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The immune system is the central regulator of tissue homeostasis, ensuring tissue regeneration and protection against both pathogens and the neoformation of cancer cells. Its proper functioning requires homeostatic properties, which are maintained by an adequate balance of myeloid and lymphoid responses. Aging progressively undermines this ability and compromises the correct activation of immune responses, as well as the resolution of the inflammatory response. A subclinical syndrome of “homeostatic frailty” appears as a distinctive trait of the elderly, which predisposes to immune debilitation and chronic low-grade inflammation (inflammaging), causing the uncontrolled development of chronic and degenerative diseases. The innate immune compartment, in particular, undergoes to a sequela of age-dependent functional alterations, encompassing steps of myeloid progenitor differentiation and altered responses to endogenous and exogenous threats. Here, we will review the age-dependent evolution of myeloid populations, as well as their impact on frailty and diseases of the elderly.

Coronavirus belongs to the family of Coronaviridae, comprising single-stranded, positive-sense RNA genome (+ ssRNA) of around 26 to 32 kilobases, and has been known to cause infection to a myriad of mammalian hosts, such as humans, cats, bats, civets, dogs, and camels with varied consequences in terms of death and debilitation. Strikingly, novel coronavirus (2019-nCoV), later renamed as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), and found to be the causative agent of coronavirus disease-19 (COVID-19), shows 88% of sequence identity with bat-SL-CoVZC45 and bat-SL-CoVZXC21, 79% with SARS-CoV and 50% with MERS-CoV, respectively. Despite key amino acid residual variability, there is an incredible structural similarity between the receptor binding domain (RBD) of spike protein (S) of SARS-CoV-2 and SARS-CoV. During infection, spike protein of SARS-CoV-2 compared to SARS-CoV displays 10–20 times greater affinity for its cognate host cell receptor, angiotensin-converting enzyme 2 (ACE2), leading proteolytic cleavage of S protein by transmembrane protease serine 2 (TMPRSS2). Following cellular entry, the ORF-1a and ORF-1ab, located downstream to 5′ end of + ssRNA genome, undergo translation, thereby forming two large polyproteins, pp1a and pp1ab. These polyproteins, following protease-induced cleavage and molecular assembly, form functional viral RNA polymerase, also referred to as replicase. Thereafter, uninterrupted orchestrated replication-transcription molecular events lead to the synthesis of multiple nested sets of subgenomic mRNAs (sgRNAs), which are finally translated to several structural and accessory proteins participating in structure formation and various molecular functions of virus, respectively. These multiple structural proteins assemble and encapsulate genomic RNA (gRNA), resulting in numerous viral progenies, which eventually exit the host cell, and spread infection to rest of the body. In this review, we primarily focus on genomic organization, structural and non-structural protein components, and potential prospective molecular targets for development of therapeutic drugs, convalescent plasm therapy, and a myriad of potential vaccines to tackle SARS-CoV-2 infection.

Background: Many studies have investigated the devastating health effects of heat waves, but less is known about health risks related to cold spells, despite evidence that extreme cold may contribute to a larger proportion of deaths. Objectives: We aimed to systematically investigate the association between cold spells and mortality in Japan. Methods: Daily data for weather conditions and 12 common causes of death during the 1972-2015 cold seasons (November- March) were obtained from 47 Japanese prefectures. Cold spells were defined as [greater than or equal to]2 consecutive days with daily mean temperatures [less than or equal to]5th percentile for the cold season in each prefecture. Quasi-Poisson regression was combined with a distributed lag model to estimate prefecture-specific associations, and pooled associations at the national level were obtained through random-effects meta-analysis. The potential influence of cold spell characteristics (intensity, duration, and timing in season) on associations between cold spells and mortality was examined using a similar two-stage approach. Temporal trends were investigated using a meta-regression model. Results: A total of 18,139,498 deaths were recorded during study period. Mortality was significantly higher during cold spell days vs. other days for all selected causes of death. Mortality due to age-related physical debilitation was more strongly associated with cold spells than with other causes of death. Associations between cold spells and mortality from all causes and several more specific outcomes were stronger for longer and more intense cold spells and for cold spells earlier in the cold season. However, although all outcomes were positively associated with cold spell duration, findings for cold spell intensity and seasonal timing were heterogeneous across the outcomes. Associations between cold spells and mortality due to cerebrovascular disease, cerebral infarction, and age-related physical debility decreased in magnitude over time, whereas temporal trends were relatively flat for all-cause mortality and other outcomes. Discussion: Our findings may have implications for establishing tailored public health strategies to prevent avoidable cold spell-related health consequences.

Aging is considered to be accelerated by insulin signaling in lower organisms, but it remained unclear whether this could hold true for mammals. Here we show that mice with skeletal muscle-specific double knockout of Akt1 / 2 , key downstream molecules of insulin signaling, serve as a model of premature sarcopenia with insulin resistance. The knockout mice exhibit a progressive reduction in skeletal muscle mass, impairment of motor function and systemic insulin sensitivity. They also show osteopenia, and reduced lifespan largely due to death from debilitation on normal chow and death from tumor on high-fat diet. These phenotypes are almost reversed by additional knocking out of Foxo1 / 4 , but only partially by additional knocking out of Tsc2 to activate the mTOR pathway. Overall, our data suggest that, unlike in lower organisms, suppression of Akt activity in skeletal muscle of mammals associated with insulin resistance and aging could accelerate osteosarcopenia and consequently reduce lifespan. Sasako et al. show that disruption of the insulin/IGF-1 signaling by suppressing Akt activity in mouse skeletal muscle can accelerate osteosarcopenia and shortens lifespan, which is reversed by inactivation of FoxOs rather than activation of mTOR, suggesting FoxOs as therapeutic targets.

Accumulating evidence suggests that epigenetic alterations lie behind the induction and maintenance of neuropathic pain. Neuropathic pain is usually a chronic condition caused by a lesion, or pathological change, within the nervous system. Neuropathic pain appears frequently after nerve and spinal cord injuries or diseases, producing a debilitation of the patient and a decrease of the quality of life. At the cellular level, neuropathic pain is the result of neuronal plasticity shaped by an increase in the sensitivity and excitability of sensory neurons of the central and peripheral nervous system. One of the mechanisms thought to contribute to hyperexcitability and therefore to the ontogeny of neuropathic pain is the altered expression, trafficking, and functioning of receptors and ion channels expressed by primary sensory neurons. Besides, neuronal and glial cells, such as microglia and astrocytes, together with blood borne macrophages, play a critical role in the induction and maintenance of neuropathic pain by releasing powerful neuromodulators such as pro-inflammatory cytokines and chemokines, which enhance neuronal excitability. Altered gene expression of neuronal receptors, ion channels, and pro-inflammatory cytokines and chemokines, have been associated to epigenetic adaptations of the injured tissue. Within this review, we discuss the involvement of these epigenetic changes, including histone modifications, DNA methylation, non-coding RNAs, and alteration of chromatin modifiers, that have been shown to trigger modification of nociception after neural lesions. In particular, the function on these processes of EZH2, JMJD3, MeCP2, several histone deacetylases (HDACs) and histone acetyl transferases (HATs), G9a, DNMT, REST and diverse non-coding RNAs, are described. Despite the effort on developing new therapies, current treatments have only produced limited relief of this pain in a portion of patients. Thus, the present review aims to contribute to find novel targets for chronic neuropathic pain treatment.

The decline in physical function and the deterioration of the neuromusculoskeletal system in older people can easily lead to reduced muscle strength and slower mobility in the joints of the lower limbs, increasing the incidence of chronic diseases such as muscle wasting disorders, osteoporosis, debilitation and fall and fracture. It may also affect the quality of life and functional independence of older people, and in serious cases, even directly threaten their health. This study was conducted to determine the differences in lower limb muscle activation characteristics between static semi-squat (SSS) and dynamic semi-squat (DSS) training in middle-aged and old women at different frequencies and amplitudes and to explore a personalized whole-body vibration (WBV) training instruction program suitable for them. Fifteen healthy middle-aged and old women (60.8 ± 4.18 years old) were recruited for SSS and DSS WBV training. Their muscle activity of the rectus femoris (RF), vastus medialis (VM), vastus lateralis (VL), biceps femoris (BF) and gastrocnemius (GS) were calculated using the BTS FreeEMG300 wireless surface electromyography (EMG), which participants were completed that the two different contraction patterns of squats on WBV training. The knee flexion was maintained at 45° while the subjects were performing the SSS training, while during the DSS training, the knee flexion fluctuates between 10° and 45°. The SSS exercise requires the subject to remain stationary in the squatting position and the DSS to be performed at a rhythm of 4 s/repetition, with 2 s of squatting, 1 s of standing up, and 1 s intervals. The vibration frequencies and amplitudes were changed to the WBV training intensity, and the vibration frequencies were set to 0 Hz, 30 Hz and 40 Hz, and the amplitudes were set to 0 mm, 2 mm and 4 mm. Each subject is randomised to participate in WBV training with 5 combinations of frequency and amplitude in both static and dynamic semi-squat patterns. These were 0 Hz 0 mm, 30 Hz 2 mm, 30 Hz 4 mm, 40 Hz 2 mm, 40 Hz 4 mm for the static and dynamic demi-squat patterns of WBV training. A two-way repeated measures ANOVA was applied to compare the changes in surface EMG of the lower limb muscles in different modes of SSS and DSS with WBV training. (1) Our results showed significantly interaction effects in the frequency × amplitude of root mean square (EMGrms) in GS (P < 0.05), while no significant differences were observed in the interaction effects of SSS/DSS patterns, frequencies and amplitude of RF, VM, VL and BF (P > 0.05). (2) Comparisons between groups showed that the EMGrms of the RF were significantly higher for the DSS than the SSS (P < 0.05). Additionally, the EMGrms of VL and BF at 30 Hz and 40 Hz were greater than 0 Hz (P < 0.05). Also, The EMGrms at 4 mm for the VM, VL and BF were significantly higher than 0 mm, the EMGrms at 4 mm for the VM and VL were significantly higher than 2 mm (P < 0.05), and the EMGrms at 2 mm of VL and BF were significantly higher than 0 mm (P < 0.05). (3) The results showed that WBV stimulation significantly increased the EMGrms of the GS in the SSS compared with the vibration free semi-squat alone (P < 0.05). However, there were no significant differences between WBV training protocols for SSS patterns with different frequencies and amplitudes (frequencies and amplitudes not were 0 Hz and 0 mm) (P > 0.05). Comparison of EMGrms for WBV training of the GS in DSS patterns showed that 40 Hz/4 mm was significantly higher than 0 Hz/0 mm (P < 0.05), but there was no significant difference between the remaining vibration conditions (P > 0.05). WBV training for DSS can significantly improve the activation of the RF compared to SSS pattern. Compared with no vibration, WBV could significantly improv the activity of the lower limb muscles. Additionally, an increase in amplitude from 2 to 4 mm could significantly improve VM and VL activation, while no significant improvement on lower limb muscle activation was observed for increasing vibration frequency from 30 to 40 Hz.

Vibrio cholerae is the etiologic agent of the severe human diarrheal disease cholera. To colonize mammalian hosts, this pathogen must defend against host-derived toxic compounds, such as nitric oxide (NO) and NO-derived reactive nitrogen species (RNS). RNS can covalently add an NO group to a reactive cysteine thiol on target proteins, a process called protein S-nitrosylation, which may affect bacterial stress responses. To better understand how V . cholerae regulates nitrosative stress responses, we profiled V . cholerae protein S-nitrosylation during RNS exposure. We identified an S-nitrosylation of cysteine 235 of AphB, a LysR-family transcription regulator that activates the expression of tcpP , which activates downstream virulence genes. Previous studies show that AphB C235 is sensitive to O 2 and reactive oxygen species (ROS). Under microaerobic conditions, AphB formed dimer and directly repressed transcription of hmpA , encoding a flavohemoglobin that is important for NO resistance of V . cholerae . We found that tight regulation of hmpA by AphB under low nitrosative stress was important for V . cholerae optimal growth. In the presence of NO, S-nitrosylation of AphB abolished AphB activity, therefore relieved hmpA expression. Indeed, non-modifiable aphB C235S mutants were sensitive to RNS in vitro and drastically reduced colonization of the RNS-rich mouse small intestine. Finally, AphB S-nitrosylation also decreased virulence gene expression via debilitation of tcpP activation, and this regulation was also important for V . cholerae RNS resistance in vitro and in the gut. These results suggest that the modulation of the activity of virulence gene activator AphB via NO-dependent protein S-nitrosylation is critical for V . cholerae RNS resistance and colonization.

Anterior cruciate ligament (ACL) injuries are a burdensome condition due to potential surgical requirements and increased risk of long term debilitation. Previous studies indicate that muscle forces play an important role in the development of ligamentous loading, yet these studies have typically used cadaveric models considering only the knee-spanning quadriceps, hamstrings and gastrocnemius muscle groups. Using a musculoskeletal modelling approach, we investigated how lower-limb muscles produce and oppose key tibiofemoral reaction forces and moments during the weight acceptance phase of unanticipated sidestep cutting. Muscles capable of opposing (or controlling the magnitude of) the anterior shear force and the external valgus moment at the knee are thought to be have the greatest potential for protecting the anterior cruciate ligament from injury. We found the best muscles for generating posterior shear to be the soleus, biceps femoris long head and medial hamstrings, providing up to 173N, 111N and 77N of force directly opposing the anterior shear force. The valgus moment was primarily opposed by the gluteus medius, gluteus maximus and piriformis, with these muscles providing contributions of up to 32 Nm, 19 Nm and 21 Nm towards a knee varus moment, respectively. Our findings highlight key muscle targets for ACL preventative and rehabilitative interventions.

Background:Patients with total knee arthroplasty (TKA) often experience pain and reduced balance control, which may predispose them to greater fall risk. The patients with revision total knee arthrooplasty (rTKA), have more pain, stiffness and physical dysfunction and less postoperative improvement compared to the patients with TKA [1]. Falls in people with gait or balance disorders have significant consequences. Fear of falling can also predispose people to inactivity, which can lead to problems of debilitation, increased handicap, and disability by itself. Most of the falls take place in the course of movement, and the trips and slips were determined as the most common cause of elderly falls. Trips are responsible of falls between 40% to 60% and slips between 10% to 15%, showing that the capability to take a quick step would prevent many falls [2]. Literature has found stepping speed to the different directions declines with aging and are lesser for fallers than for nonfallers [3].Modified four square step test (mFSST) was developed to assessing fall risk and dynamic balance by scoring time while participants stepping in multiple directions but its reliability has not been investigated in patients undergoing rTKA.Objectives:The aims of this study were to determine the test-retest reliability and the minimal clinically important change (MCID) of the mFSST in patients with rTKAMethods:mFSST administered on 22 patients undergoing rTKA. mFSST is performed by using tapes to make one horizontal and one vertical line like a cross to create 4 quadrants. Patients’ performances were timed as patients were successfully stepping clockwise and counter-clockwise while avoid touching on tapes, turning their body or losing balance. Two trials performed and patients rested between trials and were encouraged to rest as often as they required to prevent fatigue.Results:ICC(2.1) for mFSST was 0.83. The standard error of measurement and MCID were 0.67 and 1.85 respectively (95 %. confidence level).Conclusion:The mFSST has a good test-retest reliability in patients with rTKA. It is a reliable and responsive tool for measuring fall risk, dynamic balance and mobility. The mFSST is an excellent measure of gait variability, stepping in multipl directions and dynamic balance, also can easily identify real clinically important changes in patients with rTKA in simple environments and minimal equipment.References:[1]Järvenpää J, Kettunen J, Miettinen H, Kröger H. The clinical outcome of revision knee replacement after unicompartmental knee arthroplasty versus primary total knee arthroplasty: 8–17 years follow-up study of 49 patients. International Orthopaedics 2010; 34: 649-653.[2]Cumming RG, Klineberg RJ. Fall frequency and characteristics and the risk of hip fractures. Journal of the American Geriatrics Society 1994; 42: 774-778.[3]Medell JL, Alexander NB. A clinical measure of maximal and rapid stepping in older women. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences 2000; 55: M429-M433.Disclosure of Interests:None declared

Intervertebral disc injury and degeneration are among the most common causes of lower back pain and debilitation in humans. This prospective, descriptive, pilot study was designed to support our team’s long-term research goals of measuring effects of novel therapies for lumbar disc injury and degeneration using small ruminant translational research models. Our overall aim was to determine whether low-field magnetic resonance imaging (lf-MRI) would be a feasible technique for longitudinally assessing surgical microdiscectomy-induced lumbar disc injury and degeneration in goat models ( Capra hircus ). Four, female, skeletally mature, Nubian-breed goats were used. One goat was used to refine and standardize imaging and surgical protocols and the remaining three were scanned one week before and 3, 6, and 12 weeks after surgery in which two discs were injured via microdiscectomy. Gross pathologic and histologic assessments for all discs were performed at the 12-week time point. We introduced a standardized lf-MRI image acquisition protocol that required 30–60 minutes (median 47.5 minutes) and yielded good quality images. We also introduced standardized protocols for quantifying disc height index (DHI) and MRI index values from lf-MRI images. All animals tolerated anesthesia well with no signs of distress. Two of the 3 goats studied longitudinally developed unexpected, non-infectious discospondylitis at the operated disc locations. The lf-MRI characteristics of non-infectious discospondylitis in goats have not been previously reported. These findings can be used as background for future studies evaluating the feasibility of using lf-MRI as a technique for longitudinally measuring IVD injury and degeneration in goat models.