Wounding the stroma: Docetaxel's role in dormant breast cancer escape.

The mechanistic underpinnings of breast cancer recurrence following periods of dormancy are largely undetermined. A new study in PLOS Biology reveals that docetaxel-induced injury of tumour stromal cells stimulates the release of cytokines that support dormancy escape of breast cancer cells.

Excitatory drive to spinal motoneurones is necessary for serotonin to modulate motoneurone excitability via 5-HT2 receptors in humans.

Serotonin modulates corticospinal excitability, motoneurone firing rates and contractile strength via 5-HT2 receptors. However, the effects of these receptors on cortical and motoneurone excitability during voluntary contractions have not been explored in humans. Therefore, the purpose of this study was to investigate how 5-HT2 antagonism affects corticospinal and motoneuronal excitability with and without descending drive to motoneurones. Twelve individuals (aged 24 ± 4 years) participated in a double-blind, placebo-controlled, crossover study, whereby the 5-HT2 antagonist cyproheptadine was administered. Transcranial magnetic stimulation (TMS) was delivered to the motor cortex to produce motor evoked potentials (MEPs), and electrical stimulation at the cervicomedullary junction was used to generate cervicomedullary motor evoked potentials (CMEPs) in the biceps brachii at rest and during a range of submaximal elbow flexions. Evoked potentials were also obtained after a conditioning TMS pulse to produce conditioned MEPs and CMEPs (100 ms inter-stimulus interval). 5-HT2 antagonism reduced maximal torque (p < 0.001), and compared to placebo, reduced unconditioned MEP amplitude at rest (p = 0.003), conditioned MEP amplitude at rest (p = 0.033) and conditioned MEP amplitude during contractions (p = 0.020). 5-HT2 antagonism also increased unconditioned CMEP amplitude during voluntary contractions (p = 0.041) but not at rest. Although 5-HT2 antagonism increased long-interval intracortical inhibition, net corticospinal excitability was unaffected during voluntary contractions. Given that spinal motoneurone excitability was only affected when descending drive to motoneurones was present, the current study indicates that excitatory drive is necessary for 5-HT2 receptors to regulate motoneurone excitability but not intracortical circuits.

Squeezable Hydrogel Microparticles for Single Extracellular Vesicle Protein Profiling.

Extracellular vesicles (EVs) are promising for molecular diagnostics, but current analyses are limited by the rarity and compositional heterogeneity of EV protein expression. Therefore, single EV profiling methods require high sensitivity, multiplexing, and throughput to address these issues. Here a single EV analysis technique that utilizes squeezable methacrylated hyaluronic acid hydrogel microparticles (MHPs) is described as a scaffold to immobilize EVs and perform an integrated rolling circle amplification (RCA) assay for an ultra-sensitive and multiplex analysis of single EV proteins. EVs are prepared into MHPs in a high-throughput manner with droplet microfluidics and optimally labeled with antibody-oligonucleotide conjugates in MHPs without steric limitations. By designing MHPs with high compressibility, single EV protein signals are amplified as RCA products that can be aligned on the same plane by physically squeezing MHPs and visualized with low magnification. This method provides a simple and scalable single EV imaging analysis pipeline for identifying multiplex marker expression patterns from single EVs. For validation, the single EV heterogeneity of highly expressed cancer cell markers is profiled across different cancer cell lines. These findings exemplify squeezable MHPs as a robust platform with high sensitivity, multiplexing, and scalability for resolving single EV heterogeneity and advancing molecular assay technologies.

Botulinum toxin injections for the treatment of neurogenic thoracic outlet syndrome: A systematic review.

Botulinum toxin (BTX) injections into the musculature surrounding the brachial plexus have been examined as a potential treatment for neurogenic thoracic outlet syndrome (nTOS). This systematic review identified 15 publications, of which one was a randomized controlled trial. BTX injections performed with ultrasound or electromyographic guidance, and with the inclusion of the pectoralis minor muscle, in addition to the anterior and/or middle scalenes, tended to provide greater symptom improvement and may predict response to first rib resection. Importantly, most studies were of low quality; thus, the results should be interpreted with caution. Further high-quality studies are needed to confirm these findings.

Single-Cell RNA Sequencing Reveals That Adaptation of Human Aortic Endothelial Cells to Antiproliferative Therapies Is Modulated by Flow-Induced Shear Stress.

BACKGROUND: Endothelial cells (ECs) are capable of quickly responding in a coordinated manner to a wide array of stresses to maintain vascular homeostasis. Loss of EC cellular adaptation may be a potential marker for cardiovascular disease and a predictor of poor response to endovascular pharmacological interventions such as drug-eluting stents. Here, we report single-cell transcriptional profiling of ECs exposed to multiple stimulus classes to evaluate EC adaptation. METHODS: Human aortic ECs were costimulated with both pathophysiological flows mimicking shear stress levels found in the human aorta (laminar and turbulent, ranging from 2.5 to 30 dynes/cm2) and clinically relevant antiproliferative drugs, namely paclitaxel and rapamycin. EC state in response to these stimuli was defined using single-cell RNA sequencing. RESULTS: We identified differentially expressed genes and inferred the TF (transcription factor) landscape modulated by flow shear stress using single-cell RNA sequencing. These flow-sensitive markers differentiated previously identified spatially distinct subpopulations of ECs in the murine aorta. Moreover, distinct transcriptional modules defined flow- and drug-responsive EC adaptation singly and in combination. Flow shear stress was the dominant driver of EC state, altering their response to pharmacological therapies. CONCLUSIONS: We showed that flow shear stress modulates the cellular capacity of ECs to respond to paclitaxel and rapamycin administration, suggesting that while responding to different flow patterns, ECs experience an impairment in their transcriptional adaptation to other stimuli.

Evaluating the effect of targeting body shape concerns on long-term weight change.

OBJECTIVE: The goal of this follow-up to a randomized proof-of-concept study was to determine if targeting body shape concern (BSC) has a clinically significant impact on long-term weight change among adult women of higher body weight with BSC. A secondary aim was to observe the maintenance of body image improvements during follow-up. METHOD: In the original 4-week trial, women were randomized to behavioral weight loss recommendations alone (control; n = 15) or combined with the evidence-based body project intervention (n = 17). All participants were directed to continue monitoring diet and exercise through Week 8. The current analysis focused on follow-up data collected on weight, BSC, internalized weight bias, internalized thin ideal, and body appreciation at 8 weeks, 6 months, and 12 months. Percent weight change was calculated from baseline and compared against clinical milestones of -2.5% and -5%. An intent-to-treat approach was used for individuals lost to follow-up (n = 11). RESULTS: Body project participants achieved the clinically significant target of -2.5% weight loss by 12 months. Control participants did not reach the milestone and regained lost weight at 12 months. Neither condition reached the 5% clinical target. Both groups experienced improved body image, but body project participants maintained a greater magnitude of improvement in all measures except internalized thin ideal at 12 months. CONCLUSION: The current study provides preliminary evidence that targeting BSC among women with BSC who want to lose weight may improve long-term weight loss. Further intervention development and testing are warranted. PUBLIC SIGNIFICANCE: The results of this study suggest that targeting negative body image among adult women with high BSC might be a pathway to improve long-term weight loss in behavioral weight management. This is aligned with precision medicine priorities to optimize weight-related health care.

Walking Slope and Heavy Backpacks Affect Peak and Impulsive Lumbar Joint Contact Forces.

Heavy load carriage is associated with musculoskeletal overuse injury, particularly in the lumbar spine. Steep walking slopes and heavy backpacks separately require adaptation of torso kinematics, but the combined effect of sloped walking and heavy backpack loads on lumbar spine forces is unclear. Backpacks with hip belts can reduce pressure under the shoulder straps; however, it is unknown if wearing a hip belt reduces lumbar joint contact forces. We used a musculoskeletal modeling and simulation approach to quantify peak and impulsive L1L2 and L4L5 lumbar joint contact forces in the anterior/posterior shear and compressive directions during walking on 0° and ±10° slopes, with no backpack and with 40% body weight backpack load using two different configurations (hip belt assisted and shoulder-borne). Both walking slope and backpack load significantly affected shear and compressive forces. The largest peak shear and compressive forces or 1.57 and 5.23 body weights, respectively, exceed recommended limits and were observed during uphill walking with shoulder-borne loads. However, only impulsive force results revealed differences due to the backpack configuration, and this effect depended on walking slope. During downhill walking only, the hip belt assisted configuration resulted compressive impulses lower than during shoulder borne by 0.25 body weight seconds for both L1L2 and L4L5. These results indicate that walking uphill with heavy loads causes high shear and compressive lumbar forces that may increase overuse injury risk. In addition, our results suggest it is especially important to wear a hip belt when walking downhill.

The development of synthetic child speech in three South African languages.

It is well-known that children with expressive communication difficulties have the right to communicate, but they should also have the right to do so in whichever language they choose, with a voice that closely matches their age, gender, and dialect. This study aimed to develop naturalistic synthetic child speech, matching the vocal identity of three children with expressive communication difficulties, using Tacotron 2, for three under-resourced South African languages, namely South African English (SAE), Afrikaans, and isiXhosa. Due to the scarcity of child speech corpora, 2 hours of child speech data per child was collected from three 11- to 12-year-old children. Two adult models were used to "warm start" the child speech synthesis. To determine the naturalness of the synthetic voices, 124 listeners participated in a mean opinion score survey (Likert Score) and optionally gave qualitative feedback. Despite limited training data used in this study, we successfully developed a synthesized child voice of adequate quality in each language. This study highlights that with recent technological advancements, it is possible to develop synthetic child speech that matches the vocal identity of a child with expressive communication difficulties in different under-resourced languages.

Lactate Enhances Mouse ES Cell Differentiation Toward XEN Cells In Vitro.

Metabolism plays a crucial role for cell survival and function; however, recent evidence has implicated it in regulating embryonic development. In the embryo, the inner cell mass undergoes orchestrated cellular divisions resulting in the formation of pluripotent epiblast stem cells and primitive endoderm cells. However, both lineages can be captured in vitro as embryonic stem (ES) cells and extraembryonic endoderm (XEN) cells. Concomitantly, changes in the metabolic profile occurs during development, and are well documented in the embryonic lineages. However, a comprehensive multi-omic analysis of these features in XEN cells remains lacking. We observed that mouse XEN cells exhibited high sensitivity to glycolytic inhibition in addition to maintaining elevated intra- and extracellular lactate levels in vitro. Extraembryonic endoderm cells maintain high lactate levels by increased LDHA activity, and re-routing pyruvate away from the mitochondria resulting in reduced mitochondrial activity due to disruptions in electron transport chain stoichiometry. Importantly, exogenous lactate supplementation or promoting intracellular lactate accumulation enhances XEN differentiation in vitro. These results highlight how lactate contributes to XEN differentiation in vitro and may serve to enhance reprogramming efficiency of cells used for regenerative medicine.

Enhanced availability of serotonin limits muscle activation during high-intensity, but not low-intensity, fatiguing contractions.

Serotonin (5-HT) modulates motoneuron excitability during muscle contractions, where the release of 5-HT in the central nervous system (CNS) is linked to the intensity of physical activity. Although there is evidence that enhanced availability of 5-HT can exacerbate fatigue, these effects on the development of fatigue during different contraction intensities are largely unknown. The purpose of this study was to investigate how enhanced 5-HT availability affects voluntary muscle activation and corticospinal excitability during fatigue-inducing contractions. Two experiments were performed. In the first experiment (n = 11), 12 isometric elbow flexions at 20% maximal voluntary contractions (MVCs) were performed for 2 min each with 40-s rest periods. In the second experiment (n = 14), 12 maximal isometric elbow flexions were held for 10 s each with 40-s rest periods. In both experiments, the selective serotonin reuptake inhibitor (20-mg paroxetine), or a placebo, was administered in a two-way crossover design. Muscle responses to transcranial magnetic stimulation (TMS) of the motor cortex (both experiments 1 and 2), as well as motor point stimulation of the elbow flexors (experiment 2) were assessed. Paroxetine reduced both motor cortical (P = 0.018) and motor point voluntary activation (P = 0.036) during the maximal contraction protocol. Paroxetine also reduced exercise-induced lengthening of the TMS silent period during the submaximal (P = 0.037) and maximal (P = 0.002) contraction protocols. Activation of inhibitory 5-HT1A receptors on motoneurons likely exacerbated exercise-induced reductions in voluntary drive to the elbow flexors. However, 5-HT modulation of motor activity also appeared at the supraspinal level.NEW & NOTEWORTHY As serotonin release onto motoneurons may be scaled to the strength of muscle contraction, it may have different effects when neuromuscular fatigue is induced by contractions of different intensities. Enhanced levels of serotonin compromised voluntary activation of muscle when fatigue was induced by strong contractions but not weak contractions. This provides evidence that the serotonergic system has the greatest influence on fatigue that is generated with high neural drive to the target muscle.

Inhibitory signaling as a predictor of leg force control in young and older adults.

As the populations of the United States and developed nations age, motor control performance is adversely impacted, resulting in functional impairments that can diminish quality of life. Generally, force control in the lower limb worsens with age, with older adults (OA) displaying more variable and less accurate submaximal forces. Corticospinal inhibitory signaling may influence force control, with those OA who maintain corticospinal inhibitory signaling capacity achieving steadier forces. This study aimed to assess the relationships between lower limb force control and transcranial magnetic stimulation (TMS) measures of corticospinal inhibition (i.e., cortical silent period (cSP) duration and depth). 15 OA and 14 young adults (YA) were recruited for this study. All subjects underwent a TMS protocol to elicit the cSP while maintaining 15% of their maximal force in their knee extensor muscles. OA and YA did not display differences in force control metrics or corticospinal inhibitory measures. However, in OA, maximal cSP depth (%dSP max) was associated with lower force variability. No other significant relationships existed in the YA or OA groups. Future studies will benefit from evaluating a range of target forces and target muscles to assess potential relationships between sensorimotor inhibitory capacity and control of muscle force output.

I Can Step Clearly Now, the TENS Is On: Transcutaneous Electric Nerve Stimulation Decreases Sensorimotor Uncertainty during Stepping Movements.

Transcutaneous electric nerve stimulation (TENS) is a method of electrical stimulation that elicits activity in sensory nerves and leads to improvements in the clinical metrics of mobility. However, the underlying perceptual mechanisms leading to this improvement are unknown. The aim of this study was to apply a Bayesian inference model to understand how TENS impacts sensorimotor uncertainty during full body stepping movements. Thirty healthy adults visited the lab on two occasions and completed a motor learning protocol in virtual reality (VR) on both visits. Participants were randomly assigned to one of three groups: TENS on first visit only (TN), TENS on second visit only (NT), or a control group where TENS was not applied on either visit (NN). Using methods of Bayesian inference, we calculated the amount of uncertainty in the participants' center of mass (CoM) position estimates on each visit. We found that groups TN and NT decreased the amount of uncertainty in the CoM position estimates in their second visit while group NN showed no difference. The least amount of uncertainty was seen in the TN group. These results suggest that TENS reduces the amount of uncertainty in sensory information, which may be a cause for the observed benefits with TENS.

Mycobacterium tuberculosis evades macrophage defenses by inhibiting plasma membrane repair.

Induction of macrophage necrosis is a strategy used by virulent Mycobacterium tuberculosis (Mtb) to avoid innate host defense. In contrast, attenuated Mtb causes apoptosis, which limits bacterial replication and promotes T cell cross-priming by antigen-presenting cells. Here we show that Mtb infection causes plasma membrane microdisruptions. Resealing of these lesions, a process crucial for preventing necrosis and promoting apoptosis, required translocation of lysosomal and Golgi apparatus-derived vesicles to the plasma membrane. Plasma membrane repair depended on prostaglandin E(2) (PGE(2)), which regulates synaptotagmin 7 (Syt-7), the calcium sensor involved in the lysosome-mediated repair mechanism. By inducing production of lipoxin A(4) (LXA(4)), which blocks PGE(2) biosynthesis, virulent Mtb prevented membrane repair and induced necrosis. Thus, virulent Mtb impairs macrophage plasma membrane repair to evade host defenses.

Characterization of a Vimentinhigh /Nestinhigh proteome and tissue regenerative secretome generated by human pancreas-derived mesenchymal stromal cells.

Multipotent/mesenchymal stromal cells (MSCs) exist within a variety of postnatal tissues; however, global proteomic analyses comparing tissue-specific MSC are limited. Using human bone marrow (BM)-derived MSCs as a gold standard, we used label-free mass spectrometry and functional assays to characterize the proteome, secretome, and corresponding function of human pancreas-derived MSCs (Panc-MSCs) with a classical phenotype (CD90+/CD73+/CD105+/CD45-/CD31-). Both MSC subtypes expressed mesenchymal markers vimentin, α-SMA, and STRO-1; however, expression of nestin was increased in Panc-MSCs. Accordingly, these Vimentinhigh /Nestinhigh cells were isolated from fresh human pancreatic islet and non-islet tissues. Next, we identified expression of >60 CD markers shared between Panc-MSCs and BM-MSCs, including validated expression of CD14. An additional 19 CD markers were differentially expressed, including reduced pericyte-marker CD146 expression on Panc-MSCs. Panc-MSCs also showed reduced expression of proteins involved in lipid and retinoid metabolism. Accordingly, Panc-MSCs showed restricted responses to adipogenic stimuli in vitro, although both MSC types demonstrated trilineage differentiation. In contrast, Panc-MSCs demonstrated accelerated growth kinetics and competency to pro-neurogenic stimuli in vitro. The secretome of Panc-MSCs was highly enriched for proteins associated with vascular development, wound healing and chemotaxis. Similar to BM-MSCs, Panc-MSCs conditioned media augmented endothelial cell survival, proliferation, and tubule formation in vitro. Importantly, the secretome of both MSC types was capable of stimulating chemotactic infiltration of murine endothelial cells in vivo and reduced hyperglycemia in STZ-treated mice following intrapancreatic injection. Overall, this study provides foundational knowledge to develop Panc-MSCs as a unique MSC subtype with functional properties beneficial in regenerative medicine for diabetes and vascular disease.

Soticlestat, a novel cholesterol 24-hydroxylase inhibitor, reduces seizures and premature death in Dravet syndrome mice.

OBJECTIVE: Dravet syndrome is a severe developmental and epileptic encephalopathy (DEE) most often caused by de novo pathogenic variants in SCN1A. Individuals with Dravet syndrome rarely achieve seizure control and have significantly elevated risk for sudden unexplained death in epilepsy (SUDEP). Heterozygous deletion of Scn1a in mice (Scn1a+/- ) recapitulates several core phenotypes, including temperature-dependent and spontaneous seizures, SUDEP, and behavioral abnormalities. Furthermore, Scn1a+/- mice exhibit a similar clinical response to standard anticonvulsants. Cholesterol 24-hydroxlase (CH24H) is a brain-specific enzyme responsible for cholesterol catabolism. Recent research has indicated the therapeutic potential of CH24H inhibition for diseases associated with neural excitation, including seizures. METHODS: In this study, the novel compound soticlestat, a CH24H inhibitor, was administered to Scn1a+/- mice to investigate its ability to improve Dravet-like phenotypes in this preclinical model. RESULTS: Soticlestat treatment reduced seizure burden, protected against hyperthermia-induced seizures, and completely prevented SUDEP in Scn1a+/- mice. Video-electroencephalography (EEG) analysis confirmed the ability of soticlestat to reduce occurrence of electroclinical seizures. SIGNIFICANCE: This study demonstrates that soticlestat-mediated inhibition of CH24H provides therapeutic benefit for the treatment of Dravet syndrome in mice and has the potential for treatment of DEEs.

Characterization of ovarian cancer-derived extracellular vesicles by surface-enhanced Raman spectroscopy.

Ovarian cancer is the most lethal gynecological malignancy, owing to the fact that most cases are diagnosed at a late stage. To improve prognosis and reduce mortality, we must develop methods for the early diagnosis of ovarian cancer. A step towards early and non-invasive cancer diagnosis is through the utilization of extracellular vesicles (EVs), which are nanoscale, membrane-bound vesicles that contain proteins and genetic material reflective of their parent cell. Thus, EVs secreted by cancer cells can be thought of as cancer biomarkers. In this paper, we present gold nanohole arrays for the capture of ovarian cancer (OvCa)-derived EVs and their characterization by surface-enhanced Raman spectroscopy (SERS). For the first time, we have characterized EVs isolated from two established OvCa cell lines (OV-90, OVCAR3), two primary OvCa cell lines (EOC6, EOC18), and one human immortalized ovarian surface epithelial cell line (hIOSE) by SERS. We subsequently determined their main compositional differences by principal component analysis and were able to discriminate the groups by a logistic regression-based machine learning method with ∼99% accuracy, sensitivity, and specificity. The results presented here are a great step towards quick, facile, and non-invasive cancer diagnosis.

Characterization of extracellular vesicles derived from mesenchymal stromal cells by surface-enhanced Raman spectroscopy.

Extracellular vesicles (EVs) are secreted by all cells into bodily fluids and play an important role in intercellular communication through the transfer of proteins and RNA. There is evidence that EVs specifically released from mesenchymal stromal cells (MSCs) are potent cell-free regenerative agents. However, for MSC EVs to be used in therapeutic practices, there must be a standardized and reproducible method for their characterization. The detection and characterization of EVs are a challenge due to their nanoscale size as well as their molecular heterogeneity. To address this challenge, we have fabricated gold nanohole arrays of varying sizes and shapes by electron beam lithography. These platforms have the dual purpose of trapping single EVs and enhancing their vibrational signature in surface-enhanced Raman spectroscopy (SERS). In this paper, we report SERS spectra for MSC EVs derived from pancreatic tissue (Panc-MSC) and bone marrow (BM-MSC). Using principal component analysis (PCA), we determined that the main compositional differences between these two groups are found at 1236, 761, and 1528 cm-1, corresponding to amide III, tryptophan, and an in-plane -C=C- vibration, respectively. We additionally explored several machine learning approaches to distinguish between BM- and Panc-MSC EVs and achieved 89 % accuracy, 89 % sensitivity, and 88 % specificity using logistic regression.

Prone positioning for patients intubated for severe acute respiratory distress syndrome (ARDS) secondary to COVID-19: a retrospective observational cohort study.

BACKGROUND: The role of repeated prone positioning in intubated subjects with acute respiratory distress syndrome caused by COVID-19 remains unclear. METHODS: We conducted a retrospective observational cohort study of critically ill intubated patients with COVID-19 who were placed in the prone position between March 18, 2020 and March 31, 2020. Exclusion criteria were pregnancy, reintubation, and previous prone positioning at a referring hospital. Patients were followed up until hospital discharge. The primary outcome was oxygenation assessed by partial pressure of oxygen/fraction of inspired oxygen ratio (Pao2/Fio2) ratio. A positive response to proning was defined as an increase in Pao2/Fio2 ratio ≥20%. Treatment failure of prone positioning was defined as death or requirement for extracorporeal membrane oxygenation (ECMO). RESULTS: Forty-two subjects (29 males; age: 59 [52-69] yr) were eligible for analysis. Nine subjects were placed in the prone position only once, with 25 requiring prone positioning on three or more occasions. A total of 31/42 (74%) subjects survived to discharge, with five requiring ECMO; 11/42 (26%) subjects died. After the first prone positioning session, Pao2/Fio2 (mean (standard deviation)) ratio increased from 17.9 kPa (7.2) to 28.2 kPa (12.2) (P<0.01). After the initial prone positioning session, subjects who were discharged from hospital were more likely to have an improvement in Pao2/Fio2 ratio ≥20%, compared with those requiring ECMO or who died. CONCLUSION: Patients with COVID-19 acute respiratory distress syndrome frequently responded to initial prone positioning with improved oxygenation. Subsequent prone positioning in subjects discharged from hospital was associated with greater improvements in oxygenation.

Systems Analysis of the 22q11.2 Microdeletion Syndrome Converges on a Mitochondrial Interactome Necessary for Synapse Function and Behavior.

Neurodevelopmental disorders offer insight into synaptic mechanisms. To unbiasedly uncover these mechanisms, we studied the 22q11.2 syndrome, a recurrent copy number variant, which is the highest schizophrenia genetic risk factor. We quantified the proteomes of 22q11.2 mutant human fibroblasts from both sexes and mouse brains carrying a 22q11.2-like defect, Df(16)A+/- Molecular ontologies defined mitochondrial compartments and pathways as some of top ranked categories. In particular, we identified perturbations in the SLC25A1-SLC25A4 mitochondrial transporter interactome as associated with the 22q11.2 genetic defect. Expression of SLC25A1-SLC25A4 interactome components was affected in neuronal cells from schizophrenia patients. Furthermore, hemideficiency of the Drosophila SLC25A1 or SLC25A4 orthologues, dSLC25A1-sea and dSLC25A4-sesB, affected synapse morphology, neurotransmission, plasticity, and sleep patterns. Our findings indicate that synapses are sensitive to partial loss of function of mitochondrial solute transporters. We propose that mitoproteomes regulate synapse development and function in normal and pathological conditions in a cell-specific manner.SIGNIFICANCE STATEMENT We address the central question of how to comprehensively define molecular mechanisms of the most prevalent and penetrant microdeletion associated with neurodevelopmental disorders, the 22q11.2 microdeletion syndrome. This complex mutation reduces gene dosage of ∼63 genes in humans. We describe a disruption of the mitoproteome in 22q11.2 patients and brains of a 22q11.2 mouse model. In particular, we identify a network of inner mitochondrial membrane transporters as a hub required for synapse function. Our findings suggest that mitochondrial composition and function modulate the risk of neurodevelopmental disorders, such as schizophrenia.

Innovative methods measure the neural correlates of proprioception in multiple sclerosis.

The authors of the recently published article "Position sense deficits at the lower limbs in early multiple sclerosis: clinical and neural correlates" (Iandolo R, Bommarito G, Falcitano L, Schiavi S, Piaggio N, Mancardi GL, Casadio M, Inglese M. Neurorehabil Neural Repair 34: 260-270, 2020) provide strong evidence for the neural correlates leading to deficits in proprioception in multiple sclerosis. We believe their findings and innovative methodology show promise for how proprioception is measured in this and other clinical populations. We also suggest that further work should investigate the role of the corpus callosum in proprioceptive balance control.