In maturity, motor skills depend on the corticospinal tract (CST) and brainstem pathways that together synapse on interneurons and motoneurons in the spinal cord. Descending signals to spinal neurons ...that mediate voluntary control can be distinguished from peripheral sensory signals, primarily for feedback control. These motor system circuits depend initially on developmental genetic mechanisms to establish their connections and neural activity‐ and use‐dependent synaptic refinement during the early postnatal period to enable motor skills to develop. In this review we consider four key activity‐dependent developmental mechanisms that provide insights into how the motor systems establish the proper connections for skilled movement control and how the same mechanisms also inform the mechanisms of motor impairments and developmental plasticity after corticospinal system injury: (1) synaptic competition between the CSTs from each hemisphere; (2) interactions between the CST and spinal cord neurons; (3) synaptic competition between the CST and proprioceptive sensory fibres; and (4) interactions between the developing corticospinal motor system and the rubrospinal tract. Our findings suggest that the corticospinal motor system effectively ‘oversees’ development of its subcortical targets through synaptic competition and trophic‐like interactions and this has important implications for motor impairments after perinatal cortical stroke.
What this paper adds
Neural activity‐dependent processes inform the brain and spinal cord response to injury.
The corticospinal motor system may ‘oversee’ development of its downstream subcortical targets through activity, trophic‐like interactions, and synaptic competition.
Resumen
Plasticidad del sistema motor después de una lesión unilateral del cerebro perinatal
En la madurez, las habilidades motoras dependen del tracto corticoespinal (CST) y las vías del tronco encefálico, que conjuntamente, hacen sinapsis con interneuronas y motoneuronas en la médula espinal. Las señales descendientes que llegan a las neuronas espinales que median el control voluntario, pueden distinguirse de las señales sensoriales periféricas, principalmente por el control de retroalimentación. Estos circuitos del sistema motor dependen inicialmente de mecanismos genéticos de desarrollo para establecer sus conexiones y refinamiento sináptico dependiente de la actividad neuronal y del uso durante el período postnatal temprano, para permitir que las habilidades motoras se desarrollen. En esta revisión se consideran cuatro mecanismos de desarrollo dependientes de la actividad, que proporcionan ideas sobre cómo los sistemas motores establecen las conexiones adecuadas para el control de movimientos calificados, y cómo los mismos mecanismos también informan los mecanismos de las deficiencias motoras y la plasticidad de desarrollo neuronal después de la lesión del sistema corticoespinal. Los mecanismos principales que se proponen son: (1) competencia sináptica entre los CST de cada hemisferio; (2) interacciones entre el CST y las neuronas de la médula espinal; (3) la competencia sináptica entre el CST y las fibras sensoriales propioceptivas; y (4) las interacciones entre el sistema motor corticospinal en desarrollo y el tracto rubroespinal (RuST). Nuestros hallazgos sugieren que el sistema motor corticoespinal efectivamente “supervisa” el desarrollo de sus objetivos (targets) subcorticales a través de la competencia sináptica y interacciones tróficas/estimulantes, esto tiene importantes implicancias para las deficiencias motoras después del accidente cerebrovascular perinatal cortical.
Resumo
Plasticidade do sistema motor após lesão unilateral no cérebro jovem
Na maturidade, as habilidades motoras dependem do trato córtico‐espinhal (TCE) e vias do tronco cerebral para unir as sinapses nos interneurónios e motoneurônios na medula espinhal. Sinais descendentes para os neurônios espinhais que mediam o controle voluntário podem ser distintos dos sinais sensoriais periféricos, primariamente para o controle de feedback. Estes circuitos dos sistemas motores dependem inicialmente de mecanismos genéticos desenvolvimentais para estabelecer suas conexões e atividade neural –e refinamento sináptico uso‐dependente durante o período pós‐natal precoce para possibilitar o desenvolvimento das habilidades motoras. Nesta revisão, nós consideramos quatro mecanismos‐chave de plasticidade desenvolvimental atividade‐dependente que oferecem explicações sobre como os sistemas motores estabelecem as conexões adequadas para o controle do movimento habilidoso, e como os mesmos mecanismos também informam os mecanismos de deficiências motoras e plasticidade desenvolvimental após lesão do sistema córtico‐espinhal: 1) competição sináptica entre os TCEs de cada hemisfério; 2) interações entre os TCEs e neurônios da medula espinhal; 3) competição sináptica entre o TCE e fibras sensoriais proprioceptivas; 4) interações entre o sistema motor córtico‐espinhal em desenvolvimento e o trato rubro‐espinal (TRuE). Nossos achados sugerem que o sistema motor córtico‐espinhal efetivamente “cuida” de seus alvos subcorticais por meio de competição sináptica e interações tróficas, e isso tem implicações importantes para as deficiências motoras após infartos corticais perinatais.
What this paper adds
Neural activity‐dependent processes inform the brain and spinal cord response to injury.
The corticospinal motor system may ‘oversee’ development of its downstream subcortical targets through activity, trophic‐like interactions, and synaptic competition.
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The corticospinal and rubrospinal systems function in skilled movement control. A key question is how do these systems develop the capacity to coordinate their motor functions and, in turn, if the ...red nucleus/rubrospinal tract (RN/RST) compensates for developmental corticospinal injury? We used the cat to investigate whether the developing rubrospinal system is shaped by activity-dependent interactions with the developing corticospinal system. We unilaterally inactivated M1 by muscimol microinfusion between postnatal weeks 5 and 7 to examine activity-dependent interactions and whether the RN/RST compensates for corticospinal tract (CST) developmental motor impairments and CST misprojections after M1 inactivation. We examined the RN motor map and RST cervical projections at 7 weeks of age, while the corticospinal system was inactivated, and at 14 weeks, after activity returned. During M1 inactivation, the RN on the same side showed normal RST projections and reduced motor thresholds, suggestive of precocious development. By contrast, the RN on the untreated/active M1 side showed sparse RST projections and an immature motor map. After M1 activity returned later in adolescent cat development, RN on the active M1/CST side continued to show a substantial loss of spinal terminations and an impaired motor map. RN/RST on the inactivated side regressed to a smaller map and fewer axons. Our findings suggest that the developing rubrospinal system is under activity-dependent regulation by the corticospinal system for establishing mature RST connections and RN motor map. The lack of RS compensation on the non-inactivated side can be explained by development of ipsilateral misprojections from the active M1 that outcompete the RST. Significance statement: Skilled movements reflect the activity of multiple descending motor systems and their interactions with spinal motor circuits. Currently, there is little insight into whether motor systems interact during development to coordinate their emerging functions and, if so, the mechanisms underlying this process. This study examined activity-dependent interactions between the developing corticospinal and rubrospinal systems, two key systems for skilled limb movements. We show that the developing rubrospinal system competes with the corticospinal system in establishing the red nucleus motor map and rubrospinal tract connections. This is the first demonstration of one motor system steering development, and ultimately function, of another. Knowledge of activity-dependent competition between these two systems helps predict the response of the rubrospinal system following corticospinal system developmental injury.
The guanine quadruplex (G4) structure in DNA is a secondary structure motif that plays important roles in DNA replication, transcriptional regulation, and maintenance of genomic stability. Here, we ...employed a quantitative mass spectrometry-based approach to profile the interaction proteomes of three well-defined G4 structures derived from the human telomere and the promoters of cMYC and cKIT genes. We identified SLIRP as a novel G4-interacting protein. We also demonstrated that the protein could bind directly with G4 DNA with K d values in the low nanomolar range and revealed that the robust binding of the protein toward G4 DNA requires its RRM domain. We further assessed, by using CRISPR-Cas9-introduced affinity tag and ChIP-Seq analysis, the genome-wide occupancy of SLIRP, and showed that the protein binds preferentially to G-rich DNA sequences that can fold into G4 structures. Together, our results uncovered a novel cellular protein that can interact directly with G4 DNA, which underscored the complex regulatory networks involved in G4 biology.
A key outcome for spinal cord stimulation for neurorehabilitation after injury is to strengthen corticospinal system control of the arm and hand. Non-invasive, compared with invasive, spinal ...stimulation minimizes risk but depends on muscle-specific actions for restorative functions.
We developed a large-animal (cat) model, combining computational and experimental techniques, to characterize neuromodulation with transcutaneous spinal direct current stimulation (tsDCS) for facilitation of corticospinal motor drive to specific forelimb muscles.
Acute modulation of corticospinal function by tsDCS was measured using motor cortex-evoked muscle potentials (MEPs). The effects of current intensity, polarity (cathodal, anodal), and electrode position on specific forelimb muscle (biceps vs extensor carpi radialis, ECR) MEP modulation were examined. Locations of a key target, the motoneuron pools, were determined using neuronal tracing. A high-resolution anatomical (MRI and CT) model was developed for computational simulation of spinal current flow during tsDCS.
Effects of tsDCS on corticospinal excitability were robust and immediate, therefore supporting MEPs as a sensitive marker of tsDCS targeting. Varying cathodal/anodal current intensity modulated MEP enhancement/suppression, with higher cathodal sensitivity. Muscle-specificity depended on cathode position; the rostral position preferentially augmented biceps responses and the caudal position, ECR responses. Precise anatomical current-flow modeling, supplemented with target motor pool distributions, can explain tsDCS focality on muscle groups.
Anatomical current-flow modeling with physiological validation based on MEPs provides a framework to optimize muscle-specific tsDCS interventions. tsDCS targeting of representative motor pools enables muscle- and response-specific neuromodulation of corticospinal motor drive.
•Motor cortex-evoked muscle potentials (MEP) are immediate markers of tsDCS efficacy and focality.•Differential cathodal positioning produced preferential augmentation of biceps or ECR MEPs.•Current-flow models integrated with motor pool maps explain tsDCS muscle targeting.•tsDCS boost to corticospinal motor drive may confer muscle-specific neurorehabilitation.
Skilled motor control is regulated by the convergence of somatic sensory and motor signals in brain and spinal motor circuits. Cervical deafferentation is known to diminish forelimb somatic sensory ...representations rapidly and to impair forelimb movements. Our focus was to determine what effect deafferentation has on the motor representations in motor cortex, knowledge of which could provide new insights into the locus of impairment following somatic sensory loss, such as after spinal cord injury or stroke. We hypothesized that somatic sensory information is important for cortical motor map topography. To investigate this we unilaterally transected the dorsal rootlets in adult rats from C4 to C8 and mapped the forelimb motor representations using intracortical microstimulation, immediately after rhizotomy and following a 2‐week recovery period. Immediately after deafferentation we found that the size of the distal representation was reduced. However, despite this loss of input there were no changes in motor threshold. Two weeks after deafferentation, animals showed a further distal representation reduction, an expansion of the elbow representation, and a small elevation in distal movement threshold. These changes were specific to the forelimb map in the hemisphere contralateral to deafferentation; there were no changes in the hindlimb or intact‐side forelimb representations. Degradation of the contralateral distal forelimb representation probably contributes to the motor control deficits after deafferentation. We propose that somatic sensory inputs are essential for the maintenance of the forelimb motor map in motor cortex and should be considered when rehabilitating patients with peripheral or spinal cord injuries or after stroke.
Skilled motor control is regulated by the convergence of somatic sensory and motor signals. Using rats with C4–C8 dorsal rhizotomy, we investigated the effect of sensory deprivation on the cortical motor representations using ICMS. We found an immediate reduction in the distal forelimb representation, a delayed expansion of the elbow representation, and a delayed distal threshold elevation. Degradation of the distal representation likely contributes to the motor deficits after deafferentation.
TRIM proteins constitute a large, diverse and ancient protein family which play a key role in processes including cellular differentiation, autophagy, apoptosis, DNA repair, and tumour suppression. ...Mostly known and studied through the lens of their ubiquitination activity as E3 ligases, it has recently emerged that many of these proteins are involved in direct RNA binding through their NHL or PRY/SPRY domains. We summarise the current knowledge concerning the mechanism of RNA binding by TRIM proteins and its biological role. We discuss how RNA-binding relates to their previously described functions such as E3 ubiquitin ligase activity, and we will consider the potential role of enrichment in membrane-less organelles.
The fine line of defensive medicine Williams, Preston L.; Williams, Joanna P.; Williams, Bryce R.
Journal of forensic and legal medicine,
05/2021, Letnik:
80
Journal Article
Recenzirano
Defensive medicine is a practice that has been utilized by clinicians in efforts of preventing patient dissatisfaction and malpractice claims and may be done through either omission or commission. As ...much as 57% of physicians have disclosed that they practice defensive medicine. However, this practice does not necessarily prevent malpractice claims and more importantly, neither does it equate to good medical practice, with some leading to poor outcomes. Unfortunately, there is a high percentage of malpractice claims lodged against clinicians in both primary care and hospital settings. Specialists such as surgeons, obstetricians, and gynecologists face the highest claims.
In particular, during the SARS CoV-2 pandemic, with new challenges and limited treatment algorithms, there is an even greater concern for possible bourgeoning claims. Counteracting defensive medicine can be accomplished through decriminalizing malpractice claims, leaving physician oversight up to state medical boards and hospital claims management committees. Additional tort reform measures must also be taken such as caps on noneconomic damages to ensure emphasis on beneficence and nonmaleficence. Once these are in place, it may well serve to increase clinician-patient trust and improve patient independence in the shared decision-making process of their treatment, allowing clinicians to practice their full scope of practice without feeling wary of potential malpractice claims.
The red nucleus (RN) and rubrospinal tract (RST) are important for forelimb motor control. Although the RST is present postnatally in cats, nothing is known about when rubrospinal projections could ...support motor functions or the relation between the development of the motor functions of the rubrospinal system and the corticospinal system, the other major system for limb control. Our hypothesis is that the RN motor map is present earlier in development than the motor cortex (M1) map, to support early forelimb control. We investigated RN motor map maturation with microstimulation and RST cervical enlargement projections using anterograde tracers between postnatal week 3 (PW3) and PW16. Microstimulation and tracer injection sites were verified histologically to be located within the RN. Microstimulation at PW4 evoked contralateral wrist, elbow, and shoulder movements. The number of sites producing limb movement increased and response thresholds decreased progressively through PW16. From the outset, all forelimb joints were represented. At PW3, RST projections were present within the cervical intermediate zone, with a mature density of putative synapses. In contrast, beginning at PW5 there was delayed and age-dependent development of forelimb motor pool projections and putative rubromotoneuronal synapses. The RN has a more complete forelimb map early in development than previous studies showed for M1, supporting our hypothesis of preferential rubrospinal rather than corticospinal control for early movements. Remarkably, development of the motor pool, not intermediate zone, RST projections paralleled RN motor map development. The RST may be critical for establishing the rudiments of motor skills that subsequently become refined with further CST development.
In prokaryotes, RNA polymerase and ribosomes can bind concurrently to the same RNA transcript, leading to the functional coupling of transcription and translation. The interactions between RNA ...polymerase and ribosomes are crucial for the coordination of transcription with translation. Here, we report that RNA polymerase directly binds ribosomes and isolated large and small ribosomal subunits. RNA polymerase and ribosomes form a one-to-one complex with a micromolar dissociation constant. The formation of the complex is modulated by the conformational and functional states of RNA polymerase and the ribosome. The binding interface on the large ribosomal subunit is buried by the small subunit during protein synthesis, whereas that on the small subunit remains solvent-accessible. The RNA polymerase binding site on the ribosome includes that of the isolated small ribosomal subunit. This direct interaction between RNA polymerase and ribosomes may contribute to the coupling of transcription to translation.
Mass spectrometry (MS) is a valuable tool for plasma proteome profiling and disease biomarker discovery. However, wide-ranging plasma protein concentrations, along with technical and biological ...variabilities, present significant challenges for deep and reproducible protein quantitation. Here, we evaluated the qualitative and quantitative performance of timsTOF HT and timsTOF Pro 2 mass spectrometers for analysis of neat plasma samples (unfractionated) and plasma samples processed using the Proteograph Product Suite (Proteograph) that enables robust deep proteomics sampling prior to mass spectrometry. Samples were evaluated across a wide range of peptide loading masses and liquid chromatography (LC) gradients. We observed up to a 76% increase in total plasma peptide precursors identified and a >2-fold boost in quantifiable plasma peptide precursors (CV < 20%) with timsTOF HT compared to Pro 2. Additionally, approximately 4.5 fold more plasma peptide precursors were detected by both timsTOF HT and timsTOF Pro 2 in the Proteograph analyzed plasma vs neat plasma. In an exploratory analysis of 20 late-stage lung cancer and 20 control plasma samples with the Proteograph, which were expected to exhibit distinct proteomes, an approximate 50% increase in total and statistically significant plasma peptide precursors (q < 0.05) was observed with timsTOF HT compared to Pro 2. Our data demonstrate the superior performance of timsTOF HT for identifying and quantifying differences between biologically diverse samples, allowing for improved disease biomarker discovery in large cohort studies. Moreover, researchers can leverage data sets from this study to optimize their liquid chromatography–mass spectrometry (LC–MS) workflows for plasma protein profiling and biomarker discovery. (ProteomeXchange identifier: PXD047854 and PXD047839).
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