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Abstract A targeted injury to the mouse intervertebral disc (IVD) is often used to recapitulate the degenerative cascade of the human pathology. Since injuries can vary in magnitude and localization, it is critical to examine the effects of different injuries on IVD degeneration. We thus evaluated the degenerative progression resulting from either a partial- or full-width injury to the mouse lumbar IVD using contrast-enhanced micro-computed tomography and histological analyses. A lateral-retroperitoneal surgical approach was used to access the lumbar IVD, and the injuries to the IVD were produced by either incising one side of the annulus fibrosus or puncturing both sides of the annulus fibrosus. Female C57BL/6J mice of 3–4 months age were used in this study. They were divided into three groups to undergo partial-width, full-width, or sham injuries. The L5/6 and L6/S1 lumbar IVDs were surgically exposed, and then the L6/S1 IVDs were injured using either a surgical scalpel (partial-width) or a 33G needle (full-width), with the L5/6 serving as an internal control. These animals recovered and then euthanized at either 2-, 4-, or 8-weeks after surgery for evaluation. The IVDs were assessed for degeneration using contrast-enhanced microCT (CEµCT) and histological analysis. The high-resolution 3D CEµCT evaluation of the IVD confirmed that the respective injuries were localized within one side of the annulus fibrosus or spanned the full width of the IVD. The full-width injury caused significant deteriorations in the nucleus pulposus, annulus fibrous and at the interfaces after 2 weeks, which was sustained through the 8 weeks, while the partial width injury caused localized disruptions that remained limited to the annulus fibrosus. The use of CEµCT revealed distinct IVD degeneration profiles resulting from partial- and full-width injuries. The partial width injury may serve as an alternative model for IVD degeneration resulting from localized annulus fibrosus injuries.

Abstract Diabetes is associated with impaired tendon homeostasis and subsequent tendon dysfunction, but the mechanisms underlying these associations is unclear. Advanced glycation end-products (AGEs) accumulate with diabetes and have been suggested to alter tendon function. In vivo imaging in humans has suggested collagen disorganization is more frequent in individuals with diabetes, which could also impair tendon mechanical function. The purpose of this study was to examine relationships between tendon tensile mechanics in human Achilles tendon with accumulation of advanced glycation end-products and collagen disorganization. Achilles tendon specimens (n = 16) were collected from individuals undergoing lower extremity amputation or from autopsy. Tendons were tensile tested with simultaneous quantitative polarized light imaging to assess collagen organization, after which AGEs content was assessed using a fluorescence assay. Moderate to strong relationships were observed between measures of collagen organization and tendon tensile mechanics (range of correlation coefficients: 0.570–0.727), whereas no statistically significant relationships were observed between AGEs content and mechanical parameters (range of correlation coefficients: 0.020–0.210). Results suggest that the relationship between AGEs content and tendon tensile mechanics may be masked by multifactorial collagen disorganization at larger length scales (i.e., the fascicle level).

Abstract Introduction Diabetes has long been implicated as a major risk factor for intervertebral disc (IVD) degeneration, interfering with molecular signaling and matrix biochemistry, which ultimately aggravates the progression of the disease. Glucose content has been previously shown to influence structural and compositional changes in engineered discs in vitro, impeding fiber formation and mechanical stability. Methods In this study, we investigated the impact of diabetic hyperglycemia on young IVDs by assessing biochemical composition, collagen fiber architecture, and mechanical behavior of discs harvested from 3‐ to 4‐month‐old db/db mouse caudal spines. Results We found that discs taken from diabetic mice with elevated blood glucose levels demonstrated an increase in total glycosaminoglycan and collagen content, but comparable advanced glycation end products (AGE) levels to wild‐type discs. Diabetic discs also contained ill‐defined boundaries between the nucleus pulposus and annulus fibrosus, with the latter showing a disorganized and unaligned collagen fiber network at this same boundary. Conclusions These compositional and structural changes had a detrimental effect on function, as the diabetic discs were twice as stiff as their wild‐type counterparts and demonstrated a significant resistance to deformation. These results indicate that diabetes may predispose the young disc to DDD later in life by altering patterns of extracellular matrix deposition, fiber formation, and motion segment mechanics independently of AGE accumulation.

Type 2 diabetes mellitus (T2D) is an increasingly prevalent disease with numerous comorbidities including many in the spine. T2D is strongly linked with vertebral fractures, intervertebral disc (IVD) degeneration, and severe chronic spinal pain. Yet the causative mechanism for these musculoskeletal impairments remains unclear. The chronic hyperglycemic state in T2D promotes the formation of advanced glycation end-products (AGEs) in tissues, and the accumulation of AGEs may play a role in musculoskeletal complications by modifying the extracellular matrix, impairing cellular homeostasis, and perpetuating an inflammatory cascade via its receptor (RAGE). The AGE and RAGE associated alterations in extracellular matrix composition and morphological features of the vertebral bodies and IVDs are likely contributors to the incidence and severity of spinal pathologies in T2D. This review will broadly examine the effects of AGEs on tissues in the spine in the context of T2D, with an emphasis on the changes in the vertebrae and the IVD. Along with the clinical and epidemiological findings, we will provide an overview of preclinical rodent models of T2D that exhibit deficits in the IVD and vertebral bone. Elucidating the role of AGEs and RAGE will be crucial for understanding the disease mechanisms and translation therapies of musculoskeletal pathologies in T2D.

Abstract Mouse models are often used for studies of intervertebral disc (IVD) homeostasis and degeneration, yet the relatively small size of the IVD poses challenges for noninvasive, longitudinal imaging modalities. The recently developed contrast‐enhanced microCT (CEμCT) using Ioversol has been successful in detecting degenerative changes in the murine IVD ex vivo at the micrometer scale. Further leveraging the superior biocompatibility of Ioversol as a contrast agent, we demonstrate the in vivo use of this CEμCT technique to examine IVDs at multiple spinal sites. Ioversol was administered via tail vein injection (TVI) in growing and adult male FVB/NJ mice (n = 5 /group). The animals were anesthetized and underwent in vivo micro‐computed tomographic (microCT) at the coccygeal (CC5/CC6), lumbar (L5/6), and thoracic (T12/T13) IVDs. TVI of Ioversol was well‐tolerated by all animals. As Ioversol filtered through the kidneys and accumulated in the bladder, the attenuations of the mouse bladder and kidneys increased due to the high molecular weight of Ioversol, confirming that the Ioversol is biological available. Average IVD attenuations increased 3%‐15% following TVI (ANOVA; P

Leader identity theory posits that, in addition to being positional, leadership is also a malleable state of mind. This means that even employees holding positions of authority within their organization may be nudged to identify more strongly with their leader role on some days versus others. The leadership literature, however, is silent about predictors that may prime leader identity day-to-day. We draw from leader identity theory and research on expressive writing to propose that leader identity can be activated daily via positive leader self-reflection (e.g., reflecting and writing about qualities that make one a good leader) in ways that are beneficial for the leader both at work and at home. We tested our theoretical expectations in two field experiments. In the first study, as expected, we find that leaders reported higher activated leader identity and more goal progress on intervention (vs. control) days. In turn, activated leader identity and goal progress enhanced leader well-being measured in the evening at home. Surprisingly, and contrary to expectations, the well-being enhancing effects of positive leader self-reflection were weaker for leaders who were higher (vs. lower) in identity fusion with their followers. In the second study, we demonstrate the malleable nature of leader identity by showing not only that positive leader self-reflection activates leader identity, but also that negative leader self-reflection diminishes its activation. [ABSTRACT FROM AUTHOR]

Marine ascidians are an abundant source of new bioactive metabolites. The current investigation aimed at characterizing anti-mycobacterial compounds from Indonesian marine ascidian Polycarpa sp. After extracting ethanol, Ascidian Polycarpa sp. was segregated with EtOAc and H2O. Ethyl acetate extract was purified using preparative HPLC. Identification and characterization of compounds using spectroscopic analysis. Anti-mycobacterial activity testing using the disc diffusion method on Mycobacterium smegmatis. This study showed that the ethyl acetate extract of ascidian Polycarpa sp produced two known compounds polycarpine (1) and palycarpaurine A (2). Compounds 1 and 2 exhibited activity against Mycobacterium smegmatis at 50 μg/disc, with 12- and 10-mm inhibition zones, respectively. This study suggests that polycarpine (1) and palycarpaurine A (2) have potential compounds for antimycobacterium. [ABSTRACT FROM AUTHOR]

The work environment is fraught with complex demands, hardships, and challenges, highlighting the need to approach work with self‐compassion each day. We propose that work self‐compassion—a mindset of kindness, gentleness, and care toward oneself as an employee—may generate the resources and motivation needed for self‐regulation at work. Drawing from integrated self‐control theory (ISCT) and theory on self‐compassion, we suggest that on days when employees hold a work self‐compassionate mindset, they will exhibit greater work performance and wellbeing via enhanced resource capacity and motivation. In an experimental experience sampling study, we found that a work self‐compassionate mindset reduced depletion and increased work self‐esteem and thereby heightened daily work engagement and daily resilience. Consequently, employees made greater goal progress at work and experienced higher meaning in life. In a supplemental study, we show that state self‐compassion at work is associated with unique variance in work outcomes beyond compassion received from coworkers. We discuss theoretical and practical implications for self‐compassion in organizational contexts. [ABSTRACT FROM AUTHOR]

Organizations want employees to grow their skills, with companies like Microsoft embracing growth mindset interventions and policies to foster employee development. At the same time, organizations often seek to build collaborative cultures where employees frequently help one another. Thus, a question arises as to how growth mindsets impact other-directed behaviors, such as helping. To address this research question, we develop the concept of a work growth mindset—a mindset specific to growth opportunities at work—and we explore how it influences helping across a pilot study and five experimental studies. Study 1 (an online experiment) and Study 2 (a within-person field experiment) show that employees help coworkers more after participating in a work growth mindset intervention. Studies 3A–C explore the mechanisms underlying this relationship and the circumstances in which growth-oriented employees help others. These experiments show that a work growth mindset makes employees more other-oriented and likely to help, but that this effect relies on the extent to which the helping opportunities can be seen as enabling both self- and other-development, allowing for both the helper and the help recipient to grow. We discuss the implications of our findings for theory and the future of the growth mindset at work. [ABSTRACT FROM AUTHOR]

Two new tryptamine-derived alkaloids, named as leptoclinidamide (1) and (-)-leptoclinidamine B (2), were isolated from an Indonesian ascidian Leptoclinides dubius together with C2-α-D-mannosylpyranosyl-L-tryptophan (3). The structure of 1 was assigned on the basis of spectroscopic data for 1 and its N-acetyl derivative (4). Compound 1 was an amide of tryptamine with two β-alanine units. Although the planar structure of 2 is identical to that of the known compound (+)-leptoclinidamine B (5), compound 2 was determined to be the enantiomer of 5 based on amino acid analysis using HPLC methods. Compounds 1 to 4 were evaluated for cytotoxicity against two human cancer cell lines, HCT-15 (colon) and Jurkat (T-cell lymphoma) cells, but none of the compounds showed activity.

N,N-Didesmethylgrossularine-1 (DDMG-1), a compound with a rare α-carboline structure, was isolated from an Indonesian ascidian Polycarpa aurata as responsible for the observed inhibitory activity against TNF-α production in lipopolysaccharide-stimulated murine macrophage-like RAW264.7 cells. DDMG-1 inhibited the mRNA level of mTNF-α, IκB-α degradation, and binding of NF-κB to the target DNA site in LPS-stimulated RAW 264.7 cells. Moreover, DDMG-1 had an inhibitory effect on the production of IL-8, which is produced in CD14+-THP-1 cells stimulated by LPS. DDMG-1 is thus a promising drug candidate lead compound for the treatment of chronic inflammatory diseases, such as rheumatoid arthritis.

Soft coral genus Sinularia be a sources of terpenoid compounds that show efficacy in vitro cytotoxic test using cancer cell lines. The study looked at the morphological changes that occur in fungal mycelial growth of Pyricularia oryzae, such as curling effect indicating antimitotic activity. Four extracts of soft coral genus Sinularia have been examination and this is an primary test to obtain information about the soft coral genus Sinularia that used as sources of compound antimitotic. This research was conducted in several stages, ie extraction of bioactive substances, P. oryzae fungal culture test, and biological testing antimitotic activity with a qualitative assessment methods. From the examination the Sinularia 3 ethyl acetate fraction show the strongest antimitotic activity (to concentration 1,5 μg/ml). Ethyl acetate fraction was purified using column chromatography. From the examination show that fraction of ethyl acetate 1 is the best fraction because still show curling effect on concentration 0,7 μg/ml. Keywords : Antimitotic, Soft Coral, Sinularia, microtubule, Pyricularia oryzae

The effects of seven compounds 1-7, isolated from a tropical ascidian Lissoclinum cf. badium, on IL-8 production in PMA-stimulated HL-60 cells were examined. Lissoclibadins 2 (2) and 3 (3) and lissoclinotoxin F (5) increased the IL-8 production in a dose-dependent manner. Compounds 2 and 5 are structural isomers possessing dimeric structures of trans and cis-orientations, respectively, and showed a very similar activity on the induction of IL-8 levels. Compound 3 and lissoclinotoxin E (4) are also structural isomers having dimeric trans and cis-structures, respectively, but 4 did not induce the IL-8 production. Lissoclibadin 1 (1, trimeric compound) and two monomeric compounds (6 and 7) did not increase the IL-8 level. Therefore, the differences in their structures remarkably affected the IL-8 production activity, the inhibition of cell proliferation, and the survival of HL-60 cells. Lissoclibadin 2 was the most interesting compound of the seven metabolites tested in this study.

Observing system experiments have been carried out with two operational ocean data assimilation systems to assess the impact of assimilating satellite sea surface salinity (SSS) data. The SSS data reduces the errors in tropical Pacific salinity by 4% and 8% in the Met Office and Mercator Ocean systems respectively with an impact down to about 50 m depth on average. Salinity errors were reduced by up to 30% in the tropical Atlantic in both systems. There were significant reductions in near-surface temperature and sea level anomaly errors in both the central tropical Pacific and Amazon outflow regions in the Met Office system. The experiment results and characteristics of the operational ocean forecasting systems lead to a new set of requirements for satellite salinity data. The product accuracy required to significantly improve real-time ocean analysis and forecasts should be less than 0.2 pss at a resolution of at least 50 km for daily products. Improvements to spatial resolution down to the order of 10 km would represent an even more significant breakthrough. To be assimilated in near-real time, products should be available within 24 h and estimates of the systematic and random components of the uncertainty should be provided with each measurement. [ABSTRACT FROM AUTHOR]

The long term management of a production asset raises several major issues, among which rank the technical management of the plant, its economics, and the fleet level perspective one has to adopt. Decision makers are therefore faced with the need in define long term policies (up to the end of asset operation) that take into account multiple criteria including safety (which is paramount) and performance. In this paper we first remind the reader of the EDF three-level methodology for asset management. As introduced in PVP 2003 and PVP 2004, this methodology addresses the component/technical level (how to safely operate daily and invest for the future), the plant level (how to translate technical decisions into plant-wide consequences including economic performance), and the fleet level (how to manage a large number of similar assets). We then focus on the software tool that implements this methodology in order to allow decision makers to define, evaluate, and analyze long term plant operation and maintenance policies. Lastly we show how the methodology and the software tool were used on a pilot case study. The technical and economic results obtained at the plant level are described as well as the conclusions one can draw from them in order to help decision makers evaluate and analyze long term asset management strategies. [DOI: 10.1115/1.2389032]

Introduction: Diabetes has long been implicated as a major risk factor for intervertebral disc (IVD) degeneration, interfering with molecular signaling and matrix biochemistry, which ultimately aggravates the progression of the disease. Glucose content has been previously shown to influence structural and compositional changes in engineered discs in vitro, impeding fiber formation and mechanical stability. Methods: In this study, we investigated the impact of diabetic hyperglycemia on young IVDs by assessing biochemical composition, collagen fiber architecture, and mechanical behavior of discs harvested from 3‐ to 4‐month‐old db/db mouse caudal spines. Results: We found that discs taken from diabetic mice with elevated blood glucose levels demonstrated an increase in total glycosaminoglycan and collagen content, but comparable advanced glycation end products (AGE) levels to wild‐type discs. Diabetic discs also contained ill‐defined boundaries between the nucleus pulposus and annulus fibrosus, with the latter showing a disorganized and unaligned collagen fiber network at this same boundary. Conclusions: These compositional and structural changes had a detrimental effect on function, as the diabetic discs were twice as stiff as their wild‐type counterparts and demonstrated a significant resistance to deformation. These results indicate that diabetes may predispose the young disc to DDD later in life by altering patterns of extracellular matrix deposition, fiber formation, and motion segment mechanics independently of AGE accumulation. [ABSTRACT FROM AUTHOR]

Most professional employees aspire to leadership, and this suggests that a best possible leader self—a personalized representation of who an employee aspires to be at their best as a leader in the future—is likely a relevant and motivating self‐representation for employees at work. Integrating theory on best possible selves with control theory, we suggest that activating a best possible leader self can have beneficial effects for the way that any employee feels and behaves at work. Specifically, we propose that employees who reflect on their best possible leader self will enact more leader‐congruent behaviors and subsequently perceive themselves as more leaderlike due to the positive affect generated by such reflection. We found support for our theoretical expectations in an experimental experience sampling study that included both current and aspiring leaders. On days when employees reflected on their best possible leader self, they engaged in more helping and visioning via positive affect. Furthermore, employees perceived themselves as more leaderlike after performing these leader‐congruent behaviors, as captured by higher enacted leader identity and clout. We discuss theoretical and practical implications for research on leadership. [ABSTRACT FROM AUTHOR]

In this paper, we consider a system made of n components displayed on a structure (eg, a steel plate). We define a parametric model for the hazard function, which includes covariates and spatial interaction between components. The state (nonfailed or failed) of each component is observed at some inspection times. From these data, we consider the problem of model parameter estimation. To achieve this, we suggest to use the SEM algorithm based on a pseudo‐likelihood function. A definition for the time‐to‐failure of the system is given, generalizing the classical cases. A study based on numerical simulations is provided to illustrate the proposed approach. [ABSTRACT FROM AUTHOR]

Background: Auto‐immune thrombotic thrombocytopenic purpura (TTP) is a morbid multi‐organ disorder. Cardiac involvement not recognized in initial disease descriptions is a major cause of morbidity. Therapeutic plasma exchange (TPE) requires exposure to multiple plasma donors with risk of transfusion‐transmitted infection (TTI). Pathogen inactivation (PI) with amotosalen‐UVA, the INTERCEPT Blood System for Plasma (IBSP) is licensed to reduce TTI risk. Methods: An open‐label, retrospective study evaluated the efficacy of quarantine plasma (QP) and IBSP in TTP and defined treatment emergent cardiac abnormalities. Medical record review of sequential patient cohorts treated with QP and IBSP characterized efficacy by remission at 30 and 60 days (d) of treatment, time to remission, and volume (L/kg) of plasma required. Safety outcomes focused on cardiac adverse events (AE), relapse rates, and mortality. Results: Thirty‐one patients (18 IBSP and 13 QP) met study criteria for auto‐immune TTP. The proportions (%) of patients in remission at 30 d (IBSP = 61·1, QP = 46·2, P = 0·570) and 60 d (IBSP = 77·8, QP = 76·9, P = 1·00) were not different. Median days to remission were less for IBSP (15·0 vs. 24·0, P = 0·003). Relapse rates (%) 60 d after remission were not different between cohorts (IBSP = 7·1, QP = 40·0, P = 0·150). ECG abnormalities before and during TPE were frequent; however, cardiac AE and mortality were not different between treatment cohorts. Conclusions: Cardiac and a spectrum of ECG findings are common in TTP. In this study, IBSP and QP had similar therapeutic profiles for TPE. [ABSTRACT FROM AUTHOR]

Four new geranyl flavonoids 1-4 and four known flavonoids 5-8 were obtained from the leaves of Artocarpus communis collected in Indonesia. The planar structures of flavonoids were elucidated by analyses of MS and NMR spectroscopic data. Absolute configurations of 1 and 2 were determined by ECD spectroscopy. Analyses by HPLC with a chiral-phase column and ECD spectra confirmed that 3 and 4 were stereoisomeric mixtures and 7 and 8 were racemic mixtures. The compounds obtained in this study inhibited the enzymatic activities of ubiquitin-specific protease 7 (USP7) and the chymotrypsin-like activity of the proteasome. Among the geranyl flavonoids tested in this experiment, the USP7 inhibitory activity of 6 (IC50 value, 0.094 μM) was 55 times more potent than the commercially available positive control, P5091 (IC50 value, 5.2 μM). [ABSTRACT FROM AUTHOR]