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Human papillomaviruses (HPVs) cause most cervical cancers and an increasing number of anogenital and oral carcinomas, with most cases caused by HPV16 or HPV18. HPV hijacks host signalling pathways to promote carcinogenesis. Understanding these interactions could permit identification of much-needed therapeutics for HPV-driven malignancies. The Hippo signalling pathway is important in HPV+ cancers, with the downstream effector YAP playing a pro-oncogenic role. In contrast, the significance of its paralogue TAZ remains largely uncharacterised in these cancers. We demonstrate that TAZ is dysregulated in a HPV-type dependent manner by a distinct mechanism to that of YAP and controls proliferation via alternative cellular targets. Analysis of cervical cancer cell lines and patient biopsies revealed that TAZ expression was only significantly increased in HPV18+ and HPV18-like cells and TAZ knockdown reduced proliferation, migration and invasion only in HPV18+ cells. RNA-sequencing of HPV18+ cervical cells revealed that YAP and TAZ have distinct targets, suggesting they promote carcinogenesis by different mechanisms. Thus, in HPV18+ cancers, YAP and TAZ play non-redundant roles. This analysis identified TOGARAM2 as a previously uncharacterised TAZ target and demonstrates its role as a key effector of TAZ-mediated proliferation, migration and invasion in HPV18+ cancers., (© 2024. The Author(s).)

Human papillomaviruses (HPV) are a major cause of malignancy, contributing to ~5% of all human cancers worldwide, including most cervical cancer cases and a growing number of anogenital and oral cancers. The major HPV viral oncogenes, E6 and E7, manipulate many host cellular pathways that promote cell proliferation and survival, predisposing infected cells to malignant transformation. Despite the availability of highly effective vaccines, there are still no specific anti-viral therapies targeting HPV or treatments for HPV-associated cancers. As such, a better understanding of viral-host interactions may allow the identification of novel therapeutic targets. Here, we demonstrate that the actin-binding protein LASP1 is upregulated in cervical cancer and significantly correlates with a poorer overall survival. In HPV positive cervical cancer, LASP1 depletion significantly inhibited the oncogenic phenotype in vitro, whilst having minimal effects in HPV negative cervical cancer cells. Furthermore, we demonstrate that the LASP1 SH3 domain is essential for LASP1-mediated oncogenicity in these cells. Mechanistically, we show that HPV E7 regulates LASP1 at the post-transcriptional level by repressing the expression of miR-203, which negatively regulates LASP1 mRNA levels by binding to its 3'UTR. Finally, we demonstrate that LASP1 expression is required for the growth of HPV positive cervical cancer cells in an in vivo tumourigenicity model. Together, these data demonstrate that HPV induces LASP1 expression to promote proliferation and survival in cervical cancer, thus identifying a potential therapeutic target in these cancers., (© 2024. The Author(s).)

Human papillomaviruses (HPVs) infect the oral and anogenital mucosa and can cause cancer. The high-risk (HR)-HPV oncoproteins, E6 and E7, hijack cellular factors to promote cell proliferation, delay differentiation and induce genomic instability, thus predisposing infected cells to malignant transformation. cAMP response element (CRE)-binding protein 1 (CREB1) is a master transcription factor that can function as a proto-oncogene, the abnormal activity of which is associated with multiple cancers. However, little is known about the interplay between HPV and CREB1 activity in cervical cancer or the productive HPV lifecycle. We show that CREB is activated in productively infected primary keratinocytes and that CREB1 expression and phosphorylation is associated with the progression of HPV+ cervical disease. The depletion of CREB1 or inhibition of CREB1 activity results in decreased cell proliferation and reduced expression of markers of epithelial to mesenchymal transition, coupled with reduced migration in HPV+ cervical cancer cell lines. CREB1 expression is negatively regulated by the tumor suppressor microRNA, miR-203a, and CREB1 phosphorylation is controlled through the MAPK/MSK pathway. Crucially, CREB1 directly binds the viral promoter to upregulate transcription of the E6/E7 oncogenes, establishing a positive feedback loop between the HPV oncoproteins and CREB1. Our findings demonstrate the oncogenic function of CREB1 in HPV+ cervical cancer and its relationship with the HPV oncogenes., (© 2023 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Persistent infection with high-risk human papillomaviruses (HPVs) is the causal factor in multiple human malignancies, including >99% of cervical cancers and a growing proportion of oropharyngeal cancers. Prolonged expression of the viral oncoproteins E6 and E7 is necessary for transformation to occur. Although some of the mechanisms by which these oncoproteins contribute to carcinogenesis are well-characterised, a comprehensive understanding of the signalling pathways manipulated by HPV is lacking. Here, we present the first evidence to our knowledge that the targeting of a host ion channel by HPV can contribute to cervical carcinogenesis. Through the use of pharmacological activators and inhibitors of ATP-sensitive potassium ion (K ATP ) channels, we demonstrate that these channels are active in HPV-positive cells and that this activity is required for HPV oncoprotein expression. Further, expression of SUR1, which forms the regulatory subunit of the multimeric channel complex, was found to be upregulated in both HPV+ cervical cancer cells and in samples from patients with cervical disease, in a manner dependent on the E7 oncoprotein. Importantly, knockdown of SUR1 expression or K ATP channel inhibition significantly impeded cell proliferation via induction of a G1 cell cycle phase arrest. This was confirmed both in vitro and in in vivo tumourigenicity assays. Mechanistically, we propose that the pro-proliferative effect of K ATP channels is mediated via the activation of a MAPK/AP-1 signalling axis. A complete characterisation of the role of K ATP channels in HPV-associated cancer is now warranted in order to determine whether the licensed and clinically available inhibitors of these channels could constitute a potential novel therapy in the treatment of HPV-driven cervical cancer., (© 2023. The Author(s).)

The epitranscriptomic modification N 6 -methyladenosine (m 6 A) is a ubiquitous feature of the mammalian transcriptome. It modulates mRNA fate and dynamics to exert regulatory control over numerous cellular processes and disease pathways, including viral infection. Kaposi's sarcoma-associated herpesvirus (KSHV) reactivation from the latent phase leads to the redistribution of m 6 A topology upon both viral and cellular mRNAs within infected cells. Here we investigate the role of m 6 A in cellular transcripts upregulated during KSHV lytic replication. Our results show that m 6 A is crucial for the stability of the GPRC5A mRNA, whose expression is induced by the KSHV latent-lytic switch master regulator, the replication and transcription activator (RTA) protein. Moreover, we demonstrate that GPRC5A is essential for efficient KSHV lytic replication by directly regulating NFκB signalling. Overall, this work highlights the central importance of m 6 A in modulating cellular gene expression to influence viral infection.

Described herein are the synthesis, structure, and photophysics of the iodo-substituted cyclic trinuclear copper(I) complex, Cu 3 [4-I-3,5-(CF 3 ) 2 Pz] 3 supported by a highly-fluorinated pyrazolate in comparison with its previously reported 4-Br/4-Cl analogues. The crystal structure is stabilised by multiple supramolecular interactions of Cu 3 ⋯I and hydrogen/halogen bonding. The photophysical properties and supramolecular interactions are investigated experimentally/computationally for all three 4-halo complexes vis-à-vis relativistic effects.

For the last 40 years, actigraphy or wearable accelerometry has provided an objective, low-burden and ecologically valid approach to assess real-world sleep and circadian patterns, contributing valuable data to epidemiological and clinical insights on sleep and sleep disorders. The proper use of wearable technology in sleep research requires validated algorithms that can derive sleep outcomes from the sensor data. Since the publication of the first automated scoring algorithm by Webster in 1982, a variety of sleep algorithms have been developed and contributed to sleep research, including many recent ones that leverage machine learning and / or deep learning approaches. However, it remains unclear how these algorithms compare to each other on the same data set and if these modern data science approaches improve the analytical validity of sleep outcomes based on wrist-worn acceleration data. This work provides a systematic evaluation across 8 state-of-the-art sleep algorithms on a common sleep data set with polysomnography (PSG) as ground truth. Despite the inclusion of recently published complex algorithms, simple regression-based and heuristic algorithms demonstrated slightly superior performance in sleep-wake classification and sleep outcome estimation. The performance of complex machine learning and deep learning models seem to suffer from poor generalization. This independent and systematic analytical validation of sleep algorithms provides key evidence on the use of wearable digital health technologies for sleep research and care., (© 2023. The Author(s).)

Stepping-based targets such as the number of steps per day provide an intuitive and commonly used method of prescribing and self-monitoring physical activity goals. Physical activity surveillance is increasingly being obtained from wrist-worn accelerometers. However, the ability to derive stepping-based metrics from this wear location still lacks validation and open-source methods. This study aimed to assess the concurrent validity of two versions (1. original and 2. optimized) of the Verisense step-count algorithm at estimating step-counts from wrist-worn accelerometry, compared with steps from the thigh-worn activPAL as the comparator. Participants (n = 713), across three datasets, had >24 h continuous concurrent accelerometry wear on the non-dominant wrist and thigh. Compared with activPAL, total daily steps were overestimated by 913 ± 141 (mean bias ± 95% limits of agreement) and 742 ± 150 steps/day with Verisense algorithms 1 and 2, respectively, but moderate-to-vigorous physical activity (MVPA) steps were underestimated by 2207 ± 145 and 1204 ± 103 steps/day in Verisense algorithms 1 and 2, respectively. In summary, the optimized Verisense algorithm was more accurate in detecting total and MVPA steps. Findings highlight the importance of assessing algorithm performance beyond total step count, as not all steps are equal. The optimized Verisense open-source algorithm presents acceptable accuracy for derivation of stepping-based metrics from wrist-worn accelerometry.

The Verisense Step Count Algorithm facilitates generation of steps from wrist-worn accelerometers. Based on preliminary evidence suggesting a proportional bias with overestimation at low steps/day, but underestimation at high steps/day, the algorithm parameters have been revised. We aimed to establish validity of the original and revised algorithms relative to waist-worn ActiGraph step cadence. We also assessed whether step cadence was similar across accelerometer brand and wrist. Ninety-eight participants (age: 58.6±11.1 y) undertook six walks (~500 m hard path) at different speeds (cadence: 92.9±9.5-127.9±8.7 steps/min) while wearing three accelerometers on each wrist (Axivity, GENEActiv, ActiGraph) and an ActiGraph on the waist. Of these, 24 participants also undertook one run (~1000 m). Mean bias for the original algorithm was -21 to -26.1 steps/min (95% limits of agreement (LoA) ~±65 steps/min) and mean absolute percentage error (MAPE) 17-22%. This was unevenly distributed with increasing error as speed increased. Mean bias and 95%LoA were halved with the revised algorithm parameters (~-10 to -12 steps/min, 95%LoA ~30 steps/min, MAPE ~10-12%). Performance was similar across brand and wrist. The revised step algorithm provides a more valid measure of step cadence than the original, with MAPE similar to recently reported wrist-wear summary MAPE (7-11%).

Non-coding RNA (ncRNA) regulatory networks are emerging as critical regulators of gene expression. These intricate networks of ncRNA:ncRNA interactions modulate multiple cellular pathways and impact the development and progression of multiple diseases. Herpesviruses, including Kaposi's sarcoma-associated herpesvirus, are adept at utilising ncRNAs, encoding their own as well as dysregulating host ncRNAs to modulate virus gene expression and the host response to infection. Research has mainly focused on unidirectional ncRNA-mediated regulation of target protein-coding transcripts; however, we identify a novel host ncRNA regulatory network essential for KSHV lytic replication in B cells. KSHV-mediated upregulation of the host cell circRNA, circHIPK3, is a key component of this network, functioning as a competing endogenous RNA of miR-30c, leading to increased levels of the miR-30c target, DLL4. Dysregulation of this network highlights a novel mechanism of cell cycle control during KSHV lytic replication in B cells. Importantly, disruption at any point within this novel ncRNA regulatory network has a detrimental effect on KSHV lytic replication, highlighting the essential nature of this network and potential for therapeutic intervention., (© 2022 The Authors. Published under the terms of the CC BY 4.0 license.)

A series of DOSY experiments have been carried out to determine the solution stoichiometry of silver(I) 3,5-bis (trifluoromethyl)pyrazolate species. This compound exists as a trimer in the solid state (n = 3) but in solutions of chlorinated solvents, the DOSY data suggest the presence of a mixture of solvent stabilized monomer (n = 1) and dimer (n = 2) in equilibrium. Different approximations have been used including the Stokes-Einstein and the Stokes-Einstein-Gierer-Wirtz equations. Some methodological problems are discussed., (© 2021 John Wiley & Sons, Ltd.)

Homoleptic, tetranuclear copper(I) pyrazolates {[3,5-( t -Bu) 2 Pz]Cu} 4 , {[3-(CF 3 )-5-( t -Bu)Pz]Cu} 4 , and {[4-Br-3,5-( i -Pr) 2 Pz]Cu} 4 are excellent stand-alone catalysts for azide-alkyne cycloaddition reactions (CuAAC). This work demonstrates that a range of pyrazolates, including those with electron donating and electron-withdrawing groups to sterically demanding substituents on the pyrazolyl backbones, can serve as effective ligand supports on tetranuclear copper catalysts. However, in contrast to the tetramers and also highly fluorinated {[3,5-(CF 3 ) 2 Pz]Cu} 3 , trinuclear copper(I) complexes such as {[3,5-( i -Pr) 2 Pz]Cu} 3 and {[3-(CF 3 )-5-(CH 3 )Pz]Cu} 3 supported by relatively electron rich pyrazolates display poor catalytic activity in CuAAC. The behavior and degree of aggregation of several of these copper(I) pyrazolates in solution were examined using vapor pressure osmometry. Copper(I) complexes such as {[3,5-(CF 3 ) 2 Pz]Cu} 3 and {[3-(CF 3 )-5-( t -Bu)Pz]Cu} 4 with electron withdrawing pyrazolates were found to break up in solution to different degrees producing smaller aggregates while those such as {[3,5-( i -Pr) 2 Pz]Cu} 3 and {[3,5-( t -Bu) 2 Pz]Cu} 4 with electron rich pyrazolates remain intact. In addition, kinetic experiments were performed to understand the unusual activity of tetranuclear copper(I) pyrazolate systems.

Human papillomaviruses (HPV) are a major cause of malignancy worldwide, contributing to ~5% of all human cancers including almost all cases of cervical cancer and a growing number of ano-genital and oral cancers. HPV-induced malignancy is primarily driven by the viral oncogenes, E6 and E7, which manipulate host cellular pathways to increase cell proliferation and enhance cell survival, ultimately predisposing infected cells to malignant transformation. Consequently, a more detailed understanding of viral-host interactions in HPV-associated disease offers the potential to identify novel therapeutic targets. Here, we identify that the c-Jun N-terminal kinase (JNK) signalling pathway is activated in cervical disease and in cervical cancer. The HPV E6 oncogene induces JNK1/2 phosphorylation in a manner that requires the E6 PDZ binding motif. We show that blockade of JNK1/2 signalling using small molecule inhibitors, or knockdown of the canonical JNK substrate c-Jun, reduces cell proliferation and induces apoptosis in cervical cancer cells. We further demonstrate that this phenotype is at least partially driven by JNK-dependent activation of EGFR signalling via increased expression of EGFR and the EGFR ligands EGF and HB-EGF. JNK/c-Jun signalling promoted the invasive potential of cervical cancer cells and was required for the expression of the epithelial to mesenchymal transition (EMT)-associated transcription factor Slug and the mesenchymal marker Vimentin. Furthermore, JNK/c-Jun signalling is required for the constitutive expression of HPV E6 and E7, which are essential for cervical cancer cell growth and survival. Together, these data demonstrate a positive feedback loop between the EGFR signalling pathway and HPV E6/E7 expression, identifying a regulatory mechanism in which HPV drives EGFR signalling to promote proliferation, survival and EMT. Thus, our study has identified a novel therapeutic target that may be beneficial for the treatment of cervical cancer.

Protein ubiquitination is a critical regulator of cellular homeostasis. Aberrations in the addition or removal of ubiquitin can result in the development of cancer and key components of the ubiquitination machinery serve as oncogenes or tumour suppressors. An emerging target in the development of cancer therapeutics are the deubiquitinase (DUB) enzymes that remove ubiquitin from protein substrates. Whether this class of enzyme plays a role in cervical cancer has not been fully explored. By interrogating the cervical cancer data from the TCGA consortium, we noted that the DUB USP13 is amplified in ~15% of cervical cancer cases. We confirmed that USP13 expression was increased in cervical cancer cell lines, cytology samples from patients with cervical disease and in cervical cancer tissue. Depletion of USP13 inhibited cervical cancer cell proliferation. Mechanistically, USP13 bound to, deubiquitinated and stabilised Mcl-1, a pivotal member of the anti-apoptotic BCL-2 family. Furthermore, reduced Mcl-1 expression partially contributed to the observed proliferative defect in USP13 depleted cells. Importantly, the expression of USP13 and Mcl-1 proteins correlated in cervical cancer tissue. Finally, we demonstrated that depletion of USP13 expression or inhibition of USP13 enzymatic activity increased the sensitivity of cervical cancer cells to the BH3 mimetic inhibitor ABT-263. Together, our data demonstrates that USP13 is a potential oncogene in cervical cancer that functions to stabilise the pro-survival protein Mcl-1, offering a potential therapeutic target for these cancers.

Persistent infection with high-risk human papillomaviruses (HR-HPVs) is the causal factor in over 99 % of cervical cancer cases, and a significant proportion of oropharyngeal and anogenital cancers. The key drivers of HPV-mediated transformation are the oncoproteins E5, E6 and E7. Together, they act to prolong cell-cycle progression, delay differentiation and inhibit apoptosis in the host keratinocyte cell in order to generate an environment permissive for viral replication. The oncoproteins also have key roles in mediating evasion of the host immune response, enabling infection to persist. Moreover, prolonged infection within the cellular environment established by the HR-HPV oncoproteins can lead to the acquisition of host genetic mutations, eventually culminating in transformation to malignancy. In this review, we outline the many ways in which the HR-HPV oncoproteins manipulate the host cellular environment, focusing on how these activities can contribute to carcinogenesis.

Human papillomaviruses (HPV) are a major cause of malignancy worldwide. They are the aetiological agents of almost all cervical cancers as well as a sub-set of other anogenital and head and neck cancers. Hijacking of host cellular pathways is essential for virus pathogenesis; however, a major challenge remains to identify key host targets and to define their contribution to HPV-driven malignancy. The Hippo pathway regulates epithelial homeostasis by down-regulating the function of the transcription factor YAP. Increased YAP expression has been observed in cervical cancer but the mechanisms driving this increase remain unclear. We found significant down-regulation of the master Hippo regulatory kinase STK4 (also termed MST1) in cervical disease samples and cervical cancer cell lines compared with healthy controls. Re-introduction of STK4 inhibited the proliferation of HPV positive cervical cells and this corresponded with decreased YAP nuclear localization and decreased YAP-dependent gene expression. The HPV E6 and E7 oncoproteins maintained low STK4 expression in cervical cancer cells by upregulating the oncomiR miR-18a, which directly targeted the STK4 mRNA 3'UTR. Interestingly, miR-18a knockdown increased STK4 expression and activated the Hippo pathway, significantly reducing cervical cancer cell proliferation. Our results identify STK4 as a key cervical cancer tumour suppressor, which is targeted via miR-18a in HPV positive tumours. Our study indicates that activation of the Hippo pathway may offer a therapeutically beneficial option for cervical cancer treatment., Competing Interests: The authors have declared that no competing interests exist.

Increasing ocean temperatures have widespread consequences for coral reefs, one of which is coral bleaching. We analyzed a global network of associations between coral species and Symbiodiniaceae for resistance to temperature stress and robustness to perturbations. Null networks were created by changing either the physiological parameters of the nodes or the structures of the networks. We developed a bleaching model in which each link, association, is given a weight based on temperature thresholds for specific host-symbiont pairs and links are removed as temperature increases. Resistance to temperature stress was determined from the response of the networks to the bleaching model. Ecological robustness, defined by how much perturbation is needed to decrease the number of nodes by 50%, was determined for multiple removal models that considered traits of the hosts, symbionts, and their associations. Network resistance to bleaching and robustness to perturbations differed from the null networks and varied across spatial scales, supporting that thermal tolerances, local association patterns, and environment play an important role in network persistence. Networks were more robust to attacks on associations than to attacks on species. Although the global network was fairly robust to random link removals, when links are removed according to the bleaching model, robustness decreases by about 20%. Specific environmental attacks, in the form of increasing temperatures, destabilize the global network of coral species and Symbiodiniaceae. On a global scale, the network was more robust to removals of links with susceptible Symbiodiniaceae than it was to removals of links with susceptible hosts. Thus, the symbionts convey more stability to the symbiosis than the hosts when the system is under an environmental attack. However, our results also provide evidence that the environment of the networks affects robustness to link perturbations. Our work shows that ecological resistance and robustness can be assessed through network analysis that considers specific biological traits and functional weaknesses. The global network of associations between corals and Symbiodiniaceae and its distribution of thermal tolerances are non-random, and the evolution of this architecture has led to higher sensitivity to environmental perturbations., (© 2020 The Authors. Ecology published by Wiley Periodicals, Inc. on behalf of Ecological Society of America.)

Objective: In this work, a dense recurrent convolutional neural network (DRCNN) was constructed to detect sleep disorders including arousal, apnea and hypopnea using polysomnography (PSG) measurement channels provided in the 2018 PhysioNet Challenge database., Approach: Our model structure is composed of multiple dense convolutional units (DCU) followed by a bidirectional long-short term memory (LSTM) layer followed by a softmax output layer. The sleep events, including sleep stages, arousal regions and multiple types of apnea and hypopnea, are manually annotated by experts, which enables us to train our proposed network using a multi-task learning mechanism. Three binary cross-entropy loss functions, corresponding to sleep/wake, target arousal and apnea-hypopnea/normal detection tasks, are summed up to generate our overall network loss function that is optimized using the Adam method. Our model performance was evaluated using two metrics: the area under the precision-recall curve (AUPRC) and the area under the receiver operating characteristic curve (AUROC). To measure our model generalization, 4-fold cross-validation was also performed. For training, our model was applied to full night recording data., Main Results: Finally, the average AUPRC and AUROC values associated with the arousal detection task were 0.505 and 0.922, respectively, on our testing dataset. An ensemble of four models trained on different data folds improved the AUPRC and AUROC to 0.543 and 0.931, respectively., Significance: Our proposed algorithm achieved the first place in the official stage of the 2018 PhysioNet Challenge for detecting sleep arousals with an AUPRC of 0.54 on the blind testing dataset.

Coral reefs are degrading through the impacts of multiple anthropogenic stressors. How are coral reef communities going to change and how to protect them for future generations are important conservation questions. Using coral reef data from Mauritius, we examined changes in cover in 23 benthic groups for a 13-yr period and at 15 sites. Moreover, we determined which land-based stressor out of four (human population, agriculture, tourism, rainfall) correlated the most with the observed changes in coral reef cover. Among the stony corals, Acropora corals appeared to be the most impacted, decreasing in cover at many sites. However, the non- Acropora encrusting group increased in cover at several sites. The increase in abundance of dead corals and rubble at some sites also supported the observations of stony coral decline during the study period. Additionally, the decline in stony corals appeared to be more pronounced in second half of the study period for all sites suggesting that a global factor rather than a local factor was responsible for this decline. There was little change in cover for the other benthic groups, some of which were quite rare. Human population was significantly correlated with changes in coral reef cover for 11 sites, followed by tourism and agriculture. Rainfall, a proxy for runoff, did not appear to affect coral reef cover. Overall, our results showed that there has been a decline of stony coral cover especially the ones with complex morphologies, which in turn suggest that coral reefs around Mauritius have experienced a decline in habitat complexity during the study period. Our study also suggests that humans are an important factor contributing to the demise of coral reefs around the island., Competing Interests: The authors declare there are no competing interests.

Coral diseases are a leading factor contributing to the global decline of coral reefs, and yet mechanisms of disease transmission remain poorly understood. This study tested whether zooplankton can act as a vector for white band disease (WBD) in Acropora cervicornis . Natural zooplankton communities were collected from a coral reef in Bocas del Toro, Panama. Half of the zooplankton were treated with antibiotics for 24 h after which the antibiotic-treated and non-antibiotic-treated zooplankton were incubated with either seawater or tissue homogenates from corals exhibiting WBD-like symptoms. A total of 15 of the 30 asymptomatic A. cervicornis colonies exposed to zooplankton incubated in disease homogenate in tank-based experiments showed signs of WBD, regardless of prior antibiotic incubation. These results indicate that in our experimental conditions zooplankton were a vector for coral disease after exposure to disease-causing pathogens. Given the importance of heterotrophy on zooplankton to coral nutrition, this potential mode of disease transmission warrants further investigation., Competing Interests: The authors declare there are no competing interests.

Background: The drop vertical jump (DVJ) task has previously been used to identify movement patterns associated with a number of injury types. However, no current research exists evaluating people with chronic ankle instability (CAI) compared with people coping with lateral ankle sprain (LAS) (referred to as "LAS copers") during this task., Objective: The aim of this study was to identify the coping movement and motor control patterns of LAS copers in comparison with individuals with CAI during the DVJ task., Design: This was a case-control study., Methods: Seventy individuals were recruited at convenience within 2-weeks of sustaining a first-time acute LAS injury. One year following recruitment, these individuals were stratified into 2 groups: 28 with CAI and 42 LAS copers. They attended the testing laboratory to complete a DVJ task. Three-dimensional kinematic and sagittal-plane kinetic profiles were plotted for the lower extremity joints of both limbs for the drop jump phase (phase 1) and drop landing phase (phase 2) of the DVJ. The rate of impact modulation relative to body weight during both phases of the DVJ also was determined., Results: Compared with LAS copers, participants with CAI displayed significant increases in hip flexion on their "involved" limb during phase 1 of the DVJ (23° vs 18°) and bilaterally during phase 2 (15° vs 10°). These movement patterns coincided with altered moment-of-force patterns at the hip on the "uninvolved" limb., Limitations: It is unknown whether these movement and motor control patterns preceded or occurred as a result of the initial LAS injury., Conclusions: Participants with CAI displayed hip-centered changes in movement and motor control patterns during a DVJ task compared with LAS copers. The findings of this study may give an indication of the coping mechanism underlying outcome following initial LAS injury., (© 2016 American Physical Therapy Association.)

The purpose of this work is to compare temporal gait parameters from three different IMU locations to the gold standard force platform. 33 subjects (12 F, 21 M) performed twenty gait trials each while wearing inertial measurement units (IMUs) on the trunk, both shanks and both feet. Data was simultaneously collected from a laboratory embedded force plate. Step times were derived from the raw IMU data at the three IMU locations using methods that have been shown to be accurate. Step times from all locations were valid compared to the force plate. Foot IMU step time was the most accurate (Pearson = .991, CI width = 3.00e2), the trunk IMU was the next most accurate (Pearson = .974, CI width = 4.85e2) and shank step time was the least accurate (Pearson = .958, CI width = 6.80e2). All three sensing locations result in valid estimations of step time compared to the gold standard force plate. These results suggest that the foot location would be most appropriate for clinical applications where very precise temporal parameter detection is required.

Introduction: Longitudinal analyses of participants with a history of lateral ankle sprain are lacking. This investigation combined measures of lower limb interjoint coordination and stabilometry to evaluate static unipedal stance with the eyes open (condition 1) and closed (condition 2) in a group of participants with chronic ankle instability (CAI) compared to lateral ankle sprain "copers" (both recruited 12 months after sustaining an acute first-time lateral ankle sprain) and a group of noninjured controls., Methods: Twenty-eight participants with CAI, 42 lateral ankle sprain "copers," and 20 noninjured controls completed three 20-s single-limb stance trials in conditions 1 and 2. An adjusted coefficient of multiple determination statistic was used to compare stance limb three-dimensional kinematic data for similarity to establish patterns of interjoint coordination. The fractal dimension of the stance limb center of pressure path was also calculated., Results: Between-group analyses revealed that participants with CAI displayed notable increases in ankle-hip linked coordination compared with both lateral ankle sprain "copers" (-0.52 (1.05) vs 0.28 (0.9), P = 0.007) and controls (-0.52 (1.05) vs 0.63 (0.64), P = 0.006) in condition 1 and compared with controls only (0.62 (1.92) vs 0.1 (1.0) P = 0.002) in condition 2. Participants with CAI also exhibited a decrease in the fractal dimension of the center-of-pressure path during condition 2 compared with both controls and lateral ankle sprain "copers.", Conclusions: Participants with CAI present with a hip-dominant strategy of eyes-open and eyes-closed static unipedal stance. This coincided with reduced complexity of the stance limb center of pressure path in the eyes-closed condition.

To evaluate the adaptive movement and motor control patterns of a group with a 6-month history of first-time lateral ankle sprain (LAS) injury during a drop vertical jump (DVJ) task. Fifty-one participants with a 6-month history of first-time acute LAS injury and twenty controls performed a DVJ task. 3D kinematic and sagittal plane kinetic profiles were plotted for the lower extremity joints of both limbs for the drop jump (phase 1) and drop landing (phase 2) phases of the DVJ. Inter-limb symmetry and the rate of impact modulation (RIM) relative to bodyweight (BW) during both phases of the DVJ were also determined. LAS participants displayed bilateral increases in knee flexion and an increase in ankle inversion during phases 1 and 2, respectively. They also displayed reduced ankle plantar flexion on their injured limb during both phases of the DVJ (p < 0.05); increased inter-limb asymmetry of RIM was noted for both phases of the DVJ, while the moment-of-force profile exhibited bilaterally greater hip extensor dominance during phase 1. Participants with a 6-month history of first-time LAS display some movement patterns consistent with those observed in chronic ankle instability populations during similar tasks., (© 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc.)

The role of cognition is becoming increasingly central to our understanding of the complexity of walking gait. In particular, higher-level executive functions are suggested to play a key role in gait and fall-risk, but the specific underlying neurocognitive processes remain unclear. Here, we report two experiments which investigated the cognitive and neural processes underlying older adult gait and falls. Experiment 1 employed a dual-task (DT) paradigm in young and older adults, to assess the relative effects of higher-level executive function tasks (n-Back, Serial Subtraction and visuo-spatial Clock task) in comparison to non-executive distracter tasks (motor response task and alphabet recitation) on gait. All DTs elicited changes in gait for both young and older adults, relative to baseline walking. Significantly greater DT costs were observed for the executive tasks in the older adult group. Experiment 2 compared normal walking gait, seated cognitive performances and concurrent event-related brain potentials (ERPs) in healthy young and older adults, to older adult fallers. No significant differences in cognitive performances were found between fallers and non-fallers. However, an initial late-positivity, considered a potential early P3a, was evident on the Stroop task for older non-fallers, which was notably absent in older fallers. We argue that executive control functions play a prominent role in walking and gait, but the use of neurocognitive processes as a predictor of fall-risk needs further investigation.

This paper describes three retrospective case studies to illustrate the potential clinical value of a system capable of capturing objective gait metrics and environment data from older adults with a history of falls while they go about their daily lives. Participants in this study wore an inertial sensor above each ankle and a wearable camera around their neck for seven consecutive days. Selected metrics are presented to illustrate scenarios where the data collected by the system could be of clinical value. Evidence suggests that obtaining objective gait metrics and environment data from older adults may not only allow healthcare professionals to assess gait more accurately, but also to design treatment plans and falls prevention strategies that are more specifically tailored to each individual.

This paper presents an initial overview of insights gained into how older adults mobilize in the home and community, based on data from inertial sensors which were worn by study participants over a 7-day period. The addition of a wearable camera provided additional contextual information which can be used to assess mobility and understand the factors that influence it in the free living environment. Seven days of data collected from a group of older adults who had experienced one or more falls in the previous six months was compared to that of a control group with no history of falling. Results showed that both groups spent relatively little time walking in challenging environmental conditions, and that the fallers spent significantly less time walking under regular conditions (no effect on gait) and outdoors. Analysis of gait metrics showed that the fallers were slightly slower in general, and more noticeable differences were observed when the participants were regrouped according to mobility levels determined from baseline assessments using traditional methods.

Background: Recent work has shown that anterior cruciate ligament reconstructed patients exhibit an increased peak knee adduction moment during walking gait compared to healthy controls. An increased peak knee adduction moment has been suggested to be a potential mechanism of degeneration for knee osteoarthritis. The few studies in this area have not considered an exclusively female anterior cruciate ligament reconstructed group. This study tested the hypothesis that female anterior cruciate ligament-reconstructed patients would have higher peak knee adduction moments than controls., Methods: Peak knee adduction moment during walking was compared between a group of anterior cruciate ligament reconstructed females and a group of female activity matched controls over ten 15m walking trials in a laboratory at a self-selected pace., Findings: Peak knee adduction moment was lower for the anterior cruciate ligament reconstructed group (N = 17, M = 0.31 Nm/kg · m, SD = 0.08) than for the control group (N = 17, M = 0.41 Nm/kg · m, SD = 0.12; t(32) = 2.483, p = 0.010, one-tailed, eta squared effect size = 0.16)., Interpretation: A group of female anterior cruciate ligament reconstructed subjects did not exhibit a gait characteristic which has been suggested to be associated with knee osteoarthritis development and has been shown to be present in male and mixed sex anterior cruciate ligament reconstructed populations previously., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The use of inertial sensors to characterize pathological gait has traditionally been based on the calculation of temporal and spatial gait variables from inertial sensor data. This approach has proved successful in the identification of gait deviations in populations where substantial differences from normal gait patterns exist; such as in Parkinsonian gait. However, it is not currently clear if this approach could identify more subtle gait deviations, such as those associated with musculoskeletal injury. This study investigates whether additional analysis of inertial sensor data, based on quantification of gyroscope features of interest, would provide further discriminant capability in this regard. The tested cohort consisted of a group of anterior cruciate ligament reconstructed (ACL-R) females and a group of non-injured female controls, each performed ten walking trials. Gait performance was measured simultaneously using inertial sensors and an optoelectronic marker based system. The ACL-R group displayed kinematic and kinetic deviations from the control group, but no temporal or spatial deviations. This study demonstrates that quantification of gyroscope features can successfully identify changes associated with ACL-R gait, which was not possible using spatial or temporal variables. This finding may also have a role in other clinical applications where small gait deviations exist.

The objective of this work is to develop an understanding of the relationship between mobility metrics obtained outside of the clinic or laboratory and the context of the external environment. Ten subjects walked with an inertial sensor on each shank and a wearable camera around their neck. They were taken on a thirty minute walk in which they mobilized over the following conditions; normal path, busy hallway, rough ground, blind folded and on a hill. Stride time, stride time variability, stance time and peak shank rotation rate during swing were calculated using previously published algorithms. Stride time was significantly different between several of the conditions. Technological advances mean that gait variables can now be captured as patients go about their daily lives. The results of this study show that the external environment has a significant impact on the quality of gait metrics. Thus, context of external walking environment is an important consideration when analyzing ambulatory gait metrics from the unsupervised home and community setting.

Background: Previous research has used time to stabilization (TTS) from forward landing tasks to assess dynamic postural stability in ACL reconstructed (ACLR) athletes in order to identify impaired sensorimotor control and mechanical stability. This may not be an appropriate test due to the fact that research has suggested that ACL injury has a multi-planar mechanism of injury. The purpose of the present study was to compare TTS values from a forward land and a diagonal land to determine if diagonal landing TTS values are more sensitive to dynamic postural stability deficits in female ACLR athletes., Methods: A group of ACL reconstructed female athletes and a group of female control athletes performed three forward lands and three diagonal lands onto a force-plate and remained still on one foot for 15s. TTS was calculated for the anterior-posterior and medial-lateral ground reaction forces as well as the resultant vector of both forces., Results: All three TTS values were significantly increased in the ACLR group from the control group for the diagonal landing task. There was no difference in TTS values between the groups for the forward landing task., Conclusion: TTS values from a diagonal landing are more sensitive at detecting impaired dynamic postural stability in a group of female ACLR athletes compared to TTS values from a forward land., Level of Evidence: III - Casecontrolled study., (Copyright © 2013 Elsevier B.V. All rights reserved.)

The purpose of this study is to investigate how data from a foot mounted accelerometer can be used to detect motor pattern healthy subjects performed walking trails under two different conditions; normal and stiff ankle walking. Lower body kinematic data were collected as well as accelerometer data from both feet. An algorithm is presented which quantifies relevant swing phase characteristics from the foot accelerometer. Peak total acceleration during initial swing was significantly higher in the stiff ankle condition (M = 33.10, SD = 5.12) than in the normal walking condition (M = 29.47, SD = 5.75; t(7) = 4.32, p = .003, two-tailed). There was a large effect size (eta squared = 0.853). Time between peak acceleration during initial swing to foot strike was significantly shorter in the stiff ankle condition (M = 0.42, SD = 0.02) than in the normal condition (M = 0.44, SD = 0.03; t(7) = -2.54, p = .039, two- tailed). There was a large effect size (eta squared = 0.693). Simple to process metrics from tri-axial accelerometer data on the foot show potential to detect changes in ankle kinematic patterns.

The purpose of this research was to compare different adaptive algorithms in terms of their ability to determine temporal gait parameters based on data acquired from inertial measurement units (IMUs). Eight subjects performed 25 walking trials over a force plate under five different conditions; normal, fast, slow, simulated stiff ankle and simulated stiff knee walking. Data from IMUs worn on the shanks and on the feet were used to identify temporal gait features using three different adaptive algorithms (Green, Selles & Sabatini). Each method's ability to estimate temporal events was compared to the gold standard force plate method for stance time (Greene, r= .990, Selles, r= 0.865, Sabatini, r= 0.980) and double support time (Greene, r= .837, Selles, r= .583, Sabatini, r= .745). The Greene method of estimating gait events from inertial sensor data resulted in the most accurate stance and double support times.

The variability of most environments taxes foraging decisions by increasing the uncertainty of the information available. One solution to the problem is to use dynamic averaging, as do some granivores and carnivores. Arguably, the same strategy could be useful for grazing herbivores, even though their food renews and is more homogeneously distributed. Horses (Equus callabus) were given choices between variable patches after short or long delays. When patch information was current, horses returned to the patch that was recently best, whereas those without current information matched choices to the long-term average values of the patches. These results demonstrate that a grazing species uses dynamic averaging and indicate that, like granivores and carnivores, they can use temporal weighting to optimize foraging decisions., (Copyright 2005 APA, all rights reserved.)

Because of the inherent inefficiency of jet propulsion, squid are considered to be at a competitive disadvantage compared with fishes, which generally depend on forms of undulatory/oscillatory locomotion. Some squid, such as the brief squid Lolliguncula brevis, swim at low speeds in shallow-water complex environments, relying heavily on fin activity. Consequently, their swimming costs may be lower than those of the faster, more pelagic squid studied previously and competitive with those of ecologically relevant fishes. To examine aerobic respiratory swimming costs, O(2) consumption rates were measured for L. brevis of various sizes (2-9 cm dorsal mantle length, DML) swimming over a range of speeds (3-30 cm s(-1)) in swim tunnel respirometers, while their behavior was videotaped. Using kinematic data from swimming squid and force data from models, power curves were also generated. Many squid demonstrated partial (J-shaped) or full (U-shaped) parabolic patterns of O(2) consumption rate as a function of swimming speed, with O(2) consumption minima at 0.5-1.5 DML s(-1). Power curves derived from hydrodynamic data plotted as a function of swimming speed were also parabolic, with power minima at 1.2-1.7 DML s(-1). The parabolic relationship between O(2) consumption rate/power and speed, which is also found in aerial flyers such as birds, bats and insects but rarely in aquatic swimmers because of the difficulties associated with low-speed respirometry, is the result of the high cost of generating lift and maintaining stability at low speeds and overcoming drag at high speeds. L. brevis has a lower rate of O(2) consumption than the squid Illex illecebrosus and Loligo opalescens studied in swim tunnel respirometers and is energetically competitive (especially at O(2) consumption minima) with fishes, such as striped bass, mullet and flounder. Therefore, the results of this study indicate that, like aerial flyers, some negatively buoyant nekton have parabolic patterns of O(2) consumption rate/power as a function of speed and that certain shallow-water squid using considerable fin activity have swimming costs that are competitive with those of ecologically relevant fishes.

Although squid are among the most versatile swimmers and rely on a unique locomotor system, little is known about the swimming mechanics and behavior of most squid, especially those that swim at low speeds in inshore waters. Shallow-water brief squid Lolliguncula brevis, ranging in size from 1.8 to 8.9 cm in dorsal mantle length (DML), were placed in flumes and videotaped, and the data were analyzed using motion-analysis equipment. Flow visualization and force measurement experiments were also performed in water tunnels. Mean critical swimming speeds (U(crit)) ranged from 15.3 to 22.8 cm s(-1), and mean transition speeds (U(t); the speed above which squid swim exclusively in a tail-first orientation) varied from 9.0 to 15.3 cm s(-1). At low speeds, negatively buoyant brief squid generated lift and/or improved stability by positioning the mantle and arms at high angles of attack, directing high-speed jets downwards (angles >50 degrees ) and using fin activity. To reduce drag at high speeds, the squid decreased angles of attack and swam tail-first. Fin motion, which could not be characterized exclusively as drag- or lift-based propulsion, was used over 50-95 % of the sustained speed range and provided as much as 83.8 % of the vertical and 55.1 % of the horizontal thrust. Small squid (<3.0 cm DML) used different swimming strategies from those of larger squid, possibly to maximize thrust benefits from vortex ring formation. Furthermore, brief squid employed various unsteady behaviors, such as manipulating funnel diameter during jetting, altering arm position and swimming in different orientations, to boost swimming performance. These results demonstrate that locomotion in slow-swimming squid is complex, involving intricate spatial and temporal interactions between the mantle, fins, arms and funnel.

Chemical engineering theory can be used in accounting for the broad range of metabolic scaling exponents found in some aquatic invertebrates and algae. Delivery of metabolically important compounds to these organisms occurs by diffusion through a boundary layer. Dimensionless relations (Sherwood-Reynolds number functions) demonstrate the degree to which water motion and organism size affect mass transfer, and ultimately, metabolic rate. Derivation of mass exponents in the range 0.31 to 1.25 for simple geometries such as plates, spheres, and cylinders directly follows from knowledge of the Sherwood-Reynolds number relations. The range of exponents predicted is that found by allometric studies of metabolic rate in these organisms.

Measurements of flow patterns and water velocities inside the oral cavity of blackfish (Orthodon microlepidotus), made with a fiberoptic endoscope and thermistor flow probe, revealed that gill-arch structures act in blackfish as barriers that direct particle-laden water to the mucus-covered roof of the oral cavity, where particles are retained. Gill-arch structures have previously been assumed to be the site of particle retention in suspension-feeding fishes. Water does not pass between these structures in blackfish, and they do not serve as filters that separate particles from the water. These results emphasize the importance of directly assessing flow velocity and direction inside the oral cavity of vertebrate suspension feeders, particularly at the level of the filtering elements.

Feeding rate in the octocoral, Alcyonium siderium, was investigated as a function of colony size, flow speed, and prey concentration. The feeding rate decreases with time in high prey concentrations. A model of passive suspension feeding is formulated that successfully predicts feeding behavior. At low prey concentrations, the model predicts a linear feeding response as particle flux or colony size increases. The dominant constraint on feeding is the "handling time" required to transfer prey from tentacle to pharynx and to re-extend the tentacle. The time constant of prey capture shows no relation to particle flux, in agreement with the model. Another constraint, the "filtration time," is inversely related to colony size and flow speed. Filtration time becomes important only during feeding in sparse prey concentrations, when feeding rate is proportional to flow speed, colony size, and prey concentration. In the field, Alcyonium colonies reduce filtration time by orienting at right angles to the dominant flow direction. Feeding efficiency on prey patches is low and inversely related to flow speed, colony size, and prey concentration. Feeding in patches is not a simple process for this octocoral, because colonies will "saturate" with prey before all polyps have successfully captured a single prey item.

Particle capture by individual polyps and tentacles of the octocoral, Alcyonium siderium, was investigated in flows of different speed and turbulence intensity. In low flow (Umean = 2.7 cm/s; u' = 1.2 cm/s, where u' is the root mean square of the fluctuations from Umean), tentacles on the upstream side of a polyp capture the most prey. In intermediate flow (Umean = 12.2 cm/s; u' = 6.0 cm/s), downstream tentacles within a polyp catch the most prey. In high flow (Umean = 19.8 cm/s; u'= 4.0 cm/s), polyps are bent downstream, eddies form over the tentacular surfaces, and the capture distribution over tentacles becomes radially symmetric. At all flow speeds tested, particles are caught with increasing frequency nearer the tip of the tentacle relative to locations near the pharynx. At the highest flow speed tested, no particles are caught on the segment of each tentacle closest to the pharynx. The per polyp capture efficiency is low and drops markedly with increasing Reynolds number. The capture mechanism for this species appears to be direct interception; inertial impaction is shown to be unimportant. Flow modulation of particle capture by polyps is probably a general phenomenon among octocorals.

The Protein Fractionation Centre has been using the Limulus Amoebocyte Lysate test for detecting the presence of pyrogens for some five years. All tests on final plasma products have been carried out in parallel with the EP rabbit pyrogen test. Good correlation between both tests has been obtained with products such as distilled water and crystalloid solutions. However, it is more difficult to correlate results when dealing with plasma proteins. Each product appears to react differently. Some normally pass the limulus test undiluted while others, such as immune globulins and albuminoid products, have to be diluted to various concentrations before they pass. A preliminary statistical analysis has been carried out on the results of pyrogen testing on Stable Plasma Protein Solution, firstly to ascertain that a significant correlation does exist between the LAL test and the rabbit test, and secondly to try to obtain "cut off" values for the limulus test which compare well with the official EP temperature rises in the rabbit test.

Two techniques, focal spot projection and fringe projection, have been developed for profiling the edges of anterior-chamber style intraocular lenses (IOL). The techniques are based on measurement of the trajectory of reflected light when an incident beam is focused and stepped across the edge surface (spot projection) or when two focused beams combine to form an optical interference pattern on the edge (fringe projection). The optical configurations for performing the projection techniques are described along with the mathematical relationship between the reflected-beam trajectories and the edge profile. An automated system for the implementation of focal spot projection was developed. The system has the capability of positioning the IOL edge at the focal point of the incident beam, acquiring trajectory data via stepper motors and a TV camera, processing the data to generate a profile, and displaying the profile on the computer video monitor or in hard-copy form via a printer. On one lens tested, three profiles corresponding to different locations along the IOL edge could be generated without user intervention. However, the user has the option of manually positioning the IOL to permit greater versatility. The typical 300-microm wide IOL edges are profiled to a resolution of approximately 20 microm. To constrain optical and microprocessor hardware costs, compromises were made in operating speeds so that approximately 20 min is required per profile. With current trends in integrated circuit technology future generations of the system could be made faster and prove useful as a QC tool for the IOL industry. Furthermore, the present device can be used in determining appropriate IOL profile standards.

Boundary layer thickness is a potentially important component of the diffusive pathway for gas exchange in aquatic organisms. The soft coral Alcyonium siderium (Octocorallia) and sea anemone Metridium senile (Actiniaria) exhibit significant increases in respiration with water flow over a range of Reynolds numbers encountered subtidally. A nondimensional mass transfer analysis of the effect of forced convection demonstrates the importance of the state of the organism's boundary layer in regulating metabolism in these invertebrates. Flow-modulated gas exchange may limit secondary productivity in subtidal environments.

Clonal mouse skeletal muscle cells which differentiate in culture and form synapses with neuronal cells were found to secrete high levels of protease activity as measured with an 125I-fibrin assay. The secreted proteolytic activity was more than 90% dependent upon the presence of plasminogen in the medium, and had a pH optimum at 7 to 8. This activity was not inhibited by n-ethylmaleimide, pepstatin, EDTA, or EGTA. At millimolar concentrations, greater than 90% inhibition was obtained with either soybean trypsin inhibitor, epsilon aminocaproic acid, Trasylol, or leupeptin. Almost complete inhibition occurred with 1 mM diisopropylfluorophosphate suggesting the presence of a serine residue at the catalytic site. In contrast to the high levels of secreted activity, a lower steady-state level of cell-associated protease activity was detected in cell lysates. The high level of plasminogen activator secreted into the medium of cultured muscle cells suggests a role for such extracellular protease activity in myogenesis during development and remodeling following muscle injury. Such information may be useful in understanding the initial degeneration of neuromuscular contacts in experimental and pathologic denervation.