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Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic kidney disease and is caused by heterozygous germ-line mutations in either PKD1 (85%) or PKD2 (15%). It is characterised by the formation of numerous fluid-filled renal cysts and leads to adult-onset kidney failure in ~50% of patients by 60 years. Kidney cysts in ADPKD are focal and sporadic, arising from the clonal proliferation of collecting-duct principal cells, but in only 1–2% of nephrons for reasons that are not clear. Previous studies have demonstrated that further postnatal reductions in PKD1 (or PKD2) dose are required for kidney cyst formation, but the exact triggering factors are not clear. A growing body of evidence suggests that DNA damage, and activation of the DNA damage response pathway, are altered in ciliopathies. The aims of this review are to: (i) analyse the evidence linking DNA damage and renal cyst formation in ADPKD; (ii) evaluate the advantages and disadvantages of biomarkers to assess DNA damage in ADPKD and finally, (iii) evaluate the potential effects of current clinical treatments on modifying DNA damage in ADPKD. These studies will address the significance of DNA damage and may lead to a new therapeutic approach in ADPKD.
Few proteins have come under such intense scrutiny as superoxide dismutase-1 (SOD1). For almost a century, scientists have dissected its form, function and then later its malfunction in the neurodegenerative disease amyotrophic lateral sclerosis (ALS). We now know SOD1 is a zinc and copper metalloenzyme that clears superoxide as part of our antioxidant defence and respiratory regulation systems. The possibility of reduced structural integrity was suggested by the first crystal structures of human SOD1 even before deleterious mutations in the sod1 gene were linked to the ALS. This concept evolved in the intervening years as an impressive array of biophysical studies examined the characteristics of mutant SOD1 in great detail. We now recognise how ALS-related mutations perturb the SOD1 maturation processes, reduce its ability to fold and reduce its thermal stability and half-life. Mutant SOD1 is therefore predisposed to monomerisation, non-canonical self-interactions, the formation of small misfolded oligomers and ultimately accumulation in the tell-tale insoluble inclusions found within the neurons of ALS patients. We have also seen that several post-translational modifications could push wild-type SOD1 down this toxic pathway. Recently we have come to view ALS as a prion-like disease where both the symptoms, and indeed SOD1 misfolding itself, are transmitted to neighbouring cells. This raises the possibility of intervention after the initial disease presentation. Several small-molecule and biologic-based strategies have been devised which directly target the SOD1 molecule to change the behaviour thought to be responsible for ALS. Here we provide a comprehensive review of the many biophysical advances that sculpted our view of SOD1 biology and the recent work that aims to apply this knowledge for therapeutic outcomes in ALS.
The extremotolerant bacterium Deinococcus radiodurans is used as a model to explore the limits of life on Earth and beyond. In experiments performed in an ultra-high vacuum chamber with a vacuum ultraviolet (VUV) synchrotron beamline, this microorganism was exposed to conditions present on an extraterrestrial environment unprotected by an atmosphere, such as outside a spacecraft or on an asteroid, relevant in the context of planetary protection and panspermia hypothesis. Different methods were used to obtain the biologically relevant information from this investigation. Counting of colony forming units, the traditional approach for viability assessment, is limited to measuring the survival of the cells. For a more in-depth study of damage mechanisms at subcellular levels, specific molecular probes (propidium iodide and dihydrorhodamine 123) were applied and whole populations could be analysed, cell by cell, by flow cytometry. VUV radiation caused a substantial loss of viability, though only a fraction of the cells presented membrane damages even at the largest tested fluences. Additionally, intracellular oxidative stress was also detected upon exposure. These results point to significant VUV inactivating effects extending beyond the cells' outermost structures, in contrast to a more superficial role that could be expected due to the highly interacting nature of this radiation range. Nevertheless, it was observed that microscopic-level shading sufficed to allow the persistence of a small surviving subpopulation for the longer expositions. This study contributes to unveiling the response of biological systems under space conditions, assessing not just cell viability but also the mechanisms that lead to inactivation.
Tail biting is a welfare and economical concern in modern pig production. One common preventive measure used throughout the world is tail docking, which is generally considered one of the most effective methods for limiting tail biting. However, tail docking is a painful mutilation and systematic tail docking is not allowed in the EU. Therefore, the aim was to compare pig behaviour and the prevalence of tail biting in finishing pigs with intact tails housed in two different pen designs under Danish commercial conditions. PEN1 was a traditional Danish pen and PEN2 was inspired by Swedish finisher pen design and had a larger proportion of solid floor area (PEN1: 1/3 and PEN2: 2/3), reduced group size (PEN1: 15 and PEN2: 12), increased space allowance per head (PEN1: 0.7 m2 and PEN2: 0.89 m2) and straw allocated on the floor (PEN2) whereas straw was provided in a straw rack in PEN1. Tail damage observations were carried out daily by the stockperson and every 2 weeks one trained research technician assessed tail damages according to a tail scoring system. Tail lesions were observed in 51% of PEN1 and in 11% of PEN2 (P < 0.001). PEN1 had higher prevalence of tail damages than PEN2 (23% v. 5%, P < 0.001). Behavioural observations were carried out by the use of video recordings. Pigs in PEN2 tended to spend more time on tail-directed behaviour than pigs in PEN1 (P = 0.07), whereas pigs in PEN1 tended to spend more time on ear-directed behaviour (P = 0.08). Pigs in PEN2 spent more time on straw-directed behaviour compared to pigs in PEN1 (P < 0.001). Pen design did not affect time spent on other penmate-directed behaviour. In addition, the level of welfare between the two pen designs was compared using the Welfare Quality® protocol. PEN2 received an overall score of ‘excellent’ while PEN1 scored ‘enhanced’. PEN2 scored higher on all principles besides ‘good health’, where PEN1 scored better on lameness and wounds. The main measurements accounting for the differences were water supply, huddling, tail biting, social behaviour and fear of humans. In conclusion, the combination of increased space allowance, increased area of solid flooring, straw allocated onto the floor and reduced group size (PEN2) resulted in fewer tail damaged pigs and a better overall welfare assessment, despite a tendency for more tail-directed behaviour.
This study assesses the patterns of crop damage by elephants Loxodonta africana in areas adjacent to the Rungwa, Kizigo and Muhesi Game Reserves in Tanzania. We used a questionnaire survey to collect data from a total of 210 household heads from seven villages, with 30 household heads in each village, during June–August 2015. Proximity was a significant factor influencing losses, with crop farms within < 1 km from the reserves having higher losses, followed by those 1–5 km and > 5 km distant. Most households (81.0%) < 1 km from a reserve reported crop damage whereas those within 1–5 km (65.9%) and > 5 km (20.0%) reported less damage. Most of the losses (79.8%) occurred in the first half of the year (the wet season). Immigrants reported higher average losses to crops than Indigenous respondents. Noise making, flashlights, setting fire around fields and disturbance by shooting were the methods used to deter elephants from entering crop fields. We recommend that communities around these game reserves avoid areas that are < 1 km from the reserve boundary, plant crops such as chilli, use honeybee Apis mellifera fences to deter elephants from their crops, and receive education on available mitigation methods, to help minimize crop losses to elephants.
Humans have lived alongside and interacted with wild animals throughout evolutionary history. Even though wild animals can damage property, or injure humans and domesticated animals, not all interactions between humans and wildlife are negative. Yet, research has tended to focus disproportionately on negative interactions leading to negative outcomes, labelling this human–wildlife conflict. Studies have identified several factors, ranging from gender, religion, socio-economics and literacy, which influence people's responses to wildlife. We used the ISI Web of Knowledge database to assess quantitatively how human–wildlife interactions are framed in the scientific literature and to understand the hypotheses that have been invoked to explain these. We found that the predominant focus of research was on human–wildlife conflict (71%), with little coverage of coexistence (2%) or neutral interactions (8%). We suggest that such a framing is problematic as it can lead to biases in conservation planning by failing to consider the nuances of people's relationships with wildlife and the opportunities that exist for conservation. We propose a typology of human responses to wildlife impacts, ranging from negative to positive, to help moderate the disproportionate focus on conflict. We suggest that standardizing terminology and considering interactions beyond those that are negative can lead to a more nuanced understanding of human–wildlife relations and help promote greater coexistence between people and wildlife. We also list the various influential factors that are reported to shape human–wildlife interactions and, to generate further hypotheses and research, classify them into 55 proximate (correlates) and five ultimate (mechanisms) factors.
Sperm DNA fragmentation is referred to as one of the main causes of male infertility. Failures in the protamination process, apoptosis and action of reactive oxygen species (ROS) are considered the most important causes of DNA fragmentation. Action of ROS or changes in sperm protamination would increase the susceptibility of sperm DNA to fragmentation. Routine semen analysis is unable to estimate sperm chromatin damage. Sperm DNA integrity influences sperm functional capability, therefore tests that measure sperm DNA fragmentation are important to assess fertility disorders. Actually, there is a considerable number of methods for assessing sperm DNA fragmentation and chromatin integrity, sperm chromatin stability assay (SCSA modified), sperm chromatin dispersion (SCD), comet assay, transferase dUTP nick end labelling (TUNEL); and protamine evaluation in sperm chromatin assay, such as toluidine blue, CMA3, protamine expression and evaluation of cysteine radicals. This review aims to describe the main causes of sperm DNA fragmentation and the tests commonly used to evaluate sperm DNA fragmentation.
Doveweed is a problematic weed species in many agricultural ecosystems as well as on roadsides and rights-of-way. Effective POST chemical control options for doveweed are limited in many cropping systems. Greenhouse studies were conducted to evaluate the effectiveness of metsulfuron-methyl dose and the impact of mixtures and sequential applications of either trifloxysulfuron-sodium or bentazon with metsulfuron-methyl for doveweed control. By 14 d after the initial treatment, applying 0.04 kg ai ha−1 metsulfuron-methyl, either once or sequentially, provided 100% control of doveweed. Application of trifloxysulfuron-sodium at 0.04 kg ai ha−1 alone or in mixture with metsulfuron-methyl (0.04 kg ha−1) did not provide consistent doveweed control nor did it reduce biomass. Trifloxysulfuron-sodium applied alone at 0.08 kg ha−1 or in a mixture with metsulfuron-methyl (0.04 kg ha−1) provided consistent doveweed control (>80%). A single application of bentazon (0.56 kg ai ha−1) was ineffective at controlling doveweed. A single application of the bentazon and metsulfuron-methyl mixture (0.56 + 0.04 kg ha−1, respectively) or sequential applications of either bentazon alone (0.56 kg ha−1) or in mixture with metsulfuron-methyl (0.04 kg ha−1) provided excellent doveweed control (100%) by 35 d after treatment. Overall, single applications of metsulfuron-methyl (0.02 to 0.17 kg ha−1) or mixtures of metsulfuron-methyl with trifloxysulfuron-sodium (0.04 + 0.08 kg ha−1, respectively) or bentazon (0.04 + 0.56 kg ha−1, respectively) controlled doveweed and may be useful for enhancing the control spectrum for other weeds. Sequential applications of the bentazon and metsulfuron-methyl mixture (0.56 + 0.04 kg ha−1, respectively) provided doveweed control and are a resistance-management strategy for doveweed.
By conducting field research and analysing judgments delivered in Beijing courts from 2004 to 2011, we find that the popular notion held by China's trade partners of the inadequacy of intellectual property protection is only partly supported by the empirical evidence. The likelihood of winning lawsuits is higher for foreign than domestic plaintiffs and the extremely low damages ruled by Chinese courts are due to particular causes. Courts lack consistent methods to calculate incurred losses in intellectual property right (IPR) infringements and consequently routinely apply the statutory damages whose upper limit is restricted by legislation. Efforts by Chinese legislators to enhance compensation by lifting the upper limit of awardable statutory damages in the Third Amendment of Chinese Patent Law (2008) did not seem to have an effect on our sample. Chinese policymakers should instead focus on the cause of the issue by providing more implementable guidelines for courts to calculate losses. Courts need to develop applicable conventions for calculating damages, based on objective criteria of how much compensation ought to be payable, which is also the basis of calculating reasonable statutory damages. Thus, the new provision of the “right of information” on pirated goods proposed by the ongoing Fourth Amendment provides a significant weapon to combat counterfeiting.
This article analyzes a general equilibrium growth model with overlapping generations and (production-induced) environmental degradation. Individuals react to environmental damages through mitigation or adaptation. In the former case, they reduce production and its environmental impact. In the latter, they do not tackle the causes of the problem but rather its consequences (i.e., the wellbeing loss due to environmental degradation) by increasing defensive expenditures. Despite its simplicity, the model can generate different long-term outcomes: convergence to a stationary state following a unique trajectory or local/global indeterminacy. In the last scenario, initial conditions (history) and individual expectations matter and the model can generate coordination failures and endogenous fluctuations. Results cast doubt on solutions to environmental problems relying on the role of individual behavior change or adaptation.
In Georgia v. Russia (I) (Just Satisfaction), the Grand Chamber of the European Court of Human Rights (ECtHR or Court) ordered the Russian Federation to pay Georgia EUR 10 million as reparation for Russia's “coordinated policy of arresting, detaining and expelling Georgian nationals” in the autumn of 2006 (paras. 51, 80). In so doing, the Court reaffirmed its position from Cyprus v. Turkey (IV) (Just Satisfaction) that financial compensation for non-pecuniary damage can be awarded in interstate cases. Although Georgia v. Russia (I) (Just Satisfaction) marks the development of a new line of ECtHR jurisprudence, it is unlikely that the decision will effectively prevent further mass violations of the European Convention on Human Rights (ECHR or Convention) by the states parties or offer fair compensation to the victims of such violations.
This article examines the international legitimacy of unilateral dam development in an international watercourse from the perspective of international water law. Drawing upon technical analysis over the Harirud River Basin, the article discusses probable negative impacts of unilateral dam development in Afghanistan on downstream Iran and Turkmenistan. Competing claims are analyzed to assess emerging transboundary damage under customary international water law. Applying these insights to the case study, this article explores how legal norms and principles can contribute to transboundary water cooperation. It investigates how equitable and reasonable utilization, as required by the United Nations Watercourse Convention, could be reached and whether current activities are in conformity with international norms. Based on this analysis and in the light of international customary law, the article questions the compatibility of unilateral control and capture of water resources in Afghanistan, particularly through the Salma Dam, with ‘equitable and reasonable utilization’ and ‘no significant harm’ rules. The article also argues that building the Salma Dam results in significant transboundary harm to downstream states. Hence, such harm could be considered as significant transboundary damage. Conclusions point to an understanding of water law as a form of institutional guidance in order to provide a transparent setting for transboundary water cooperation among riparian states.
Coccidial infections reduce fat-soluble vitamin status and bone mineralisation in broiler chickens. We hypothesised that broilers infected with Eimeria maxima would benefit from increased dietary supplementation with vitamin D (vitD) or with 25-hydroxycholecalciferol (25(OH)D3 or 25D3). Broilers were assigned to diets with low (L) or commercial (M) vitD levels (25 v. 100 μg/kg) supplemented as cholecalciferol (D3) or 25D3. At day 11 of age, birds were inoculated with water or 7000 E. maxima oocysts. Pen performance was calculated over the early (days 1–6), acute (days 7–10) and recovery periods (days 11–14) post-infection (pi). At the end of each period, six birds per treatment were dissected to assess long bone mineralisation, plasma levels of 25D3, Ca and P, and intestinal histomorphometry. Parasite replication and transcription of cytokines IL-10 and interferon-γ (IFN-γ) were assessed at day 6 pi using quantitative PCR. Performance, bone mineralisation and plasma 25D3 levels were significantly reduced during infection (P < 0·05). M diets or diets with 25D3 raised plasma 25D3, improved performance and mineralisation (P < 0·05). Offering L diets compromised feed efficiency pi, reduced femur breaking strength and plasma P levels at day 10 pi in infected birds (P < 0·05). Contrastingly, offering M diets or diets with 25D3 resulted in higher parasite loads (P < 0·001) and reduced jejunal villi length at day 10 pi (P < 0·01), with no effect on IL-10 or IFN-γ transcription. Diets with M levels or 25D3 improved performance and mineralisation, irrespective of infection, while M levels further improved feed efficiency and mineralisation in the presence of coccidiosis.
In the western Serengeti of Tanzania, African elephant Loxodonta africana populations are increasing, which is rare across the species’ range. Here, conservation objectives come into conflict with competing interests such as agriculture. Elephants regularly damage crops, which threatens livelihoods and undermines local support for conservation. For damage reduction efforts to be successful, limited resources must be used efficiently and strategies for mitigation and prevention should be informed by an understanding of the spatial and temporal distribution of crop damage. We assessed historical records of crop damage by elephants to describe the dynamics and context of damage in the western Serengeti. We used binary data and generalized additive models to predict the probability of crop damage at the village level in relation to landscape features and metrics of human disturbance. During 2012–2014 there were 3,380 reports of crop damage by elephants submitted to authorities in 42 villages. Damage was concentrated in villages adjacent to a reserve boundary and peaked during periods of crop maturity and harvest. The village-level probability of crop damage was negatively associated with distance from a reserve, positively with length of the boundary shared with a reserve, and peaked at moderate levels of indicators of human presence. Spatially aggregated historical records can provide protected area managers and regional government agencies with important insights into the distribution of conflict across the landscape and between seasons, and can guide efforts to optimize resource allocation and future land use planning efforts.
To explore whether the improvement in self-awareness induced by a structured intervention programme in patients suffering a brain injury is associated with an enhancement in their functional outcomes.
This study uses a pre- and post-test control group design with a sample of 56 patients with acquired brain injury randomly assigned to an experimental and a control group. Pre- and post-intervention measurements were self-awareness (using a previously developed scale) and functional outcome (using the Lawton Instrumental Activities of Daily Living Scale).
Patients who received the intervention programme showed a greater improvement in their self-awareness level and functional outcome than patients in the control group. Additionally, the correlation analyses between improvements at both measures showed a relation between improvement in self-awareness and improvement in functional outcome, especially when the pre-treatment self-awareness level was considered.
Implementing an intervention programme in self-awareness, in the context of a global rehabilitation process of patients with acquired brain injury, is useful for improving their self-awareness level and the functionality in their daily activities.
Single crystals of synthetic reidite and natural radiation-damaged zircon from Okueyama, Japan were investigated using X-ray diffraction. The pressure-induced zircon–reidite transition is described by the twisting and translations of SiO4 tetrahedra with disappearance of the SiO4–ZrO8 shared edges. The lattice of radiation-damaged zircons expands mainly from α-decays of radioactive elements such as U and Th. Although old radiation-damaged zircons show anomolous lattice distortion, young radiation-damaged zircons do not show such distortions. These distortions are caused by thermal recovery that suppresses the Si4+–Zr4+ repulsion between the SiO4 tetrahedron and ZrO8 dodecahedron. These changes in structure can be understood by considering the cation–cation repulsion between the SiO4–ZrO8 shared edges.