Recently, due to tremendous progress in prognosis, diagnosis, and treatment of different kinds of malignancies, demands on fertility preservation were raised significantly in developed countries. Fertility failure is one of the most detrimental consequences of radio/cytotoxic treatment procedures in women who could overcome their cancer disease. For women who are involved in cancer diseases, there are multiple options regarding their fertility preservation and those could be selected according to patient’s age, the risk of ovarian involvement, the available time and the type of cancer with different levels of advantages and disadvantages. Although there are multiple options, but embryo cryopreservation and ovarian tissue cryopreservation are the most reliable methods for permature and post-mature puberty, respectively. In addition, other approaches like artificial ovary, isolation and cryopreservation of follicles and mature and immature oocyte preservation are under investigations and the success rate of oocyte vitrification is increasing. Therefore, the techniques have the potential to be used in clinic in near future. The presence of comprehensive consultation, before the onset of any kind of cancer treatment procedures, is an indispensable issue which would help patients to make up their mind in choosing the immediate and the best available fertility preservation option. The incidence rate of cancer among reproductive-age women is 7%, and current cancer treatment methods and strategies have increased survival rate five years following cancer treatment , 2. One In Vitro activation (IVA) of primordial follicles have increased the hopes and allow premature ovarian failure (POF) and primary ovarian insufficiency (POI) patients to conceive using their own eggs  has recently updated its guidelines for fertility preservation in cancer patients according to same pregnancy rate results obtained from both oocyte and embryo cryopreservation which were reported by American Society for Reproductive Medicine (ASRM) . Ovarianown eggs , 12.There are different strategies for fertility preservation which can be applied based on patient’s age and status as well as the risk of ovarian involvement . Some ofMost of the possible strategies for fertility preservation in pubertal patients are costly and invasive, and none of them are as reliable as sperm banking in men. There are multiple strategies with different levels of efficiency, applicability, advantages, and disadvantages regarding fertility preservation among adult women at ART centers , whereinCryopreservation of embryo is the most relevant and well-established option for fertility preservation and was the only method endorsed by the ASRM until 2012. The effectiveness and safety of this option have been proved so that this technique is routinely used in ART centers for infertile women to store supernumerary embryos, prevent ovarian hyperstimulation syndrome (OHSS) and in cases of impaired endometrial development and impractical embryo transfer , 17. MeaAlthough the success rate of oocyte vitrification is increasing, embryo cryopreservation, based on obtained satisfactory rate, is still the best option that can be offered to post-pubertal women who desire fertility preservation, especially for those who are mature and have enough time prior to onset of aggressive treatments and have a partner or sperm donor as well. This is noteworthy to mention that transfer of cryopreserved embryos leads to improvement of pregnancy rate compared to fresh embryo transfer strategy, due to improved embryo–endometrium synchrony .Cryopreservation of oocyte is another option especially for those women who are single and are not pleasant to have sperm donation. Recent reports are showing that the success rate and efficiency of oocyte vitrification significantly have improved and are comparable with obtained results from fresh oocytes , 20. In in vitro culture system. In autotransplantation, that is the only clinically applicable strategy at recent, ovarian tissues can be returned to the patient by autotransplantation  ” which allows POF patients to conceive using their own eggs via activation of residual dormant follicles. Multiple pregnancies have been reported using this strategy wherein stimulation of phosphatidylinositol-3-kinase (PI3K) and AKT-forkhead box O3 (FOXO3) pathways followed by disruption of Hippo signaling pathway using ovarian fragmentation, leads to activation of primordial follicle growth and subsequently, ovarian tissue autotransplantation may help to achieve successful pregnancies  . Some stpically) , which wgrafting . The xengrafting , 30, whignancies . Also, ignancies .Based on recent reports, almost 100 children were born or will be born in the near future using OTC. All gestational age and birth weight in these newborns were within internationally recognized normal standards and it can be suggected that frozen-thawed ovarian tissue transplantations is going to be a routine fertility preservation .Oophoropexy is an applicable method which is routinely used in clinics for Hodgkin disease and other patients for whom abdominal surgery is necessary before irradiation, in order to minimize harmful effects of ionizing irradiation on ovarian function . In thisIn one clinical trial, it was indicated that 94% of treated patients with GnRH agonist showed initiation of spontaneous menstruation within 3–8 months after termination of chemotherapy demonstrating that GnRH agonist can prevent the ovaries from being damaged during chemotherapy . AlthougSome other promising methods have been recently developed, wherein devastating consequences of radio/cytotoxic treatment procedures are diminished by suppressing apoptosis pathways in the germ cells. Sphingosine-1-Phosphate (S1P) , AS101  and imatThere are multiple possible options that might be helpful for prepubertal girls to preserve their fertility before the onset of aggressive cancer treatment. Among them, the most applicable and valid option for adolescent female patients is OTC that is considered as an experimental method yet and needs some more investigations and approval by Institutional Review Board (IRB) . In the in vitro to produce off-spring by in vitro fertilization. This is worthy to mention that shielding ovaries or oophoropexy is another possible approach, wherein ovaries can be removed from irritation field  can be isolated from patient’s ovarian tissues and be differentiated toward competent oocyte either by injecting back into ovarian tissue  culture –53. This culture –56.Current advances and successful reported pregnancies using ovarian cryopreservation and transplantation and artificial ovary and also utilization of multistep culture system of primordial follicles as well as allografting option, have increased hopes in cancer survivors. Following transplantation, follicles loss is one of the results of non-efficient revascularization of the graft and tissue ischemia; however, these consequences could be prevented by using S1P, Vascular Endothelial Growth Factor (VEGF), Anti Mullerian Hormone (AMH), antioxidants and innovative stem cells therapy approaches , 57–61.


Increased cortical excitability has been hypothesized to play a critical role in various neurological disorders, such as restless legs syndrome, epilepsy and migraine. Particularly for migraine, local hyperexcitability has been reported. Levels of regional excitatory and inhibitory neurotransmitters are related to cortical excitability and hence may play a role in the origin of the disease. Consequently, a mismatch of the excitatory-inhibitory neurotransmitter network might contribute to local hyperexcitability and the onset of migraine attacks. In this study we sought to assess local levels of glutamate / glutamine (GLX) and gamma-aminobutyric acid (GABA) in the occipital cortex and right thalamus of migraineurs and healthy subjects.We measured interictally local biochemical concentrations in the occipital lobe and the right thalamus in patients with migraine (without aura) and healthy controls (HCs) using proton magnetic resonance spectroscopy at 3 T. GLX levels were acquired using PRESS and GABA levels using the GABA-sensitive editing sequence MEGA-PRESS. Regional GLX and GABA levels were compared between groups.Statistical analyses revealed significantly increased GLX levels in both the primary occipital cortex and thalamus. However, we found no group differences in GABA levels for these two regions. Correlation analyses within the migraine group revealed no significant correlations between pain intensity and levels of GLX or GABA in either of the two brain regions.Further research is needed to investigate the role of GABA/GLX ratios in greater depth and to measure changes in neurotransmitter levels over time, i.e. during migraine attacks and interictally. Migraine is one of the most common neurological disorders, thought to affect up to 6% of men and 18% of women in western industrialized countries , sterile1H-MRS), however, can be used to measure local concentrations of neurometabolites in the human brain non-invasively. Recent studies have investigated altered neurometabolite levels in migraine patients during interictal periods and have presented evidence of both, increased GLX levels in the occipital cortex  separately for each of the two MRS voxel regions (THAL and OCC) to detect differences between migraneurs and HCs. Relationships between local GABA and/or GLX concentrations and pain measures were determined using a Spearman correlation. Statistical significance was set at p < .05.Mann-Whitney tests (MWU) were performed on each MRS measure [GABA+/Cr, GLX/Crp > 0.7)) were included in the statistical analyses. Quality control of the MRS spectra excluded 4 patients and 3 HCs from the GABA thalamus, GLX thalamus and GLX occipital analyses, as well as 2 patients and 1 HC from the GABA occipital voxel.Originally 19 migraineurs and 18 healthy controls were scanned using PRESS and MEGA-PRESS sequences. After careful examination 4 migraine patients were removed for the following reasons: One patient due to the presence of ninety headache days during the observation period making a chronic migraine or medication overuse headache the likely diagnosis, two patients due to a lack of any migraine attacks during the observation period, and one due to recurrent aura symptoms. Exclusion of four migraine patients did not affect the group statistic: Fifteen migraine patients  and fifteen control subjects . There were no significant correlations between pain measures and BDI scores (p > .05).Within the migraine group both average pain intensity and number of headache days were both positively correlated with the MIDAS score  and OCC  voxel locations .MWU tests revealed higher levels of Glx/CrThe purpose of this study was to further elucidate the role of the neurotransmitters GLX and GABA in migraine. We specifically investigated local GLX and GABA concentrations in the occipital lobe including the primary visual cortex, and the right thalamus of migraine patients and HCs. Migraine patients had increased GLX levels in both the occipital cortex and the right thalamus, but showed no group differences in GABA in these two regions. Within the migraine group, no association between neurotransmitter concentrations and pain intensity or disability scores were found.Our results support recent findings indicating that higher regional GLX levels are linked to the presence of migraine . ZielmanThe thalamus, our second region of interest, is known to play a crucial role in relaying not only nociception, but almost all sensory modalities , 18. DurInterestingly, increased GLX levels have also been observed in other pain conditions . Harris With respect to GABA, several studies have investigated local GABA concentrations in migraine patients. Bigal et al. reported no significant differences in occipital GABA concentrations between migraine patients and HCs . When poTaking all studies investigating local GABA concentrations in migraine patients into account, the results are not yet conclusive. The studies conducted so far looked at similar group sizes and age ranges, as well as cohorts with female predominance. Furthermore, all patients were investigated interictally. However, there were differences with respect to data acquisition, especially voxel placement, and migraine subtypes. As outlined above, our data do not support the notion of altered GABA levels in the occipital lobe of patients with migraine without aura and we speculate that altered GABA levels in that region might either be specific to migraine with aura or a characteristic of the migraine attack, but not of the interictal state.Importantly, GABA has been found to be decreased in several other pain conditions such as fibromyalgia, diabetic neuropathic pain and trigeminal pain. Decreased GABA levels were found in the insular cortex of fibromyalgia patients  and patiThere are several limitations in our study that need to be pointed out. One drawback of this and other studies is the cross-sectional nature at a time point outside the actual migraine attack. As we measured GLX interictally, it cannot be derived from our data, if the elevated GLX level is a rebound phenomenon of a migraine attack, or if it is permanently elevated and facilitates nociceptive transmission. It will be of major importance to assess GLX and GABA levels during a migraine attack (or the day before), with the option to also account for laterality effects, or even longitudinally in- and outside a migraine attack to assess dynamic changes in neurotransmitters as they related to the pain event. Furthermore, with respect to headache frequency the group was rather heterogeneous, with number of headache days ranging from 2 to 40 (within 3 months). In future studies it will be important to investigate more homogeneous (and larger cohorts) to capture potential associations between neurotransmitter ratios and disease burden.Another drawback from a methodological point of view is that GLX reflects both glutamate and glutamine levels. One might criticize that our interpretation of local hyperexcitability is based on the assumption that increased GLX levels are primarily caused by glutamate rather than glutamine, which is not necessarily the case. However, glutamate is one of the major components of the glutamic acid cycles taking place in both astrocytes and neurons, as such GLX is likely to also reflect the glutamate pool and/or turn around. Higher field strengths hold promise to separate both metabolites which will be helpful to further shed light onto the underlying pathophysiology .We report increased GLX levels in the right thalamus and occipital cortex in migraineurs, but no changes in local GABA levels, supporting an extended network of cortical hyperexcitability.We propose that thalamic GLX plays a role in the pathophysiology of migraine, but the full relevance of both neurotransmitters remains to be elucidated. Further research is needed to investigate the role of GLX-GABA-ratios in more depth, particularly over time and within larger cohorts, with migraineurs with and without aura and possibly other subgroups, since different pathomechanisms might play a role in migraine subtypes. It will also be interesting to relate thalamic metabolite levels during the migraine attack not only to headache intensity, but also to decreased pain thresholds, as well as phono- and photophobia, symptoms often present during migraine attacks, indicating altered multisensory perception.


Neighborhood disorder has received attention as a determinant of health in urban contexts, through pathways that include psychosocial stress, perceived safety, and physical activity. This review provides a summary of data collection methods, descriptive terms, and specific items employed to assess neighborhood disorder/order.The proliferation of methods and terminology employed in measuring neighborhood disorder (or neighborhood order) noted over the past two decades has made related studies increasingly difficult to compare. Following a search of peer-reviewed articles published from January 1998 to May 2018, this rapid literature review identified 18 studies that described neighborhood environments, yielding 23 broad terms related to neighborhood disorder/order, and a total of 74 distinct measurable items.A majority of neighborhood disorder/order measurements were assessed using primary data collection, often relying on resident self-report or investigatory observations conducted in person or using stored images for virtual audits. Items were balanced across signs of order or disorder, and further classification was proposed based on whether items were physically observable and relatively stable over time. Exposure Science in the 21stCentury: A Vision and a Strategy report released in 2012 by the National Research Council (NRC) pointed out a need for more comprehensive exposure data collection procedures that include environmental and community characteristics in addition to individual-level exposures [Neighborhood conditions are increasingly recognized as having an important impact on the health of neighborhood residents beyond what can be explained by individual-level characteristics alone . Neighboxposures .As the body of literature on neighborhood characteristics has grown, so has the list of terms used to describe these characteristics, and several distinct classification schemes have been proposed •, 10–12.Neighborhood disorder/order has emerged as a particularly prominent term that is cited in a large collection of health-related research •, 10, 17In this review, we aim to provide an orientation to some common terms used in describing neighborhoods, including broader terms related to the disorder/order spectrum and the specific items measured to characterize these terms. This will help contextualize current findings and guide the description and consolidation of measurement strategies which to date have been highly variable.A rapid review of the literature on neighborhood disorder and health was conducted to identify common terminology and to provide guidance on measurement options relevant to future data collection for neighborhood-scale investigations globally.Social Science and Medicine in 2018. Informed by this search, cited articles with similar and related terms were also identified.To begin the search, the terms “neighborhood disorder” and “physical disorder” were in turn entered in a search box that was restricted to article titles only on the National Center for Biotechnology Information (NCBI) web database, PubMed. Peer-reviewed English language articles published from the year 1998 through May 2018 (20 years span) were then selected through a snowball approach  startingInclusion criteria were 1) assessment of neighborhood disorder/order and related terms using measurable items (or descriptions) via primary data  and/or secondary data sources and (2) complete information about assessed neighborhood characteristics   of each other. For example, Zandieh, Martinez  measuredFollowing this initial extraction of items, the team of authors developed through consensus a stratification system based on three ways to divide the items: 1) order/disorder, whereby each item was determined as indicating either order or disorder; (2) physical/social, whereby each item was assessed for whether it would be apparent through observing the physical environment or through social dynamics; and (3) temporary/stable, whereby each item was assessed for likely short-term variation  or relative stability . This scheme to stratify items was devised with attention to both capturing a range of positive and negative aspects of urban areas, as well as to show how the nature of items might restrict our options for measurement. For example, physical factors such as litter and graffiti may be more suitable to systematic observation, whereas social dynamics such as trust in neighbors and community unity may not be as readily observable by investigators using virtual or even in-person audits. Although all aspects of neighborhood disorder in general have social causes and psychosocial consequences, not all are detectible from the visible features of the environment. Finally, our classification of items as relatively temporary versus stable is relevant to reliability in capturing a state of the environment such as noise or litter which can vary throughout the day or week. Further refinement to our assessment of which items are stable may be particularly well captured through carefully timed, repeated in-person audits. Where short-term fluctuations are relatively large, the timing of virtual audits that rely on available imagery may be an important limitation. Likewise, self-reported neighborhood characteristics that generally rely on observations over an unspecified period may mask important variation over time. Stable items such as deteriorated buildings may be more reliably observable across a range of data collection techniques, while still being amenable to deliberate community investment efforts such as urban redevelopment  used to describe neighborhood environments with a total of 74 specific items measured to assess them  yielded the following results: 43 items described During the categorization of the 23 neighborhood disorder/order related terms identified , we noted that different data collection methods were varyingly suited to certain groups of street-level items. For example, relatively stable items and those capturing aspects of the physical environment are amenable to data collection using virtual audits, whereas social disorder and related social environment characteristics are more amenable to data collection using self-report or ecometric  measures. Across data collection approaches, we note the potential to characterize a spectrum from items signaling order/care to those signaling disorder/deterioration.The broad range of terminology obtained from this brief review is important to understand given the rapid growth of interest in measuring and describing neighborhood characteristics. A majority of neighborhood disorder/order measurements were assessed using primary data collection, often relying on resident self-report or investigatory observations conducted in person or using stored images for virtual audits. Items were balanced across signs of order or disorder, and further classification was proposed based on whether items were physically observable and relatively stable over time.Research focused more on items posited to be stable rather than temporary. Empirical observation can be used to refine our classification of which items are observed to exhibit stability across months, years, and even decades.Neighborhood disorder, often broken down into two distinct constructs  , 36, is Even though our snowball sampling was initiated with the terms physical and neighborhood disorder, we did not include only studies using these specific two terms. The methodology employed entailed actively searching for and reviewing papers that used synonymous or related terms to describe neighborhood environments. We are, however, aware that this strategy made it more likely than not to capture articles that employed these two specific terms, so the proportions of studies under each term in Table Planned neighborhood observations may benefit from considering whether aspects such as the temporal permanence (temporary/stable) and the physical observability  of the specific items is well matched to the measurement strategy, and considering strategies to improve the accuracy and precision of these measurements. As physical disorder/order assessment is extended to new settings, individual items may need to be assessed for differential item functioning and for alignment with what residents understand as representing physical disorder/order. For example, vegetation may be an indicator of disorder in rural settings but an indicator of order in urban settings. Also, graffiti could in some instances be part of urban renovation in informal settlements and may be considered as art potentially indicating order. Hence, certain items may need to be adapted prior to measurement depending on the setting. In addition, many items relevant to physical disorder/order incorporate subjective evaluation such as distinguishing between graffiti and a mural based on aesthetic value and inferred purpose, further rendering the systematization of protocols more challenging.The current rapid review provides an orientation to the data collection methods, terms, and items commonly used in health-relevant research on neighborhood disorder/order. However, our focus on title searching followed by a snowball approach to expanding the pool of included articles was not comprehensive, and there may be additional available terminology and measurable items that warrant consideration for future work describing neighborhoods. Although the included articles suggest a wide range of terms and items have been used, this review may have omitted literature with relevance to the subject matter and thus underestimated the heterogeneity of terms and items used.Understanding the influence of neighborhood disorder/order on population health is challenging due to the diversity of terms and items used. Clear definitions and consolidation of terminology in the neighborhood disorder/order literature would facilitate comparisons and synthesis across related studies. Efforts toward standardization of research and terminology on the neighborhood disorder/order concept may benefit from consolidating measurement items within our proposed strata, as well as refinement of how items are classified and empirical investigation of how items are most reliably measured. Where specific settings require the inclusion of more novel or tailored items, these could be used alongside a common set of items to ease comparisons across settings and clarify the added value of setting-specific additions.


These animal models should have direct biological and translational relevance to the underlying disease they are supposed to mimic. Aging dogs not only naturally develop a cognitive decline in many aspects including learning and memory deficits, but they also exhibit human-like individual variability in the aging process. Neurodegenerative processes that can be observed in both human and canine brains include the progressive accumulation of β-amyloid (Aβ) found as diffuse plaques in the prefrontal cortex (PFC), including the gyrus proreus , as well as the hippocampus and the cerebral vasculature. Tau pathology, a marker of neurodegeneration and dementia progression, was also found in canine hippocampal synapses. Various epidemiological data show that human patients with neurodegenerative diseases have concurrent intestinal lesions, and histopathological changes in the gastrointestinal (GI) tract occurs decades before neurodegenerative changes. Gut microbiome alterations have also been reported in many neurodegenerative diseases including Alzheimer’s (AD) and Parkinson’s diseases, as well as inflammatory central nervous system (CNS) diseases. Interestingly, the dog gut microbiome more closely resembles human gut microbiome in composition and functional overlap compared to rodent models. This article reviews the physiology of the gut-brain axis (GBA) and its involvement with neurodegenerative diseases in humans. Additionally, we outline the advantages and weaknesses of current in vitro and in vivo models and discuss future research directions investigating major human neurodegenerative diseases such as AD and Parkinson’s diseases using dogs.Identifying appropriate animal models is critical in developing translatable  The gut-brain axis (GBA) is a highly complex interactive network between the gut and the brain, composed of endocrinological, immunological and neural mediators, as summarized in Various studies suggest that intestinal health has a significant impact on neurodegeneration despite the anatomical distance between the gut and the brain  fibrils and oligomers  are known to possess the ability to metabolize glutamate, a well-known primary excitatory neurotransmitter, to produce GABA, a well-known primary inhibitory neurotransmitter  culture systems have been utilized to mimic both physiologic and pathophysiologic intestinal conditions in vitro contributing to defining gut-cross talk with local environment  culture systems  has emerged , including AD and PD, have well-studied clinical analogs in dogs  is a fatal, inheritable movement disorder first described in Kerry Blue Terriers  which catalyze the oxidation of aldehydes or N-heterocycles  is neurology  located in Rochester, MN, USA. AK has an equity interest in PK Biosciences Corporation located in Ames, IA, USA. The terms of this arrangement have been reviewed and approved by Iowa State University in accordance with its conflict of interest policies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Heart paper, Gomez-Stallons et al histologically present the progression of calcification and associated matrix changes in tissues obtained from postmortem valves with no prior diagnosis of aortic valve stenosis (AS) and patients with AS.Performing basic translational research to elucidate the underlying mechanisms driving calcific aortic valve disease (CAVD) pathogenesis is a critical step for the development of early intervention strategies. CAVD is a significant worldwide healthcare burden that is increased in ageing populations, and currently no therapies exist to delay or prevent its onset and progression. In their Future investigations should consider two important factors to help accelerate CAVD mechanistic discovery: terminology standardisation and optimised tissue utilisation. Standardised nomenclature of anatomical features and types of calcification is vital for facilitating cross-translational comparisons. Anatomically, human valve leaflets are divided into three portions: base, middle and tip.Access to a large bank of postmortem, non-diseased and surgical tissue is quite rare, and care should be taken to maximise the information gained from such precious samples. ‘Omics’ analysis on the two cohorts  could have led to the identification of novel proteins involved in early stages of disease. Big data analysis coupled with artificial intelligence is becoming more routine in biomedical sciences, and large ‘omics’ datasets are attractive candidates for the application of machine learning.ex vivo CT analysis of postmortem samples was not performed. Second, diffuse microcalcifications found in the base region would be impossible to detect with CT, which suffers from low spatial sensitivity/resolution (≈200 µm). This technical limitation is most likely why only nodular calcification in the middle of the leaflet was detected. The incorporation of advanced molecular imaging tools may help address this discrepancy. 18F-Fluoride ligand labelled positron emission tomography (PET) coupled with CT has been shown to identify the presence of microcalcifications in atherosclerotic plaques.in vivo applications would not have been possible, ex vivo PET-CT in the current study would have been a potential way to track clinical progression from microcalcifications/‘diffuse’ into macrocalcifications/‘nodular’. Advancement to slow the progression of CAVD has been delayed due to our inability to identify, quantify and resolve microcalcifications and the events that lead to the initial alterations in valvular biology. Future studies should implement the in vivo applications of tracer technologies and advanced imaging with PET-CT.A compelling finding is the apparent disparity between the histological analyses and the three-dimensional CT reconstructions. Histology detected diffuse microcalcifications at the base region, whereas CT detected a predominance of nodular calcification in the middle region. Two main factors should be considered to avoid over-interpretation of these results. First, CT was only performed on the surgical samples obtained from patients undergoing transcatheter aortic valve implantation (TAVI), and in vitro, ex vivo and in vivo analyses with advanced clinical imaging and systems biology will accelerate the rate of target discovery. Systems biology and network analysis can help identify novel pathways involved in CAVD pathogenesis and reveal potential perturbagens to revert abnormal cellular phenotypes. Over the past decade, a paradigm shift has occurred in the treatment of CAVD with TAVI set to outpace surgical aortic valve replacement in the coming years.


Magnetic resonance imaging (MRI) is the mainstay method for the radiological imaging of the small bowel in patients with inflammatory bowel disease without the use of ionizing radiation. There are circumstances where imaging using ionizing radiation is required, particularly in the acute setting. This usually takes the form of computed tomography (CT). There has been a significant increase in the utilization of computed tomography (CT) for patients with Crohn's disease as patients are frequently diagnosed at a relatively young age and require repeated imaging. Between seven and eleven percent of patients with IBD are exposed to high cumulative effective radiation doses (CEDs) (>35–75 mSv), mostly patients with Crohn's disease . This is primarily due to the more widespread and repeated use of CT, which accounts for 77% of radiation dose exposure amongst patients with Crohn's disease . Reports of the projected cancer risks from the increasing CT use  have led to increased patient awareness regarding the potential health risks from ionizing radiation . Our responsibilities as physicians caring for these patients include education regarding radiation risk and, when an investigation that utilizes ionizing radiation is required, to keep radiation doses as low as reasonably achievable: the “ALARA” principle. Recent advances in CT technology have facilitated substantial radiation dose reductions in many clinical settings, and several studies have demonstrated significantly decreased radiation doses in Crohn's disease patients while maintaining diagnostic image quality. However, there is a balance to be struck between reducing radiation exposure and maintaining satisfactory image quality; if radiation dose is reduced excessively, the resulting CT images can be of poor quality and may be nondiagnostic. In this paper, we summarize the available evidence related to imaging of Crohn's disease, radiation exposure, and risk, and we report recent advances in low-dose CT technology that have particular relevance. Crohn's disease is characterized by transmural inflammation that may affect any part of the gastrointestinal tract, and it is a life-long condition that relapses and remits throughout its course . ImproveThe use of imaging modalities that do not require ionizing radiation is the preferred method of reducing radiation exposure among patients with Crohn's disease. These include magnetic resonance imaging (MRI), ultrasound, and capsule endoscopy.MRI is used to a great effect to identify both acute and chronic features of Crohn's disease . MagnetiThe absence of ionizing radiation is a strong advantage of MR imaging. These advantages often outweigh the disadvantage of the relatively long time it takes to perform MR enterography and increased cost relative to CT , 12. In Diffusion-weighted imaging (DWI) can be used as a valuable sequence for the depiction of lesions and can change the MRI protocol and obviate the need for gadolinium administration. While long used in other parts of the body such as the brain, the use of DWI to assess bowel is relatively new. Increased T2 signal intensity and restricted diffusion on DWI of the bowel wall have been shown to relate to acute inflammation .The ability of DWI to differentiate between actively inflamed small bowel segments and normal small bowel in CD has been demonstrated, showing superior sensitivity versus dynamic contrast-enhanced MR . A prospHowever, improved spatial resolution to facilitate thinner image slices is required before DWI can replace gadolinium-enhanced sequences or be used as a reliable quantitative biomarker for monitoring disease activity .Recent developments in MRI technology, such as faster gradient sequences and refined receiver coils, will boost its convenience and allow for more efficient MR imaging. Not only should these advances increase patient through-put but these will also reduce motion artifact and improve image spatial resolution which are current limitations of MRI compared with CT. Being radiation-free, these advances are most significant for younger cohorts of patients with CD and those undergoing serial and repeated imaging studies for known CD .The pathognomonic finding of Crohn's disease is discontinuous and dishomogeneous transmural inflammation extending through all layers of the intestinal wall. The presence of these features forms the basis of ultrasound (US) diagnosis of Crohn's disease. Standard B-mode ultrasound is of limited utility in this setting, but some recent papers have suggested that contrast-enhanced US may be of use in determining disease activity –24, althUS assessment in patients with CD typically reveals stiff and thickened bowel walls variably associated with an alteration of normal peristaltic activity in the small bowel as well as the absence of colonic haustral folds. Contrast-enhanced, power, and color Doppler ultrasound allow for increased accuracy in the assessment of the small bowel CD . Recent Capsule endoscopy (CE), introduced in 2000 , is an iCT uses ionizing radiation in the form of X-rays, to form an image of a patient. The traditional method of image reconstruction  used by the computer to form the images is called filtered back projection (FBP). This method relies on the patient being exposed to a relatively large dose of radiation in order to create diagnostic quality images. Image noise becomes an issue at low radiation doses with FBP, and images with large amounts of noise can significantly impair the ability of the interpreting radiologist to form an accurate opinion of the images. Recent advances in the computational power and efficiency have facilitated the use of iterative reconstruction of CT images. These new iterative reconstruction (IR) techniques have some major advantages over FBP: they reduce image noise, reduce the occurrence of artefacts , and facilitate the acquisition of CT images at much lower radiation doses while maintaining diagnostic image quality .vol measured in milligrays (mGy); the dose over the total length of the scan is represented by the dose-length product (DLP) measured in mGy·cm; the effective dose (ED), measured in millisieverts (mSv), which represents the equivalent whole-body dose that would have the same risk of the biologic effect, can be derived by multiplying DLP by a conversion factor based on the CT scan parameters and the body part imaged [Three main metrics are used to estimate patient radiation exposure in CT. The radiation dose output from the scanner is represented by the CT dose index (CTDI)t imaged . A standt imaged . The radt imaged .High-dose radiation exposure leads to predictable deterministic effects that only occur above a certain threshold dose, and the severity of the injury once this threshold is reached is dose dependent; examples of this include skin burns (threshold 2 Gy) , 36 and The current widely accepted model of cancer risk from low-level radiation exposure is called the linear no-threshold model, whereby any exposure to ionizing radiation, however small, has the potential to cause harm. Several clinical studies have attempted to quantify cancer risk from CT radiation exposure , 39, butAge at the time of radiation exposure is known to be an independent risk factor for subsequent cancer mortality , and thiPatient knowledge of the risk associated with radiation exposure is generally low , and theSome published estimates of cancer risk include a 3-fold increased risk of leukaemia with 50 mGy exposure as a child , a 3-folHowever, the issue of estimation of risk associated with exposure to ionizing radiation in the diagnostic range remains extremely controversial. With increased attention to this subject in the media and more alarmingly on the internet and in social media, physicians must ensure that misinformation does not lead to situations where clinically indicated CT scans are being refused by patients because of exaggerated fears of developing malignancy.Medical imaging now accounts for approximately 50% of total population radiation dose , and CT CT imaging as an alternative of MRI and ultrasound is often used for imaging in Crohn's disease due to its availability, accessibility, familiarity, rapid acquisition time, and ability to evaluate mural, extramural, and extraintestinal manifestations in a single examination . There aCTE is indicated in symptomatic patients, older patients (over 35 years old), and when there are contraindications to MR imaging . ConventLow-dose CTE using iterative reconstruction techniques  has been found to be sensitive and specific for the detection of active inflammatory changes of CD while utilizing radiation doses significantly lower than those associated with conventional techniques.  There arWhile there is no standard definition for what constitutes a low-dose abdominal CT protocol, we consider scans where the effective dose delivered approaches that of a standard abdominal plain film or KUB radiograph to be a low-dose CT examination. There have been huge strides made recently in the attempts to reduce the radiation exposure to patients from CT. Dose reduction techniques include automatic tube current modulation , truncatAn example of parameters for a low-dose abdominal CT protocol at our institution is shown in Low-dose CT lends itself well to thoracic imaging, partly due to the high inherent tissue contrast in the lungs. Low-dose CT in the abdomen and pelvis is challenging due to similar densities of adjacent structures and little difference between the attenuations of normal and pathological processes that can be easily obscured by increased image noise in the low-dose setting. For example, the identification of subtle stranding of the fat or prominence of the vasa recta associated with inflamed loops of small bowel is sometimes vital in the detection of active disease. Image noise in low-dose CT images may potentially impact detection of these subtleties.New reconstructive algorithms, termed iterative reconstruction, use a more complex process of image formation from raw projectional data by taking into account the scanner geometry and noise statistics and in some cases mathematical models to incorporate the shape and nonlinear polychromatic nature of the X-ray beam, the focal spot geometry, and the three-dimensional shape of the voxels. This more computationally intense method of image reconstruction results in lower levels of image noise, and therefore, the CT scans may be acquired using a reduced amount of radiation while maintaining equivalent image quality. Hybrid IR methods blend FBP with a percentage of iterative reconstruction whereas pure model-based IR is a fully IR-based image reconstruction algorithm. Many IR algorithms have been shown to be reliable for image reconstruction in a number of clinical settings including but not limited to cystic fibrosis , urolith1Iterative reconstruction methods for low-dose CT rely on the modelling of statistical characteristics in the image domain. The current methods for this direct processing of reconstructed images lead to significant amounts of image noise. Innovative application of deep learning technology has demonstrated a great potential of deep learning for noise suppression, structural preservation, and lesion detection at a high computational speed for low-dose CT imaging . This de∗, Siemens Healthcare, Erlangen, Germany), with the standard filtered back projection (FBP). It was found that half-dose CT datasets reconstructed with SAFIRE∗ maintained acceptable image quality compared with full-dose CT datasets reconstructed with FBP [A recent retrospective study comparing a novel IR algorithm improved sinogram-affirmed iterative reconstruction (SAFIREwith FBP . The IR While preliminary low-dose protocol optimization can be performed with anthropomorphic and quality insurance phantoms, individual patient size characteristics, such as body weight, body-mass-index, and effective diameter, can readily change the performance of some dose-reduction tools. As iterative reconstruction algorithms are nonlinear, results from phantom measurements will not predict performance in humans. Also, the alteration of low-dose protocol parameters is not usually feasible during routine clinical practice because adequate diagnostic image quality must be ensured for all CT studies. This problem has led to the development of simulation tools that subsequently simulate low-dose data from clinically acquired high-dose scans allowing clinicians to improve low-dose protocols using patient data acquired during clinical practice .This tool has been used to determine the lowest achievable radiation dose using iterative reconstruction for CT imaging of the appendix in young adults . A 1.0 mThe projection data from previously acquired patient scans enable researchers to optimize the performance of iterative reconstruction algorithms. With standardized data sets, researchers from any discipline could evaluate IR algorithms against the results of competing methods, helping them to more rapidly determine which methods optimally reduce radiation dose .With the number of CT study acquisitions increasing annually, it is paramount to further develop innovative dose reduction tools while expanding the utility of abdominal CT diagnostics.Another important aspect of low-dose CT acquisitions is patient positioning. A recent study investigated the effect of patient off-centering in human cadavers . FailurePatients with Crohn's disease are susceptible to high cumulative radiation exposures, particularly patients with recurrent disease and those who require steroid administration or surgery. In order to minimise radiation exposure to patients with Crohn's disease, imaging methods which do not entail ionizing radiation need to be used where possible. Nevertheless, there is a continuous global trend towards increased use of CT in medical imaging which is particularly relevant for patients with Crohn's disease who are frequently young at diagnosis and require lifelong imaging . Recent


This paper demonstrates how implicit cultural evolution theory (CE) is used in adaptive management of grassroots campaigns of resistance against environmentally destructive industry and government to facilitate sustainable outcomes. For an action to be sustainable, it must be stable against political pressures. By bringing attention to the effects of social transmission—recruitment to a cause, learning across campaigns, and the transmission or cultivation of solidarity sentiments—cultural evolution presents a framework for tracking social dynamics essential for the sustainability of resistance projects. This is illustrated with examples from direct action grassroots activism in First Nations communities in northern British Columbia, Canada in the context of fights against unsustainable industrial projects. Specifically, grassroots activists work with an implicit CE theory of social transmission of values that posits that expansive, large-group organizing can get large numbers moderately committed to cause but that organizing focusing on small groups is more successful at transmitting intense commitment and adherence to First Nations norms. In the case of direct action resistance, such intense commitment is more vital than numbers for success. Further, grassroots activists have self-consciously developed institutions for the rapid transmission of policy innovations, accelerating the constructive evolution of tactics. Communities successfully engaging in such direct action where I have conducted field work include Unist’ot’en, Gitksan, Tsimshian, Tahltan, and Haida communities , Nlaka’pamux , and Nuu-chah-nulth (Clayoquot Sound). Yet these early campaigns also came with cross cultural conflict and cross purposes, particularly as First Nations concerns were not universally recognized amongst non-indigenous activists.Activist organizers are concerned with educating people about causes, motivating them to participate, and inculcating commitment levels sufficient to overcome resistance and endure sacrifices particular to the campaign and strategies. These are questions of social transmission, the subject of CE theory. While not framed in academic terms, activist organizers express sophisticated understandings of social transmission dynamics and their adaptive management. They discuss issues of match of medium to message, mechanisms of direct social transmission through explicit messaging and leading by example, and more indirect mechanisms of social transmission. The latter is exemplified by the bonding that arises through participation in direct action; socially transmitted action participation creates the circumstances where individuals change their beliefs and values, and thus future behavior. This is the purposeful management of cultural evolution. Many activists with whom I communicated expressed specifically a tradeoff: focus on transmitting high commitment levels through practices which diffuse slowly vs rapid transmission and higher adoption of behaviors and beliefs which generate lower commitment levels. This section describes this working model in the negotiation of cultural evolution and is a synthesis of beliefs I found to be widely held amongst direct action-oriented activists, expressed in interviews and based in many cases on personal experience.Organizing around large groups is held to lead to shallow commitment and the threat of cooptation via large NGOs. Small-group organizing, however, is held to facilitate higher levels of solidarity amongst more tightly knit activists, more willing to engage in high sacrifice direct action and less likely to be coopted. Where campaign goals necessitate high levels of individual sacrifice, grassroots organizers express the belief that emphasizing small-tight groups is necessary to socially transmit intense commitment.Large-scale organizing emphasizes getting information to many and actions requiring relatively lower amounts of individual sacrifice—street demonstrations, letter writing, boycotts, fundraising, etc. Large numbers of solidarity partners create economic threats through boycott and threats to politicians up for re-election. Campaigns emphasizing expansive organizing can access more donors, generating more income. These financial resources make possible a professional staff and researchers. It is very hard, however, to make a rapid jump to a large infrastructure, making collaboration with an existing NGO useful if not necessary for large-scale organizing where time is critical. Such large NGOs bring developed infrastructure, expansive social networks, and funding. This can certainly help grassroots campaigns but can also lead to cooptation as NGOs hijack social mobilization and media attention with large budgets, devoted media professionals, and established media relationships. NGOs juggle multiple priorities. They balance mission success with their own institutional survival. It is a concern that large NGOs will spend too much income on institutional support rather than on the mission. Funding is based on the appearance of success to donors, creating economic pressures to assert fast victories and take responsibility for them. Well-packaged compromises based on cosmetic success can generate such appearances of success, serving the fundraising needs of the large NGOs but failing to satisfy grassroots standards of success. Where the calamities entailed in compromise are not directly visible to non-locals, this creates a greater willingness for NGOs supported by non-locals to compromise. Describing this dynamic, I have heard many activists use the invective, “More income oriented than outcome oriented”.By commandeering attention, NGOs divert money flows from grassroots campaigns and cause the supporting solidarity network to dissolve once cosmetic success has been achieved. Where there are conflicts in goals and lack of institutions for maintaining grassroots control, this can lead to unwanted compromise. For example, sovereignty may not be a sincere priority for urban NGOs, setting up a conflict. While there is an acknowledgement that NGOs vary in respect for indigenous grassroots leadership, conversations with grassroots activists across a variety of settings reveal general cynicism about large NGOs.In response, many grassroots activists tightly control and minimize involvement of NGOs and cultivate smaller, tighter groups for actions. Such campaigns do well by relying on direct action tactics that can succeed with smaller groups of highly committed individuals, like occupations of transport choke points or proposed industrial sites. Such actions rely more on individual sacrifice than numbers for success.With smaller groups, organizers can better filter for people with higher levels of commitment. When actions need to be done clandestinely, smaller groups are also less easily surveilled, and as one spends more time with each member, it is easier to know each other, decreasing the likelihood of infiltration. However, at least as important as these logistical considerations are the experienced feeling of bonding that comes with such small group organization, especially with shared sacrifice. This is the indirect social transmission of commitment. In conversations and interviews, many independently reported how engagement together in intense actions helped them bond to small activist groups and inspired adherence to sacred values, engendering greater levels of willingness to sacrifice for shared cause. These intense bonding activities can take many forms, from a confrontational action, like a pipeline blockade or building lock down, to sacrifice of time and effort in the construction projects such as at Unist’ot’en Camp and other occupations. Through greater willingness to sacrifice, more resistance to compromise, and strong adherence to group values (and thus First Nations objectives), such small-intense groups can potentially hold out longer against industry/government in more high-pressure circumstances. While investing in social transmission of direct action participation is perhaps slower and results in lower numbers of ‘adopters’, those who adopt are both filtered for higher commitment and induced into higher commitment through participation.Actual organizing is more complex than a simple dichotomy, often involving mixed strategies. Small and large group organizing are not necessarily opposed. Work defending First Nations traditional territories often involves small groups of intensely devoted activists aided by extensive supporter networks, in managed coalition with NGOs. Small groups can be formed in large-scale actions. Large-scale actions can use the space and time provided by small-scale direct action to potentially mobilize large numbers for change at the ballot box. Large support networks can help maintain visibility for front-line actions, pressuring police to act within the rule of law and reducing the risk of violence against front-line activists.Under what circumstances may a strategy succeed? Time pressure, levels of sacrifice, and choke points are considerations. Where industrial action can be achieved quickly, it is often necessary to engage in direct action to prevent irreversible destruction. In such instances, legal cases alone are inadequate. Legal ambiguity allows for large-scale destruction to proceed during the slow, strategically drawn-out process of court proceedings. Once a company builds an oil pipeline, it is far harder to fight the flow of oil. In these spaces where street protests are too slow to mobilize or have effect, ‘illegal’, high risk, confrontational action is often required.‘Choke points’, where industrial processes pass through a small area, create opportunities where small groups of actors can have large effects. If a forest is only accessible through one logging road; obstructing such a road could block a logging operation. Pipelines going through mountains only have a finite number of possible routes. If there are choke points, then small numbers of devoted actors can have powerful effects. If solidarity commitments are shallow, industry/government erodes resistance by increasing individual consequences . Where government can inflict severe individual consequences, in such cases commitment is more important than numbers.While CE and ‘social learning’ are not terms bandied about amongst activists generally, in attending to recruitment and how action participants acquire commitment, grassroots organizers attend to social transmission dynamics in adaptively managing campaigns: these are implicit theories of cultural evolution. Cultivation of solidarity and commitment to values both are themselves socially transmitted and result from recruitment to specific  actions. Framed in terms of CE, participation in high-sacrifice direct action diffuses slowly for a given investment in transmission, limited by the intimacy necessary for transmission. It, however, both directly transmits high commitment and sets up the circumstances where people acquire yet higher commitment. In contrast, large-scale campaigns rely on fast, extensive diffusion of values and elicit lower commitment. While large numbers can facilitate powerful actions, lower individual commitment limits what actions can be successfully pursued. Grassroots campaigns exhibit adaptive management of these processes through ongoing attention to campaign needs and support, shifting investment in large- or small-scale aspects of campaigns.Activist theory of small vs large group organizing closely parallels three bodies of social-science research: the works of Ostrom, Whitehouse, and Atran. While these theories do not reference cultural evolution, they all describe dynamics of social transmission and collective maintenance of values and behaviors.Ostrom’s SES framework identifies design principles that facilitate the evolution of institutions which successfully manage common pool resource problems Ostrom . These pdivergent forms of bonding amongst religions, associated with different society scales  rationally update their beliefs based on evidence. However, under the combination of conditions where a rhetorical position is a marker of identity, group identity is held strongly, and there is a perception of ‘group threat’, people react emotionally to offers of negotiation or to information that threatens the truth value of the rhetoric as a ‘group threat’. Experiencing group threat, individuals amplify group markers—in this case, values. Emotional provocation is hard to avoid around sacred group markers, and when thus agitated, the individual will counter-intuitively react with an amplification of values or belief rather than with compromise or incorporation of new information. This parallels earlier anthropological findings . Instead of large NGO support, activists relied on small-group organizing and direct action, including tree sits and other forms of obstruction. While the Clayoquot protests resulted in arrests, the kind of treatment received was different in the less populated Elaho, with more severe violence against activists and severe legal repercussions Blunt . HoweverOne of the latest large-scale campaigns has been the Great Bear Rainforest Initiative to protect the temperate rainforest of the central coast of BC, spanning the traditional territories of many First Nations Macleod . Formal The Unist’ot’en Camp land occupation is the most well known of the current wave of First Nations grassroots campaigns Frost . Their tA particularly impactful tool of the Unist’ot’en has been hosting gatherings combining volunteer work, direct action training, and activist networking. The first annual Action Camp was organized in 2010 so the Unist’ot’en themselves could learn from other experienced activists, including previous blockaders in other territories. These yearly gatherings serve many functions: the horizontal transmission of skills and techniques for activism, the active recruitment of new supporters for Camp, and bonding of activists through shared investing of time and energy in construction projects. Action Camp itself is a local adaptation of the practice in the wider activist community of gatherings for horizontal information/skill sharing. Activists come together to share lessons from their experiences, allowing the accumulation and synthesis of useful information.Learning from each other’s successes and failures facilitates the constructive evolution of practice.Participating in construction work builds community, motivating people to return, contribute further, and bring friends. As activists stay to participate in the ongoing year-round occupation in sometimes tense interactions with pipeline workers, sense of commitment intensifies. Many with whom I have talked expressed how the shared experience of volunteering served to increase their sense of commitment to shared group values of environmental protection and de-colonization.The pattern of First Nations land occupations asserting sovereignty continues to be replicated across northern BC, with each subsequent manifestation picking up on lessons from past actions. The Unist’ot’en Camp land occupation has served as a model for other successful occupations, like the Lelu Island occupation by Gitwilgyoots (Tsimshian) and the Luutkudziiwus (Gitksan) occupation at Madii Lii. In these cases, there is a similar dynamic where a geographic bottleneck means that a specific site can be occupied by a smaller group of devoted activists, engaging in community-focused construction projects on proposed industrial sites. As Madii Lii is quite close to Gitksan communities in the Hazleton, they have been able to strongly emphasize use of the blockade camp for cultural revival as they successfully assert control over hunting in their territories while also preventing pipeline work. The Lelu Island occupation particularly mirrors the Unist’ot’en case, where a bottleneck allows a small group to fend off an enormous industrial project. Pursuing direct action occupation with small numbers, the Lelu Island action successfully delayed the $30 billion Petronas LNG export facility to the point where Petronas gave up on the project Frost . Both caThe campaigns learn from each other strategies for adaptive management of recruitment and commitment. They balance investment in small-group and large-group organizing to maintain sufficient levels of recruitment to the small circle of highly committed activists at camp and to the wider networks necessary to support the campaigns. They also invest in practices of information exchange to accelerate social learning amongst campaigns. By strictly regulating and sometimes rejecting involvement of NGOs, they maintain local control and resist compromise.CE is the theory of changes of behavior through social transmission. Other models that do not focus on how information, behavior, and sentiment are socially transmitted miss critical details of the unfolding of grass roots activism. While an individual decision model may capture how individuals make decisions based on their values, a CE approach emphasizes how people acquire those values. The adaptive management of campaigns illustrates how attention to values transmission and recruitment is central to mission success. In cases like those of Unist’ot’en Camp and Lelu Island, industry work crews were ready and waiting for years to carry out work. It was the ongoing and determined resistance of front-line activists that held off construction and avoided irreversible destruction. This commitment was cultivated using strategies of campaign organizing learned over a history of blockades and occupations and paralleling several threads of social science research. As with other blockades in Haida, Tahltan, Gitksan, and Squamish territory, waiting for legally sanctioned resistance to run its course would have been environmentally devastating. Reliance solely on large-scale organizing would have thus been unlikely to provide the intensity of emotional commitment necessary for direct action. While Clayoquot demonstrated how large groups could be motivated to offer sacrifice, the remoteness in many of these other cases and the levels of sacrifice necessary make such mobilization less plausible. It is a different level of sacrifice to risk a week in jail with hundreds of comrades and small fines than physical violence and years in jail on felony charges, as is sometimes at risk in more isolated areas.There are many variables in a campaign that shape how much sacrifice is required of individuals for success. A bottleneck may create a situation where a small group willing to engage in high sacrifice can hold off an enormous industrial project long enough for legal processes or large-scale political organizing to enact longer term change. This is illustrated by the Unist’ot’en, Lelu, and Madii Lii cases. A campaign closer to a more privileged white urban community may be able to concentrate more on rapid large-scale organizing tactics, as less severe consequences are likely to be applied to them for a given level of resistance. In a case where a specific industrial action may be carried out rapidly with irreversible consequences, small group direct action tactics may be essential. It is also certainly the case that shifts in the energy economy have played into the hands of grassroots activists. In the case of Lelu, a primary justification given by Petronas for withdrawal was lower prices of natural gas. Direct action bought time for the changing economy to stop the project.The legal circumstances of non-treaty First Nations in Canada are an important consideration. The Delgamukw and Tsilhqot’in rulings established strong rights for non-treaty nations. These nations were also some of the last to be colonially dominated in North America. In many cases, their cultures have been maintained remarkably well and their formal government persisted with continuity. The Canadian government still allows industrial actions in violation of these rulings, forcing Nations to go to court to defend their rights. The fact that these rulings exist, though, means that direct action has greater perceived legitimacy and potentially can achieve positive results in shorter spaces of time when done in parallel with law suits. Direct action tactics could play out differently in places with less rule of law or legal rights.Small-group organizing has the drawback that the scope of individual campaign networking is small, limiting the transfer of tactics. Practices like Action Camp have developed over the years addressing this problem, to support recruitment and information transfer, accelerating the positive evolution of direct action strategies and the spread of their use.For non-indigenous solidarity partners, it is important to see how the relative speed of transmission of messages that urban environmental networks access can be a two-edged sword. Urban, non-indigenous activists can numerically overwhelm an action with rapid recruitment via urban-centered media. Non-indigenous activists wanting to challenge colonial legacies need to act collaboratively rather than in a way that perpetuates racially structured power. The rise and ubiquity of First Nations protocol practices are a response to this, helping shift the culture of nonindigenous urban environmentalists to respect First Nations rights and leadership. It is now de rigor to begin any sort of progressive public gathering in BC with protocol, acknowledging that the meeting itself occurs on unceded First Nations territory.In these cases, solidarity between First Nations and non-indigenous environmental activists has led to successful outcomes for both sides, with some growing pains with regards how to work together. A fear sometimes expressed in environmental circles about investing everything in such collaborations regards what happens when there is environmental conflict that does not have a First Nations group coming forward to defend the land with a clear territorial claim. A current example is Digby Island Frost . Digby pWhile large urban NGOs have been criticized for perceived sidelining of First Nations, small local NGOs like the SWCC have supported First Nations leadership. The big NGOs also to varying degrees are adapting to the shifting landscape of sentiment and law with more explicit support for First Nations leadership. The Great Bear Rainforest Initiative, while critiqued, critically involved First Nations voices in negotiations. Some, like the David Suzuki Foundation, have been quite active in supporting First Nations voices and are well received for that. It is likely that as grassroots First Nations activists achieve more successes that large NGOs will continue to strategically adapt to support First Nations.Social transmission of grassroots strategies is not simply blind replication. Details are learned from different sources and local context requires innovation and ongoing experimentation. The Madii Lii camp of the Luutkudziiwus followed and was both inspired by and able to learn from the Unist’ot’en Camp occupation. However, the circumstances were different, both geographically and socially, with Madii Lii much closer and easier to access for the clan. It is easier then for Madii Lii to emphasize use of the camp for cultural practices of the clan and de-emphasize large gatherings of non-indigenous solidarity partners. This ongoing experimentation with alternatives allows for practical ongoing research on decolonizing strategies as well as solutions that better fit local circumstances.Reality is always more complex than our simple models. The range of commitment displayed by large groups includes impressive displays of self-sacrifice. The masses willing to be arrested at Clayoquot were impressive. Likewise, at Unist’ot’en Camp, hundreds of people have over the years spent weeks or months at a time at the camp volunteering long hours of construction work. The levels of individual commitment that large groups can mobilize are not insignificant. There is also both a mix of strategies within campaigns and a blurring of levels. Large group aspects of campaigns, like Action Camp, serve as recruiting grounds for those willing to engage in more intense direct action. While differences in the experiences and effects of these kinds of actions should be recognized, we also should not hold them as completely distinct processes.While some view the Clayoquot Sound and Great Bear Rainforest outcomes uncritically as successes and most would agree that there were positive outcomes relative to the status quo, some grassroots activists and traditional hereditary leaders see failures that could have been avoided. With Clayoquot, the necessity for buying timber licenses on their own traditional territories is an example of a compromise that some feel could have been avoided. With the Great Bear Rainforest, it is too new to tell exactly how it will unfold, but some problems have already been pointed to and excluded actors feel that their views were not represented. On the other hand, actions like Unist’ot’en Camp, Lelu Island, and Madii Lii have thus far avoided compromises that were entailed in both Clayoquot and the Great Bear Rainforest campaigns.There has been a steep learning curve for grassroots activists in navigating relationship with NGOs. With attention to maintenance of First Nations leadership, NGOs can be very helpful in generating support networks. The positive outcomes in the cases of the Madii Lii and Lelu cases were in part facilitated by the help of local NGOs committed to First Nations leadership and agency. Unist’ot’en Camp’s less formal network of supporters has been likewise enormously helpful. Large-scale organizing can be used to fundraise and gain political support in far-flung networks. The financial support can also convert high sacrifice situations into lower ones. Unist’ot’en Camp, with financial support from a large network of donors, built winterized buildings to house activists comfortably year-round, lessening their sacrifice to manageable levels. In the direct action campaigns, visibility maintained by a large network of supporters helps keep industry and police behavior in check. Support from larger groups can shift away some part of the burden faced by front-line activists.Several threads of behavioral studies highlight the increased ability of small-group organizing to cultivate tight bonds that facilitate high levels of altruism and adherence to group values. Observation in the context of First Nations grassroots struggles in northern BC replicates these findings. The practice-based theory of small- vs large-scale organizing examined in this paper highlights the increased efficacy of working in small groups in contexts of direct action resistance requiring large individual sacrifices. First Nations led grassroots organizations negotiate the social transmission of values, recruitment, and strategies of resistance amongst causes, adaptively attending to the details of these social learning processes as campaigns unfold. This is adaptive management of CE. Using small-scale organizing of direct action campaigns, they have been able to successfully transmit amongst activists sufficiently high levels of solidarity to achieve group objectives in often quite stressful circumstances requiring large sacrifice. By relying less centrally on large-scale organizing via urban centered NGOs, they have been able to maintain local control of the campaigns, making unnecessary compromise less likely. In the case of remote communities with less resources, direct action is often necessary to prevent irreversible environmental damage that legally sanctioned tactics would be incapable of stopping. Matching medium to message, the necessity for high commitment suggests, then, small-scale organizing.Valuable lessons have successfully been passed on from campaign to campaign. Institutions of transmission have developed in these communities, increasing the ability to copy and modify successful strategies from context to context. Grassroots activists not only adaptively manage social transmission of participation and commitment, but manage the process of strategy evolution itself via strategy exchange institutions like Action Camp. Attention to social transmission dynamics (CE) is leading to remarkable successes in fights for environmentally and politically sustainable outcomes.CE does not supply a cookie cutter solution, simple conclusions like “small-scale organizing is better”. Rather, CE reveals elements that need attention as campaigns unfold. In this case, it is attention to the transmission of not just information, but of commitment, requiring a matching of medium to message. One applies CE by tracking dynamics of social transmission, using this information to reshape investment in different levels of organization continuously. Adaptive management entails ongoing attending to recruitment, commitment levels required by current actions, and innovation and information flow amongst campaigns. Without a rich, practice-informed theory of social transmission dynamics (CE) of action participation, activists would not be able to successfully manage campaigns.Future research could constructively focus on the synthesis of small- and large-scale organizing.While Whitehouse’s DMR posits that highly arousing practices bond small groups, cases like Clayoquot demonstrate that large groups have been inspired to significant levels of self-sacrifice through shared experiences and values. Several research questions arise. What are the differences in longevity, stability and intensity of solidarity that arise from similar amounts of sacrifice in larger vs more intimate actions? How are large-scale events recruiting grounds for intense small-scale actions? What institutional patterns have developed for synthesizing small- and large-group organizing, and are these patterns replicated across campaigns? What are the various ways that large-scale solidarity networks shift burden away from front-line defenders? Also, while there is a common belief amongst grassroots activists that large NGOs have conflicts of interest as they juggle mission success and institutional survival and expansion, it would be a constructive future line of research to see to what extent this affects mission success, what variance there is amongst NGOs, and how this variance affects the survival, rise, and fall of NGOs.The research of Ostrom, Atran, and Whitehouse would come as no surprise to many grassroots activists. While direct action campaigns are pursued for functional goals of stopping destructive industrial action and there is clear understanding that solidarity is essential, by highlighting the function of the actions themselves in developing commitment to values, activists may be able to fine tune these actions to best facilitate solidarity.This paper contributes to the field of cultural evolution by presenting how processes of social transmission are self-consciously adaptively managed. It contributes to sustainability literature by demonstrating how processes of social transmission are in some cases vital for environmentally sustainable outcomes.


Thus, we focused on experimental studies—those in which experimental manipulation of a single gene had clear antagonistic effects on fitness components in early versus late life as Williams predicted. Experimental studies establish cause-and-effect in a way that correlational studies such as those cited by Byars and Voskarides cannot.Byars and Voskarides, responding to our review of empirical support for George Williams’ antagonistic pleiotropy (AP) theory of the evolution of aging , feel thIt is an unfortunate truth about research on humans that because experimental studies are often impossible, results are almost inevitably correlational, which in our view makes virtually any single study highly suggestive at best, but never compelling. To illustrate why, we consider one of the studies adduced by Byars and Voskarides, although we could have chosen any of the others. That study identifies numerous human alleles (or Single nucleotide Polymorphisms) pre-disposing individuals to coronary artery disease (CAD) but also conferring reproductive advantages early in life . As to tThis is a very nice study given the limitations of human research. The best that could be done with available data was done. Note, however, that one of the first lessons of statistical reasoning is that correlation does not equal causation and, yes, genomic associations are correlations. Further, their assumption about the early life CAD across human evolutionary history is supported by evidence from modern populations plus a study of the existence and extent of vascular calcification as revealed by whole body CT scans in modern Egyptians and Egyptian mummies who lived as long as 5000 years ago . Again, et al.’s study or the other studies cited by the authors. These are some very fine studies using state-of-the-art genomic analyses. We simply wanted to explain why we consider such studies less compelling as support for Williams’ AP theory than experimental studies done in model laboratory organisms with specific and purposeful manipulation of specific individual genes.Our point in noting these things is certainly not to denigrate Byars Conflict of interest: None declared.


SCOPe also incorporates and updates the ASTRAL compendium, which provides multiple databases and tools to aid in the analysis of the sequences and structures of proteins classified in SCOPe. Protein structures are classified using a combination of manual curation and highly precise automated methods. In the current release of SCOPe, 2.07, we have focused our manual curation efforts on larger protein structures, including the spliceosome, proteasome and RNA polymerase I, as well as many other Pfam families that had not previously been classified. Domains from these large protein complexes are distinctive in several ways: novel non-globular folds are more common, and domains from previously observed protein families often have N- or C-terminal extensions that were disordered or not present in previous structures. The current monthly release update, SCOPe 2.07–2018-10–18, classifies 90 992 PDB entries (about two thirds of PDB entries).The SCOPe (Structural Classification of Proteins—extended,  The Structural Classification of Proteins (SCOP) database  is a manFamily contains related proteins with similar sequences but typically distinct functions. The Superfamily level brings together protein families with common functional and structural features inferred to share a common ancestor. Near the root, the basis of classification is purely structural: similar superfamilies without compelling evidence of a common evolutionary origin are grouped into Folds, which are arranged into Classes based mainly on secondary structure content and organization  roughly once each year, in which the hierarchy itself is updated by manual curation, primarily to add new superfamilies. Manual curation of superfamilies is a key feature of SCOPe, in which proteins with similar three-dimensional structure and no recognizable sequence similarity are examined by an expert curator to determine if they possess structural and functional features indicative of homology. If convincing evidence is found of an evolutionary relationship, this is annotated in SCOPe by grouping the homologous domains into a single superfamily; if the evidence is not compelling, the domains are annotated as having a common fold but not grouped into a superfamily. Once at least one structure from each SCOPe family has been classified by a human expert, most other structures from that family are added automatically using our rigorously validated software pipeline . BecauseIn addition to adding new superfamilies, manual curation in each stable SCOPe release can also involve other changes to the hierarchy. If two formerly distinct superfamilies are discovered to be related, for example on the basis of a newly discovered structure of an evolutionary intermediate, our curator would merge the two superfamilies into one. Manual curation is also used to make changes to domain boundaries; for example, a single domain may be split into multiple domains if different parts of the domain are discovered in different evolutionary contexts ,7. FinalBased on a study of 571 recent articles that cited SCOP , we founWe prioritized manual curation of new structures by focusing on those Pfam ,20 familRecent advances in high resolution cryo-electron microscopy have contributed a wealth of novel structures . Many ofIn SCOPe 2.07, we classified cryo-EM structures of several spliceosome complexes: the first structure of the yeast spliceosome , the cases where we identified new families in existing superfamilies are also quite interesting, as in each case the spliceosome structure confirmed remote homology to other proteins that was not readily apparent from sequence alone. Remarkably, for three domains in Prp8 Figure , remote Each of the other macromolecular structures we characterized yielded a wealth of new SCOPe folds, superfamilies and families as well. The four additional spliceosome complexes include an additional 19 Pfam families that had not been previously classified in SCOPe. After classification in SCOPe, these structures yielded 10 new folds, 1 new superfamily in an existing fold and 1 new family in an existing superfamily. Although some individual proteasome subunits had previously been structurally determined in isolation and classified in SCOP, the crystal structure of the entire 26S proteasome  yielded As cryo-EM is used to solve the structures of more macromolecular complexes, we anticipate that more new superfamilies from non-globular folds will be structurally characterized and added to SCOPe, and currently classified superfamilies will expand to contain a more diverse set of structures than they currently do. The increased structural heterogeneity may pose challenges for bioinformatic analyses of the data, especially those methods that depend on structural alignments. We expect to discover more examples of domain swapping, as the greater number of inter-domain contacts will lead to more chances for this to happen, as we observed in the large complexes discussed here.More structural heterogeneity will also pose some challenges for automatic identification of domains. Although the current algorithm for automated domain classification is sequence-based and does not rely on information from structural superposition , we antiAs shown in Table Although manual curation was re-introduced to SCOPe in version 2.04 , the pro


Dear editor,Drosophila melanogaster is shown to play an essential role in unraveling the genetics of learning and memory. Various behavioral assays on Drosophila model of human neurodegenerative diseases have been employed in a number of studies. Classical olfactory conditioning, courtship conditioning, and newly-introduced method based on predator-mediated fear induction are among the most widely applicable and reproducible ones. In this letter I wish to address some critical aspects of each protocol, though the given points can be considered as a general criticism for such kinds of experiments.An urgent need for better understanding of memory is increasing as our aged population gets older and older. Extensive research on the biology of learning, memory and neurodegeneration is accelerating to meet this challenge. The classical olfactory conditioning pairs a conditioned stimulus such as an odor with an unconditioned (training-free) stimulus such as a painful electric shock, heat shock, or starvation. Usually two aversive chemicals are used in each experimental setup. One odor is associated with a painful electric shock, while the other is not. Memory of this conditioning is subsequently evaluated by investigating the fly preference between the two scents. Fly avoidance of the electric shock-paired odor is the basis for quantifying the performance indices . ThoughDrosophila predator, such as a wasp, to provoke conventional defense behaviors (Kacsoh et al., 2015[The fear conditioning protocol employs a Understanding memory in both genders is important to our society. Therefore, it would seem prudent to use a versatile sex-bias free behavioral test. Classical olfactory conditioning experiments offer many advantages where seeking the result of a genetic mutation, environmental factors, or neurotoxic agents.


Functional movement disorders are common and disabling causes of abnormal movement control. Here, we review the current state of the evidence on the use of neuroimaging in Functional movement disorders, particularly its role in helping to unravel the pathophysiology of this enigmatic condition.In recent years, there has been a shift in thinking about functional movement disorder, away from a focus on high-level psychological precipitants as in Freudian conversion theories, or even an implicit belief they are ‘put-on’ for secondary gain. New research has emphasised novel neurobiological models incorporating emotional processing, self-representation and agency.Neuroimaging has provided new insights into functional movement disorders, supporting emerging neurobiological theories implicating dysfunctional emotional processing, self-image and sense of agency. Recent studies have also found subtle structural brain changes in patients with functional disorders, arguing against a strict functional/structural dichotomy. Functional neurological disorders (FND) are common, accounting for 16% of all referrals to general neurology clinics but have historically been rather neglected in research and clinical service development [A wide variety of terms have been used to describe FNDs including ‘hysterical’, ‘conversion’ and ‘somatisation’, each with implications about the underlying mechanism. ‘Functional neurological symptoms’ is now used as a neutral umbrella term for all ‘non-organic’ symptoms which is non-judgemental and acceptable to patients. This has helped to create a shift in thinking about FNDs, away from a focus on high-level psychological precipitants as in Freudian conversion theories, or even an implicit belief they are ‘put-on’ for secondary gain. New research has emphasised novel neurobiological models incorporating emotional processing, self-representation and agency . AdvanceIn all patients who present with a new neurological symptom, the first concern is to exclude conditions requiring urgent treatment. In FND, the clinical history and examination is often clear enough to do this. If there is any uncertainty, especially as organic and functional symptoms may co-exist, structural neuroimaging such as CT and MRI can be used to exclude a co-morbid organic disorder in specific circumstances.This is particularly important where multiple disease processes produce a mixed clinical picture, or where an underlying organic process is associated functional ‘overlay’. Functional symptoms may be triggered by a ‘stressor’ which can be physical, such as limb injury, psychological or both . Elmalı In certain patients, specific imaging techniques can provide greater diagnostic certainty—an example is idiopathic Parkinson’s disease and functional parkinsonism. Functional overlay appears to be commoner than expected in patients with idiopathic Parkinson’s disease while pure functional parkinsonism seems comparatively rare , 8. The parkin gene mutation [Dopamine transporter-single-photon emission computer tomography (DaTSCAN) uses a radioactive ligand which binds to dopamine transporters and is highly sensitive to the pattern of nigrostriatal denervation characteristic of idiopathic Parkinson’s disease , 10. DaTmutation . These sRecent neuroimaging studies have implicated abnormal emotional processing, sense of agency, and top-down regulation from frontal areas as important pathophysiological components in FMD . FunctioThere has been considerable interest in how traumatic experiences and emotional factors might be involved in the pathogenesis of FMD. Voon and colleagues found that patients with functional weakness showed reduced activity in the left supplementary motor area (SMA), which is involved in movement initiation, when performing movement tasks . They alIncreased activity in the amygdala, insula and cingulate cortices may indicate FMD patients have greater involvement of emotional processing areas in movement. In 1997, Marshall and colleagues recorded regional cerebral blood flow (rCBF) of a patient with unilateral functional leg weakness . She hadA further study by Voon and colleagues in 2010 found that patients with functional weakness showed less difference in activation of the right amygdala on exposure to fearful or happy faces than healthy controls . These pIn 2018, Espay and colleagues investigated emotional processing in patients with functional tremor, comparing them with patients with essential tremor and controls in finger tapping, basic-emotion and intense-emotion tasks . PatientThese studies support the link between emotional processing and FMDs by showing altered activation of brain areas involved in emotional processing and increased functional connectivity between emotional and movement-related brain areas. This could provide a mechanism for emotional dysregulation to interfere with movement.Functional motor symptoms show some features of voluntary movement, such as distractibility and variability with attention. Despite this, patients perceive their movements, or lack of movement, as involuntary. This suggests that part of the pathology of FMDs may be related to a patient’s sense of agency. ‘Agency’ is the experience of being the cause of our own actions , 24 and Advances in functional imaging allow us to investigate this feature of FMD and identify the brain regions involved. One benefit is to show conclusive differences between the neuroimaging correlates of functional weakness and a subject intentionally feigning weakness.Voon and colleagues found reduced activation of the right temporo-parietal junction (TPJ) and reduced connectivity between it and the sensorimotor cortex and cerebellum in patients with functional tremor compared to voluntarily mimicked tremor in the same patients . AnotherBaek and colleagues used the Libet’s Clock task to assess FND patients’ accuracy in measuring their agency over the movement of a dot on the screen . CompareVan Beilen and colleagues reported decreased activity in the supramarginal gyrus in FND patients , thoughtAnother study compared patients with functional tremor, essential tremor and controls during a tremor-inducing motor task and at rest . During These results highlight the difference between patients feigning weakness and those with functional symptoms. They demonstrate differences in the activation and connectivity of a network, including the right TPJ and precuneus, which is believed to integrate sensory and motor feedback to generate a sense of agency.Burgmer and colleagues analysed fMRI activity during observation and imitation tasks in patients with functional hand weakness . They foSpence and colleagues used PET imaging to show that attempted movement of a functionally weak hand was associated with hypoactivation of the left dorsolateral prefrontal cortex, while attempted movement of a feigned weak hand was associated with hypoactivation of the right anterior prefrontal cortex . They arThere has been comparatively little research looking at the involvement of subcortical structures in functional movement disorders. Vuilleumier and colleagues used SPECT scanning to investigate patients with functional unilateral sensorimotor impairment during hand vibratory stimulation and found decreased activation of the contralateral thalamus and basal ganglia . When thSchrag and colleagues used PET to compare functional and organic dystonia patients at rest, during fixed posturing and paced movements . Both foConsiderable efforts have been made to promote the use of the word “functional” in recent times, but emerging imaging evidence suggests that replacing one dualistic simplification  with another  is not without its problems. New studies have highlighted structural changes in the brains of patients with FMDs. Morphometric MRI techniques have detected subtle changes in volume and cortical thickness, particularly in areas thought to be involved in stress-related neuroplasticity , 43•, 44Both FMD and psychological conditions such as posttraumatic stress disorder (PTSD) have been associated with changes in areas responsible for emotional processing, such as the insula, cingulate cortex and amygdala . These aAybek and colleagues used MRI voxel based cortical thickness analysis (VBCT) to show significantly increased thickness in the premotor cortex of patients with functional hemiparesis compared to controls . AnotherThere is a growing body of evidence to suggest that subtle changes in brain area volume and cortical thickness may occur in functional neurological disorders. These may be secondary changes due to limb disuse in the case of thalamic or motor areas, but the changes in cingulo-insular structures more likely reflects stress-mediated neuroplasticity. This provides further evidence linking abnormal emotional processing to the neurobiology of FMDs.Functional neurological disorders are an exciting and rapidly expanding field of research within neuroscience. Functional movement disorders are especially amenable to investigation due to the nature of the symptoms and the comparative ease of constructing experimental paradigms, and this has placed them at the forefront of research. Neuroimaging has for a long time been a part of diagnosis of functional movement disorders primarily for assisting in the diagnosis of co-morbid organic disorders. More targeted forms of imaging, such as DaTSCANs are additionally useful in specific circumstances.More recent developments in functional imaging have provided many new insights into the brain networks involved, as well as providing some supportive evidence for pathophysiological theories. Most recently, volumetric analysis has detected possible structural changes in the brains of FND patients.Caution is needed, because as with all research in people with FMD, the patients themselves are very heterogenous in terms of symptoms and co-morbidities, with a high incidence of psychiatric co-morbidities and potentially relevant early life or more recent stressors. So far imaging research in FMD has used diverse paradigms, patient types and relatively small numbers for each study. It is also important that functional imaging can only give correlations, and these are vulnerable to confounding factors. Nevertheless, there is converging evidence about the underlying neurobiology of functional movement disorders and neuroimaging will continue to play a key role as the field develops.