A major constraint for developing new anti-tuberculosis drugs is the limited number of validated targets that allow eradication of persistent infections. Here, we uncover a vulnerable component of Mycobacterium tuberculosis (Mtb) persistence metabolism, the aspartate pathway. Rapid death of threonine and homoserine auxotrophs points to a distinct susceptibility of Mtb to inhibition of this pathway. Combinatorial metabolomic and transcriptomic analysis reveals that inability to produce threonine leads to deregulation of aspartate kinase, causing flux imbalance and lysine and DAP accumulation. Mtb’s adaptive response to this metabolic stress involves a relief valve-like mechanism combining lysine export and catabolism via aminoadipate. We present evidence that inhibition of the aspartate pathway at different branch-point enzymes leads to clearance of chronic infections. Together these findings demonstrate that the aspartate pathway in Mtb relies on a combination of metabolic control mechanisms, is required for persistence, and represents a target space for anti-tuberculosis drug development.

Background: The Buffalo Concussion Treadmill Test (BCTT) is a graded exertion test for assessing exercise tolerance after concussion, but its utility is limited for certain populations. Hypothesis: We developed the Buffalo Concussion Bike Test (BCBT) and tested its comparability with the BCTT. We hypothesize that heart rate (HR) at symptom exacerbation on the BCBT will be equivalent to the BCTT. Study Design: Case-control study. Level of Evidence: Level 3. Methods: Adolescents with acute concussion (AC) (n = 20; mean age, 15.9 ± 1.1 years; 60% male) presenting to a concussion clinic within 10 days of injury and age- and sex-matched healthy controls (n = 20; mean age, 15.9 ± 1.1 years; 60% male) performed the BCTT at first visit and returned within 3 days to perform the BCBT. Test duration, HR, symptom severity (measured using a visual analog scale), and exertion (measured using the Borg Rating of Perceived Exertion) were collected during each test. Results: Adolescents with AC who were exercise intolerant on the BCTT were also intolerant on the BCBT, with symptom exacerbation occurring at a mean 8.1 ± 2.8 minutes on the BCTT versus 14.6 ± 6.0 minutes on the BCBT ( P < 0.01). Two 1-sided t tests showed that the HR at symptom exacerbation in AC patients (137 ± 28 bpm on BCTT vs 135 ± 25 bpm on BCBT; 95% CI, <0.01-0.03) and at voluntary exhaustion for controls (175 ± 13 bpm on BCTT vs 175 ± 13 bpm on BCBT; 95% CI, 0.03-0.03) on each test were statistically equivalent. Conclusion: The HR at symptom exacerbation on BCBT is equivalent to the BCTT for the assessment of exercise tolerance after concussion in adolescents. Clinical Relevance: The BCBT can be used in patients with limited mobility or for research interventions that require limited participant motion.

Background: Early, accurate diagnosis of mild traumatic brain injury (mTBI) can improve clinical outcomes for patients, but mTBI remains difficult to This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

The key motor symptoms in Parkinson's disease (PD) include tremor at rest, bradykinesia (slowness of movement), rigidity and, later in the disease, gait disorder/postural instability. These clinical features of PD have assumed to be the direct and indirect result of unexplained degeneration of dopaminergic substantia nigra pars compacta (SNpc) cells of the basal ganglia. Given that many of the motor symptoms in PD can be attributed to dopamine cell loss in the SNpc, the classic model of PD has emphasized the role of basal ganglia dysfunction in PD pathology. However, several key features of the disease cannot be explained adequately by basal ganglia dysfunction alone, including the apparent heterogeneity of the disease (i.e., the existence of PD subtypes) 1 , why patients with akinetic-rigiditydominant PD subtype have a worse prognosis than those with a tremor-dominant PD presentation 2-7 , why PD tremor is less reliably responsive to dopaminergic medications compared to the symptoms of bradykinesia and rigidity 8,9 , or why there is no correlation between rest tremor and striatal 18 F-fluorodopa uptake in PD patients 10 . it is likely that other brain structures outside the basal ganglia play a role in the pathophysiology of the disease. The purpose of this review is to summarize the evidence that cerebellar structures and their connections also may contribute significantly to the signs and symptoms of PD. ABSTRACT:Parkinson's disease (PD), the most common neurodegenerative movement disorder, has traditionally been considered a "classic" basal ganglia disease, as the most obvious pathology is seen in the dopaminergic cells in the substantia nigra pars compacta. Nevertheless recent discoveries in anatomical connections linking the basal ganglia and the cerebellum have led to a re-examination of the role of the cerebellum in the pathophysiology of PD. This review summarizes the role of the cerebellum in explaining many curious features of PD: the significant variation in disease progression between individuals; why severity of dopaminergic deficit correlates with many features of PD such as bradykinesia, but not tremor; and why PD subjects with a tremor-predominant presentation tend to have a more benign prognosis. it is clear that the cerebellum participates in compensatory mechanisms associated with the disease and must be considered an essential contributor to the overall pathophysiology of PD.RÉSUMÉ: Rôle du cervelet dans la physiopathologie de la Maladie de Parkinson. La Maladie de Parkinson (MP), le trouble du mouvement de nature neurodégénérative le plus fréquent, a traditionnellement été considérée comme une maladie « classique » des noyaux gris centraux, étant donné que la pathologie la plus évidente se retrouve dans les cellules dopaminergiques de la substance noire de la pars compacta. Néanmoins, des découvertes récentes concernant les connections anatomiques liant les noyaux gris centraux et le cervelet ont mené à un nouvel examen du rôle du cervelet dans la physiopathologie de la MP. Cette revue expl...

Saddle height is one of the most researched areas of bike fit. The current accepted method for adjusting saddle height involves the use of a goniometer to adjust saddle height so that a knee angle between 25° and 35° is obtained. This measurement is taken while the cyclist maintains a static position with the pedal at the 6-o'-clock position. However, the act of pedaling is dynamic, and angles may alter during movement. The purpose of this study was to examine the alterations to knee and ankle angle occurring from static measures to active pedaling across intensities experienced by cyclists during a graded exercise protocol. Thirty-four recreational to highly trained cyclists were evaluated using 2D analysis of stationary position and 3 active levels (level 1, respiratory exchange ratio of 1.00, and max). Dependent measures were compared using repeated measures analysis of variance (p = 0.05). When examining the results, it is evident that significant alterations to pedal stroke occur from stationary measures to active pedaling and as intensity increases toward maximal. Plantar flexion increased when moving from stationary measures to active pedaling, which resulted in an increase in knee angle. Although still greater than stationary measures, less plantar flexion occurred at higher intensities when compared with lower intensity cycling. Less plantar flexion at higher intensities is most likely a result of application of a larger downward torque occurring because of greater power requirements at higher intensities. There appeared to be greater variability in angle when examining novice cyclists in relation to more experienced cyclists. Although stationary measures are where a bike fit session will begin, observation during the pedal cycle may be needed to fine-tune the riders' fit.