Evaluation of objective methods for analyzing ipsilateral motor evoked potentials in stroke survivors with chronic upper extremity motor impairment.

Ipsilateral motor evoked potentials (iMEPs) are believed to represent cortically evoked excitability of uncrossed brainstem-mediated pathways. In the event of extensive injury to (crossed) corticospinal pathways, which can occur following a stroke, uncrossed ipsilateral pathways may serve as an alternate resource to support the recovery of the paretic limb. However, iMEPs, even in neurally intact people, can be small, infrequent, and noisy, so discerning them in stroke survivors is very challenging.

Role of Kindlin 2 in prostate cancer.

Kindlin-2 is a cytoskeletal adapter protein that is present in many different cell types. By virtue of its interaction with multiple binding partners, Kindlin-2 intercalates into numerous signaling pathways and cytoskeletal nodes. A specific interaction of Kindlin-2 that is of paramount importance in many cellular responses is its direct binding to the cytoplasmic tails of integrins, an interaction that controls many of the adhesive, migratory and signaling responses mediated by members of the integrin family of cell-surface heterodimers.

Corticospinal inhibition investigated in relation to upper extremity motor function in cervical spinal cord injury.

Objective: Corticospinal inhibitory mechanisms are relevant to functional recovery but remain poorly understood after spinal cord injury (SCI). Post-injury characteristics of contralateral silent period (CSP), a measure of corticospinal inhibition evaluated using transcranial magnetic stimulation (TMS), is inconsistent in literature. We envisioned that investigating CSP across muscles with varying degrees of weakness may be a reasonable approach to resolve inconsistencies and elucidate the relevance of corticospinal inhibition for upper extremity function following SCI.

Paired DBS and TMS Reveals Dentato-Cortical Facilitation Underlying Upper Extremity Movement in Chronic Stroke Survivors.

Background: Cerebellum shares robust di-synaptic dentato-thalamo-cortical (DTC) connections with the contralateral motor cortex. Preclinical studies have shown that DTC are excitatory in nature. Structural integrity of DTC is associated with better upper extremity (UE) motor function in people with stroke, indicating DTC are important for cerebellar influences on movement.

Contralaterally controlled functional electrical stimulation video game therapy for hand rehabilitation after stroke: a randomized controlled trial.

Purpose: To estimate the effect of integrating custom-designed hand therapy video games (HTVG) with contralaterally controlled functional electrical stimulation (CCFES) therapy.

Methods: Fifty-two stroke survivors with chronic (>6 months) upper limb hemiplegia were randomized to 12 weeks of CCFES or CCFES + HTVG. Treatment involved self-administration of technology-mediated therapy at home plus therapist-administered CCFES-assisted task practice in the lab.

Targeting the αVβ3/NgR2 pathway in neuroendocrine prostate cancer.

Highly aggressive, metastatic, neuroendocrine prostate cancer, which typically develops from prostate cancer cells acquiring resistance to androgen deprivation therapy, is associated with limited treatment options and hence poor prognosis. We have previously demonstrated that the αVβ3 integrin is over-expressed in neuroendocrine prostate cancer. We now show that LM609, a monoclonal antibody that specifically targets the human αVβ3 integrin, hinders the growth of neuroendocrine prostate cancer patient-derived xenografts in vivo.

Parkin ubiquitination of Kindlin-2 enables mitochondria-associated metastasis suppression.

Mitochondria are signaling organelles implicated in cancer, but the mechanisms are elusive. Here, we show that Parkin, an E3 ubiquitination (Ub) ligase altered in Parkinson's disease, forms a complex with the regulator of cell motility, Kindlin-2 (K2), at mitochondria of tumor cells. In turn, Parkin ubiquitinates Lys581 and Lys582 using Lys48 linkages, resulting in proteasomal degradation of K2 and shortened half-life from ∼5 h to ∼1.

A mechanism of platelet integrin αIIbβ3 outside-in signaling through a novel integrin αIIb subunit-filamin-actin linkage.

The communication of talin-activated integrin αIIbβ3 with the cytoskeleton (integrin outside-in signaling) is essential for platelet aggregation, wound healing, and hemostasis. Filamin, a large actin crosslinker and integrin binding partner critical for cell spreading and migration, is implicated as a key regulator of integrin outside-in signaling. However, the current dogma is that filamin, which stabilizes inactive αIIbβ3, is displaced from αIIbβ3 by talin to promote the integrin activation (inside-out signaling), and how filamin further functions remains unresolved.

Aging-induced alterations in EEG spectral power associated with graded force motor tasks.

Background: It has been demonstrated that in young and healthy individuals, there is a strong association between the amplitude of EEG-derived motor activity-related cortical potential or EEG spectral power (ESP) and voluntary muscle force. This association suggests that the motor-related ESP may serve as an index of central nervous system function in controlling voluntary muscle activation Therefore, it may potentially be used as an objective marker to track changes in functional neuroplasticity due to neurological disorders, aging, and following rehabilitation therapies. To this end, the relationship between the band-specific ESP-combined spectral power of EEG oscillatory and aperiodic (noise) components-and voluntary elbow flexion (EF) force has been analyzed in elder and young individuals.

Stimulation of the Premotor Cortex Enhances Interhemispheric Functional Connectivity in Association with Upper Limb Motor Recovery in Moderate-to-Severe Chronic Stroke.

Transcranial direct current stimulation (tDCS) targeting the primary motor cortex is modestly effective for promoting upper-limb motor function following stroke. The premotor cortex (PMC) represents an alternative target based on its higher likelihood of survival and dense motor-network connections. The objective of this study was to determine whether ipsilesional PMC tDCS affects motor network functional connectivity (FC) in association with reduction in motor impairment, and to determine whether this relationship is influenced by baseline motor severity.

Kindlin-3 deficiency leads to impaired erythropoiesis and erythrocyte cytoskeleton.

Kindlin-3 (K3) is critical for the activation of integrin adhesion receptors in hematopoietic cells. In humans and mice, K3 deficiency is associated with impaired immunity and bone development, bleeding, and aberrant erythrocyte shape. To delineate how K3 deficiency (K3KO) contributes to anemia and misshaped erythrocytes, mice deficient in erythroid (K3KO∖EpoR-cre) or myeloid cell K3 (K3KO∖Lyz2cre), knockin mice expressing mutant K3 (Q597W598 to AA) with reduced integrin-activation function (K3KI), and control wild-type (WT) K3 mice were studied.

The NOGO receptor NgR2, a novel αVβ3 integrin effector, induces neuroendocrine differentiation in prostate cancer.

Androgen deprivation therapies aimed to target prostate cancer (PrCa) are only partially successful given the occurrence of neuroendocrine PrCa (NEPrCa), a highly aggressive and highly metastatic form of PrCa, for which there is no effective therapeutic approach. Our group has demonstrated that while absent in prostate adenocarcinoma, the αVβ3 integrin expression is increased during PrCa progression toward NEPrCa. Here, we show a novel pathway activated by αVβ3 that promotes NE differentiation (NED).

Cortico-Cerebellar Connectivity Underlying Motor Control in Chronic Poststroke Individuals.

The robust, reciprocal anatomic connections between the cerebellum and contralateral sensorimotor cerebral hemisphere underscore the strong physiological interdependence between these two regions in relation to human behavior. Previous studies have shown that damage to sensorimotor cortex can result in a lasting reduction of cerebellar metabolism, the magnitude of which has been linked to poor rehabilitative outcomes. A better understanding of movement-related cerebellar physiology as well as cortico-cerebellar coherence (CCC) in the chronic, poststroke state may be key to developing novel neuromodulatory techniques that promote upper limb motor rehabilitation.

Contralaterally Controlled Functional Electrical Stimulation Combined With Brain Stimulation for Severe Upper Limb Hemiplegia-Study Protocol for a Randomized Controlled Trial.

Background: Approximately two-thirds of stroke survivors experience chronic upper limb paresis, and of them, 50% experience severe paresis. Treatment options for severely impaired survivors are often limited. Rehabilitation involves intensively engaging the paretic upper limb, and disincentivizing use of the non-paretic upper limb, with the goal to increase excitability of the ipsilesional primary motor cortex (iM1) and suppress excitability of the undamaged (contralesional) motor cortices, presumed to have an inhibitory effect on iM1.

Efficacy of contralaterally controlled functional electrical stimulation compared to cyclic neuromuscular electrical stimulation and task-oriented training for recovery of hand function after stroke: study protocol for a multi-site randomized controlled trial.

Background: Multi-site studies in stroke rehabilitation are important for determining whether a technology and/or treatment can be successfully administered by sites other than the originating site and with similar positive outcomes. This study is the first multi-site clinical trial of a novel intervention for post-stroke upper limb rehabilitation called contralaterally controlled functional electrical stimulation (CCFES). Previous pilot and single-site studies showed positive effects of CCFES on upper limb impairment and hand dexterity in stroke survivors.

Mechanism of integrin activation by talin and its cooperation with kindlin.

Talin-induced integrin binding to extracellular matrix ligands (integrin activation) is the key step to trigger many fundamental cellular processes including cell adhesion, cell migration, and spreading. Talin is widely known to use its N-terminal head domain (talin-H) to bind and activate integrin, but how talin-H operates in the context of full-length talin and its surrounding remains unknown. Here we show that while being capable of inducing integrin activation, talin-H alone exhibits unexpectedly low potency versus a constitutively activated full-length talin.

Histone 2B Facilitates Plasminogen-Enhanced Endothelial Migration through Protease-Activated Receptor 1 (PAR1) and Protease-Activated Receptor 2 (PAR2).

Plasminogen and its multiple receptors have been implicated in the responses of many different cell types. Among these receptors, histone 2B (H2B) has been shown to play a prominent role in macrophage responses. The contribution of H2B to plasminogen-induced endothelial migration, an event relevant to wound healing and angiogenesis, is unknown.

Ghost mitochondria drive metastasis through adaptive GCN2/Akt therapeutic vulnerability.

Cancer metabolism, including in mitochondria, is a disease hallmark and therapeutic target, but its regulation is poorly understood. Here, we show that many human tumors have heterogeneous and often reduced levels of Mic60, or Mitofilin, an essential scaffold of mitochondrial structure. Despite a catastrophic collapse of mitochondrial integrity, loss of bioenergetics, and oxidative damage, tumors with Mic60 depletion slow down cell proliferation, evade cell death, and activate a nuclear gene expression program of innate immunity and cytokine/chemokine signaling.

Targeted Deletion of Kindlin-2 in Mouse Mammary Glands Inhibits Tumor Growth, Invasion, and Metastasis Downstream of a TGF-β/EGF Oncogenic Signaling Pathway.

Breast cancer (BC) is one of the leading causes of cancer-related deaths due in part to its invasive and metastatic properties. Kindlin-2 (FERMT2) is associated with the pathogenesis of several cancers. Although the role of Kindlin-2 in regulating the invasion-metastasis cascade in BC is widely documented, its function in BC initiation and progression remains to be fully elucidated.

Integrin mediates cell entry of the SARS-CoV-2 virus independent of cellular receptor ACE2.

Coronavirus disease 2019 (COVID-19) is a highly contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is broadly accepted that SARS-CoV-2 utilizes its spike protein to recognize the extracellular domain of angiotensin-converting enzyme 2 (ACE2) to enter cells for viral infection. However, other mechanisms of SARS-CoV-2 cell entry may occur.

Repetitive Transcranial Magnetic Stimulation of the Contralesional Dorsal Premotor Cortex for Upper Extremity Motor Improvement in Severe Stroke: Study Protocol for a Pilot Randomized Clinical Trial.

Up to 50% of stroke survivors have persistent, severe upper extremity paresis even after receiving rehabilitation. Repetitive transcranial magnetic stimulation (rTMS) can augment the effects of rehabilitation by modulating corticomotor excitability, but the conventional approach of facilitating excitability of the ipsilesional primary motor cortex (iM1) fails to produce motor improvement in stroke survivors with severe loss of ipsilesional substrate. Instead, the undamaged, contralesional dorsal premotor cortex (cPMd) may be a more suitable target.

Repetitive Peripheral Sensory Stimulation as an Add-On Intervention for Upper Limb Rehabilitation in Stroke: A Randomized Trial.

Introduction: Repetitive peripheral sensory stimulation (RPSS) followed by 4-hour task-specific training (TST) improves upper limb motor function in subjects with stroke who experience moderate to severe motor upper limb impairments. Here, we compared effects of RPSS vs sham followed by a shorter duration of training in subjects with moderate to severe motor impairments in the chronic phase after stroke.

Methods: This single-center, randomized, placebo-controlled, parallel-group clinical trial compared effects of 18 sessions of either 1.