Erythropoietin Interacts with Specific S100 Proteins

Erythropoietin (EPO) is a clinically significant four-helical cytokine, exhibiting erythropoietic, cytoprotective, immunomodulatory, and cancer-promoting activities. Despite vast knowledge on its signaling pathways and physiological effects, extracellular factors regulating EPO activity remain underexplored. Here we show by surface plasmon resonance spectroscopy, that among eighteen members of Ca2+-binding proteins of the S100 protein family studied, only S100A2, S100A6 and S100P proteins specifically recognize EPO with equilibrium dissociation constants ranging from 81 nM to 0.5 µM. The interactions occur exclusively under calcium excess. Bioinformatics analysis showed that the EPO-S100 interactions could be relevant to progression of neoplastic diseases, including cancer, and other diseases. The detailed knowledge of distinct physiological effects of the EPO-S100 interactions could favor development of more efficient clinical implications of EPO. Summing up our data with previous findings, we conclude that S100 proteins are potentially able to directly affect functional activities of specific members of all families of four-helical cytokines, and cytokines of other structural superfamilies.

Engineering a Clinical Force Measuring Walker for Patients Recovering from Median Sternotomy

Background: Patients often need the use of their arms to assist with functional activities, but after median sternotomy, pushing is frequently limited to less than 4.5 kg. No method exists to objectively measure arm weight bearing in clinical settings. This project aimed to design, construct, and test a walker for patients recovering from median sternotomy to prevent excessive bone stress during ossification. Methods: First, a qualitative study was conducted to obtain critiques of a Clinical Force Measuring (CFM) Walker prototype from rehabilitation professionals. Key statements and phrases were coded that allowed “themes” to emerge from transcribed interviews, which guided device revisions. Next, a second CFM Walker prototype was designed based on the qualitative data and device criteria/constraints and finally tested. Results: The result was fabrication of a new lightweight, streamlined, and cost-effective prototype walker with a simple visual display and auditory cue with upper limit alarms. Key features included attachments for medical equipment and thin film force-sensing resistors integrated into the walker handles that progressively activated 3 LEDs and a buzzer when arm force exceeded programmed thresholds. Conclusions: The innovative CFM Walker will help patients with restricted upper extremity weight bearing, especially elderly adults, recover safer and faster in the future.

Structural basis of HLX10 PD-1 receptor recognition, a promising anti-PD-1 antibody clinical candidate for cancer immunotherapy

Cancer immunotherapies, such as checkpoint blockade of programmed cell death protein-1 (PD-1), represents a breakthrough in cancer treatment, resulting in unprecedented results in terms of overall and progression-free survival. Discovery and development of novel anti PD-1 inhibitors remains a field of intense investigation, where novel monoclonal antibodies (mAbs) and novel antibody formats (e.g., novel isotype, bispecific mAb and low-molecular-weight compounds) are major source of future therapeutic candidates. HLX10, a fully humanized IgG4 monoclonal antibody against PD-1 receptor, increased functional activities of human T-cells and showed in vitro, and anti-tumor activity in several tumor models. The combined inhibition of PD-1/PDL-1 and angiogenesis pathways using anti-VEGF antibody may enhance a sustained suppression of cancer-related angiogenesis and tumor elimination. To elucidate HLX10’s mode of action, we solved the structure of HLX10 in complex with PD-1 receptor. Detailed epitope analysis showed that HLX10 has a unique mode of recognition compared to the clinically approved PD1 antibodies Pembrolizumab and Nivolumab. Notably, HLX10’s epitope was closer to Pembrolizumab’s epitope than Nivolumab’s epitope. However, HLX10 and Pembrolizumab showed an opposite heavy chain (HC) and light chain (LC) usage, which recognizes several overlapping amino acid residues on PD-1. We compared HLX10 to Nivolumab and Pembrolizumab and it showed similar or better bioactivity in vitro and in vivo, providing a rationale for clinical evaluation in cancer immunotherapy.

Mapping the allosteric effects that define functional activity of SARS-CoV-2 specific antibodies

Previous studies on the structural relationship between human antibodies and SARS-CoV-2 have focused on generating static snapshots of antibody complexes with the Spike trimer. However, antibody-antigen interactions are dynamic, with significant binding-induced allosteric effects on conformations of antibody and its target antigen. In this study, we employ hydrogen-deuterium exchange mass spectrometry, in vitro assays, and molecular dynamics simulations to investigate the allosteric perturbations linked to binding events between a group of human antibodies with differential functional activities, and the Spike trimer from SARS-CoV-2. Our investigations have revealed key dynamic features that define weakly or moderately neutralizing antibodies versus those with strong neutralizing activity. These results provide mechanistic insights into the functional modes of human antibodies against COVID-19, and provide a rationale for effective antiviral strategies.TeaserDifferent neutralizing antibodies induce site-specific allosteric effects across SARS-CoV-2 Spike protein

Advances in Metagenomics and Its Application in Environmental Microorganisms

Metagenomics is a new approach to study microorganisms obtained from a specific environment by functional gene screening or sequencing analysis. Metagenomics studies focus on microbial diversity, community constitute, genetic and evolutionary relationships, functional activities, and interactions and relationships with the environment. Sequencing technologies have evolved from shotgun sequencing to high-throughput, next-generation sequencing (NGS), and third-generation sequencing (TGS). NGS and TGS have shown the advantage of rapid detection of pathogenic microorganisms. With the help of new algorithms, we can better perform the taxonomic profiling and gene prediction of microbial species. Functional metagenomics is helpful to screen new bioactive substances and new functional genes from microorganisms and microbial metabolites. In this article, basic steps, classification, and applications of metagenomics are reviewed.

Manual Therapy Interventions for Adhesive Capsulitis: A Review

Adhesive Capsulitis is a debilitating condition which causes the capsule of the Gleno-humeral joint to get thickened and contracted progressively. The prevalence of the disease is much higher in the middle aged and elderly community. It is characterized by pain in the shoulder, and advance towards the restriction of the active and passive glenohumeral motions and thereby obstructing the overall functional activities of the daily living. The effectiveness of various non-operative methods in the treatment of Adhesive Capsulitis has been demonstrated in the literature. Corticosteroid injections and the oral medications are known to be alleviating the pain levels and the inflammatory reactions but not the mobility of the affected joint. Joint mobilization techniques, electrotherapeutic modalities and other manual treatment methods are also found to be effective. In summary, this review focuses on the pathophysiology of the adhesive capsulitis, stages of the condition progress and various manual therapy interventions. Keywords: Gleno-humeral joint, frozen shoulder, rehabilitation, active and passive movements, functional activities.

The effect of new scalp acupuncture on qi, 5 elements and acupuncture of meridians in patients with chronic stroke – pilot study

Introduction. Individuals affected by stroke often lead to loss of autonomy, dependence in activities of daily living, and social disruption, possibly leading to a reduced quality of life. Most survivors present residual sensory-motor deficits that interfere with the performance of functional activities. Reducing complications and improving the functional recovery of these individuals is an important starting point for rehabilitation professionals. Objective. To analyze the effect of the new Yamamoto scalp acupuncture (SA) YNSA on Qi, 5 elements and acupuncture of meridians in chronic stroke patients. Method. This is a quasi-experimental pilot study composed of nine chronic stroke patients. All participants diagnosed with chronic stroke aged from 38 to 79 years underwent energetic electrodiagnosis. Patients received a SA session on the contralateral hemisphere of the damaged side corresponding to the motor and sensory area for 30 minutes. The Shapiro-Wilk test was applied, followed by the paired t-test. Results: There was a significant reduction in the Yin, Fire (Pericarium) and Fire (heart). The following organs and viscera also presented a reduction: lung, right pericardium, left small intestine, and right spleen. Conclusions. It is concluded that AE YNSA can promote Qi balance, reduction in the fire element and reduction in the action of some acupuncture meridians in chronic stroke patients in the analysed sample.

Inter and Intra Rater Reliability of Different Measurement Techniques of Weight Bearing Ankle Dorsiflexion Range of Motion

Background: Measurement of range of motion is a crucial parameter in the physiotherapeutic evaluation and follow up. Ankle dorsiflexion is important for functional activities like running, jogging, waking, stair climbing. Restricted ankle dorsiflexion is seen in various lower limb injuries. Therefore, assessment of dorsiflexion is important to assess function. Goniometer, tape measure, mobile goniometer, inclinometer is used to measure ankle dorsiflexion range of motion in weight bearing and non-weight bearing positions. Weight bearing dorsiflexion has reported higher intra and inter-rater reliability as compared to non-weight bearing ankle dorsiflexion. All these measures may be taken by the same and by different therapists in the management of one patient. Therefore, it is necessary to determine if the measurements used are reliable both within and between the therapists. Material and Methods: 50 healthy subjects were recruited and their role was explained in the study. Written consent was taken from all the subjects. Weight bearing lunge was done in which the subject was asked to stand with the heel in contact with the ground and the great toe 10 cm away from the wall and the knee touching the wall. Inclinometer, standard goniometer, mobile goniometer and tape measure were administered to check for ankle dorsifexion range of motion. Results: ICC for inter rater reliability was almost perfect for tape measure and goniometer (0.968 and 0.837 respectively) and it was substantial for inclinometer and mobile goniometer (0.746 and 0.796 respectively). ICC for intra rater reliability was almost perfect for tape measure, inclinometer and goniometer (0.965,0.894 and 0.837 respectively) and it was substantial for mobile goniometer (0.802). Conclusion: The inter-rater reliability of tape measure, goniometer is almost perfect and for mobile goniometer, inclinometer is substantial. The intra rater reliability of tape measure, inclinometer, goniometer is almost perfect and mobile goniometer is substantial. KEY WORDS: Dorsiflexion, Mobile goniometer, Tape measure, Goniometer, Inclinometer, Reliability.

Long Noncoding RNA RROL Provides Chromatin Scaffold for MYC-WDR82 Interaction to Impact Lipid Metabolism and Tumor Cell Growth in Multiple Myeloma

Long noncoding RNAs (lncRNA) can drive the tumorigenesis and be susceptible to therapeutic intervention. To define the landscape of therapeutically actionable lncRNA dependencies in multiple myeloma (MM), we coupled our extensive lncRNA transcriptomic profile with lncRNA targeted CRISPR interference viability screen and identified RNA Regulator of Lipogenesis (RROL) as a leading lncRNA dependency in MM. RROL shares its origin with the microRNA locus MIR17HG, however supports the proliferation and survival of MM cells in a microRNA- and DROSHA- independent manner. We found that RROL provides a chromatin scaffold for the functional interaction between c-MYC and WDR82 to promote the regulation of the lipogenic pathways via the transcriptional control of the rate-limiting enzyme ACC1 in MM cells. Inhibition of RROL with clinically applicable antisense molecules disrupts its transcriptional and functional activities causing potent anti-tumor effects both in vitro and in vivo in two pre-clinical animal models. This study establishes lncRNA RROL as a therapeutically actionable dependency with a unique mechanism of action in support of myeloma cell growth.