Purpose: Studies suggested that drug pricing might be a risk factor for drug shortage; however, a few provided a quantitative assessment of this possible causal association. This study aimed to assess whether drug prices are associated with drug shortage incidents. Methods: This was a retrospective database analysis study. Drugs with shortage notifications (one drug per notification) that were sent to the Saudi Food and Drug Authority (SFDA) from Jan/2017 to Dec/2020 by different stakeholders were included in the study. For each drug, the foreign-to-Saudi-price ratio (FTSPR) was calculated (FTSPR= mean international price/Saudi price). Accordingly, drugs were split into three groups: Group 1 (FTSPR >1]), Group 2 (FTSPR =1]), and Group 3 (FTSPR <1]). The primary outcomes were the ratio of mean counts (mCR) between the three groups with Group 3 chosen as a control group. The study outcomes were analyzed using a negative binomial regression model adjusting for the measured confounders. All study analyses were conducted using RSudio Version 1.2.5033. Results: A total of 900 drugs were included (Group 1=348, Group 2=345, Group 3=209). The mean count of Group 1 higher was higher than Group 3 (mCR: 1.88; 95% confidence interval [CI] 1.24 to 2.83), while and mean counts of Group 2 vs. Group 3 were comparable (mCR: 1.39; 95%CI 0.92 to 2.09). Conclusions: The results of our study showed that shortage was associated with drugs that are more expensive outside Saudi Arabia. Additional international studies are needed to explore this causal association.

Understanding what regulates ecosystem functional resistance – the ecosystem-wide capacity to withstand process change following disturbance – is essential in this era of global change. However, many guiding theories relevant to ecosystem ecologists were developed prior to rapid global change and before tools were available to test them. In light of new knowledge and conceptual advances across biological disciplines, we summarize four disturbance theoretical frameworks relevant to ecosystem ecologists: a) the directionality of disturbance response; b) functional thresholds; c) disturbance-succession interactions; and d) diversity-functional resistance relationships. Our brief viewpoint and synthesis considers how knowledge, theory, and terminology developed by several biological disciplines, when integrated, can enhance how ecosystem ecologists analyze and interpret ecosystem-scale disturbance responses. For example, frameworks considering thresholds and disturbance-succession interactions should incorporate regime change, typically the domain of population and community ecologists. Similarly, the interpretation of ecosystem functional responses to disturbance requires analytical approaches that recognize disturbance can promote, inhibit, or fundamentally change ecosystem functions such as primary production. Moreover, embracing an encompassing definition of biological diversity is critical to identifying the ecosystem properties that confer high functional resistance to disturbance. We suggest that, moving forward, cross-disciplinary, integrative knowledge is essential to advancing and refining knowledge in the area of ecosystem functional resistance to disturbance.

Metastatic seminoma presenting in kidney and cervical lymph node after a 25-year intervalKeywords: Seminoma, Germ cell tumor, Testicular tumor, Distant metastasisAbstract: Seminoma comprises approximately 50% of testicular germ cell tumors. retroperitoneal lymph nodes being the most common initial metastatic site but Renal metastases are infrequent and the majority of renal tumors represent primary neoplasm. In this study, we present a 48-year-old male with metastases of seminoma to the cervical lymph node and kidney after a 25-year of interval.

Under salt and toxic metal stress condition, genetic make-up and proteins including some enzymes undergo specific changes to combat the posed harsh environment. Carbonic anhydrase is ubiquitous enzyme associated with respiratory disorder and cancerous condition. Strategies investigated and adopted by microorganisms to cope with hypersaline by bioinformatics analysis including homology modeling, Zinc metal interaction prediction, sequence analysis for Carbonic Anhydrase. This study shows that carbonic anhydrase acquired more acidic residues on its surface as countermeasure and may form salt bridges with positive ions in response to hypersaline environment. It also reduced its surface area and had more polar residues. Zinc metal interaction with Nitrogen of Histidine residues were almost conserved in the studied and modelled structure with fewer changes in catalytic region of sequence pattern. Salt tolerance achieved by foster promising approaches at the genetic and proteomic level by modifying protein sequence. Surface residues are exposed to a hypersaline medium and are mainly composed of polar and acidic residues. The enzyme exists in its compact form and reduces its surface footprint exposed to outside environment. Beta pleated secondary structure configuration increases flexibility to counter, ions disruptive effect.

Radiative cooling materials continue to underperform compared to their theoretical potential due to parasitic heating from contact with ambient air. Solutions to this problem are expensive or complex to fabricate. Here, a potentially inexpensive, simply fabricated material that improves cooling performance by reducing parasitic heating was created using naturally abundant salts. NaCl and KCl are not typically considered for radiative cooling because of their high hygroscopicity and low mechanical strength; however, these compounds are highly infrared-transparent and can be fabricated into aerogel-like structures to provide thermally insulating properties. Salt aerogels, described herein, scattered (reflected) visible light, transmitted infrared radiation, and provided thermal insulation. They were packaged into mechanical supporting panels to avoid physical disruption and the nanostructure was stabilized to moisture by adding anti-caking agent. The panels were able to keep an underlying surface below ambient temperature for a full 24-hour cycle and reduced parasitic heating rate by more than half (compared to an uncovered surface). The panels were able to cool a variety of underlying surfaces, even highly absorbing surfaces that are normally well above ambient temperature during the day. This work demonstrates an affordable, easily produced, electricity-free cooling technology with potential to be manufactured for large-scale practical applications.

DYT1 dystonia is a form of generalized dystonia associated with abnormalities in striatal dopamine release in mouse models and likely in humans. In the present study, we examined the possibility that ultrastructural changes in the morphology of nigrostriatal dopamine terminals could contribute to this neurochemical imbalance using a Serial-Block Face/Scanning Electron Microscope (SBF/SEM) and three-dimensional reconstruction approach to analyze striatal tyrosine hydroxylase-immunoreactive (TH-IR) terminals and their synapses in a DYT1(ΔE) Knockin (DYT1-KI) mouse model of DYT1 dystonia. Furthermore, to study possible changes in vesicle packaging capacity of dopamine, we used transmission electron microscopy to assess possible changes in the size of synaptic vesicles in striatal dopamine terminals between wild type (WT) and the DYT1-KI mice. Quantitative analysis of 80 fully reconstructed TH-IR terminals in the WT and DYT1-KI mice indicate: 1) No significant difference in the volume of TH-IR terminals between WT and DYT1-KI mice, 2) No major change in the proportion of axo-spinous vs axo-dendritic synapses formed by TH-IR terminals between the two groups, 3) No significant change in the post-synaptic density (PSD) area of axo-dendritic synapses, while the PSDs of axo-spinous synapses were significantly smaller in DYT1-KI mice, 4) No significant difference in the mean volume of mitochondria between WT mice and 5) No significant difference in the surface area of synaptic vesicles between the two groups. Altogether, these findings suggest that abnormal morphometric changes of nigrostriatal dopamine terminals and their post-synaptic targets are unlikely to be a major source of reduced striatal dopamine release in DYT1 dystonia.

Background: Postnatal overnutrition has been associated with lasting impairment of cognitive function. On the other hand, virgin coconut oil (CO) and environmental enrichment (EE) have been associated with the improvement of memory function. Objectives: To evaluate whether CO and EE could counteract any possible memory impairment caused by overnutrition during rats’ postnatal period. Methods: Rats were suckled in litters of either 9 (N, nourished) or 3 (ON, overnourished) pups. At 7 to 30 days of life, N and ON animals were treated with CO (10 ml/kg/d) or vehicle (V). At 36 days old, rats were exposed to EE during a 4-week period. Recognition memory was investigated in young and adult groups to evaluate rats’ memory after CO supplementation period and after exposure to an EE, respectively. Lastly, murinometric evaluation and blood collection were performed. Results: ON young rats displayed a treatment-dependent impairment of memory (p < 0.001). Additionally, CO coupled with overnutrition had age-dependent effects on memory. At adulthood, CO&ON rats were not able to recognize novel object placement (novel versus familiar, p > 0.05); however, CO&ON rats that were exposed to EE performed this task successfully (p < 0.0001). Conclusions: The etiology of diseases characterized by memory impairment can date back to lactation. Nutrition during this critical period can influence cognitive function. Early-life overnutrition, coupled with CO, has age-dependent effects on recognition memory. Our data suggests EE can rescue the memory impairment found in CO&ON adult rats.

Pelvic dimensions and hypotheses on duration of active second stage of labourTilde Broach OstborgStavanger University HospitalTM EggeboTrondheium University HospitalWe would like to thank Jan Novák and Petr Sedlak for their interest and comments to our manuscript. We found that increasing BMI was associated with shorter estimated median duration of the active second stage of labour.1We could not find any obvious causal mechanism for our findings; but suggested some possible explanations. The shorter active second stage may be related to increased abdominal pressure with increasing BMI, or perhaps increased strength when pushing.2, 3 Increased infiltration of fat in the muscular pelvic floor may decrease its strength and resistance.4 The presence of fat in the birth canal of obese women may delay the urge to bear down, thereby postponing active pushing until the head is lower in the maternal pelvis.Novak et al. measured the bi-ilac and bi-cristal diameters of the greater pelvis and found a broader pelvis in individuals with a history of obesity from adolescence.5 We supposed that there would be an association between the size of the greater pelvis and the size of the birth canal. We agree to the limitations commented by Novák and Sedlak. However, our proposed causal mechanisms are merely hypotheses, and cannot be accepted nor rejected based on current knowledge.1. Ostborg TB, Sande RK, Kessler J, Tappert C, von Brandis P, Eggebo TM. Put your weight behind it-Effect of body mass index on the active second stage of labour: A retrospective cohort study. BJOG. 2022;129:2166-2174.2. Lambert DM, Marceau S, Forse RA. Intra-abdominal pressure in the morbidly obese. Obes Surg. 2005;15:1225-1232.3. Tomlinson DJ, Erskine RM, Morse CI, Winwood K, Onambele-Pearson G. The impact of obesity on skeletal muscle strength and structure through adolescence to old age. Biogerontology. 2016;17:467-483.4. Pomian A, Lisik W, Kosieradzki M, Barcz E. Obesity and Pelvic Floor Disorders: A Review of the Literature. Med Sci Monit. 2016;22:1880-1886.5. Novak JM, Bruzek J, Zamrazilova H, Vankova M, Hill M, Sedlak P. The relationship between adolescent obesity and pelvis dimensions in adulthood: a retrospective longitudinal study. PeerJ. 2020;8:e8951.

Objective: To investigate programming effects of maternal testosterone on offspring birth anthropometrics. Design: Population-based prospective cohort study. Setting: University Hospital. Population: 1,486 mother-child dyads from Odense Child Cohort. Methods: Maternal blood samples were collected at gestational week 27-30 and free testosterone (FT) levels were calculated using the Vermeulen equation from total testosterone (TT) analyzed by mass spectrometry and sex hormone binding globulin (SHBG). Associations between FT or TT levels and birth anthropometrics were analyzed with multiple linear regression models according to offspring sex with adjustment for maternal age, parity, smoking and educational level. Analyses were repeated with polycystic ovary syndrome (PCOS) as exposure for offspring birth anthropometrics. Main outcome measures: Offspring birth weight (BW), birth length, abdominal- and head circumferences. Results: Maternal mean (SD) age was 30.2 (4.5) years and pre-pregnancy body mass index (BMI) was 23.5 (5.3) kg/m2. In boys (n=787), higher FT was associated with lower BW (adjusted doubling constant=-65.53, p=0.010), shorter birth length (adjusted doubling constant=-0.43, p<0.001), and lower abdominal circumference (adjusted doubling constant=-0.39, p<0.001); Higher TT was associated with lower abdominal circumference (adjusted doubling constant=-0.25, p=0.028). In girls, no associations were found between maternal FT or TT and offspring anthropometrics. Conclusions: Higher maternal free testosterone exposure was linked to reduced birth weight, length and abdominal circumference in boys, whereas girls were not susceptible to maternal testosterone exposure.

Objective: To evaluate the effectiveness of an ergonomic infant carrier for increasing postpartum parent-infant physical contact and reducing postpartum depression risk. Design: A randomized two-arm, parallel-group trial. Setting: Study participants’ homes from February 2018 to June 2019. Population or Sample: 100 participants in an income-constrained urban community in the United States. Methods: At 30-weeks gestation, 50 participants were randomly assigned to receive an ergonomic infant carrier and instruction on use (intervention), and 50 participants were assigned to a waitlist (control). Follow-up data were collected at 6-weeks postpartum from 78 participants (intervention n = 41; waitlist control n = 37). Main Outcome Measures: Edinburgh Postpartum Depression Scale (EPDS) score and extent of infant carrier utilization. Results: Participants in the carrier condition reported using their carriers for an average of 1.95 hours per day ( SD = 1.59) with participants in the intervention condition using an infant carrier significantly more often at 6-weeks (β = 2.69, SE = .347, p < .001, 95% CI = 2.08-3.41). The intervention group reported significantly fewer depressive symptoms at 6-weeks postpartum than the waitlist control group (β = -.541, p = .042). Participants who used an infant carrier more hours per day reported significantly fewer depressive symptoms (β = -1.60, SE = .069, p = .019, 95% CI = -.30 to -.025). Conclusions: An infant carrier intervention reduced postpartum depression at 6-weeks postpartum, with a significant dose-response association where increased infant carrier use predicted decreased postpartum depression symptomology. Funding: ErgoBaby donated all infant carriers used in this study but did not participate in any part of the research.

A document by Kobe Haenen. Click on the document to view its contents.

During thyroid surgery fast and reliable intra-operative pathological feedback has the potential to avoid a two-stage procedure and significantly reduce health care costs in patients undergoing a diagnostic hemithyroidectomy (HT). We explored higher harmonic generation (HHG) microscopy, which combines second harmonic generation (SHG), third harmonic generation (THG), and multiphoton excited autofluorescence (MPEF) for this purpose. With a compact, portable HHG microscope, images of freshly excised healthy tissue, benign nodules (follicular adenoma) and malignant tissue (papillary carcinoma, follicular carcinoma and spindle cell carcinoma) were recorded. The images were generated on unprocessed tissue within minutes and show relevant morphological thyroid structures in good accordance with the histology images. The thyroid follicle architecture, cells, cell nuclei (THG), collagen organization (SHG) and the distribution of thyroglobulin and/or thyroid hormones T3 or T4 (MPEF) could be visualized. We conclude that SHG/THG/MPEF imaging is a promising tool for clinical intraoperative assessment of thyroid tissue.

The mutualistic relationship between plants and arbuscular mycorrhizal fungi (AMF) is essential for optimal plant nutrition, enabling the plant to better withstand biotic and abiotic stressors and enhancing its chances of survival, reproduction, and colonization of new environments. Urban soil nutrient enrichment may reduce the benefits of AMF for plant nutrition, potentially reducing interaction with AMF in urban environments. Here, we test this prediction by studying how urbanization alter the plant-AMF interaction between the invasive herb Ruellia nudiflora (Acanthaceae) and AMF in Mérida city. We collected soil and plants from deep urban sites (DUS; e.g. sidewalks), open urban sites (OUS; parks), and rural sites (RS) to analyze the soil nutrient content, plant morphology, AMF-colonization rates, spore density, richness, and diversity. Unexpectedly, DUS showed the lowest soil nutrient concentrations except for phosphorus. Higher phosphorus levels in these sites reduced AMF colonization, supporting the prediction of reduced plant-AMF interactions in urban environments. We discovered that potassium affects the plant-AMF association, an understudied effect. Finally, urban plants produced smaller and more compact roots than rural plants, and no differences on AMF communities were found between urban and rural environments. To gain a better understanding of how AMF contributes to plant colonization in urban environments, further studies are required.

Brassicaceae plants have the glucosinolate-myrosinase defense system, jointly active against herbivory. Glucosinolates (GLS) are hydrolysed by myrosinase to produce isothiocyanates as soon as herbivory begins. Isothiocyanates exert detrimental effects on the feeding insects. However, constitutive GLS defense is observed to occur at levels that do not deter all insects from feeding. That prompts the question of why Brassicaceae plants have not evolved a high constitutive defense. The answer may lie in the contrasting relationship between plant defense and host plant preference of specialist and generalist herbivores. One of the reasons plants are in this dilemma is that they do not know what kind of herbivore will attack them in any given year, and thus have to be prepared for different possibilities. GLS content increases the susceptibility to specialist insects because these are attracted to plants with a high GLS content and are capable of coping with the toxin. In contrast, generalists are deterred by the plant GLS. Although GLS can attract the natural enemies (predators and parasitoids) of these herbivores, enemies can reduce herbivore pressure to some extent only. So, plants can be overrun by specialists if GLS content is too high, whereas generalists can invade the plants if it is too low. Therefore, an optimal constitutive plant defense can minimize the overall herbivore pressure. To explain optimal defense theoretically, we represent the contrasting host selection behavior of insect herbivores and, in addition, the emergence of their natural enemies by a non-autonomous ordinary differential equation model, where the independent variable is the plant GLS concentration. From the model, we quantify the optimal amount of GLS, which minimizes the total herbivore (specialists and generalists) pressure. That quite successfully explains the evolution of constitutive defense in plants from the perspective of optimality theory.

The effect of the simultaneous presence of fluorine (0.15-1.2 mg L -1), bicarbonates (83.6-596 mg L -1), and synthesized goethite (0.3 mg L -1) at typical concentrations often found in natural groundwater samples was evaluated on the degradation of 2,4-dichlorophenoxyacetic acid (2,4-D) at pH 6.9 under simulated sunlight irradiation (300 W m -2) and H 2O 2 concentrations of 10 mg L -1. 2,4-D removal was strongly enhanced by the presence of fluoride. F - could modify the surface of iron (hydr)oxide leading to the formation of surficial Fe-F bonds benefiting the formation of free •OH radicals, producing upward band bending, reducing the electron-hole recombination, and enhancing the electron transfer to H 2O 2. On the other hand, bicarbonate may react with •OH radicals generating CO 3 -• species which could be able to participate in pollutant oxidation as well while solar light-induced H 2O 2 photolysis also played an important role in removing 2,4-D. These findings suggest that “natural” tuning of iron (hydr)oxides by fluoride could take place in natural groundwater generating “natural” photocatalysts with a high activity which could participate, by adding H 2O 2, in the enhancing of sunlight photoinduced natural abiotic processes to pollutants abatement.

Fractionation of proteoforms is currently the most challenging topic in the field of protein purification. The need for considering the existence of proteoforms into experimental approaches is not only important in Life Science research in general but especially in the manufacturing of therapeutic proteins (TPs) like recombinant therapeutic antibodies (mAbs). Some of the proteoforms of TPs have significantly decreased actions or even cause side effects. The identification and removal of proteoforms differing from the main species, having the desired action, is challenging because the difference in the composition of atoms often is very small and their concentration in comparison to the main proteoform can be small. In this study we demonstrate that sample displacement batch chromatography (SDBC) is an easy to handle, economic and efficient method for fractionating proteoforms. As a model sample a commercial ovalbumin fraction was used, containing many ovalbumin proteoforms. The most promising parameters for the SDBC were determined by a screening approach and applied for a 10-segment fractionation of the ovalbumin with cation exchange chromatography resin. Mass spectrometry of intact proteoforms was used for characterizing the SDBC fractionation process. By SDBC a significant separation of different proteoforms was obtained.

A document by Amna Siddiqui. Click on the document to view its contents.

Aims: Therapeutic non-compliance remains the main difficulty for people with psychotic disorders, standing around 50% in people with schizophrenia. Lack of treatment adherence, either partial or total, to medication has economic and clinical consequences. E-health technologies may be a promising therapeutic tool to improve adherence, with the subsequent reduction in clinical and economic burden. Incorporating Information and Communication Technologies (ICT) has improved the information patients receive and the relationship between health professionals and patients. Our aims were to know the preferences on how technologies in mental health treatment should be for use in clinical practice, and to learn about the opinion and preferences on the use of technologies in mental health treatment from the perspectives of patients with FEP, their relatives, and mental health professionals. Methods: A cross-sectional quantitative study was carried out by experts in psychosis and technologies. 41 patients with a diagnosis of first-episode psychosis (FEP), 18 relatives and 49 mental health professionals were included in the study. Results: An app directed to people with psychosis would be well received by users if it contains psychoeducational material, offers reminders for scheduled visits and treatment and allows online consultations. Conclusions: Co-creating an app with users, their families and mental health professionals allows incorporating their preferences to increase its use, improve outpatient care and creating an app that is viable in clinical practice.

Understanding the controlling factors of spatial and temporal changes in runoff is critical for the integrated management and utilization of water resources. This study used the stepwise regression analysis to determine the expressions of eight regional controlling parameters and their climate and human factors in the middle Yellow River (MYR) based on the Budyko framework of the Fu equation. The contribution rate of climate and human factors to runoff change was analyzed using the elastic coefficient. The results showed that climate change caused runoff increase, and comprehensive human activities played an important role in runoff reduction. Human factors affecting runoff varied greatly in different regions. Vegetation restoration could lead to runoff reduction while constructing terraces and check-dams could cause an increase in runoff. Urban expansion contributed to runoff collection, and its contribution rate to runoff change was more than 200% in absolute value. The runoff change in the arid and semi-arid regions in the north was more sensitive to human factors.

Objective: The prevalence of smoking and depressive symptoms in patients with schizophrenia (SCZ) is high. However, few studies have examined the relationship between smoking and depressive symptoms in patients with first-episode SCZ. In this study, we investigated the prevalence and risk factors of smoking and its relationship with depressive symptoms in Chinese male patients with first-episode drug-naïve (FEDN) SCZ. Methods: We recruited 164 male patients with FEDN SCZ, including 58 current smokers and 106 nonsmokers. Patients completed a detailed questionnaire about smoking status, age of onset, body mass index (BMI), and other socio-demographic data. We used the Positive and Negative Syndrome Scale (PANSS), the 24-item Hamilton Rating Scale for Depression (HDRS), and the Hamilton Rating Scale for Anxiety (HARS) to assess the clinical symptoms of patients. Results: The current smoking rate of FEDN SCZ patients was 35.36%. Compared to nonsmokers, current smokers were older, had a later age of onset, fewer years of education, and a larger BMI. Smoking patients had higher HDRS score than nonsmoking patients (39.83±12.32 vs. 34.97±11.88, F1,162=6.10, p<0.05). Logistic regression analysis showed that the HDRS score was significantly associated with patients’ smoking status (Wald χ2 =4.01, df=1, p<0.05, OR=1.05; 95%CI: 1.001~1.104). Conclusions: Our results suggest that the prevalence of smoking in patients with FEDN SCZ is similar to that of healthy individuals. Some demographic and clinical variables, especially depressive symptoms, may be strongly associated with smoking status in patients with FEND SCZ.

We report here a 58-year-old patient with clonal FIP1L1-PDGFRA-positive hypereosinophilic syndrome (HES), with skin and lung involvement, treated with Imatinib, in clinical, hematological and molecular remission. After 77 months of treatment, Imatinib was stopped and at 9 months of discontinuation, the patient remained in complete molecular remission.

Habitat loss and habitat fragmentation usually occur together, at the same time and place. However, while there is consensus that habitat loss is the preeminent threat to biodiversity, the effects of fragmentation are contentious. Some argue that habitat fragmentation is not bad for biodiversity, and even that it is good. Generally, the studies that find no harm or positive outcomes of fragmentation invariably assume that it is independent of habitat loss. However, dissociating the effects of habitat fragmentation from habitat loss is questionable because of the two are essentially coupled. Accordingly, we evaluated how forest area and fragmentation (via edge effects) influenced dung beetles per se, and through their effects on the abundance of mammals, using structural equation modeling (SEM). Dung beetles are very sensitive to forest habitat loss and fragmentation, and to changes in the abundance of mammals on which they depend for dung. Our study area was in the Tana River, Kenya, where forest fragments are depauperate of mammals except for two endemic species of monkeys. We mapped 12 forests, counted the resident monkeys, and sampled 113,959 beetles from 288 plots. Most of the 87 species of beetles were small, affirming the endemic monkeys as the main source of dung. After implementing a fully latent Structural Regression SEM, the optimal model explained a significant 26% of the variance in abundance, and 89% of diversity. The main drivers of beetle abundance were positive, direct, effects of forest area and number of monkeys, and negative edge effects. The main drivers of diversity were the direct effects of the beetle abundance, indirect effects of forest area and abundance of mammals, and indirect negative edge effects. Thus forest area, fragmentation (via edge effects) and the number of monkeys jointly influenced the abundance and diversity of the beetles directly and indirectly.

Economic model predictive control (EMPC) has received increasing attention in the wind energy community due to its ability to trade off economic objectives with ease. However, for wind turbine applications, inherent nonlinearities, such as from aerodynamics, pose difficulties in attaining a convex optimal control problem (OCP), by which real-time deployment is not only possible but also a globally optimal solution is guaranteed. A variable transformation can be utilized to obtain a convex OCP, where nominal variables, such as rotational speed, pitch angle, and torque, are exchanged with an alternative set in terms of power and energy. The ensuing convex EMPC (CEMPC) possesses linear dynamics, convex constraints, and concave economic objectives and has been successfully employed to address power control and tower fatigue alleviation. This work focuses on extending the blade loads mitigation aspect of the CEMPC framework by exploiting its individual pitch control (IPC) capabilities, resulting in a novel CEMPC-IPC technique. This extension is made possible by reformulating static blade and rotor moments in terms of individual blade aerodynamic powers and rotational kinetic energy of the drivetrain. The effectiveness of the proposed method is showcased in a mid-fidelity wind turbine simulation environment in various wind cases, in which comparisons with a basic CEMPC without load mitigation capability and a baseline IPC are made. Results indicate that CEMPC-IPC can achieve better reduction in rotating blade loads, as well as similar performance in the mitigation of shaft and yaw bearing loads, with the added advantage of convenient economic objectives trade-off tuning.

Hepatocellular carcinoma (HCC) is a deadly cancer, with the dominant driver mutations such as p53 yet undruggable. There is urgent demand to search for novel agents and therapeutic targets for HCC treatment. Andrographolide (Andro, a clinical-available anti-inflammation phytochemical agent) could inhibit different types of cancer including HCC, but the molecular mechanisms involved are yet unclear. The present study thus determined how Andro mechanistically cause HCC cell death in both in vitro and in vivo models. Andro dose- and time-dependently induced HCC cell death but spared normal hepatocyte HL-7702. Furthermore, Andro caused ROS-mediated DNA damage, which was critical for cell death. Since p53 could induce G2/M cell cycle arrest, the p53-present tumour cells were found to be more resistant to Andro-induced cell death, compared to the p53-deficient cells. Notably, Andro-induced p62 aggregation promoted proteasomal degradation of RAD51 and 53BP1, two essential proteins involved in DNA damage repair. As a result, either silencing or knocking-out p62 promoted DNA damage repair and consequently protected HCC cells from Andro- induced cell death. Consistently, xenograft tumour developed by p62-knockout cells were more resistant to Andro treatment. In addition, p53 and p62 were independent with each other, since disrupting any one protein did not affect expression of the other protein. Taken together, the present study may shed light on repurposing Andro in the treatment of both p53-present and p53-deficient HCC.