAs and Rheumatoid Arthritis: From Identifying Mechanisms to Clinical Investigation

Rheumatoid arthritis (RA) is a systemic chronic autoinflammatory disease, and the synovial hyperplasia, pannus formation, articular cartilage damage and bone matrix destruction caused by immune system abnormalities are the main features of RA. The use of Disease Modifying Anti-Rheumatic Drugs (DMARDs) has achieved great advances in the therapy of RA. Yet there are still patients facing the problem of poor response to drug therapy or drug intolerance. Current therapy methods can only moderate RA progress, but cannot stop or reverse the damage it has caused. Recent studies have reported that there are a variety of long non-coding RNAs (LncRNAs) that have been implicated in mediating many aspects of RA. Understanding the mechanism of LncRNAs in RA is therefore critical for the development of new therapy strategies and prevention strategies. In this review, we systematically elucidate the biological roles and mechanisms of action of LncRNAs and their mechanisms of action in RA. Additionally, we also highlight the potential value of LncRNAs in the clinical diagnosis and therapy of RA.

Anatomy, Sonographic Features, and Dimensional Variations of Spleen among Individuals with Different Sociodemographic and Anthropometric Measurement

The spleen is a vital lymphoid soft organ located in the left hypochondrium region. It is a multi-dimensional organ that enlarges in all dimensions during some disease conditions. Recently, splenomegaly prevalence has been increasing throughout the world. Due to the lack of attention in clinical practice, splenomegaly has become quite a common problem in all parts of the world. The detection of the spleen by palpation is not approval of enlarged spleen because normal spleen may be palpable. A detailed knowledge of morphometric variations of the spleen is of great value in diagnosing splenomegaly clinically, radiologically, and for surgical procedures. Measurement of spleen size by sonography is important as it gives true result than splenic palpation and for identification of disorders present with enlargement or reduction of the spleen. Therefore, this study aimed to assess the anatomy, sonography, and dimensional variation of spleen among individuals with different sociodemographic and anthropometric measurements. The current study reviews different types of literature conducted on spleen all over the world. The result from overall spleen dimensions review shows measurements vary: spleen length (7–14 cm), spleen width (2–7.5 cm), spleen thickness (2–7 cm), and spleen volume (20–350 cm3). The literature revealed that spleen dimensions are affected by geographical differences, races, nutritional status, physical exercise, and anthropometric measurements. The result from reviews shows that spleen dimensions are larger in males than females. As age increases, spleen dimensions significantly decrease. Spleen dimensions positively correlate with height, weight, body mass index, and body surface of individuals. The spleen dimensions were higher in males than in females and have significant positive correlation with height, weight, body mass index, and body surface area. Clinicians, radiologists, and surgeons should confirm splenomegaly by both palpation and sonography. Spleen dimensions variation due to geographical sex, age, and other anthropometric measurements should be taken into consideration during their clinical investigation. Radiologists should measure all dimensions of spleen rather than the length to rule out splenomegaly correctly.

The use of AVF.SIM system for the surgical planning of arteriovenous fistulae in routine clinical practice

Background: The number of patients treated with hemodialysis (HD) in Europe is more than half a million and this number increases annually. The arteriovenous fistula (AVF) is the vascular access (VA) of first choice, but the clinical outcome is still poor. A consistent number of AVFs fails to reach the desired blood flow rate for HD treatment, while some have too high flow and risk for cardiac complications. Despite the skill of the surgeons and the possibility to use Ultrasound investigation for mapping arm vasculature, it is still not possible to predict the blood flow volume that will be obtained after AVF maturation. Methods: We evaluated the potential of using a computational model (AVF.SIM) to predict the blood flow volume that will be achieved after AVF maturation, within a multicenter international clinical investigation aimed at assessing AVF.SIM predictive power. The study population included 231 patients, with data on AVF maturation in 124 patients, and on long-term primary patency in 180 patients. Results: At 1 year of follow-up, about 60% of AVFs were still patent, with comparable primary patency in proximal and distal anastomosis. The correlation between predicted and measured blood flow volume in the brachial artery at 40 days after surgery was statistically significant, with an overall correlation coefficient of 0.58 ( p < 0.001). The percent difference between measured and predicted brachial blood flow 40 days after surgery was less than 30% in 72% of patients investigated. Conclusions: The results indicate that the use of the AVF.SIM system allowed to predict with a good accuracy the blood flow volume achievable after VA maturation, for a given location and type of anastomosis. This information may help in AVF surgical planning, reducing the AVFs with too low or too high blood flow, thus improving AVF patency rate and clinical outcome of renal replacement therapy.

Tumor-Associated Macrophages in Hepatocellular Carcinoma Pathogenesis, Prognosis and Therapy

Hepatocellular carcinoma (HCC) constitutes a major health burden globally, and it is caused by intrinsic genetic mutations acting in concert with a multitude of epigenetic and extrinsic risk factors. Cancer induces myelopoiesis in the bone marrow, as well as the mobilization of hematopoietic stem and progenitor cells, which reside in the spleen. Monocytes produced in the bone marrow and the spleen further infiltrate tumors, where they differentiate into tumor-associated macrophages (TAMs). The relationship between chronic inflammation and hepatocarcinogenesis has been thoroughly investigated over the past decade; however, several aspects of the role of TAMs in HCC development are yet to be determined. In response to certain stimuli and signaling, monocytes differentiate into macrophages with antitumor properties, which are classified as M1-like. On the other hand, under different stimuli and signaling, the polarization of macrophages shifts towards an M2-like phenotype with a tumor promoting capacity. M2-like macrophages drive tumor growth both directly and indirectly, via the suppression of cytotoxic cell populations, including CD8+ T cells and NK cells. The tumor microenvironment affects the response to immunotherapies. Therefore, an enhanced understanding of its immunobiology is essential for the development of next-generation immunotherapies. The utilization of various monocyte-centered anticancer treatment modalities has been under clinical investigation, selectively targeting and modulating the processes of monocyte recruitment, activation and migration. This review summarizes the current evidence on the role of TAMs in HCC pathogenesis and progression, as well as in their potential involvement in tumor therapy, shedding light on emerging anticancer treatment methods targeting monocytes.

EasyMicroPlot: An Efficient and Convenient R Package in Microbiome Downstream Analysis and Visualization for Clinical Study

Advances in next-generation sequencing (NGS) have revolutionized microbial studies in many fields, especially in clinical investigation. As the second human genome, microbiota has been recognized as a new approach and perspective to understand the biological and pathologic basis of various diseases. However, massive amounts of sequencing data remain a huge challenge to researchers, especially those who are unfamiliar with microbial data analysis. The mathematic algorithm and approaches introduced from another scientific field will bring a bewildering array of computational tools and acquire higher quality of script experience. Moreover, a large cohort research together with extensive meta-data including age, body mass index (BMI), gender, medical results, and others related to subjects also aggravate this situation. Thus, it is necessary to develop an efficient and convenient software for clinical microbiome data analysis. EasyMicroPlot (EMP) package aims to provide an easy-to-use microbial analysis tool based on R platform that accomplishes the core tasks of metagenomic downstream analysis, specially designed by incorporation of popular microbial analysis and visualization used in clinical microbial studies. To illustrate how EMP works, 694 bio-samples from Guangdong Gut Microbiome Project (GGMP) were selected and analyzed with EMP package. Our analysis demonstrated the influence of dietary style on gut microbiota and proved EMP package's powerful ability and excellent convenience to address problems for this field.