Analysis of Infiltrating Immune Cells Following Intervertebral Disc Injury Reveals Recruitment of Gamma-Delta (γδ) T cells in Female Mice.

Inadequate repair of injured intervertebral discs (IVD) leads to degeneration and contributes to low back pain. Infiltrating immune cells into damaged musculoskeletal tissues are critical mediators of repair, yet little is known about their identities, roles, and temporal regulation following IVD injury. By analyzing longitudinal changes in gene expression, tissue morphology, and the dynamics of infiltrating immune cells following injury, we characterize sex-specific differences in immune cell populations and identify the involvement of previously unreported immune cell types, γδ and NKT cells. Cd3+Cd4-Cd8- T cells are the largest infiltrating lymphocyte population with injury, and we identified the presence of γδ T cells in this population in female mice specifically, and NKT cells in males. Injury-mediated IVD degeneration was prevalent in both sexes, but more severe in males. Sex-specific degeneration may be associated with the differential immune response since γδ T cells have potent anti-inflammatory roles and may mediate IVD repair.

Neopetromin, a Cyclic Tripeptide with a C-N Cross-Link, from the Marine Sponge Neopetrosia sp., That Causes Vacuole Fragmentation in Tobacco BY-2 Cells.

HPLC-MS analysis revealed the presence of an unreported peptide in the extract of the marine sponge Neopetrosia sp. Its structure was determined as a tripeptide, named neopetromin (1), composed of two tyrosine and one tryptophan residues with a heteroaromatic C-N cross-link between side chains. The absolute configuration of amino acids was determined using Marfey's method after ozonolysis and hydrolysis of 1. Compound 1 promoted vacuole fragmentation in an actin-independent manner in tobacco BY-2 cells.

Survival of cemented short Exeter femoral components in primary total hip arthroplasty.

Aims: The aim of this study was to report the long-term follow-up of cemented short Exeter femoral components when used in primary total hip arthroplasty (THA). Methods: We included all primary 394 THAs with a cemented short Exeter femoral component (≤ 125 mm) used in our tertiary referral centre between October 1993 and December 2021. A total of 83 patients (21%) were male. The median age of the patients at the time of surgery was 42 years (interquartile range (IQR) 30 to 55). The main indication for THA was a childhood hip disease (202; 51%). The median follow-up was 6.7 years (IQR 3.1 to 11.0). Kaplan-Meier survival analyses were performed to determine the rates of survival with femoral revision for any indication, for septic loosening, for fracture of the femoral component and for aseptic loosening as endpoints. The indications for revision were evaluated. Fractures of the femoral component were described in detail. Results: The 20-year rate of survival was 85.4% (95% confidence interval (CI) 73.9 to 92.0) with revision for any indication, 96.2% (95% CI 90.5 to 98.5) with revision for septic loosening and 92.7% (95% CI 78.5 to 97.6) with revision for fracture of the femoral component. No femoral components were revised for aseptic loosening. There were 21 revisions of the femoral component; most (seven) as part of a two-stage management of infection. Fracture of the femoral component occurred in four THAs (1.0%) at 6.6, 11.6, 16.5, and 18.2 years of follow-up, respectively. Three of these were transverse fractures and occurred at the level of the lesser trochanter. In one THA, there was a fracture of the neck of the component. Conclusion: THAs using cemented short Exeter femoral components showed acceptable rates of survival of the femoral component at long-term follow-up, in this young cohort of patients. Although fracture is a rare complication of these components, surgeons should be aware of their incidence and possible risk factors.

Aaptocarbamates A-G, chlorinated terpene carbamates with antiosteoclastogenic activities from the marine sponge Aaptos sp.

Six undescribed chlorinated sesquiterpene carbamates, aaptocarbamates A-F, and a chlorinated tris-norsesquiterpene carbamate, aaptocarbamate G, were isolated from the marine sponge Aaptos sp. collected in Indonesia. Aaptocarbamates D-F and G possess tetrahydrofurans and a tetrahydrofuranone, respectively. The relative configurations of the tetrahydrofuran units were determined by the NOE correlations and DFT-based calculation of the 13C chemical shifts. This is the first time that chlorinated terpene carbamates have been reported from natural sources. Various aaptamine derivatives have been reported from the Aaptos sponges so far, the isolation of chlorinated terpene carbamates is very rare. Aaptocarbamates A, B, and D showed 60% inhibition of the RANKL-induced formation of multinucleated osteoclasts in RAW264 macrophages at 20 µM.

Logical modelling of myelofibrotic microenvironment predicts dysregulated progenitor stem cell crosstalk.

Primary myelofibrosis is an untreatable age-related disorder of haematopoiesis in which a break in the crosstalk between progenitor Haematopoietic Stem Cells (HSCs) and neighbouring mesenchymal stem cells causes HSCs to rapidly proliferate and migrate out of the bone marrow. Around 90% of patients harbour mutations in driver genes that all converge to overactivate haematopoietic JAK-STAT signalling, which is thought to be critical for disease progression, as well as microenvironment modification induced by chronic inflammation. The trigger to the initial event is unknown but dysregulated thrombopoietin (TPO) and Toll-Like Receptor (TLR) signalling are hypothesised to initiate chronic inflammation which then disrupts stem cell crosstalk. Using a systems biology approach, we have constructed an intercellular logical model that captures JAK-STAT signalling and key crosstalk channels between haematopoietic and mesenchymal stem cells. The aim of the model is to decipher how TPO and TLR stimulation can perturb the bone marrow microenvironment and dysregulate stem cell crosstalk. The model predicted conditions in which the disease was averted and established for both wildtype and ectopically JAK mutated simulations. The presence of TPO and TLR are both required to disturb stem cell crosstalk and result in the disease for wildtype. TLR signalling alone was sufficient to perturb the crosstalk and drive disease progression for JAK mutated simulations. Furthermore, the model predicts probabilities of disease onset for wildtype simulations that match clinical data. These predictions might explain why patients who test negative for the JAK mutation can still be diagnosed with PMF, in which continual exposure to TPO and TLR receptor activation may trigger the initial inflammatory event that perturbs the bone marrow microenvironment and induce disease onset.

The importance of leader recovery for leader identity and behavior.

For individuals who hold leadership positions in their organizations, identifying as a leader day-to-day can have significant implications for their performance and interactions with followers. Despite the importance of leader identity, however, little is known about how leaders can start their workday in a cognitive state that allows them to identify more strongly with their leader role. Integrating recovery research with leader identity theory, we investigated the implications of psychological detachment and affect-focused rumination for leader identity and leader performance on a day-to-day basis at work. We conducted two experience sampling studies to test our expectations. In the first experience sampling study, we found that psychological detachment after hours helped leaders identify more strongly with their leader role the next day because they felt recuperated (i.e., lower levels of depletion), whereas affect-focused rumination after hours hindered leader identity via depletion. In turn, leader identity influenced leaders' enactment of transformational behaviors and power that day at work, as rated by their followers. We also found that the downstream effects of affect-focused rumination on leader behaviors via depletion and leader identity were weaker for more (vs. less) experienced leaders. We constructively replicated the negative effects of depletion on transformational behaviors and enacted power via leader identity in a supplemental experience sampling study using leaders' self-reports of their behaviors. We discuss theoretical and practical implications of our research for leaders at work. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Cyclopsammocinamides A and B, Enantiomeric Cyclic Peptides of Cyclocinamide A, from the Marine Sponge Psammocinia sp.

LC-MS and molecular networking analyses of the extract of the marine sponge Psammocinia sp. indicated the presence of two new compounds with multiple halogens. LC-MS-guided isolation yielded cyclic peptides, cyclopsammocinamides A (1) and B (2), in an enantiomeric relationship to cyclocinamide A (3). Planar structures of 1 and 2 were elucidated by NMR and mass spectroscopic analyses and the absolute configurations of the amino acid residues were determined using Marfey's method with their acid hydrolysates. The sponge extract exhibited cytotoxicity and the bioassay-guided isolation afforded a dimeric dilactone macrolide, swinholide A, as the cytotoxic compound.

Contrast-enhanced microCT evaluation of degeneration following partial and full width injuries to the mouse lumbar intervertebral disc.

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.

The degenerative impact of hyperglycemia on the structure and mechanics of developing murine intervertebral discs.

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.

When leader self-care begets other care: Leader role self-compassion and helping at work.

Integrating research on self-compassion with leader identity theory, we propose that leader role self-compassion-a mindset in which a leader takes a supportive, kind, and nonjudgmental stance toward himself or herself in relation to challenges faced in a leader role-matters for subsequent leader behaviors and stakeholder perceptions by strengthening leader identity. To test these theoretical ideas, we developed and tested a leader role self-compassion intervention in two field experiments. In the first field experiment, we show that on days when leaders engage in leader role self-compassion, they help others more with both task-related and personal problems because they identify more strongly with their leader role. Consequently, on such days, stakeholders perceive these leaders as more competent and civil. In exploratory analyses, we also find that these effects are stronger for leaders with lower (vs. higher) structural power, suggesting that novice leaders may benefit more from leader role self-compassion. In the second field experiment, we conceptually replicate the effect of the leader role self-compassion intervention on leader identity and establish the distinctiveness of this intervention from other types of interventions. We discuss implications for theory and research. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Human Achilles tendon mechanical behavior is more strongly related to collagen disorganization than advanced glycation end-products content.

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).

Halichonic Acid B, a Rearranged Nitrogenous Bisabolene-Type Sesquiterpene from a Marine Sponge Axinyssa sp.

A new rearranged nitrogenous bisabolone-type sesquiterpene, halichonic acid B (1), was isolated from a marine sponge Axinyssa sp. together with halichonic acid (2) and (6R,7S)-7-amino-7,8-dihydro-α-bisabolene (3). The structure of 1 was determined by extensive NMR and MS analyses, revealing an unprecedented carbon framework, and its absolute configuration was elucidated by time-dependent density-functional theory (TDDFT)-based electronic circular dichroism (ECD) spectrum calculation. We propose that 1 and 2 may be biosynthesized in the same pathway, involving the reaction between farnesyl pyrophosphate and glycine, followed by cyclization.

Fluorescent image-based high-content screening of extracts of natural resources for cell cycle inhibitors and identification of a new sesquiterpene quinone from the sponge, Dactylospongia metachromia.

Natural products are important sources for drug development. Discovery of natural products that inhibit cell cycle progression significantly contributes to the progress of cancer biology and the development of new antitumor agents. In this study, cell cycle inhibitory activity was evaluated with our extract library of natural resources, including marine invertebrates, fungi, and bacteria, using HeLa/Fucci2 cells which allow classification of the cell cycle phases of living cells. Screening of the extract library revealed that the extract of the marine sponge Dactylospongia metachromia inhibited cell cycle progression at S/G2/M phases. Bioassay-guided fractionation afforded a new sesquiterpene quinone, neoisosmenospongine (1), and four known compounds, nakijiquinone I, N, and Q (2-4) and (-)-dictyoceratin-C (5). The chemical structure of 1 was elucidated by interpretating the NMR and mass spectroscopic data, and the absolute configuration was determined by comparison of the experimental and calculated ECD spectra. Fluorescent imaging of HeLa/Fucci2 cells revealed that 1-4 inhibited the cell cycle progression at S/G2/M phases. This study demonstrated that fluorescent image-based high-content screening using HeLa/Fucci2 cells is an effective approach for isolating cell cycle inhibitors from natural resources.

Complications in the spine associated with type 2 diabetes: The role of advanced glycation end-products.

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.

Is one the loneliest number? A within-person examination of the adaptive and maladaptive consequences of leader loneliness at work.

Although leaders' daily work is inherently relational, it is possible that leaders can feel lonely and isolated from followers. Integrating theoretical ideas from regulatory loop models of loneliness with evolutionary perspectives of loneliness, we posit that daily leader loneliness (i.e., feelings of isolation stemming from one's followers) may prompt harmful self-perpetuating as well as beneficial self-correcting cycles of loneliness at work via different rumination processes. We expect that leader loneliness will relate to 2 forms of rumination after work-maladaptive affect-focused rumination and adaptive problem-solving pondering. We expect that each form of rumination will hinder or facilitate next-day work engagement and helping, which will then matter for subsequent leader loneliness. In a 10-day experience sampling investigation of 86 leaders, we found that daily leader loneliness exhibits a self-perpetuating pattern via affect-focused rumination because this type of rumination reduces next-day work engagement and helping. At the same time, daily leader loneliness exhibits a self-correcting pattern via problem-solving pondering, as this type of forward-thinking rumination facilitates work engagement and helping the next day. Furthermore, leader self-efficacy enhances the extent to which problem-solving pondering occurs when leaders feel lonely. In a supplemental experience sampling study with leaders and followers, we further show that daily leader loneliness is negatively related to followers' perceptions of leader effectiveness above and beyond more generalized loneliness. In summary, our work sheds theoretical and empirical light on the complex nature of leader loneliness. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

A Combinatorial Exploration of Boolean Dynamics Generated by Isolated and Chorded Circuits.

Most studies of motifs of biological regulatory networks focus on the analysis of asymptotical behaviours (attractors, and even often only stable states), but transient properties are rarely addressed. In the line of our previous study devoted to isolated circuits (Remy et al. in Bioinformatics (Oxford, England) 19(Suppl. 2):172-178, 2003), we consider chorded circuits, that are motifs made of an elementary positive or negative circuit with a chord, possibly a self-loop. We provide detailed descriptions of the boolean dynamics of chorded circuits versus isolated circuits, under the synchronous and asynchronous updating schemes within the logical formalism. To this end, we address the description of the trajectories in the dynamics of isolated circuits with coding techniques and adapt them for chorded circuits. The use of the logical modeling gives access to mathematical tools (group actions, analysis of recurrent sequences, coding of trajectories, specific abacus...) allowing complete analytical analysis of basic yet important motifs. In particular, we show that whatever the chosen updating rule, the dynamics depends on a small number of parameters.

Putting leaders in a bad mood: The affective costs of helping followers with personal problems.

Although leaders spend considerable time helping followers with personal problems, little research has investigated how such helping acts may impact leaders themselves. Drawing from affective events theory and the helping literature, we examine how responding to followers' help requests with personal problems influences leaders' own affect. As expected, we found that helping followers with personal problems was associated with an increase in leaders' negative affect. The strength of the association between personal helping and negative affect, however, depended on the day and on the leader. Specifically, personal helping increased negative affect less on days when leaders perceived their prosocial impact of personal helping to be high (vs. low). On the other hand, personal helping increased negative affect more on days when leaders also helped with task-related problems. Furthermore, at the between-person level, leaders with high (vs. low) managerial experience were less affected by personal helping. In exploratory analyses, we also investigated how followers reacted to leaders' helping. We found that whereas leader task-related helping was associated with follower perceptions of leader work engagement, leader personal helping was not. Additionally, helping with personal problems detracted from followers' increased perceptions of work engagement derived from leaders' task-related helping. Specifically, followers rated leaders who helped with task-related problems as more engaged on days when these leaders provided less (vs. more) personal helping. We discuss implications for research on helping and leadership. (PsycINFO Database Record (c) 2020 APA, all rights reserved).

In vivo contrast-enhanced microCT for the monitoring of mouse thoracic, lumbar, and coccygeal intervertebral discs.

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 < .01). The presence of Ioversol in the IVD combined with high-resolution microCT allow for nondestructive visualization of structural features of the IVD. These results demonstrate CEµCT with Ioversol as a viable strategy for the in vivo monitoring of multiple mouse IVDs during degeneration, disease, and injury.

The anti-myeloma effects of the selective JAK1 inhibitor (INCB052793) alone and in combination in vitro and in vivo.

The Janus kinase (JAK) pathway has been shown to play key roles in the growth and resistance to drugs that develop in multiple myeloma (MM) patients. The anti-MM effects of the selective JAK1 inhibitor INCB052793 (INCB) alone and in combination with anti-MM agents were evaluated in vitro and in vivo. Significant inhibition of cell viability of primary MM cells obtained fresh from MM patients, and the MM cell lines RPMI8226 and U266, was observed with single agent INCB and was enhanced in combination with other anti-MM agents including proteasome inhibitors and glucocorticosteroids. Single-agent INCB resulted in decrease in tumor growth of the MM xenograft LAGκ-1A growing in severe combined immunodeficient mice. Mice dosed with INCB (30 mg/kg) showed significant reductions in tumor volume on days 28, 35, 42, 49, 56, and 63. Similarly, INCB at 10 mg/kg showed anti-tumor effects on days 56 and 63. Tumor-bearing mice receiving combinations of INCB with carfilzomib, bortezomib, dexamethasone, or lenalidomide showed significantly smaller tumors when compared to vehicle control and mice treated with single agents. These results provide further support for the clinical evaluation of INCB052793 alone and in combination treatment for MM patients.

Tetradehydrohalicyclamine B, a new proteasome inhibitor from the marine sponge Acanthostrongylophora ingens.

A new halicyclamine derivative, tetradehydrohalicyclamine B (1), was isolated from the marine sponge Acanthostrongylophora ingens, along with halicyclamine B (2) as proteasome inhibitors. Compound 1 is the second example found to have a pyridinium ring in the halicyclamine family. Although the relative configuration of 2 was previously determined by X-ray crystallographic analysis, here we determined the absolute configuration of 2 by ECD experiment. Compounds 1 and 2 inhibited the constitutive proteasome as well as the immunoproteasome. The inhibitory activities of 2 were 4- to 10-fold more potent than those of 1.