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The purpose of this study was to compare gait biomechanics between limbs and to matched uninjured controls (i.e., sex, age, and body mass index) preoperatively and at 2, 4, 6, and 12 months following primary unilateral anterior cruciate ligament reconstruction (ACLR). Functional mixed effects models were used to identify differences in gait biomechanics throughout the stance phase between the a) ACLR limb and uninvolved limb, b) ACLR limb and controls, and c) uninvolved limb and controls. Compared with the uninvolved limb, the ACLR limb demonstrated lesser knee extension moment (KEM; within 8–37% range of stance) during early stance as well as lesser knee flexion moment (KFM; 45–84%) and greater knee flexion angle (KFA; 43–90%) during mid‐ to late stance at all timepoints. Compared with controls, the ACLR limb demonstrated lesser vertical ground reaction force (vGRF; 5–26%), lesser KEM (7–47%), and lesser knee adduction moment (KAM; 12–35%) during early stance as well as greater vGRF (39–63%) and greater KFA (34–95%) during mid‐ to late stance at all timepoints. Compared with controls, the uninvolved limb demonstrated lesser KFA (1–56%) and lesser KEM (12–54%) during early to mid‐stance at all timepoints. While gait becomes more symmetrical over the first 12 months post‐ACLR, the ACLR and uninvolved limbs both demonstrate persistent aberrant gait biomechanics compared to controls. Biomechanical waveforms throughout stance can be generally described as less dynamic following ACL injury and ACLR compared with uninjured controls. Clinical Significance: Individuals with ACLR demonstrate less dynamic gait biomechanics waveforms bilaterally from the preop timepoint up to 12 months post‐ACLR, which may contribute to knee joint tissue breakdown. Further, gait retraining interventions need to consider bilateral approaches to normalize gait following unilateral ACLR. [ABSTRACT FROM AUTHOR]

Lesser peak vertical ground reaction force (vGRF) has been widely reported among individuals with anterior cruciate ligament reconstruction (ACLR). Peak vGRF remains less than uninjured controls and relatively stable during the first year following ACLR. However, it is unknown whether there are subgroups of individuals exhibiting consistently greater peak vGRF in the first 6‐months following ACLR and if individuals with consistently greater peak vGRF exhibit kinematic and kinetic gait differences compared to individuals with low vGRF. The purpose of this study was to determine if distinct clusters exist based upon magnitude of peak vGRF 2‐ and 6‐months post‐ACLR. Subsequently, we explored between cluster differences in vGRF, knee flexion angle, and sagittal and frontal plane knee kinetics throughout stance between clusters. Forty‐three individuals (58.1%female, 21.4 ± 4.4 years‐old, 95.3% patellar‐tendon autograft) completed five gait trials at their habitual walking speed 2‐ and 6‐months post‐ACLR. A single K‐means cluster analysis was used to identify clusters of individuals based on peak vGRF at 2‐ and 6‐months post‐ACLR. Functional waveform analyses were used to compare gait outcomes between clusters with and without controlling for gait speed and age. We identified two clusters that included a subgroup with high vGRF (n = 16) and low vGRF (n = 27). The cluster with high vGRF demonstrated greater vGRFs, knee flexion angles, and knee extension moments during early stance as compared to the low vGRF cluster 2‐ and 6‐months post‐ACLR. Individuals with peak vGRF ≥1.02 times body‐weight 2‐months post‐ACLR had 35.4 times greater odds of being assigned to the high vGRF cluster. [ABSTRACT FROM AUTHOR]

Arguments against inflicting violence on people to defend animal rights have relied on the view that inflicting violence is always wrong. But these arguments end up prohibiting too much, as defensive violence should be permissible in certain extreme cases. We argue that considerations about the counterproductiveness of defensive violence are better at distinguishing permissible and impermissible instances of animal rights violence than a blanket rejection of violence. We respond to the objection that assuming violence to be counterproductive is ad hoc, discussing real‐world and fictional examples of animal rights violence. We argue that defensive violence on behalf of animals should almost always be assumed to be counterproductive because it threatens to trigger self‐reinforcing reactions on the part of the socio‐technical regimes that violate animal rights in the first place. [ABSTRACT FROM AUTHOR]

Thermal runaway is a ductile localization mechanism that has been linked to deep‐focus earthquakes and pseudotachylyte formation. In this study, we investigate the dynamics of this process using one‐dimensional, numerical models of simple shear deformation. The models employ a visco‐elastic rheology where viscous creep is accommodated with a composite rheology encompassing diffusion and dislocation creep as well as low‐temperature plasticity. To solve the nonlinear system of differential equations governing this rheology, we utilize the pseudo‐transient iterative method in combination with a viscosity regularization to avoid resolution dependencies. To determine the impact of different model parameters on the occurrence of thermal runaway, we perform a parameter sensitivity study consisting of 6,000 numerical experiments. We observe two distinct behaviors, namely a stable regime, characterized by transient shear zone formation accompanied by a moderate (100–300 K) temperature increase, and a thermal runaway regime, characterized by strong localization, rapid slip and a temperature surge of thousands of Kelvin. Nondimensional scaling analysis allows us to determine two dimensionless groups that predict the model behavior. The ratio tr/td ${t}_{\mathrm{r}}/{t}_{\mathrm{d}}$ represents the competition between heat generation from stress relaxation and heat loss due to thermal diffusion while the ratio Uel/Uth ${U}_{\text{el}}/{U}_{\text{th}}$ compares the stored elastic energy to thermal energy in the system. Thermal runaway occurs if tr/td ${t}_{\mathrm{r}}/{t}_{\mathrm{d}}$ is small and Uel/Uth ${U}_{\text{el}}/{U}_{\text{th}}$ is large. Our results demonstrate that thermal runaway is a viable mechanism driving fast slip events that are in line with deep‐focus earthquakes and pseudotachylyte formation at conditions resembling cores of subducting slabs. Plain Language Summary: Thermal runaway is a mechanism that concentrates material deformation into thin layers without breaking the material and has been linked to earthquakes more than 70 km below the surface. This study uses one‐dimensional computer models with a complex material behavior and conducts 6,000 numerical experiments to investigate the influence of different parameters like temperature, deformation rate and material properties. Results show two distinct behaviors, namely a stable regime with slow sliding and a temperature rise of 100–300 K or thermal runaway with fast movement and a temperature increase of a few thousand Kelvin. We find two dimensionless ratios that are combinations of the input parameters and can predict the behavior. The ratio tr/td ${t}_{\mathrm{r}}/{t}_{\mathrm{d}}$ compares heat production to heat loss, and the ratio Uel/Uth ${U}_{\text{el}}/{U}_{\text{th}}$ compares stored elastic energy to thermal energy. If the first ratio is small and the second ratio is large, thermal runaway occurs. Our results show that thermal runaway could cause fast deformation events like earthquakes and produce thin layers of molten rock in conditions that are typical for subducting plates. Key Points: Numerical investigation of thermal runaway in visco‐elastic material with diffusion creep, dislocation creep and low‐temperature plasticityNondimensional scaling analysis reveals two dimensionless groups governing the occurrence of thermal runawayDuctile localization can cause slip events in line with deep earthquakes and pseudotachylyte formation at subducting slab core conditions [ABSTRACT FROM AUTHOR]

Our body stores energy mostly in form of fatty acids (FAs) in lipid droplets (LDs). From there the FAs can be mobilized and transferred to peroxisomes and mitochondria. This transfer is dependent on close opposition of LDs and mitochondria and peroxisomes and happens at membrane contact sites. However, the composition and the dynamics of these contact sites is not well understood, which is in part due to the dependence on the metabolic state of the cell and on the cell‐ and tissue‐type. Here, we summarize the current knowledge on the contacts between lipid droplets and mitochondria both in mammals and in the yeast Saccharomyces cerevisiae, in which various contact sites are well studied. We discuss possible functions of the contact site and their implication in disease. [ABSTRACT FROM AUTHOR]

Most mitochondrial proteins are synthesized on cytosolic ribosomes and imported into mitochondria in a post-translational reaction. Mitochondrial precursor proteins which use the ER-SURF pathway employ the surface of the endoplasmic reticulum (ER) as an important sorting platform. How they reach the mitochondrial import machinery from the ER is not known. Here we show that mitochondrial contact sites play a crucial role in the ER-to-mitochondria transfer of precursor proteins. The ER mitochondria encounter structure (ERMES) and Tom70, together with Djp1 and Lam6, are part of two parallel and partially redundant ER-to-mitochondria delivery routes. When ER-to-mitochondria transfer is prevented by loss of these two contact sites, many precursors of mitochondrial inner membrane proteins are left stranded on the ER membrane, resulting in mitochondrial dysfunction. Our observations support an active role of the ER in mitochondrial protein biogenesis. Synopsis: ER-mitochondria contact sites are essential for the import of hydrophobic mitochondrial precursor proteins to the inner mitochondrial membrane via the ER-SURF pathway. Mitochondrial precursors use ER-mitochondria contact sites for targeting. ERMES and Tom70 serve as alternative transfer structures for precursor proteins. Hydrophobic proteins of the inner membrane are the predominant ER-SURF clients. ER-mitochondria contact sites are essential for the import of hydrophobic mitochondrial precursor proteins to the inner mitochondrial membrane via the ER-SURF pathway. [ABSTRACT FROM AUTHOR]

Post‐translational modifications are key in the regulation of activity, structure, localization, and stability of most proteins in eukaryotes. Phosphorylation is potentially the most studied post‐translational modification, also due to its reversibility and thereby the regulatory role this modification often plays. While most research attention was focused on kinases in the past, phosphatases remain understudied, most probably because the addition and presence of the modification is more easily studied than its removal and absence. Here, we report the identification of an uncharacterized protein tyrosine phosphatase PPH‐7 in C. elegans, a member of the evolutionary conserved PTPN family of phosphatases. Lack of PPH‐7 function led to reduction of fertility and embryonic lethality at elevated temperatures. Proteomics revealed changes in the regulation of targets of the von Hippel–Lindau (VHL) E3 ligase, suggesting a potential role for PPH‐7 in the regulation of VHL. [ABSTRACT FROM AUTHOR]

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Background: Attachment quality may affect psychological functioning. However, evidence on attachment representations and their correlates in children born to parents with schizophrenia and bipolar disorder is sparse. Methods: We compared attachment representations in a Danish sample of 482 children aged 7 years at familial high risk of schizophrenia, bipolar disorder, and population‐based controls and examined associations between attachment and mental disorders and daily functioning. Attachment representations were examined with the Story Stem Assessment Profile (SSAP). Mental disorders were ascertained in diagnostic interviews. Daily functioning was assessed with the Children's Global Assessment Scale. Results: We found no between‐group differences in attachment. Higher levels of secure attachment were associated with decreased risk of concurrent mental disorders in the schizophrenia high‐risk group. Higher levels of insecure and disorganized attachment were associated with increased risk of mental disorders across the cohort. Higher levels of secure and insecure attachment were associated with better and poorer daily functioning, respectively. In the current study, results regarding defensive avoidance could not be reported due to methodological limitations. Conclusion: Familial high risk of schizophrenia (FHR‐SZ) or bipolar disorder is not associated with less secure or more insecure attachment at age 7. Insecure and disorganized attachment representations index risk of mental disorders and poorer functioning. Secure attachment may be a protective factor against mental disorders in children at FHR‐SZ. Validation of the SSAP is needed. [ABSTRACT FROM AUTHOR]

Background: Primary care physicians (PCP) play a key role in the care of people living with dementia. However, the implementation and practicability of the German S3 Dementia Guideline in primary care remain unclear. The main objective of the present study was to evaluate an intervention for improving guideline‐based dementia care in primary care. Design: A two‐arm, 9‐month follow‐up cluster‐randomized controlled trial with two parallel groups. Setting: 28 primary care practices in Berlin and the surrounding area in Germany. Participants: A total of N = 28 PCP, N = 91 people living with dementia, and N = 88 informal caregivers participated in the trial. Intervention: A tablet‐based intervention to improve adherence to the German S3 Dementia Guideline in primary care was compared to a control group (care as usual plus a handbook on dementia). MeasurementsAdherence to dementia guideline (primary outcome) was measured on PCP' (23 items) and informal caregivers' level (19 items) with a self‐developed checklist. Secondary outcomes (quality of life, neuropsychiatric symptoms, activities of daily living, general health status, depression, and caregiver burden) were measured with standardized assessments. Also, post‐hoc per‐protocol analyses were conducted. Results: No differences in guideline adherence between the intervention and the control group were observed. Further, no significant impact of the intervention on secondary outcomes was detected. Conclusion: The DemTab Study did not improve self‐reported guideline adherence in PCP. However, important implementation barriers such as lack of interoperability and low applicability of existing German S3 Dementia Guideline in the primary care setting were identified and are being discussed. Trial registration: The DemTab trial was prospectively registered with the ISRCTN registry (Trial registration number: ISRCTN15854413). Registered 01 April 2019, https://doi.org/10.1186/ISRCTN15854413. [ABSTRACT FROM AUTHOR]

The origin of complex cellular life is a key puzzle in evolutionary research, which has broad implications for various neighbouring scientific disciplines. Naturally, views on this topic vary widely depending on the world view and context from which this topic is approached. In the following, I will share my perspective about our current scientific knowledge on the origin of eukaryotic cells, that is, eukaryogenesis, from a biological point of view focusing on the question as to whether an archaeon was the ancestor of eukaryotes. [ABSTRACT FROM AUTHOR]

Increases in global meat demands cannot be sustainably met with current methods of livestock farming, which has a substantial impact on greenhouse gas emissions, land use, water consumption, and farm animal welfare. Cultivated meat is a rapidly advancing technology that produces meat products by proliferating and differentiating animal stem cells in large bioreactors, avoiding conventional live‐animal farming. While many companies are working in this area, there is a lack of existing infrastructure and experience at commercial scale, resulting in many technical bottlenecks such as scale‐up of cell culture and media availability and costs. In this study, we evaluate theoretical cultivated beef production facilities with the goal of envisioning an industry with multiple facilities to produce in total 100,000,000 kg of cultured beef per year or ~0.14% of the annual global beef production. Using the computer‐aided process design software, SuperPro Designer®, facilities are modeled to create a comprehensive analysis to highlight improvements that can lower the cost of such a production system and allow cultivated meat products to be competitive. Three facility scenarios are presented with different sized production reactors; ~42,000 L stirred tank bioreactor (STR) with a base case cost of goods sold (COGS) of $35/kg, ~211,000 L STR with a COGS of $25/kg, and ~262,000 L airlift reactor (ALR) with a COGS of $17/kg. This study outlines how advances in scaled up bioreactors, alternative bioreactor designs, and decreased media costs are necessary for commercialization of cultured meat products. [ABSTRACT FROM AUTHOR]

Background: Swedish social policy enables ageing in place with support from home‐based care services despite high age and/or declining health. Aim: This study aims to describe the daily life experiences behind the decision to apply for a nursing home placement in older adults ageing in place. Materials and Methods: A qualitative design was chosen, and 11 semi‐structured interviews were conducted and analysed using inductive qualitative content analysis. Results: The participants described a feeling of dependence in which they had to ignore their personal privacy when receiving home‐based care. They reached a turning point when ageing in place was, for several reasons, no longer considered an acceptable option. This influenced their choice to apply to a nursing home where they expected that they could maintain control over their lives. Discussion and Conclusion: The results indicate that when enhancing ageing in place it is important to enable older adults to receive support to maintain autonomy in daily activities and to have the opportunity to age in the right place. [ABSTRACT FROM AUTHOR]

Studies of host rock deformation around magmatic intrusions usually focus on the development of stresses directly related to the intrusion process. This is done either by considering an inflating region that represents the intruding body, or by considering multiphase deformation. Thermal processes, especially volume changes caused by thermal expansion are typically ignored. We show that thermal stresses around upper crustal magma bodies are likely to be significant and sufficient to create an extensive fracture network around the magma body by brittle yielding. At the same time, cooling induces decompression within the intrusion, which can promote the appearance of a volatile phase. Volatile phases and the development of a fracture network around the inclusion may thus be the processes that control magmatic‐hydrothermal alteration around intrusions. This suggests that thermal stresses likely play an important role in the development of magmatic systems. To quantify the magnitude of thermal stresses around cooling intrusions, we present a fully compressible 2D visco‐elasto‐plastic thermo‐mechanical numerical model. We utilize a finite difference staggered grid discretization and a graphics processing unit based pseudo‐transient solver. First, we present purely thermo‐elastic solutions, then we include the effects of viscous relaxation and plastic yielding. The dominant deformation mechanism in our models is determined in a self‐consistent manner, by taking into account stress, pressure, and temperature conditions. Using experimentally determined flow laws, the resulting thermal stresses can be comparable to or even exceed the confining pressure. This suggests that thermal stresses alone could result in the development of a fracture network around magmatic bodies. Plain Language Summary: Quantifying the stresses that magma bodies exert on the surrounding rocks is an important part of understanding mechanical processes that control the evolution of magmatic systems and volcanic eruptions. Previous analytical or numerical models typically describe the mechanical response to changes in magma volume due to intrusion or extraction of magma. However, volume changes related to thermal expansion/contraction around a cooling magma body are often neglected. Here, we develop a new software which runs on modern graphics processing unit machines, to quantity the effect of this process. The results show that stresses due to thermal expansion/contraction are significant, and often large enough to fracture the rocks nearby the magma body. Such fracture networks may form permeable pathways for the magma or for fluids such as water and CO2, thus influencing the evolution of magmatic and hydrothermal systems. Finally we show that cooling and shrinking of magma bodies causes significant decompression which can influence the chemical evolution of the magma during crystallization and devolatilization. Key Points: We present a numerical quantification of the effect of thermal stresses in visco‐elasto‐plastic rock with tensile and dilatant shear failureThe pressure drop in thermally contracting upper crustal magma bodies can exceed 100 MPa, potentially triggering devolatilizationThermal cracking can create an extensive fracture network around an upper crustal magma body [ABSTRACT FROM AUTHOR]

Home-based care is expanding, and we need to know more about what kind of support older adults need and how such support should be designed. One way to gain more knowledge is to study the experiences that underlie a nursing home application. However, older adults in need of nursing homes are often too weak to participate in research. Thus, this study aimed to describe the experiences of close relatives of the daily life of older adults in need of a nursing home. A qualitative approach was used, where fifteen relatives of nursing home applicants in central Sweden were interviewed using a study-specific interview guide. The interviews were analysed using thematic analysis. The findings are presented in one main theme "Being the person who manages a fragile life situation" with three underlying themes: Balancing and fulfilling expectations, striving to achieve a status quo, experiencing a breaking point, a change is inevitable, and waiting and moving into a nursing home, a period of tension. The main theme describes how the participants contributed to managing the older adults' life situation and acted as a representative in contacts with health and social care. They tried to offer support in their daily life but over time experienced a breaking point when ageing in place was no longer sustainable, resulting in a nursing home application. The rationale for a nursing home application was often a combination of the older adult's own wishes and the fact that their relatives felt there was a combined need for extensive care and physical proximity to staff, which cannot be provided in ordinary housing. Sometimes the decision to apply was also based on relatives no longer having the capacity to continue managing an older adult's fragile situation. [ABSTRACT FROM AUTHOR]

Intercellular communication is an essential process in all multicellular organisms. During this process, molecules secreted by one cell will bind to a receptor on the cognate cell leading to the subsequent uptake of the receptor‐ligand complex. Once inside, the cell then determines the fate of the receptor‐ligand complex and any other proteins that were endocytosed together. Approximately 80% of endocytosed material is recycled back to the plasma membrane either directly or indirectly via the Golgi apparatus and the remaining 20% is delivered to the lysosome for degradation. Although most pathways have been identified, we still lack understanding on how specificity in sorting of recycling cargos into different pathways is achieved, and how the cell reaches high accuracy of these processes in the absence of clear sorting signals in the bulk of the client proteins. In this review, we will summarize our current understanding of the mechanism behind recycling cargo sorting and propose a model of differential affinities between cargo and cargo receptors/adaptors with regards to iterative sorting in endosomes. [ABSTRACT FROM AUTHOR]

Objectives: Emotion regulation is a predictor of overall life outcome. Problems of emotion regulation are associated with multiple psychiatric disorders and could be a potential treatment target for improving well-being and functioning. Children at familial high risk of severe mental illness have a markedly increased risk of various psychopathology and constitute a group at significant risk of emotion regulation problems. Investigations of emotion regulation in children at familial high risk of severe mental illness are sparse. Methods: We applied an instrument for assessing emotion regulation, the Tangram Emotion Coding Manual (TECM), to a population-based cohort of 522 7-year-old children born to parents diagnosed with either schizophrenia or bipolar disorder and matched controls. The TEC-M is an ecologically valid, clinician-rated observational test measure of spontaneous emotion regulation. We aimed to compare emotion regulation between risk groups and to investigate associations between emotion regulation and psychopathology and daily life functioning, and between emotion regulation and an acknowledged questionnaire-based dysregulation profile. Results: In this early developmental phase, we found no between group differences in emotion regulation. We found a significant but weak negative association between emotion regulation and both child psychopathology and the presence of a dysregulation profile on the Child Behavior Checklist and a weak positive association between emotion regulation and current level of functioning. Conclusions: These findings contribute to the understanding of emotion regulation in familial high-risk children and further studies of emotion regulation in children at familial high risk of severe mental illness are warranted. [ABSTRACT FROM AUTHOR]

Objectives: Childhood trauma increases the risk of developing mental illness as does being born to parents with schizophrenia or bipolar disorder. We aimed to compare prevalence of lifetime childhood trauma among 11-year-old children at familial high risk of schizophrenia (FHR-SZ) or bipolar disorder (FHR-BP) compared with populationbased controls (PBCs). Design: The study is a longitudinal, prospective cohort study of children at FHR-SZ, FHR-BP, and PBCs. Methods: A cohort of 512 children at FHR-SZ (N = 199), FHR-BP (N = 118), and PBCs (N = 195) were examined at baseline (mean age 7.8, SD 0.2) and 451 children at FHR-SZ (N = 172), FHR-BP (N = 104), and PBCs (N = 175) were examined at four-year follow-up (mean age 11.9, SD 0.2, retention rate 87.3%). Childhood trauma was measured with a semi-structured interview. Results: Children at FHR-BP had an elevated risk of exposure to any lifetime trauma (age 0–11 years) compared with PBCs (OR 2.082, 95%CI 1.223–3.545, p = .007) measured with binary logistic regression. One-way ANOVA revealed that both FHR-groups had a higher lifetime prevalence of exposure to a greater number of types of trauma compared with PBCs (FHR-SZ: observed mean: 1.53, 95%CI 1.29– 1.77; FHR-BP: observed mean: 1.56, 95%CI 1.26–1.85; PBCs: observed mean: 0.99, 95%CI 0.82–1.17; p < .001). Binary logistic regression showed that the lifetime risk of exposure to interpersonal trauma (age 0–11 years) was elevated for both FHR-groups (FHR-SZ: OR 3.773, 95%CI 2.122–6.710, p < .001; FHR-BP: OR 3.602, 95%CI 1.913– 6.783, p < .001). Conclusions: Children at FHR-SZ and FHR-BP are at increased risk for being exposed to childhood trauma compared with PBCs. This study underscores the need for early detection, support, and prevention of childhood trauma in children at FHR-SZ and FHR-BP. [ABSTRACT FROM AUTHOR]

Aberrant joint loading contributes to the development of posttraumatic knee osteoarthritis (PTOA) following anterior cruciate ligament reconstruction (ACLR); yet little is known about the association between joint loading due to daily walking and cartilage health post‐ACLR. Accelerometer‐based measures of daily steps and cadence (i.e., rate of steps/min) provide information regarding daily walking in a real‐world setting. The purpose of this study was to determine the association between changes in serum cartilage oligomeric matrix protein (COMP; %∆COMP), a mechanosensitive biomarker that is associated with osteoarthritis progression, following a standardized walking protocol and daily walking in individuals with ACLR and uninjured controls. Daily walking was assessed over 7 days using an accelerometer worn on the right hip in 31 individuals with ACLR and 21 controls and quantified as mean steps/day and time spent in ≥100 steps/min. Serum COMP was measured before and following a 3000‐step walking protocol at a preferred speed. %∆COMP was calculated as a change in COMP relative to the prewalking value. Linear regressions were used to examine associations between daily walking and %∆COMP after adjusting for preferred speed. Fewer daily steps (ΔR2 = 0.18, p = 0.02) and fewer minutes spent in ≥100 steps/min (ΔR2 = 0.16, p = 0.03) were associated with greater %∆COMP following walking in individuals with ACLR; no statistically significant associations existed in controls (daily steps: ΔR2 = 0.03, p = 0.47; time ≥100 steps/min: ΔR2 < 0.01, p = 0.81). Clinical significance: Individuals with ACLR who engage in less daily walking undergo greater %ΔCOMP, which may represent greater cartilage degradation or turnover in response to walking. [ABSTRACT FROM AUTHOR]

Pediatric anterior cruciate ligament (ACL) injuries are on the rise, and females experience higher ACL injury risk than males during adolescence. Studies in skeletally immature patients indicate differences in ACL size and joint laxity between males and females after the onset of adolescence. However, functional data regarding the ACL and its anteromedial and posterolateral bundles in the pediatric population remain rare. Therefore, this study uses a porcine model to investigate the sex‐specific morphology and biomechanics of the ACL and its bundles throughout skeletal growth. Hind limbs from male and female Yorkshire pigs aged early youth to late adolescence were imaged using magnetic resonance imaging to measure the size and orientation of the ACL and its bundles, then biomechanically tested under anterior‐posterior drawer using a robotic testing system. Joint laxity decreased (p < 0.001) while joint stiffness increased (p < 0.001) throughout skeletal growth in both sexes. The ACL was the primary stabilizer against anterior tibial loading, while the functional role of the anteromedial bundle increased with age (p < 0.001), with an earlier increase in males. ACL and posterolateral bundle cross‐sectional area and ACL and anteromedial bundle length were larger in males than females during adolescence (p < 0.01 for all), while ACL and bundle sagittal angle remained similar between sexes. Additionally, in situ ACL stiffness versus cross‐sectional area regressions were significant across skeletal growth (r2 = 0.75, p < 0.001 in males and r2 = 0.64, p < 0.001 in females), but not within age groups. This study has implications for age and sex‐specific surgical intervention strategies and suggests the need for human studies. [ABSTRACT FROM AUTHOR]

Objective: To compare T1ρ relaxation times of the medial and lateral regions of the patella and femoral trochlea at 6 and 12 months following anterior cruciate ligament reconstruction (ACLR) on the ACLR and contralateral extremity. Greater T1ρ relaxation times are associated with a lower proteoglycan density of articular cartilage. Methods: This study involved 20 individuals (11 males, 9 females; mean ± SD age 22 ± 3.9 years, weight 76.11 ± 13.48 kg, and height 178.32 ± 12.32 cm) who underwent a previous unilateral ACLR using a patellar tendon autograft. Magnetic resonance images from both extremities were acquired at 6 and 12 months post‐ACLR. Voxel by voxel T1ρ relaxation times were calculated using a 5‐image sequence. The medial and lateral regions of the femoral trochlea and patellar articular cartilage were manually segmented on both extremities. Separate extremity (ACLR and contralateral extremity) by time (6 months and 12 months) analysis of variance tests were performed for each region (P < 0.05). Results: For the medial patella and lateral trochlea, T1ρ relaxation times increased in both extremities between 6 and 12 months post‐ACLR (medial patella P = 0.012; lateral trochlea P = 0.043). For the lateral patella, T1ρ relaxation times were significantly greater on the contralateral extremity compared to the ACLR extremity (P = 0.001). The T1ρ relaxation times of the medial trochlea on the ACLR extremity were significantly greater at 6 (P = 0.005) and 12 months (P < 0.001) compared to the contralateral extremity. T1ρ relaxation times of the medial trochlea significantly increased from 6 to 12 months on the ACLR extremity (P = 0.003). Conclusion: Changes in T1ρ relaxation times occur within the first 12 months following ACLR in specific regions of the patellofemoral joint on the ACLR and contralateral extremity. [ABSTRACT FROM AUTHOR]

Anterior cruciate ligament (ACL) injuries are increasingly common in adolescents, and injuries in this age‐group are associated with many unique challenges. Recent large animal studies suggest that the size and function of the major bundles of the ACL change differently throughout skeletal growth. To better aid clinical treatment of pediatric partial ACL tears and better predict outcomes from age‐specific treatments, there is a need to measure changes in ACL bundle size in humans during growth. As such, the objective of this study was to compare changes in the length and cross‐sectional area (CSA) of the ACL and its primary bundles in adolescent human subjects. Magnetic resonance imaging (MRI) scans were analyzed to determine the visibility and integrity of the ACL and its anteromedial and posterolateral bundles. MRI scans were considered from a retrospective database of subjects ranging from 10 to 18 years of age. The ACL and its anteromedial and posterolateral bundles were segmented and reconstructed into 3D models, and length and CSA were calculated. Total ACL length and CSA were greater in males compared with females, with a statistically significant interaction between age and sex for CSA. Sex had a significant effect on the CSA of both bundles. These sex‐dependent differences emerge with moderate to large effect sizes (range: d = 0.50 to d = 1.23) beginning around 13 years of age. Along with ACL bundle structure–function relationships previously established in preclinical animal models, these findings may point toward biomechanical changes in the adolescent human ACL. [ABSTRACT FROM AUTHOR]

Geodynamic codes have become fast and efficient enough to facilitate sensitivity analysis of rheological parameters. With sufficient data, they can even be inverted for. Yet, the geodynamic inverse problem is often regularized by assuming a constant geometry of the geological setting (e.g., shape, location and size of salt diapirs or magma bodies) or approximating irregular bodies with simple shapes like boxes, spheres or ellipsoids to reduce the parameter space. Here, we present a simple and intuitive method to parameterize complex 3D bodies and incorporate them into geodynamic inverse problems. The approach can automatically create an entire ensemble of initial geometries, enabling us to account for uncertainties in imaging data. Furthermore, it allows us to investigate the sensitivity of the model results to geometrical properties and facilitates inverting for them. We demonstrate the method with two examples. A salt diapir in an extending regime and free subduction of an oceanic plate under a continent. In both cases, small differences in the model's initial geometry lead to vastly different results. Be it the formation of faults or the velocity of plates. Using the salt diapir example, we demonstrate that, given an additional geophysical observation, we are able to invert for uncertain geometric properties. This highlights that geodynamic studies should investigate the sensitivity of their models to the initial geometry and include it in their inversion framework. We make our method available as part of the open‐source software geomIO. Plain Language Summary: Computer models of geological settings have become a popular tool of research. They require the user to provide information on where the different geological units (rock layers, salt domes, magma bodies etc.) start and end as well as material parameters like density and strength of the units. As many of these input parameters are not well known, a lot of studies perform multiple simulations with different parameter combinations to investigate the influence the individual parameters and their uncertainties have. However, the initial geometry often remains fixed as it is difficult to describe with only few parameters and therefore unrealistic to vary. Here, we present a new method to describe and manipulate the geometry of geological units with a small number of parameters. This allows us to also vary the initial geometry and investigate how the model results depend on it. We apply our method to a salt diapir and a subduction zone to demonstrate the impact of initial geometry on the simulation results. To make our method available to the community, we implement it as a tool into geomIO, an open‐source software package to generate initial geometries for geodynamic models. Key Points: New, simple, intuitive and open‐source method to describe and manipulate complex 3D bodies with a small number of parametersAllows for the integration of uncertainties of the initial geometry and enables inverting for geometric properties in numerical modelsApplications to a salt diapir with uncertain initial geometry and a subduction zone with uncertain initial subduction angle [ABSTRACT FROM AUTHOR]

Crustal‐stored magma reservoirs contain exsolved volatiles which accumulate in the reservoir roof, exerting a buoyancy force on the crust. This produces surface uplift and sudden loss of volatiles through eruption results in syn‐eruptive subsidence. Here, we present three‐dimensional, visco‐elasto‐plastic, numerical modeling results which quantify the ground deformation arising from the growth and release of a volatile reservoir. Deformation is mostly independent of crustal thermal distribution and volatile reservoir shape, but is a function of volatile volume, density and depth and crustal rigidity. We present a scaling law for the volatiles' contribution to syn‐eruptive subsidence and show this contributes ∼20% of the observed subsidence associated with the 2015 Calbuco eruption. Our results highlight the key role that volatile‐driven buoyancy can have in volcano deformation, show a new link between syn‐eruptive degassing and deflation, and highlight that shallow volatile accumulation and release may have a significant impact on ground deformation of volcanoes. Plain Language Summary: Magma contains a lot of gases which separate from it when it approaches the surface. These gases can collect right above the magma storage region a few kilometers below the surface. They have a much lower density than the rocks surrounding them and push upwards like a balloon filled with air that is pressed under water. In this study, we use computer models to understand how much a volcano would grow from the push of the gases below and how much it would shrink when the gases escape because of an eruption. We find that the gases can cause the volcano to grow and shrink up to a few centimeters during accumulation and release, respectively. The amount of surface movement depends on the volume, density and depth of the gas reservoir as well as on the toughness of the rocks above it. We derive a simple equation which allows us to compute the surface movement using the aforementioned parameters. With this equation and estimates about the amount of accumulated gas at the 2015 Calbuco eruption, we can assume that about 20% of the observed surface movement was caused by the release of the magmatic gases. Key Points: Exsolving volatiles accumulate at the roof of a magma storage zone and contribute to surface deformation through buoyancy forces3D numerical models show that surface deformation is a function of the volatiles' volume, density and depth as well as crustal rigidityVolatile release during eruption can cause syn‐eruptive subsidence of a few cm, which is 20% of the observed signal at Calbuco in 2015 [ABSTRACT FROM AUTHOR]

Purpose: Anterior cruciate ligament rupture is associated with characteristic bone contusions in approximately 80% of patients, and these have been correlated with higher pain scores. Bone bruising may indicate joint damage that increases inflammation and the likelihood of posttraumatic osteoarthritis. We sought to characterize the severity of bone bruising following acute anterior cruciate ligament injury and determine if it correlates with synovial fluid and serum levels of the proinflammatory chemokine monocyte chemoattractant protein-1 associated with posttraumatic osteoarthritis. Methods: This was a retrospective analysis of data collected prospectively from January 2014 through December 2016. All patients who sustained an acute ligament rupture were evaluated within 15 days of injury, obtained a magnetic resonance imaging study, and underwent bone-patellar-tendon-bone autograft reconstruction were offered enrollment. The overall severity of bone bruising on magnetic resonance imaging was graded (sum of 0–3 grades in 13 sectors of the articular surfaces). Serum and synovial fluid levels of monocyte chemoattractant protein-1 were measured within 14 days of injury, and serum levels were again measured 6 and 12 months following surgery. Separate univariate linear regression models were constructed to determine the association between monocyte chemoattractant protein-1 and bone bruising severity at each time point. Results: Forty-eight subjects were included in this study. They had a mean age of 21.4 years and were 48% female. Median overall bone bruising severity was 5 (range 0–14). Severity of bone bruising correlated with higher synovial fluid concentrations of monocyte chemoattractant protein-1 preoperatively (R2 = 0.18, p = 0.009) and with serum concentrations at 12 months post-reconstruction (R2 = 0.12, p = 0.04). Conclusions: The severity of bone bruising following anterior cruciate ligament rupture is associated with higher levels of the proinflammatory cytokine monocyte chemoattractant protein-1 in synovial fluid acutely post-injury and in serum 12-months following anterior cruciate ligament reconstruction. This suggests that severe bone bruising on magnetic resonance imaging after ligament rupture may indicate increased risk for persistent joint inflammation and posttraumatic osteoarthritis. Level of evidence: III ― retrospective cohort study. [ABSTRACT FROM AUTHOR]

Summary: Sporadic Burkitt lymphoma (BL) is the most frequent tumour of children and adolescents but a rare subtype of lymphomas in adults. To date most molecular data have been obtained from lymphomas arising in the young. Recently, Epstein–Barr virus (EBV) positive and negative BL in young patients was shown to differ in molecular features. In the present study, we present a large age‐overarching cohort of sporadic BL (n = 162) analysed by immunohistochemistry, translocations of MYC proto‐oncogene, basic helix‐loop‐helix transcription factor (MYC), B‐cell leukaemia/lymphoma 2 (BCL2) and B‐cell leukaemia/lymphoma 6 (BCL6) and by targeted sequencing. We illustrate an age‐associated inter‐tumoral molecular heterogeneity in this disease. Mutations affecting inhibitor of DNA binding 3, HLH protein (ID3), transcription factor 3 (TCF3) and cyclin D3 (CCND3), which are highly recurrent in paediatric BL, and expression of sex determining region Y‐box transcription factor 11 (SOX11) declined with patient age at diagnosis (P = 0·0204 and P = 0·0197 respectively). In contrast, EBV was more frequently detected in adult patients (P = 0·0262). Irrespective of age, EBV‐positive sporadic BL showed significantly less frequent mutations in ID3/TCF3/CCND3 (P = 0·0088) but more often mutations of G protein subunit alpha 13 (GNA13; P = 0·0368) and forkhead box O1 (FOXO1; P = 0·0044) compared to EBV‐negative tumours. Our findings suggest that among sporadic BL an EBV‐positive subgroup of lymphomas increases with patient age that shows distinct pathogenic features reminiscent of EBV‐positive endemic BL. [ABSTRACT FROM AUTHOR]

The thioether diadducts [(SMe2)2BeCl2], [(SMe2)2BeBr2] and [(SMe2)2BeI2] have been prepared and converted to the corresponding μ2‐halido bridged monoadducts [(SMe2)BeCl2]2, [(SMe2)BeBr2]2 and [(SMe2)BeI2]2. These complexes have been characterized with IR and NMR spectroscopy as well as X‐ray crystallography. Furthermore, their long term stability in chlorinated solvents was tested, which yielded beryllate salts containing the [SMe3]+ cation. [ABSTRACT FROM AUTHOR]

There is a need for the development of effective treatments for focal articular cartilage injuries. We previously developed a multiphasic 3D‐bioplotted osteochondral scaffold design that can drive site‐specific tissue formation when seeded with adipose‐derived stem cells (ASC). The objective of this study was to evaluate this scaffold in a large animal model. Osteochondral defects were generated in the trochlear groove of Yucatan minipigs and repaired with scaffolds that either contained or lacked an electrospun tidemark and were either unseeded or seeded with ASC. Implants were monitored via computed tomography (CT) over the course of 4 months of in vivo implantation and compared to both open lesions and autologous explants. ICRS II evaluation indicated that defects with ASC‐seeded scaffolds had healing that most closely resembled the aulogous explant. Scaffold‐facilitated subchondral bone repair mimicked the structure of native bone tissue, but cartilage matrix staining was not apparent within the scaffold. The open lesions had the highest volumetric infill detected using CT analysis (p < 0.05), but the repair tissue was largely disorganized. The acellular scaffold without a tidemark had significantly more volumetric filling than either the acellular or ASC seeded groups containing a tidemark (p < 0.05), suggesting that the tidemark limited cell infiltration into the cartilage portion of the scaffold. Overall, scaffold groups repaired the defect more successfully than an open lesion but achieved limited repair in the cartilage region. With further optimization, this approach holds potential to treat focal cartilage lesions in a highly personalized manner using a human patient's own ASC cells. [ABSTRACT FROM AUTHOR]

Continuous Interferometric Synthetic Aperture Radar (InSAR) monitoring (>25 years) has revealed a concentric surface deformation pattern above the Altiplano‐Puna magma body (APMB) in the central Andes. Here, we use a joint interpretation of seismic imaging, gravity anomalies, and InSAR data to constrain location, 3D geometry, and density of the magma body. By combining gravity modeling, thermomechanical modeling, scaling law analysis, and Bayesian inference, we are able to create a relationship between the geometry of a mid‐crustal magma body and surface observations. Furthermore, we can estimate the uncertainties associated with the geometry of the APMB and identify the most important parameters that control the dynamics of the system. We constrain the density contrast between the APMB and the surrounding host rock to 90–130 kg m−3 (2σ) and the associated melt fraction to 15%–22%. Our visco‐elasto‐plastic 3D thermomechanical model reproduces the observed surface deformation self‐consistently by buoyancy driven magma transport without the need for additional pressure sources. The flow pattern is controlled by a central rise at the top of the APMB whose geometry can be constrained with the help of InSAR observations while Bouguer anomalies constrain the deeper parts of the APMB. Automated scaling law analysis shows that the rheology of the upper crust and the magma mush as well as the density contrast between the two are the most important parameters in the system and need to be constrained for a better understanding of the subsurface processes. Plain Language Summary: Volcanoes can have a big impact on economic infrastructure, the security of the population and the creation of ore deposits. They are fed and controlled by magmatic systems in the crust beneath them and we currently have no techniques to directly observe these systems. In our study, we show how numerical (computer) models that obey the laws of physics allow us to compute the observations that we would make at the surface, given a certain set of physical and geometrical parameters. By automatically changing these parameters and comparing our modeling results to real surface observations, we can discover which parameter ranges and combinations are likely. This way, we can constrain location, size, geometry, density and melt content of the Altiplano‐Puna magma body in the central Andes, using only surface observations. We are able to show that different surface observables are sensitive to different parts of the magmatic system which emphasizes the importance of including multiple data sets and modeling techniques in numerical studies. Key Points: 3D visco‐elasto‐plastic thermomechanical modeling of the Altiplano‐Puna magma system, constraining density, melt content and geometry of the Altiplano‐Puna magma body (APMB)Joint, dynamically consistent, interpretation of seismic imaging, gravity anomalies, and surface velocities, including uncertainty estimationAPMB has a central rise of about 80 km diameter, a density contrast of 90–130 kg/m3 to the crust and a melt content of 15%–22% [ABSTRACT FROM AUTHOR]

Background: Explosive outbursts occur in 25%–70% of children with Tourette syndrome (TS) and may cause more distress than the tics themselves. Previous studies have indicated that a comorbid diagnosis of attention‐deficit/hyperactivity disorder (ADHD) is associated with emotional dysregulation in TS; however, this relationship has almost exclusively been studied using parent‐reported questionnaires. Methods: We examined emotion regulation (ER) with an observational measure in 150 medication‐naïve children aged 7–12 allocated to four groups: Forty‐nine children with TS, 23 children with ADHD, 16 children with TS + ADHD, and 62 typically developing controls. We assessed participants' ER ability, as well as parent–child interactions in the context of a complex puzzle task, and coded the observed behavior with the Tangram Emotion Coding Manual (TEC‐M). We examined group differences in ER, as well as associations between ER and severity of symptoms pertaining to TS and ADHD. Results: Children with TS did not differ from controls in their ER ability. However, children with ADHD and TS + ADHD had more problems with ER than those with TS only and controls. Finally, parents of children with ADHD displayed more tension during the experimental task. ER ability was not associated with tic severity nor premonitory urges; however, better ER ability was associated with less severe symptoms of ADHD. Conclusions: This study is the first to evaluate ER with an observational, clinician‐rated measure in a controlled social setting in children with TS. Our findings support earlier questionnaire‐based studies by showing impaired ER in children with TS + ADHD, but not in children with TS without comorbidity. These findings inform our understanding of the phenomenology of emotional dysregulation in TS and the role of comorbid disorders. [ABSTRACT FROM AUTHOR]

Polar stratospheric clouds (PSCs) play important roles in stratospheric ozone depletion during winter and spring at high latitudes (e.g., the Antarctic ozone hole). PSC particles provide sites for heterogeneous reactions that convert stable chlorine reservoir species to radicals that destroy ozone catalytically. PSCs also prolong ozone depletion by delaying chlorine deactivation through the removal of gas‐phase HNO3 and H2O by sedimentation of large nitric acid trihydrate (NAT) and ice particles. Contemporary observations by the spaceborne instruments Michelson Interferometer for Passive Atmospheric Sounding (MIPAS), Microwave Limb Sounder (MLS), and Cloud‐Aerosol Lidar with Orthogonal Polarization (CALIOP) have provided an unprecedented polar vortex‐wide climatological view of PSC occurrence and composition in both hemispheres. These data have spurred advances in our understanding of PSC formation and related dynamical processes, especially the firm evidence of widespread heterogeneous nucleation of both NAT and ice PSC particles, perhaps on nuclei of meteoritic origin. Heterogeneous chlorine activation appears to be well understood. Reaction coefficients on/in liquid droplets have been measured accurately, and while uncertainties remain for reactions on solid NAT and ice particles, they are considered relatively unimportant since under most conditions chlorine activation occurs on/in liquid droplets. There have been notable advances in the ability of chemical transport and chemistry‐climate models to reproduce PSC temporal/spatial distributions and composition observed from space. Continued spaceborne PSC observations will facilitate further improvements in the representation of PSC processes in global models and enable more accurate projections of the evolution of polar ozone and the global ozone layer as climate changes. Plain Language Summary: Polar stratospheric clouds (PSCs) occur during winter and early spring in the polar stratosphere, when temperatures are low enough to enable cloud formation despite the extremely dry conditions. Ground‐based PSC sightings date back to the late 19th century, but they were little more than a scientific curiosity until the discovery of the Antarctic ozone hole in 1985. Soon thereafter, it was shown that PSCs play a crucial role in converting stable halogen (mainly chlorine) species of anthropogenic origin into reactive gases that rapidly destroy ozone. Considerable progress was made over the next two decades in quantifying these processes through laboratory studies, field campaigns, and limited spaceborne observations. We are now reaping the benefits of new PSC observations over the entire polar regions from three complementary 21st century spaceborne instruments. This study reviews these instruments and highlights new findings on PSC occurrence and composition. These datasets have also triggered advances in understanding how PSCs form and the influence of atmospheric dynamics, as well as improvements in how detailed cloud processes are approximated in global models. This will ultimately lead to better predictions of how quickly the stratospheric ozone layer will recover from human influence as global climate changes in the future. Key Points: We provide a new vortex‐wide climatology of polar stratospheric cloud occurrence and composition based on 21st century satellite dataWe review advances in understanding cloud formation, the role of dynamical processes, and heterogeneous chlorine activationWe highlight improvements in techniques for parameterizing polar stratospheric clouds and their effects in global models [ABSTRACT FROM AUTHOR]

Anterior cruciate ligament reconstruction (ACLR) incurs a high risk of posttraumatic knee osteoarthritis (PTOA). Aberrant gait biomechanics contribute to PTOA and are attributable in part to quadriceps dysfunction. Vibration improves quadriceps function following ACLR, but its effects on gait biomechanics are unknown. The purpose of this study was to evaluate the effects of whole‐body vibration (WBV) and local muscle vibration (LMV) on gait biomechanics in individuals with ACLR. Seventy‐five volunteers (time since ACLR 27 ± 16 months) were randomized to WBV, LMV, or Control interventions. Walking biomechanics were assessed prior to and following a single exposure to the interventions. Outcomes included pre‐post change scores in the ACLR limb for the peak vertical ground reaction force (vGRF) and its loading rate, peak internal knee extension (KEM) and abduction moments, and peak knee flexion and varus angles. LMV produced a significant decrease in the vGRF loading rate (−3.6 BW/s) that was greater than the changes in the WBV (−0.3 BW/s) and Control (0.5 BW/s) groups. Additionally, WBV produced an increase in the peak KEM (0.27% BW × Ht) that was greater than the change in the Control group (−0.17% BW × Ht) but not the LMV group (0.01% BW × Ht). Lower KEM and greater loading rates have been linked to declines in joint health following ACLR. WBV acutely increased the peak KEM and LMV decreased loading rates. These data suggest that vibration has the potential to mitigate aberrant gait biomechanics, and may represent an effective approach for reducing PTOA risk following ACLR. [ABSTRACT FROM AUTHOR]

Biologics such as peptides and proteins possess a number of attractive attributes that make them particularly valuable as therapeutics, including their high activity, high specificity, and low toxicity. However, one of the key challenges associated with this class of drugs is their propensity to aggregate. Given the safety and immunogenicity concerns related to polypeptide aggregates, it is particularly important to sensitively detect aggregates in therapeutic drug formulations as part of the quality control process. Here, we report the development of conformation‐specific antibodies that recognize polypeptide aggregates composed of a GLP‐1 receptor agonist (liraglutide) and their integration into a sensitive immunoassay for detecting liraglutide amyloid fibrils. We sorted single‐chain antibody libraries against liraglutide fibrils using yeast surface display and magnetic‐activated cell sorting, and identified several antibodies with high conformational specificity. Interestingly, these antibodies cross‐react with amyloid fibrils formed by several other polypeptides, revealing that they recognize molecular features common to different types of fibrils. Moreover, we find that our immunoassay using these antibodies is >50‐fold more sensitive than the conventional method for detecting liraglutide aggregation (Thioflavin T fluorescence). We expect that our systematic approach for generating a sensitive, aggregate‐specific immunoassay can be readily extended to other biologics to improve the quality and safety of formulated drug products. [ABSTRACT FROM AUTHOR]

The endo‐lysosome system is involved in endocytosis, protein sorting, and degradation as well as autophagy. Numerous toxins and pathogens exploit this system to enter host cells and exert their deleterious effects. Modulation of host endo‐lysosome pathway may restrict multiple toxins intoxication as well as pathogen infection. ABMA, selected from a high‐throughput screening against the cytotoxicity of ricin toxin, exhibits a broad‐spectrum antitoxin and antipathogen activity. Here, we show that ABMA selectively retains endocytosed protein and toxin to late endosomes and thus delaying their intracellular trafficking. It also impairs the autophagic flux by excessive fusion of late endosomes and autophagosomes. Its exclusive action on late endosomes and corresponding consequences on the endo‐lysosomal pathway and autophagic flux are distinct from known inhibitors such as bafilomycin A1, EGA, or chloroquine. Hence, besides being a broad‐spectrum inhibitor of endocytosed toxins and pathogens, ABMA may serve as a molecular tool to dissect endo‐lysosome system‐related cellular physiology and mechanisms of pathogenesis. [ABSTRACT FROM AUTHOR]

Osteoarthritis is a degenerative joint disease that limits mobility of the affected joint due to the degradation of articular cartilage and subchondral bone. The limited regenerative capacity of cartilage presents significant challenges when attempting to repair or reverse the effects of cartilage degradation. Tissue engineered medical products are a promising alternative to treat osteochondral degeneration due to their potential to integrate into the patient's existing tissue. The goal of this study was to create a scaffold that would induce site‐specific osteogenic and chondrogenic differentiation of human adipose‐derived stem cells (hASC) to generate a full osteochondral implant. Scaffolds were fabricated using 3D‐bioplotting of biodegradable polycraprolactone (PCL) with either β‐tricalcium phosphate (TCP) or decellularized bovine cartilage extracellular matrix (dECM) to drive site‐specific hASC osteogenesis and chondrogenesis, respectively. PCL‐dECM scaffolds demonstrated elevated matrix deposition and organization in scaffolds seeded with hASC as well as a reduction in collagen I gene expression. 3D‐bioplotted PCL scaffolds with 20% TCP demonstrated elevated calcium deposition, endogenous alkaline phosphatase activity, and osteopontin gene expression. Osteochondral scaffolds comprised of hASC‐seeded 3D‐bioplotted PCL‐TCP, electrospun PCL, and 3D‐bioplotted PCL‐dECM phases were evaluated and demonstrated site‐specific osteochondral tissue characteristics. This technique holds great promise as cartilage morbidity is minimized since autologous cartilage harvest is not required, tissue rejection is minimized via use of an abundant and accessible source of autologous stem cells, and biofabrication techniques allow for a precise, customizable methodology to rapidly produce the scaffold. [ABSTRACT FROM AUTHOR]

The food and agriculture sectors contribute significantly to climate change, but are also particularly vulnerable to its effects. Industrial ecology has robustly addressed these sectors' contributions to climate change, but not their vulnerability to climate change. Climate change vulnerability must be addressed through development of climate change adaptation and resiliency strategies. However, there is a fundamental tension between the primary objectives of industrial ecology (efficiency, cyclic flows, and pollution prevention) and what is needed for climate change adaptation and resiliency. We develop here two potential ways through which the field can overcome (or work within) this tension and combine the tools and methods of industrial ecology with the science and process of climate change adaptation. The first layers industrial ecology tools on top of climate change adaptation strategies, allowing one to, for example, compare the environmental impacts of different adaptation strategies. The other embeds climate change adaptation and resiliency within industrial ecology tools, for example, by redefining the functional unit in life cycle assessment (LCA) to include functions of resiliency. In both, industrial ecology plays a somewhat narrow role, informing climate change adaptation and resilience decision‐making by providing quantitative indicators of environmental performance. This role for industrial ecology is important given the significant contributions and potential for mitigation of greenhouse gas emissions from food and agriculture. However, it suggests that industrial ecology's role in climate adaptation will be as an evaluator of adaptation strategies, rather than an originator. [ABSTRACT FROM AUTHOR]

Language is one of the cognitive domains often impaired across many neurodevelopmental disorders. While for some disorders the linguistic deficit is the primary impairment (e.g., specific language impairment, SLI), for others it may accompany broader behavioral problems (e.g., autism). The precise nature of this phenotypic overlap has been the subject of debate. Moreover, several studies have found genetic overlaps across neurodevelopmental disorders. This raises the question of whether these genetic overlaps may correlate with phenotypic overlaps and, if so, in what manner. Here, we apply a genome‐wide approach to the study of the linguistic deficit in SLI, autism spectrum disorder (ASD), and attention deficit/hyperactivity disorder (ADHD). Using a discovery genome‐wide association study of SLI, we generate polygenic risk scores (PRS) in an independent sample which includes children with language impairment, SLI, ASD or ADHD and age‐matched controls and perform regression analyses across groups. The SLI‐trained PRS significantly predicted risk in the SLI case–control group (adjusted R2 = 6.24%; P = 0.024) but not in the ASD or ADHD case‐control groups (adjusted R2 = 0.0004%, 0.01%; P = 0.984, 0.889, respectively) nor for height, used as a negative control (R2 = 0.2%; P = 0.452). Additionally, there was a significant difference in the normalized PRS between children with SLI and children with ASD (common language effect size = 0.66; P = 0.044). Our study suggests no additive common‐variant genetic overlap between SLI and ASD and ADHD. This is discussed in the context of phenotypic studies of SLI and related disorders. Autism Res 2020, 13: 369–381. © 2019 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. Lay Summary: Language deficits are characteristic of specific language impairment (SLI), but may also be found in other neurodevelopmental disorders, such as autism spectrum disorder (ASD) and attention deficit/hyperactivity disorder (ADHD). Many studies examined the overlaps and differences across the language deficits in these disorders, but few studies have examined the genetic aspect thereof. In this study, we use a genome‐wide approach to evaluate whether common genetic variants increasing risk of SLI may also be associated with ASD and ADHD in the same manner. Our results suggest that this is not the case, and we discuss this finding in the context of theories concerning the etiologies of these disorders. [ABSTRACT FROM AUTHOR]

Osteoarthritis is common following anterior cruciate ligament reconstruction (ALCR), and aberrant gait biomechanics are considered a primary contributor. Somatosensory dysfunction potentially alters gait biomechanics, but this association is unclear. Therefore, the purposes of this investigation were to compare somatosensory function between limbs and evaluate associations between somatosensory function and gait biomechanics linked to osteoarthritis development in individuals with ALCR. Seventy‐three volunteers with ALCR participated. Gait biomechanics (peak vertical ground reaction force magnitude and loading rate, peak internal knee extension and valgus moments, peak knee flexion and varus angles, and quadriceps/hamstrings co‐activation) were assessed as subjects walked at their preferred speed. The somatosensory function was assessed via joint position sense error (knee flexion) and vibratory perception threshold (femoral epicondyles, malleoli, and first metatarsal). Though somatosensory function did not differ between the ACLR and contralateral limbs, poorer joint position sense in the ACLR limb was associated with lower loading rates and internal knee extension moments, and greater co‐activation. Poorer vibratory perception at the medial and lateral malleoli and first metatarsal head in the ACLR limb was associated with lower loading rates, greater internal knee valgus moments and varus angles, and greater co‐activation. Poorer vibratory perception at the medial malleolus and first metatarsal head in the contralateral limb was associated with greater peak knee varus angles and internal knee valgus moments. These results suggest that future research evaluating rehabilitation approaches for improving somatosensory function is warranted as a potential approach for restoring normal gait biomechanics and reducing osteoarthritis risk. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:620–628, 2020 [ABSTRACT FROM AUTHOR]

Objective: The home environment provided by the caregivers of a child is an influential single factor for development and well‐being. We aimed to compare the quality of the home environment of children at familial high risk of schizophrenia or bipolar disorder with population‐based controls. Methods: Danish nationwide registers were used to retrieve a cohort of 522 7‐year‐old children of parents diagnosed with schizophrenia (N = 202), bipolar disorder (N = 120) or none of these diagnoses (N = 200). The home environment was assessed using the Middle Childhood‐Home Observation for Measurement of the Environment Inventory (MC‐HOME Inventory). Results: The proportion of children living in home environments that were evaluated not to meet the needs of a 7‐year‐old child was significantly larger in the two familial high‐risk groups. This was true for 21% of the children with familial predisposition for schizophrenia and 7% of children with familial disposition for bipolar disorder. Conclusion: Children born to parents diagnosed with schizophrenia and to a lesser extent bipolar disorder are at an increased risk of growing up in a home environment with an insufficient level of stimulation and support. Identifying families with inadequate home environments is a necessary step towards specialized help and support to at‐risk families. [ABSTRACT FROM AUTHOR]

Sensitive detection of protein aggregates is important for evaluating the quality of biopharmaceuticals and detecting misfolded proteins in several neurodegenerative diseases. However, it is challenging to detect extremely low concentrations (<10 ppm) of aggregated protein in the presence of high concentrations of soluble protein. Glucagon, a peptide hormone used in the treatment of extreme hypoglycemia, is aggregation‐prone and forms amyloid fibrils. Detection of glucagon fibrils using conformation‐specific antibodies is an attractive approach for identifying such aggregates during process and formulation development. Therefore, we have used yeast surface display and magnetic‐activated cell sorting to sort single‐chain antibody libraries to identify antibody variants with high conformational specificity for glucagon fibrils. Notably, we find several high‐affinity antibodies that display excellent selectivity for glucagon fibrils, and we have integrated these antibodies into a sensitive immunoassay. Surprisingly, the sensitivity of our assay—which involves direct (nonantibody mediated) glucagon immobilization in microtiter plates—can be significantly enhanced by pretreating the microtiter plates with various types of globular proteins before glucagon immobilization. Moreover, increased total concentrations of glucagon peptide also significantly improve the sensitivity of our assay, which appears to be due to the strong seeding activity of immobilized fibrils at high glucagon concentrations. Our final assay is highly sensitive (fibril detection limit of ~0.5–1 ppm) and is >20 times more sensitive than detection using a conventional, amyloid‐specific fluorescent dye (Thioflavin T). We expect that this type of sensitive immunoassay can be readily integrated into the drug development process to improve the generation of safe and potent peptide therapeutics. [ABSTRACT FROM AUTHOR]

Summary: In this crystal ball, we discuss emerging methodologies that can help reaching a synthesis on the biodiversity of Archaea and Bacteria and thereby inform a central enigma in microbiology, i.e. the fundamental split between these primary domains of life and the apparent lower diversity of the Archaea. [ABSTRACT FROM AUTHOR]

Several long non‐coding RNAs (lncRNAs) act as regulators of cellular homeostasis; however, few of these molecules were functionally characterized in a mature human tissue environment. Here, we report that the lncRNA LINC00941 is a crucial regulator of human epidermal homeostasis. LINC00941 is enriched in progenitor keratinocytes and acts as a repressor of keratinocyte differentiation. Furthermore, LINC00941 represses SPRR5, a previously uncharacterized molecule, which functions as an essential positive regulator of keratinocyte differentiation. Interestingly, 54.8% of genes repressed in SPRR5‐deficient epidermal tissue are induced in LINC00941‐depleted organotypic epidermis, suggesting a common mode of action for both molecules. Synopsis: lncRNA LINC00941 inhibits premature differentiation in weakly differentiated strata of the human epidermis through repression of previously uncharacterized SPRR5, shown here to promote keratinocyte differentiation. The lncRNA LINC00941 regulates human epidermal homeostasis.SPRR5 functions as an essential positive regulator of keratinocyte differentiation.LINC00941 and SPRR5 conversely regulate a common set of target genes. lncRNA LINC00941 inhibits premature differentiation in weakly differentiated strata of the human epidermis through repression of previously uncharacterized SPRR5, shown here to promote keratinocyte differentiation. [ABSTRACT FROM AUTHOR]

The study sought to determine the association between gait biomechanics (vertical ground reaction force [vGRF], vGRF loading rate [vGRF‐LR]) collected 6 months following anterior cruciate ligament reconstruction (ACLR) with patient‐reported outcomes at 12 months following ACLR. Walking gait biomechanics and all subsections of the Knee Injury and Osteoarthritis Outcomes Score (KOOS) were collected at 6 and 12 months following ACLR, respectively, in 25 individuals with a unilateral ACLR. Peak vGRF and peak instantaneous vGRF‐LR were extracted from the first 50% of the stance phase. Limb symmetry indices (LSI) were used to normalize outcomes in the ACLR limb to that of the uninjured limb (ACLR/uninjured). Linear regression analyses were used to determine associations between biomechanical outcomes and KOOS while accounting for walking speed. Receiver operator characteristic curves were used to determine the accuracy of 6‐month biomechanical outcomes for identifying individuals with acceptable patient‐reported outcomes, using previously defined KOOS cut‐off scores, 12 months post‐ACLR. Individuals with lower peak vGRF LSI 6 months post‐ACLR demonstrated worse patient‐reported outcomes (KOOS Pain, Activities of Daily life, Sport and Recreation, Quality of Life) at the 12‐month exam. A peak vGRF LSI ≥0.99 6 months following ACLR associated with 13.33× higher odds of reporting acceptable patient‐reported outcomes 12 months post‐ACLR. Lesser peak vGRF LSI during walking at 6‐months post‐ACLR may be a critical indicator of worse future patient‐reported outcomes. Clinical significance achieving early symmetrical lower extremity loading and minimizing under‐loading of the ACLR limb during walking may be a potential therapeutic target for improving patient‐reported outcomes post‐ACLR. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2932–2940, 2018. [ABSTRACT FROM AUTHOR]

The synthetic pathway to the functional phosphonium cation [Cy3PCHCl2]+ (3) has been evaluated by using in situ 31P NMR spectroscopy and mass spectrometry. The synthesis is only successful if CCl4/CHCl3 mixtures are used. A mechanism for the varying reactivity in different solvents is given as well as a mechanism for the observed equilibrium between ions [Cy3PCHCl2]+ and [Cy3PCH2Cl]+ (12). Through the anticipated hydrogen bonding interaction between [Cy3PCHCl2]+ and the corresponding anion, crystal structures of the compounds [Cy3PCHCl2]Cl·2CHCl3 (3a) and [Cy3PCHCl2]3[H3O][H5O2]Cl5·C6D6 (3b) could be obtained and evaluated. [ABSTRACT FROM AUTHOR]

Objective: To determine whether walking speed, collected at 6 and 12 months following anterior cruciate ligament reconstruction (ACLR), is associated with inter-extremity differences in proteoglycan density, measured via T1ρ magnetic resonance imaging, in tibiofemoral articular cartilage 12 months following ACLR.Methods: Twenty-one individuals with a unilateral patellar-tendon autograft ACLR (10 women and 11 men, mean ± SD age 23.9 ± 2.7 years, mean ± SD body mass index 23.9 ± 2.7 kg/m2 ) were recruited for participation in this study. Walking speed was collected using 3-dimensional motion capture at 6 and 12 months following ACLR. The articular cartilage of the medial femoral condyle (MFC) and lateral femoral condyle and medial and lateral tibial condyles was manually segmented and subsectioned into 3 regions of interest (anterior, central, and posterior) based on the location of the meniscus in the sagittal plane. Inter-extremity mean T1ρ relaxation time ratios (T1ρ ACLR extremity / T1ρ contralateral extremity) were calculated and used for analysis. Pearson product-moment correlations were used to determine associations between walking speed and inter-extremity differences in T1ρ relaxation time ratios.Results: Slower walking speed 6 months post-ACLR was significantly associated with higher T1ρ relaxation time ratios in the MFC of the ACLR extremity 12 months following ACLR (posterior MFC, r = -0.51, P = 0.02; central MFC, r = -0.47, P = 0.04). Similarly, slower walking speed at 12 months post-ACLR was significantly associated with higher T1ρ relaxation time ratios in the posterior MFC ACLR extremity (r = -0.47, P = 0.04) 12 months following ACLR.Conclusion: Slower walking speed at 6 and 12 months following ACLR may be associated with early proteoglycan density changes in medial femoral compartment cartilage health in the first 12 months following ACLR. [ABSTRACT FROM AUTHOR]

ABSTRACT Musculoskeletal injuries in pediatric patients are on the rise, including significant increases in anterior cruciate ligament (ACL) injuries. Previous studies have found major anatomical changes during skeletal growth in the soft tissues of the knee. Specifically, the ACL and the posterior cruciate ligament (PCL) change in their relative orientation to the tibial plateau throughout growth. In order to develop age-specific treatments for ACL injuries, the purpose of this study was to characterize orientation changes in the cruciate ligaments of the Yorkshire pig, a common pre-clinical model, during skeletal growth in order to verify the applicability of this model for pediatric musculoskeletal studies. Hind limbs were isolated from female Yorkshire pigs ranging in age from newborn to late adolescence and were then imaged using high field strength magnetic resonance imaging. Orientation changes were quantified from the magnetic resonance images using image segmentation software. Statistically significant increases were found in the coronal and sagittal angles of the ACL relative to the tibial plateau during pre-adolescent growth. Additional changes were observed in the PCL angle, Blumensaat angle, intercondylar roof angle, and the aspect ratio of the intercondylar notch. Only the sagittal angle of the ACL relative to the tibial plateau experienced statistically significant changes through late adolescence. The age-dependent properties of the ACL and PCL in the female pig mirrored results found in female human patients, suggesting that the porcine model may provide a pre-clinical platform to study the cruciate ligaments during skeletal growth. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2725-2732, 2017. [ABSTRACT FROM AUTHOR]

Reaktionen von [K(crypt ‐ 222)]2(TlBi3)⋅0.5en (1 b) mit [Ru(cod)(H2CC(Me)CH2)2] (A) in 1,2 ‐ Diaminoethan (en) führten zur Bildung zweier Verbindungen mit neuen, Bi ‐ reichen Clusteranionen, [K(crypt ‐ 222)]3[Bi9{Ru(cod)}2]⋅1.5en (2) und [K(crypt ‐ 222)]2[Tl2Bi6 {Ru(cod)}]⋅2tol (3), sowie zur Bildung des Salzes eines binären nido ‐ Clusters, [K(crypt ‐ 222)]3(Tl4Bi5)⋅2en (4). Die Anionen in 2 und 3 gehören zu den seltenen heterometallischen Clustern mit Ru ‐ Atomen. Da in beiden Fällen je ein cod ‐ Ligand pro Ru ‐ Atom gebunden blieb, lassen sich die Anionen als Intermediate auf dem Weg zur Bildung größerer, Liganden ‐ freier intermetalloider Cluster ansehen. Quantenchemischen Studien zufolge liegen im Anion von 2 elektronenpräzise und elektronendefizitäre Bereiche kombiniert vor. Elektrospray ‐ Ionisations ‐ Massenspektrometrie (ESI ‐ MS) weist auf eine schrittweise Fragmentierung der Cluster hin. Ein bisschen von beidem: DFT ‐ Studien bestätigen eine hybride Bindungssituation in [Bi9{Ru(cod)}2]3− mit lokalisierten neben delokalisierten Bindungen. Dieser Cluster und [Tl2Bi6{Ru(cod)}]2− wurden nach Umsetzung von (TlBi3)2− mit [Ru(cod)(H2CC(Me)CH2)2] erhalten. Beides sind seltene Beispiele für Zintl ‐ Anionen, die Ru ‐ Atome enthalten. Sie illustrieren die elektronische Flexibilität von Gruppe ‐ 15 ‐ Polyanionen mit realen oder pseudo ‐ Atomen anderer Gruppen. [ABSTRACT FROM AUTHOR]

Reactions of [K(crypt-222)]2(TlBi3)⋅0.5 en ( 1 b) with [Ru(cod)(H2CC(Me)CH2)2] ( A) in 1,2-diaminoethane (en) led to the formation of two compounds with new bismuth-rich cluster anions, [K(crypt-222)]3[Bi9{Ru(cod)}2]⋅1.5 en ( 2) and [K(crypt-222)]2[Tl2Bi6{Ru(cod)}]⋅2 tol ( 3), alongside the salt of a binary nido cluster, [K(crypt-222)]3(Tl4Bi5)⋅2 en ( 4). The anions in 2 and 3 are two further examples of rare heterometallic clusters containing Ru atoms. As one cod ligand is retained on each Ru atom in both clusters, the anions may be viewed as intermediates on the way towards larger, ligand-free intermetalloid clusters. Quantum-chemical studies provided insight into the bonding situation in these clusters. According to these studies, the anion of 2 features both electron-precise and electron-deficient parts. Electrospray ionization mass spectrometry analysis indicated that the clusters undergo stepwise fragmentation. [ABSTRACT FROM AUTHOR]

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