Temporal discrimination: Mechanisms and relevance to adult-onset dystonia

Temporal discrimination is the ability to determine that two sequential sensory stimuli are separated in time. For any individual, the temporal discrimination threshold (TDT) is the minimum interval at which paired sequential stimuli are perceived as being asynchronous; this can be assessed, with high test-retest and inter-rater reliability, using a simple psychophysical test. Temporal discrimination is disordered in a number of basal ganglia diseases including adult-onset dystonia, of which the two most common phenotypes are cervical dystonia and blepharospasm. The causes of adult-onset focal dystonia are unknown; genetic, epigenetic, and environmental factors are relevant. Abnormal TDTs in adult-onset dystonia are associated with structural and neurophysiological changes considered to reflect defective inhibitory interneuronal processing within a network which includes the superior colliculus, basal ganglia, and primary somatosensory cortex. It is hypothesized that abnormal temporal discrimination is a mediational endophenotype and, when present in unaffected relatives of patients with adult-onset dystonia, indicates non-manifesting gene carriage. Using the mediational endophenotype concept, etiological factors in adult-onset dystonia may be examined including (i) the role of environmental exposures in disease penetrance and expression; (ii) sexual dimorphism in sex ratios at age of onset; (iii) the pathogenesis of non-motor symptoms of adult-onset dystonia; and (iv) subcortical mechanisms in disease pathogenesis

Feral swine damage to globally imperiled wetland plant communities in a significant biodiversity hotspot in Florida

We studied rooting damage during five-years of feral swine control at Avon Park Air Force Range, a significant botanical biodiversity hotspot in peninsular Florida with many globally imperiled plant species and communities. While control reduced swine abundance, remaining animals consistently rooted the 49 studied sites in both middle-dry season (MDS) and late-dry season (LDS) each year. At each study site, we measured rooting with sub-meter accuracy. Neither total nor proportional area rooted differed in either season, across study years, or among plant community types: herbaceous seepage slopes, wet pine savannas, wet grasslands. The proportion of sites with damage during MDS was at least 25 % less than pre-control baseline. During LDS, the proportion of sites with damage increased over years but remained below the initial 2 years’ MDS results. Fresh rooting frequency (rooting \u3c1 \u3eweek-old) across sites dropped precipitously from baseline and remained low for MDS. Fresh rooting frequency among sites during LDS was lower than MDS for all but year two of the study. Canopied habitatwetlands, integrating swine control into other compatible land use practices, and improving swine control efficacy. While we measured damage amounts at each site very accurately, our approach of also considering frequency of rooting and frequency of fresh rooting across sites offers low-labor means to broadly assess swine damage and control efficacy at large geographic scales because in-field measurements of damage amounts are not needed

Feral swine damage to globally imperiled wetland plant communities in a significant biodiversity hotspot in Florida

We studied rooting damage during five-years of feral swine control at Avon Park Air Force Range, a significant botanical biodiversity hotspot in peninsular Florida with many globally imperiled plant species and communities. While control reduced swine abundance, remaining animals consistently rooted the 49 studied sites in both middle-dry season (MDS) and late-dry season (LDS) each year. At each study site, we measured rooting with sub-meter accuracy. Neither total nor proportional area rooted differed in either season, across study years, or among plant community types: herbaceous seepage slopes, wet pine savannas, wet grasslands. The proportion of sites with damage during MDS was at least 25 % less than pre-control baseline. During LDS, the proportion of sites with damage increased over years but remained below the initial 2 years’ MDS results. Fresh rooting frequency (rooting \u3c1 \u3eweek-old) across sites dropped precipitously from baseline and remained low for MDS. Fresh rooting frequency among sites during LDS was lower than MDS for all but year two of the study. Canopied habitatwetlands, integrating swine control into other compatible land use practices, and improving swine control efficacy. While we measured damage amounts at each site very accurately, our approach of also considering frequency of rooting and frequency of fresh rooting across sites offers low-labor means to broadly assess swine damage and control efficacy at large geographic scales because in-field measurements of damage amounts are not needed

On the cost of electrodialysis for the desalination of high salinity feeds

We propose the use of electrodialysis to desalinate produced waters from shale formations in order to facilitate water reuse in subsequent hydraulic fracturing processes. We focus on establishing the energy and equipment size required for the desalination of feed waters containing total dissolved solids of up to 192,000 ppm, and we do this by experimentally replicating the performance of a 10-stage electrodialysis system. We find that energy requirements are similar to current vapour compression desalination processes for feedwaters ranging between roughly 40,000-90,000 ppm TDS, but we project water costs to potentially be lower. We also find that the cost per unit salt removed is significantly lower when removed from a high salinity stream as opposed to a low salinity stream, pointing towards the potential of ED to operate as a partial desalination process for high salinity waters. We then develop a numerical model for the system, validate it against experimental results and use this model to minimise salt removal costs by optimising the stack voltage. We find that the higher the salinity of the water from which salt is removed the smaller should be the ratio of the electrical current to its limiting value. We conclude, on the basis of energy and equipment costs, that electrodialysis processes are potentially feasible for the desalination of high salinity waters but require further investigation of robustness to fouling under field conditions.Massachusetts Institute of Technology. Office of the Dean for Graduate Education (Hugh Hampton Young Memorial Fellowship)MIT Energy Initiativ

Multitargeted Imidazoles: Potential Therapeutic Leads for Alzheimer's and Other Neurodegenerative Diseases

Alzheimer’s disease (AD) is a complex, multifactorial disease in which different neuropathological mechanisms are likely involved, including those associated with pathological tau and Aβ species as well as neuroinflammation. In this context, the development of single multitargeted therapeutics directed against two or more disease mechanisms could be advantageous. Starting from a series of 1,5-diarylimidazoles with microtubule (MT)-stabilizing activity and structural similarities with known NSAIDs, we conducted structure−activity relationship studies that led to the identification of multitargeted prototypes with activities as MT-stabilizing agents and/or inhibitors of the cyclooxygenase (COX) and 5-lipoxygenase (5-LOX) pathways. Several examples are brain-penetrant and exhibit balanced multitargeted in vitro activity in the low μM range. As brain-penetrant MT-stabilizing agents have proven effective against tau-mediated neurodegeneration in animal models, and because COX- and 5-LOX-derived eicosanoids are thought to contribute to Aβ plaque deposition, these 1,5-diarylimidazoles provide tools to explore novel multitargeted strategies for AD and other neurodegenerative diseases

Loss of Fgfr1 and Fgfr2 in Scleraxis-lineage cells leads to enlarged bone eminences and attachment cell death

BACKGROUND Tendons and ligaments attach to bone are essential for joint mobility and stability in vertebrates. Tendon and ligament attachments (ie, entheses) are found at bony protrusions (ie, eminences), and the shape and size of these protrusions depend on both mechanical forces and cellular cues during growth. Tendon eminences also contribute to mechanical leverage for skeletal muscle. Fibroblast growth factor receptor (FGFR) signaling plays a critical role in bone development, and Fgfr1 and Fgfr2 are highly expressed in the perichondrium and periosteum of bone where entheses can be found. RESULTS AND CONCLUSIONS We used transgenic mice for combinatorial knockout of Fgfr1 and/or Fgfr2 in tendon/attachment progenitors (ScxCre) and measured eminence size and shape. Conditional deletion of both, but not individual, Fgfr1 and Fgfr2 in Scx progenitors led to enlarged eminences in the postnatal skeleton and shortening of long bones. In addition, Fgfr1/Fgfr2 double conditional knockout mice had more variation collagen fibril size in tendon, decreased tibial slope, and increased cell death at ligament attachments. These findings identify a role for FGFR signaling in regulating growth and maintenance of tendon/ligament attachments and the size and shape of bony eminences

Disrupted Superior Collicular Activity May Reveal Cervical Dystonia Disease Pathomechanisms

Cervical dystonia is a common neurological movement disorder characterised by muscle contractions causing abnormal movements and postures affecting the head and neck. The neural networks underpinning this condition are incompletely understood. While animal models suggest a role for the superior colliculus in its pathophysiology, this link has yet to be established in humans. The present experiment was designed to test the hypothesis that disrupted superior collicular processing is evident in affected patients and in relatives harbouring a disease-specific endophenotype (abnormal temporal discrimination). The study participants were 16 cervical dystonia patients, 16 unaffected first-degree relatives with abnormal temporal discrimination, 16 unaffected first-degree relatives with normal temporal discrimination and 16 healthy controls. The response of participant’s superior colliculi to looming stimuli was assessed by functional magnetic resonance imaging. Cervical dystonia patients and relatives with abnormal temporal discrimination demonstrated (i) significantly reduced superior collicular activation for whole brain and region of interest analysis; (ii) a statistically significant negative correlation between temporal discrimination threshold and superior collicular peak values. Our results support the hypothesis that disrupted superior collicular processing is involved in the pathogenesis of cervical dystonia. These findings, which align with animal models of cervical dystonia, shed new light on pathomechanisms in humans

Disrupted Superior Collicular Activity May Reveal Cervical Dystonia Disease Pathomechanisms

Cervical dystonia is a common neurological movement disorder characterised by muscle contractions causing abnormal movements and postures affecting the head and neck. The neural networks underpinning this condition are incompletely understood. While animal models suggest a role for the superior colliculus in its pathophysiology, this link has yet to be established in humans. The present experiment was designed to test the hypothesis that disrupted superior collicular processing is evident in affected patients and in relatives harbouring a disease-specific endophenotype (abnormal temporal discrimination). The study participants were 16 cervical dystonia patients, 16 unaffected first-degree relatives with abnormal temporal discrimination, 16 unaffected first-degree relatives with normal temporal discrimination and 16 healthy controls. The response of participant’s superior colliculi to looming stimuli was assessed by functional magnetic resonance imaging. Cervical dystonia patients and relatives with abnormal temporal discrimination demonstrated (i) significantly reduced superior collicular activation for whole brain and region of interest analysis; (ii) a statistically significant negative correlation between temporal discrimination threshold and superior collicular peak values. Our results support the hypothesis that disrupted superior collicular processing is involved in the pathogenesis of cervical dystonia. These findings, which align with animal models of cervical dystonia, shed new light on pathomechanisms in humans