Biology subjects

Mari, S.

Publications and source records attributed to Mari, S..

7 recordsLinked to original sources

bioRxiv2024

Ninjurin-1 mediated plasma membrane rupture is a two-step process requiring cell swelling

Ninjurin-1 (NINJ1) executes cell lysis by polymerizing into filaments, yet how these form membrane lesions is unknown. Integrating cell-based assays with molecular dynamics simulations, we demonstrate that NINJ1-driven membrane rupture starts with the lateral association of NINJ1 dimers into double filaments. Subsequently, swelling of necrotic cells increases plasma membrane tension, leading to separation of the filament interface and NINJ1 lesion opening. Inhibiting cell swelling prevents this increase in tension, blocking NINJ1-mediated plasma membrane rupture without disrupting NINJ1 oligomerization, implicating membrane tension as key for opening NINJ1 lesions. The NINJ1 homolog NINJ2 oligomerizes but fails to form membrane lesions during cell death due to the greater stability of its dimer. Finally, using atomic force microscopy of NINJ1-containing proteoliposomes, we show that NINJ1 forms large pores by stabilizing membrane edges. In summary, our findings support a model whereby membrane tension drives a zipper-like opening of NINJ1 double filaments, initiating necrotic cell lysis.

immunology↗

bioRxiv2024

Changes in intra- and interlimb reflexes from forelimb cutaneous afferents after staggered thoracic lateral hemisections during locomotion in cats

In quadrupeds, such as cats, cutaneous afferents from the forepaw dorsum signal external perturbations and send signals to spinal circuits to coordinate the activity in muscles of all four limbs. How these cutaneous reflex pathways from forelimb afferents are reorganized after an incomplete spinal cord injury is not clear. Using a staggered thoracic lateral hemisections paradigm, we investigated changes in intralimb and interlimb reflex pathways by electrically stimulating the left and right superficial radial nerves in seven adult cats and recording reflex responses in five forelimb and ten hindlimb muscles. After the first (right T5-T6) and second (left T10-T11) hemisections, forelimb-hindlimb coordination was altered and weakened. After the second hemisection, cats required balance assistance to perform quadrupedal locomotion. Short-, mid- and long- latency homonymous and crossed reflex responses in forelimb muscles and their phase modulation remained largely unaffected after staggered hemisections. The occurrence of homolateral and diagonal mid- and long-latency responses in hindlimb muscles evoked with left and right superficial radial nerve stimulation was significantly reduced at the first time point after the first hemisection, but partially recovered at the second time point with left superficial radial nerve stimulation. These responses were lost or reduced after the second hemisection. When present, all reflex responses, including homolateral and diagonal, maintained their phase-dependent modulation. Therefore, our results show a considerable loss in cutaneous reflex transmission from cervical to lumbar levels after incomplete spinal cord injury, albeit with preservation of phase modulation, likely affecting functional responses to external perturbations. Key pointsO_LICutaneous afferent inputs coordinate muscle activity in the four limbs during locomotion when the forepaw dorsum contacts an obstacle. C_LIO_LIThoracic spinal cord injury disrupts communication between spinal locomotor centers located at cervical and lumbar levels, impairing balance and limb coordination. C_LIO_LIWe investigated cutaneous reflexes from forelimb afferents during quadrupedal locomotion by electrically stimulating the superficial radial nerve bilaterally, before and after staggered lateral thoracic hemisections in cats. C_LIO_LIWe showed a loss/reduction of mid- and long-latency homolateral and diagonal reflex responses in hindlimb muscles early after the first hemisection that partially recovered with left superficial radial nerve stimulation, before being reduced after the second hemisection. C_LIO_LITargeting cutaneous reflex pathways from forelimb afferents projecting to the four limbs could help develop therapeutic approaches aimed at restoring transmission in ascending and descending spinal pathways. C_LI Figure Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=76 SRC="FIGDIR/small/590723v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@1ef94c1org.highwire.dtl.DTLVardef@f2ec5org.highwire.dtl.DTLVardef@c7c30aorg.highwire.dtl.DTLVardef@d5ce21_HPS_FORMAT_FIGEXP M_FIG C_FIG Contacting an obstacle during locomotion activates cutaneous afferents to maintain balance and coordinate all four limbs. Spinal cord injuries disrupt neural communications between spinal networks controlling the fore- and hindlimbs, impairing balance and limb coordination. Cutaneous reflex pathways can be used to develop therapeutic approaches for restoring ascending and descending transmission to facilitate locomotor recovery.

neuroscience↗

bioRxiv2024

Forelimb movements contribute to hindlimb cutaneous reflexes during locomotion in cats

During quadrupedal locomotion, central circuits interacting with somatosensory feedback coordinate forelimb and hindlimb movements. How this is achieved is not clear. To determine if forelimb movements modulate hindlimb cutaneous reflexes involved in responding to an external perturbation, we stimulated the superficial peroneal nerve in six intact cats during quadrupedal locomotion and during hindlimb-only locomotion (with forelimbs standing on stationary platform) and in two spinal-transected cats during hindlimb-only locomotion. We compared cutaneous reflexes evoked in six ipsilateral and four contralateral hindlimb muscles. Results showed similar occurrence and phase-dependent modulation of short-latency inhibitory and excitatory responses during quadrupedal and hindlimb-only locomotion in intact cats. However, the depth of modulation was reduced in the ipsilateral semitendinosus during hindlimb-only locomotion. Additionally, longer-latency responses occurred less frequently in extensor muscles bilaterally during hindlimb-only locomotion while short-latency inhibitory and longer-latency excitatory responses occurred more frequently in the ipsilateral and contralateral sartorius anterior, respectively. After spinal transection, short-latency inhibitory and excitatory responses were similar to both intact conditions, while mid- or longer-excitatory responses were reduced or abolished. Our results suggest that the absence of forelimb movements suppresses inputs from supraspinal structures and/or cervical cord that normally contribute to longer-latency reflex responses in hindlimb extensor muscles. NEW & NOTEWORTHYDuring quadrupedal locomotion, the coordination of forelimb and hindlimb movements involves central circuits and somatosensory feedback. To demonstrate how forelimb movement affects hindlimb cutaneous reflexes during locomotion, we stimulated the superficial peroneal nerve in intact cats during quadrupedal and hindlimb-only locomotion, as well as in spinal-transected cats during hindlimb-only locomotion. We show that forelimb movement influences the modulation of hindlimb cutaneous reflexes, particularly the occurrence of long-latency reflex responses.

neuroscience↗

bioRxiv2023

Changes in intra- and interlimb reflexes from hindlimb cutaneous afferents after staggered thoracic lateral hemisections during locomotion in cats

When the foot dorsum contacts an obstacle during locomotion, cutaneous afferents signal central circuits to coordinate muscle activity in the four limbs. Spinal cord injury disrupts these interactions, impairing balance and interlimb coordination. We evoked cutaneous reflexes by electrically stimulating left and right superficial peroneal nerves before and after two thoracic lateral hemisections placed on opposite sides of the cord at 9-13 weeks interval in seven adult cats (4 males and 3 females). We recorded reflex responses in ten hindlimb and five forelimb muscles bilaterally. After the first (right T5-T6) and second (left T10-T11) hemisections, coordination of the fore- and hindlimbs was altered and/or became less consistent. After the second hemisection, cats required balance assistance to perform quadrupedal locomotion. Short-latency reflex responses in homonymous and crossed hindlimb muscles largely remained unaffected after staggered hemisections. However, mid- and long-latency homonymous and crossed responses in both hindlimbs occurred less frequently after staggered hemisections. In forelimb muscles, homolateral and diagonal mid- and long-latency response occurrence significantly decreased after the first and second hemisections. In all four limbs, however, when present, short-, mid- and long-latency responses maintained their phase-dependent modulation. We also observed reduced durations of short-latency inhibitory homonymous responses in left hindlimb extensors early after the first hemisection and delayed short-latency responses in the right ipsilesional hindlimb after the first hemisection. Therefore, changes in cutaneous reflex responses correlated with impaired balance/stability and interlimb coordination during locomotion after spinal cord injury. Restoring reflex transmission could be used as a biomarker to facilitate locomotor recovery. Key pointsO_LICutaneous afferent inputs coordinate muscle activity in the four limbs during locomotion when the foot dorsum contacts an obstacle. C_LIO_LIThoracic spinal cord injury disrupts communication between spinal locomotor centers located at cervical and lumbar levels, impairing balance and limb coordination. C_LIO_LIWe investigated cutaneous reflexes during quadrupedal locomotion by electrically stimulating the superficial peroneal nerve bilaterally, before and after staggered lateral thoracic hemisections of the spinal cord in cats. C_LIO_LIWe showed a loss/reduction of mid- and long-latency responses in all four limbs after staggered hemisections, which correlated with altered coordination of the fore- and hindlimbs and impaired balance. C_LIO_LITargeting cutaneous reflex pathways projecting to the four limbs could help develop therapeutic approaches aimed at restoring transmission in ascending and descending spinal pathways. C_LI

neuroscience↗

bioRxiv2023

Spinal sensorimotor circuits play a prominent role in hindlimb locomotor recovery after staggered thoracic lateral hemisections but cannot restore posture and interlimb coordination during quadrupedal locomotion in adult cats

Spinal sensorimotor circuits interact with supraspinal and peripheral inputs to generate quadrupedal locomotion. Ascending and descending spinal pathways ensure coordination between the fore-and hindlimbs. Spinal cord injury disrupts these pathways. To investigate the control of interlimb coordination and hindlimb locomotor recovery, we performed two lateral thoracic hemisections placed on opposite sides of the cord (right T5-T6 and left T10-T11) at an interval of approximately two months in eight adult cats. In three cats, we then made a complete spinal transection caudal to the second hemisection at T12-T13. We collected electromyography and kinematic data during quadrupedal and hindlimb-only locomotion before and after spinal lesions. We show that 1) cats spontaneously recover quadrupedal locomotion following staggered hemisections but require balance assistance after the second one, 2) coordination between the fore-and hindlimbs displays 2:1 patterns and becomes weaker and more variable after both hemisections, 3) left-right asymmetries in hindlimb stance and swing durations appear after the first hemisection and reverse after the second, and 4) support periods reorganize after staggered hemisections to favor support involving both forelimbs and diagonal limbs. Cats expressed hindlimb locomotion the day following spinal transection, indicating that lumbar sensorimotor circuits play a prominent role in hindlimb locomotor recovery after staggered hemisections. These results reflect a series of changes in spinal sensorimotor circuits that allow cats to maintain and recover some level of quadrupedal locomotor functionality with diminished motor commands from the brain and cervical cord, although the control of posture and interlimb coordination remains impaired. Significance StatementCoordinating the limbs during locomotion depends on pathways in the spinal cord. We used a spinal cord injury model that disrupts communication between the brain and spinal cord by sectioning half of the spinal cord on one side and then about two months later, half the spinal cord on the other side at different levels of the thoracic cord in cats. We show that despite a strong contribution from neural circuits located below the second spinal cord injury in the recovery of hindlimb locomotion, the coordination between the forelimbs and hindlimbs weakens and postural control is impaired. We can use our model to test approaches to restore the control of interlimb coordination and posture during locomotion after spinal cord injury.

neuroscience↗

bioRxiv2023

Neuromechanical strategies for obstacle negotiation during overground locomotion following an incomplete spinal cord injury in adult cats

Following incomplete spinal cord injury in animals, including humans, substantial locomotor recovery can occur. However, functional aspects of locomotion, such as negotiating an obstacle remains challenging. We collected kinematic and electromyography data in ten adult cats before and at weeks 1-2 and 7-8 after a lateral mid-thoracic hemisection while they negotiated obstacles of three different heights. Intact cats always cleared obstacles without contact. At weeks 1-2 after hemisection, the ipsilesional hindlimb contacted obstacles in ~50% of trials, triggering a stumbling corrective reaction or lack of response. When complete clearance occurred, we observed exaggerated ipsilesional hindlimb flexion when it crossed the obstacle with the contralesional limbs leading. At weeks 7-8 after hemisection, complete clearance increased in favor of absent responses while the proportion of stumbling corrective reactions remained relatively the same. We found redistribution of weight support after hemisection, with reduced diagonal supports and increased homolateral supports, particularly on the contralesional side. The main neural strategy for complete clearance in intact cats consisted of increased activation of muscles that flex the knee. After hemisection, knee flexor activation remained but it was insufficient or more variable as the limb approached the obstacle. Intact cats also increased their speed when stepping over an obstacle, an increase that disappeared after hemisection. The increase in complete clearance over time after hemisection paralleled the recovery of muscle activation patterns or new strategies. Our results suggest partial recovery of anticipatory control through neuroplastic changes in the locomotor control system.

neuroscience↗

bioRxiv2020

Identification of blood autosomal cis-expression quantitative trait methylation (cis-eQTMs) in children

BackgroundThe identification of expression quantitative trait methylation (eQTMs), defined as associations between DNA methylation levels and gene expression, might help the biological interpretation of epigenome-wide association studies (EWAS). We aimed to identify autosomal cis eQTMs in childrens blood, using data from 832 children of the Human Early Life Exposome (HELIX) project. MethodsBlood DNA methylation and gene expression were measured with the Illumina 450K and the Affymetrix HTA v2 arrays, respectively. The relationship between methylation levels and expression of nearby genes (1 Mb window centered at the transcription start site, TSS) was assessed by fitting 13.6 M linear regressions adjusting for sex, age, cohort, and blood cell composition. ResultsWe identified 39,749 blood autosomal cis eQTMs, representing 21,966 unique CpGs (eCpGs, 5.7% of total CpGs) and 8,886 unique transcript clusters (eGenes, 15.3% of total transcript clusters, equivalent to genes). In 87.9% of these cis eQTMs, the eCpG was located at <250 kb from eGenes TSS; and 58.8% of all eQTMs showed an inverse relationship between the methylation and expression levels. Only around half of the autosomal cis-eQTMs eGenes could be captured through annotation of the eCpG to the closest gene. eCpGs had less measurement error and were enriched for active blood regulatory regions and for CpGs reported to be associated with environmental exposures or phenotypic traits. 40.4% of eQTMs had at least one genetic variant associated with methylation and expression levels. The overlap of autosomal cis eQTMs in childrens blood with those described in adults was small (13.8%), and age-shared cis eQTMs tended to be proximal to the TSS and enriched for genetic variants. ConclusionsThis catalogue of autosomal cis eQTMs in childrens blood can help the biological interpretation of EWAS findings and is publicly available at https://helixomics.isglobal.org/. Funding: The study has received funding from the European Communitys Seventh Framework Programme (FP7/2007-206) under grant agreement no 308333 (HELIX project); the H2020-EU.3.1.2. - Preventing Disease Programme under grant agreement no 874583 (ATHLETE project); from the European Unions Horizon 2020 research and innovation programme under grant agreement no 733206 (LIFECYCLE project), and from the European Joint Programming Initiative "A Healthy Diet for a Healthy Life" (JPI HDHL and Instituto de Salud Carlos III) under the grant agreement no AC18/00006 (NutriPROGRAM project). The genotyping was supported by the project PI17/01225, funded by the Instituto de Salud Carlos III and co-funded by European Union (ERDF, "A way to make Europe") and the Centro Nacional de Genotipado-CEGEN (PRB2-ISCIII).

genomics↗