The formation of well-defined protein bioconjugates is critical for many studies and technologies in chemical biology. Tried-and-true methods for accomplishing this typically involve the targeting of ...cysteine residues, but the rapid growth of contemporary bioconjugate applications has required an expanded repertoire of modification techniques. One very powerful set of strategies involves the modification of proteins at their N termini, as these positions are typically solvent exposed and provide chemically distinct sites for many protein targets. Several chemical techniques can be used to modify N-terminal amino acids directly or convert them into unique functional groups for further ligations. A growing number of N-terminus-specific enzymatic ligation strategies have provided additional possibilities. This Perspective provides an overview of N-terminal modification techniques and the chemical rationale governing each. Examples of specific N-terminal protein conjugates are provided, along with their uses in a number of diverse biological applications.
We used ultra-high field MRI to visualize cortical lesion types described by neuropathology in 16 patients with multiple sclerosis (MS) compared with 8 age-matched controls; to characterize the ...contrast properties of cortical lesions including T2*, T2, T1, and phase images; and to investigate the relationship between cortical lesion types and clinical data.
We collected, on a 7-T scanner, 2-dimensional fast low-angle shot (FLASH)-T2*-weighted spoiled gradient-echo, T2-weighted turbo spin-echo (TSE) images (0.33 x 033 x 1 mm(3)), and a 3-dimensional magnetization-prepared rapid gradient echo.
Overall, 199 cortical lesions were detected in patients on both FLASH-T2* and T2-TSE scans. Seven-tesla MRI allowed for characterization of cortical plaques into type I (leukocortical), type II (intracortical), and type III/IV (subpial extending partly or completely through the cortical width) lesions as described histopathologically. Types III and IV were the most frequent type of cortical plaques (50.2%), followed by type I (36.2%) and type II (13.6%) lesions. Each lesion type was more frequent in secondary progressive than in relapsing-remitting MS. This difference, however, was significant only for type III/IV lesions. T2*-weighted images showed the highest, while phase images showed the lowest, contrast-to-noise ratio for all cortical lesion types. In patients, the number of type III/IV lesions was associated with greater disability (p < 0.02 by Spearman test) and older age (p < 0.04 by Spearman test).
Seven-tesla MRI detected different histologic cortical lesion types in our small multiple sclerosis (MS) sample, suggesting, if validated in a larger population, that it may prove a valuable tool to assess the contribution of cortical MS pathology to clinical disability.
Objective Acute lower extremity ischemia (ALI) is a common vascular surgery emergency associated with high rates of morbidity and mortality. The purpose of this study was to assess contemporary ...trends in the incidence of ALI, the methods of treatment, and the associated mortality and amputation rates in the U.S. Medicare population. Methods This was an observational study using Medicare claims data between 1998 and 2009. Outcomes examined included trends in the incidence of ALI; trends in interventions for ALI; and trends in amputation, mortality, and amputation-free survival rates. Results Between 1998 and 2009, the incidence of hospitalization for ALI decreased from 45.7 per 100,000 to 26.0 per 100,000 ( P for trend < .001). The percentage of patients undergoing surgical intervention decreased from 57.1% to 51.6% ( P for trend < .001), whereas the percentage of patients undergoing endovascular interventions increased from 15.0% to 33.1% ( P for trend < .001). In-hospital mortality rates decreased from 12.0% to 9.0% ( P for trend < .001), whereas 1-year mortality rates remained stable at 41.0% and 42.5% ( P for trend not significant). In-hospital amputation rates remained stable at 8.1% and 6.4% ( P for trend not significant), whereas 1-year amputation rates decreased from 14.8% to 11.0% ( P for trend < .001). In-hospital amputation-free survival after hospitalization for ALI increased from 81.2% to 85.4% ( P for trend < .001); however, 1-year amputation-free survival remained unchanged. Conclusions Between 1998 and 2009, the incidence of ALI among the U.S. Medicare population declined significantly, and the percentage of patients treated with endovascular techniques markedly increased. During this time, 1-year amputation rates declined. Furthermore, although in-hospital mortality rates declined after presentation with ALI, 1-year mortality rates remained unchanged.
Although increases in obesity over the past 30 years have adversely affected the health of the U.S. population, there have been concomitant improvements in health because of reductions in smoking. ...Having a better understanding of the joint effects of these trends on longevity and quality of life will facilitate more efficient targeting of health care resources.
For each year from 2005 through 2020, we forecasted life expectancy and quality-adjusted life expectancy for a representative 18-year-old, assuming a continuation of past trends in smoking (based on data from the National Health Interview Survey for 1978 through 1979, 1990 through 1991, 1999 through 2001, and 2004 through 2006) and past trends in body-mass index (BMI) (based on data from the National Health and Nutrition Examination Survey for 1971 through 1975, 1988 through 1994, 1999 through 2002, and 2003 through 2006). The 2003 Medical Expenditure Panel Survey was used to examine the effects of smoking and BMI on health-related quality of life.
The negative effects of increasing BMI overwhelmed the positive effects of declines in smoking in multiple scenarios. In the base case, increases in the remaining life expectancy of a typical 18-year-old are held back by 0.71 years or 0.91 quality-adjusted years between 2005 and 2020. If all U.S. adults became nonsmokers of normal weight by 2020, we forecast that the life expectancy of an 18-year-old would increase by 3.76 life-years or 5.16 quality-adjusted years.
If past obesity trends continue unchecked, the negative effects on the health of the U.S. population will increasingly outweigh the positive effects gained from declining smoking rates. Failure to address continued increases in obesity could result in an erosion of the pattern of steady gains in health observed since early in the 20th century.
Behavioral and economic theories have long maintained that actions are chosen so as to minimize demands for exertion or work, a principle sometimes referred to as the "law of less work". The data ...supporting this idea pertain almost entirely to demands for physical effort. However, the same minimization principle has often been assumed also to apply to cognitive demand. The authors set out to evaluate the validity of this assumption. In 6 behavioral experiments, participants chose freely between courses of action associated with different levels of demand for controlled information processing. Together, the results of these experiments revealed a bias in favor of the less demanding course of action. The bias was obtained across a range of choice settings and demand manipulations and was not wholly attributable to strategic avoidance of errors, minimization of time on task, or maximization of the rate of goal achievement. It is remarkable that the effect also did not depend on awareness of the demand manipulation. Consistent with a motivational account, avoidance of demand displayed sensitivity to task incentives and covaried with individual differences in the efficacy of executive control. The findings reported, together with convergent neuroscientific evidence, lend support to the idea that anticipated cognitive demand plays a significant role in behavioral decision making. (Contains 2 tables and 7 figures.)
The lateral central nucleus of the amygdala (CeA
) and the dorsolateral bed nucleus of the stria terminalis (BNST
) coordinate the expression of shorter- and longer-lasting fears, respectively. Less ...is known about how these structures communicate with each other during fear acquisition. One pathway, from the CeA
to the BNST
, is thought to communicate via corticotropin-releasing factor (CRF), but studies have yet to examine its function in fear learning and memory. Thus, we developed an adeno-associated viral-based strategy to selectively target CRF neurons with the optogenetic silencer archaerhodopsin tp009 (CRF-ArchT) to examine the role of CeA
CRF neurons and projections to the BNST
during the acquisition of contextual fear. Expression of our CRF-ArchT vector injected into the amygdala was restricted to CeA
CRF neurons. Furthermore, CRF axonal projections from the CeA
clustered around BNST
CRF cells. Optogenetic silencing of CeA
CRF neurons during contextual fear acquisition disrupted retention test freezing 24 h later, but only at later time points (>6 min) during testing. Silencing CeA
CRF projections in the BNST
during contextual fear acquisition produced a similar effect. Baseline contextual freezing, the rate of fear acquisition, freezing in an alternate context after conditioning and responsivity to foot shock were unaffected by optogenetic silencing. Our results highlight how CeA
CRF neurons and projections to the BNST
consolidate longer-lasting components of a fear memory. Our findings have implications for understanding how discrete amygdalar CRF pathways modulate longer-lasting fear in anxiety- and trauma-related disorders.
Measles was declared eliminated in the United States in 2000, but the risk of outbreaks owing to international importations remains. An outbreak of measles in New York City began when one ...unvaccinated child returned home from Israel with measles; onset of rash occurred on September 30, 2018, 9 days after the child returned home.
We investigated suspected cases of measles by conducting interviews, reviewing medical and immunization records, identifying exposed persons, and performing diagnostic testing. Measles-mumps-rubella (MMR) vaccine (given as either MMR or measles-mumps-rubella-varicella vaccine and collectively referred to as MMR vaccine) uptake was monitored with the use of the Citywide Immunization Registry. The total direct cost to the New York City Department of Health and Mental Hygiene was calculated.
A total of 649 cases of measles were confirmed, with onsets of rash occurring between September 30, 2018, and July 15, 2019. A majority of the patients (93.4%) were part of the Orthodox Jewish community, and 473 of the patients (72.9%) resided in the Williamsburg area of Brooklyn, New York. The median age was 3 years; 81.2% of the patients were 18 years of age or younger, and 85.8% of the patients with a known vaccination history were unvaccinated. Serious complications included pneumonia (in 37 patients 5.7%) and hospitalization (in 49 patients 7.6%); among the patients who were hospitalized, 20 (40.8%) were admitted to an intensive care unit. As a result of efforts to promote vaccination, the percentage of children in Williamsburg who received at least one dose of MMR vaccine increased from 79.5% to 91.1% among children 12 to 59 months of age. As of September 9, 2019, a total of 559 staff members at the Department of Health and Mental Hygiene (7% of the agency) had been involved in the measles response. The cost of the Department of Health and Mental Hygiene response was $8.4 million.
Importation of measles and vaccination delays among young children led to an outbreak of measles in New York City. The outbreak response was resource intensive and caused serious illness, particularly among unvaccinated children.
Hand function after nerve repair Lundborg, G.; Rosén, B.
Acta Physiologica,
February 2007, Letnik:
189, Številka:
2
Journal Article, Conference Proceeding
Recenzirano
Odprti dostop
Treatment of injuries to major nerve trunks in the hand and upper extremity remains a major and challenging reconstructive problem. Such injuries may cause long‐lasting disabilities in terms of lost ...fine sensory and motor functions. Nowadays there is no surgical repair technique that can ensure recovery of tactile discrimination in the hand of an adult patient following nerve repair while very young individuals usually regain a complete recovery of functional sensibility. Post‐traumatic nerve regeneration is a complex biological process where the outcome depends on multiple biological and environmental factors such as survival of nerve cells, axonal regeneration rate, extent of axonal misdirection, type of injury, type of nerve, level of the lesion, age of the patient and compliance to training. A major problem is the cortical functional reorganization of hand representation which occurs as a result of axonal misdirection. Although protective sensibility usually occurs following nerve repair, tactile discriminative functions seldom recover – a direct result of cortical remapping. Sensory re‐education programmes are routinely applied to facilitate understanding of the new sensory patterns provided by the hand. New trends in hand rehabilitation focus on modulation of central nervous processes rather than peripheral factors. Principles are being evolved to maintain the cortical hand representation by using the brain capacity for visuo‐tactile and audio‐tactile interaction for the initial phase following nerve injury and repair (phase 1). After the start of the re‐innervation of the hand (phase 2), selective de‐afferentation, such as cutaneous anaesthesia of the forearm of the injured hand, allows expansion of the nerve‐injured cortical hand representation, thereby enhancing the effects of sensory relearning. Recent data support the view that training protocols specifically addressing the relearning process substantially increase the possibilities for improved functional outcome after nerve repair.
•Acircularity index and axis ratio can quantify FAZ abnormalities in diabetics.•They do not require axial length measurement.•They can be used to noninvasively stage severity of diabetic retinopathy ...using OCTA.•These metrics show promise as methods to monitor disease over time.
Given the complexity of the current system used to stage diabetic retinopathy (DR) and the risks and limitations associated with intravenous fluorescein angiography (IVFA), noninvasive quantification of DR severity is desirable. We examined the utility of acircularity index and axis ratio of the foveal avascular zone (FAZ), metrics that can noninvasively quantify the severity of diabetic retinopathy without the need for axial length to correct for individual retinal magnification. A retrospective review was performed of type 2 diabetics and age-matched controls imaged with optical coherence tomography angiography (OCTA). Diabetic eyes were divided into three groups according to clinical features: No clinically observable diabetic retinopathy (NoDR), nonproliferative diabetic retinopathy (NPDR), and proliferative diabetic retinopathy (PDR). OCTAs of the superficial and deep vascular layers centered at the fovea were superimposed to form a full vascular layer on which the FAZ was manually traced. Acircularity index and axis ratio were calculated for each FAZ. Significant differences in acircularity index were observed between all groups except for controls vs. NoDR. Similar results were found for axis ratio, although there was no significant difference observed between NPDR and PDR. We demonstrate that acircularity index and axis ratio can be used to help noninvasively stage DR using OCTA, and show promise as methods to monitor disease progression and detect response to treatment.
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