The transcriptional response of cortical neurons to concussion reveals divergent fates after injury.

Traumatic brain injury (TBI) is a risk factor for neurodegeneration, however little is known about how different neuron types respond to this kind of injury. In this study, we follow neuronal populations over several months after a single mild TBI (mTBI) to assess long ranging consequences of injury at the level of single, transcriptionally defined neuronal classes. We find that the stress responsive Activating Transcription Factor 3 (ATF3) defines a population of cortical neurons after mTBI. We show that neurons that activate ATF3 upregulate stress-related genes while repressing many genes, including commonly used markers for these cell types. Using an inducible reporter linked to ATF3, we genetically mark damaged cells to track them over time. Notably, we find that a population in layer V undergoes cell death acutely after injury, while another in layer II/III survives long term and retains the ability to fire action potentials. To investigate the mechanism controlling layer V neuron death, we genetically silenced candidate stress response pathways. We found that the axon injury responsive kinase MAP3K12, also known as dual leucine zipper kinase (DLK), is required for the layer V neuron death. This work provides a rationale for targeting the DLK signaling pathway as a therapeutic intervention for traumatic brain injury. Beyond this, our novel approach to track neurons after a mild, subclinical injury can inform our understanding of neuronal susceptibility to repeated impacts.

A cellular taxonomy of the adult human spinal cord.

The mammalian spinal cord functions as a community of cell types for sensory processing, autonomic control, and movement. While animal models have advanced our understanding of spinal cellular diversity, characterizing human biology directly is important to uncover specialized features of basic function and human pathology. Here, we present a cellular taxonomy of the adult human spinal cord using single-nucleus RNA sequencing with spatial transcriptomics and antibody validation. We identified 29 glial clusters and 35 neuronal clusters, organized principally by anatomical location. To demonstrate the relevance of this resource to human disease, we analyzed spinal motoneurons, which degenerate in amyotrophic lateral sclerosis (ALS) and other diseases. We found that compared with other spinal neurons, human motoneurons are defined by genes related to cell size, cytoskeletal structure, and ALS, suggesting a specialized molecular repertoire underlying their selective vulnerability. We include a web resource to facilitate further investigations into human spinal cord biology.

DLK-dependent mitochondrial fission drives axon degeneration and neuronal cell death.

Currently there are no effective treatments for an array of neurodegenerative disorders to a large part because cell-based models fail to recapitulate disease. Here we developed a robust human iPSCbased model where laser axotomy causes retrograde axon degeneration leading to neuronal cell death. Time-lapse confocal imaging revealed that damage triggers a wave of mitochondrial fission proceeding from the site of injury to the soma. We demonstrated that mitochondrial fission and resultant cell death is entirely dependent on phosphorylation of dynamin related protein 1 (DRP1) by dual leucine zipper kinase (DLK). Importantly, we show that CRISPR mediated Drp1 depletion protected mouse retinal ganglion neurons from mitochondrial fission and degeneration after optic nerve crush. Our results provide a powerful platform for studying degeneration of human neurons, pinpoint key early events in damage related neural death and new focus for therapeutic intervention.

A harmonized atlas of mouse spinal cord cell types and their spatial organization.

Single-cell RNA sequencing data can unveil the molecular diversity of cell types. Cell type atlases of the mouse spinal cord have been published in recent years but have not been integrated together. Here, we generate an atlas of spinal cell types based on single-cell transcriptomic data, unifying the available datasets into a common reference framework. We report a hierarchical structure of postnatal cell type relationships, with location providing the highest level of organization, then neurotransmitter status, family, and finally, dozens of refined populations. We validate a combinatorial marker code for each neuronal cell type and map their spatial distributions in the adult spinal cord. We also show complex lineage relationships among postnatal cell types. Additionally, we develop an open-source cell type classifier, SeqSeek, to facilitate the standardization of cell type identification. This work provides an integrated view of spinal cell types, their gene expression signatures, and their molecular organization.

Single nucleus RNA-sequencing defines unexpected diversity of cholinergic neuron types in the adult mouse spinal cord.

In vertebrates, motor control relies on cholinergic neurons in the spinal cord that have been extensively studied over the past hundred years, yet the full heterogeneity of these neurons and their different functional roles in the adult remain to be defined. Here, we develop a targeted single nuclear RNA sequencing approach and use it to identify an array of cholinergic interneurons, visceral and skeletal motor neurons. Our data expose markers for distinguishing these classes of cholinergic neurons and their rich diversity. Specifically, visceral motor neurons, which provide autonomic control, can be divided into more than a dozen transcriptomic classes with anatomically restricted localization along the spinal cord. The complexity of the skeletal motor neurons is also reflected in our analysis with alpha, gamma, and a third subtype, possibly corresponding to the elusive beta motor neurons, clearly distinguished. In combination, our data provide a comprehensive transcriptomic description of this important population of neurons that control many aspects of physiology and movement and encompass the cellular substrates for debilitating degenerative disorders.

Poor Corticospinal Motor Neuron Health Is Associated with Increased Symptom Severity in the Acute Phase Following Repetitive Mild TBI and Predicts Early ALS Onset in Genetically Predisposed Rodents.

Traumatic brain injury (TBI) is a well-established risk factor for several neurodegenerative disorders including Alzheimer's disease and Parkinson's disease, however, a link between TBI and amyotrophic lateral sclerosis (ALS) has not been clearly elucidated. Using the SOD1G93A rat model known to recapitulate the human ALS condition, we found that exposure to mild, repetitive TBI lead ALS rats to experience earlier disease onset and shortened survival relative to their sham counterparts. Importantly, increased severity of early injury symptoms prior to the onset of ALS disease symptoms was linked to poor health of corticospinal motor neurons and predicted worsened outcome later in life. Whereas ALS rats with only mild behavioral injury deficits exhibited no observable changes in corticospinal motor neuron health and did not present with early onset or shortened survival, those with more severe injury-related deficits exhibited alterations in corticospinal motor neuron health and presented with significantly earlier onset and shortened lifespan. While these studies do not imply that TBI causes ALS, we provide experimental evidence that head injury is a risk factor for earlier disease onset in a genetically predisposed ALS population and is associated with poor health of corticospinal motor neurons.

Tellurene Photodetector with High Gain and Wide Bandwidth.

Two-dimensional (2D) semiconductors have been extensively explored as a new class of materials with great potential. In particular, black phosphorus (BP) has been considered to be a strong candidate for applications such as high-performance infrared photodetectors. However, the scalability of BP thin film is still a challenge, and its poor stability in the air has hampered the progress of the commercialization of BP devices. Herein, we report the use of hydrothermal-synthesized and air-stable 2D tellurene nanoflakes for broadband and ultrasensitive photodetection. The tellurene nanoflakes show high hole mobilities up to 458 cm2/V·s at ambient conditions, and the tellurene photodetector presents peak extrinsic responsivity of 383 A/W, 19.2 mA/W, and 18.9 mA/W at 520 nm, 1.55 µm, and 3.39 µm light wavelength, respectively. Because of the photogating effect, high gains up to 1.9 × 103 and 3.15 × 104 are obtained at 520 nm and 3.39 µm wavelength, respectively. At the communication wavelength of 1.55 µm, the tellurene photodetector exhibits an exceptionally high anisotropic behavior, and a large bandwidth of 37 MHz is obtained. The photodetection performance at different wavelength is further supported by the corresponding quantum molecular dynamics (QMD) simulations. Our approach has demonstrated the air-stable tellurene photodetectors that fully cover the short-wave infrared band with ultrafast photoresponse.

Takotsubo syndrome in a teen health centre.

BACKGROUND: Takotsubo syndrome is also referred to as stress cardiomyopathy and typically occurs in females aged 55 years and older. This demographic represents a significant part of the healthcare workforce and they have over recent decades experienced increasing levels of violence from patients and clients. AIMS: Our study describes a Takotsubo syndrome that occurred following an incident of physical and verbal aggression at work in a teen health centre. CASE REPORT: We report the case of a 56-year-old female community educator who suffered chest pain 48 h after suffering an aggressive incident at work. She had no history of cardiovascular disease. During hospitalization she was investigated with an electrocardiogram, echocardiography, coronary angiography, left ventriculography and a cardiac magnetic resonance imaging. Examinations confirmed the diagnosis of Takotsubo cardiomyopathy. This was deemed to be a work-related accident. With the help of her occupational physician, the patient was able to return to work with work adjustments. CONCLUSIONS: Increasing levels of violent behaviours towards staff in the health care sector underscores the need for measures in the workplace to help prevent precipitation of this syndrome in workers.

Radiation protection for surgeons and anesthetists: practices and knowledge before and after training.

The use of radiological activity in the operating room (OR) and a regulatory decrease of the eye lens dose warrant an assessment of how medical staff are protected from radiation. This study aims to evaluate practices and knowledge in radiation protection (RP) for OR doctors before and after training. A descriptive study of surgeons and anesthetists in a French public hospital center was conducted in 2016. An ad hoc questionnaire concerning occupational practices and knowledge about RP was distributed before and one month after RP training. Among 103 doctors attending the training, 90 answered the questionnaire before the training. Results showed a lack of knowledge and good practice in RP. Most of the participants (86.7%) had never been trained in RP and recognized insufficient knowledge. Most of them (92.2%) wore a lead apron, 50.0% a thyroid-shield, 5.6% lead glasses, 53.3% a passive dosimeter and 17.8% an electronic dosimeter. None of them benefitted from collective protective equipment such as a ceiling suspended screen. The questionnaire following the training was completed by only 35 doctors. A comparison before and after training results showed an improvement in knowledge (scores of correct responses: 5.5/16 before and 9.5/16 after training) but not in RP good practices (scores of correct responses: 3.2/7 before and 3.3/7 after training). One training session appears to be insufficient to improve the application of the safety rules when x-rays are used. Communication needs to be improved regarding RP among anesthetists and surgeons, such as training renewal, workstation analysis in OR related to x-ray use and occupational medical follow-up. Otherwise, radiological risks in OR need to be given better consideration, such as radio-induced cataract risk. It is necessary to encourage the use of dosimeters and protective equipment and to strengthen access to lead glasses and collective protective equipment, such as ceiling suspended screens. All these recommendations ensure the received dose is reduced to as low as is reasonably achievable.

Metformin enhances clearance of chylomicrons and chylomicron remnants in nondiabetic mildly overweight glucose-intolerant subjects.

OBJECTIVE: To assess the effect of metformin on the metabolism of intestinally derived lipoproteins in nondiabetic individuals who were mildly overweight and glucose intolerant. RESEARCH DESIGN AND METHODS: A total of nine subjects with a BMI > or = 25 kg/m(2) and fasting serum glucose < or = 6.1 mmol/l and who were glucose intolerant were studied. The subjects underwent a vitamin A fat-loading test before and after a 3-month treatment with 850 mg metformin twice a day. The metabolic behavior of the postprandial lipoproteins was compared with that found in a group of 19 healthy normolipidemic individuals who participated in a previous study. RESULTS: Mean total plasma, chylomicron fraction, and nonchylomicron fraction retinyl palmitate (RP) pretreatment levels were 3.4-fold, 3.59-fold, and 3-fold higher, respectively, in the study group than in the normolipidemic group and were reduced by 50, 56, and 32%, respectively, after 3 months of metformin treatment. The decrease of chylomicron levels after treatment was positively correlated to the fasting triglyceride values before treatment (r = 0.73, P = 0.039) and to the serum insulin level at 120 min of standard glucose loading before treatment (r = 0.91, P = 0.002). CONCLUSIONS: Metformin was shown to be beneficial in the clearance of postprandial lipoproteins in nondiabetic individuals who were mildly overweight and glucose intolerant.

Bezafibrate therapy in patients with isolated low high-density lipoprotein cholesterol levels may have a beneficial effect in prevention of atherosclerosis.

Although a low plasma high-density lipoprotein cholesterol (HDL-C) level is a well-accepted risk factor for coronary artery disease (CAD), it is unclear whether pharmacologic agents can effectively increase HDL-C levels and/or reduce the incidence of CAD in patients with isolated low HDL-C levels. An important determinant of HDL levels is the efficiency of postprandial lipoprotein catabolism. The purpose of the present study was to evaluate the efficacy of bezafibrate therapy in increasing HDL-C levels in these patients and to examine its effect on postprandial lipoprotein levels. Fasting and postprandial lipid and lipoprotein levels were studied in 23 patients with isolated low HDL-C levels before and during 3 and 6 months of bezafibrate treatment. Postprandial lipoprotein levels were evaluated using the vitamin A-fat loading test, in which these intestinally derived lipoproteins are specifically labeled with retinyl palmitate (RP). Patients with isolated low HDL had significantly higher levels of chylomicron RP than a control group of 19 normolipidemic subjects. The area below the chylomicron RP curve was 17,773 +/- 6,821 versus 13,936 +/- 6,217 micrograms/L.h, respectively (P < .005). No differences were found in chylomicron remnant levels between the groups. Bezafibrate therapy reduced the chylomicron RP area by 27%, from 17,773 +/- 6,821 to 12,895 +/- 2,576, and the nonchylomicron RP area by 25%, from 6,059 +/- 3,310 to 4,430 +/- 1,963 (P < .0001). It increased fasting HDL-C levels from 35 +/- 3 to 38 +/- 1.4 mg/dL after 3 months (P < .001) and to 40 +/- 2.2 mg/dL after 6 months (P < .001).(ABSTRACT TRUNCATED AT 250 WORDS)

[Coronary artery bypass without extra corporeal circulation].

240 patients underwent coronary artery bypass grafting (CABG) without extracorporeal circulation (ECC). Mean grafts per patient was 1.9 (range 1-5). The internal mammary artery (IMA) was used in 210 cases (87%), but in only 53 (22%) were there grafts to the circumflex marginals. Unfavorable results included an operative mortality of 7 cases (2.9%), nonfatal perioperative myocardial infarction (MI) (2.5%), stroke (0.4%), and sternal infection (1.7%). There were 2 deaths among 17 patients (12%) with calcified aorta, and 4 among 40 (10%) who underwent emergency operation. Multivariate analysis showed these 2 risk factors to be the only predictors of early mortality: emergency operation odds ratio 9.8, and calcified aorta odds ratio 8.0. Perioperative risk factors that were not major predictors of early mortality or unfavorable outcome included left ventricular dysfunction (EF < 35%: 52 patients, 22%), congestive heart failure (53, 22%), cardiogenic shock (8, 3%), acute MI (67, 28%), age > 70 years (64, 27%), renal failure (22, 9%), and stroke or carotid disease (12, 5%). Followup ranged from 1-31 months (mean 12). There were 9 late deaths (4 cardiac), and 18 cases (7.5%) of early return of angina. 1-year actuarial survival was 92%; 192 patients (80%) had uneventful outcomes and are doing well. Calcified aorta, nonuse of the IMA, reoperation, and diabetes mellitus were independent predictors of unfavorable events. We conclude that CABG without ECC can be performed with relatively low operative mortality, but there seems to be increased risk of early return of angina. It should therefore be considered for those patients with appropriate coronary anatomy in whom ECC poses a very high risk. However, it is still a hazardous procedure when used as as an emergency operation, and for cases with calcified aorta.

Alteration of pulmonary function by filtration of intravenous nutrient mixture.

In view of contradicting results concerning alteration in lung function during hyperalimentation and the administration of intravenous lipid emulsion, a study was planned to determine possible changes in pulmonary blood perfusion during administration of total nutrient admixture (TNA) and the effect of filtration. Sixteen patients (8 men, 8 women; mean age 65.6 yr) with no previous lung disease received TNA at the rate of 4-5 g lipid/h as preoperative treatment for 5-9 days (mean 6.7 days). The 5-microns filter was randomly used in eight patients. The lung blood perfusion parameters measured repeatedly during this period included blood gases, percentage of the predicted value of vital capacity (VC), and pulmonary diffusing capacity for carbon monoxide (DLCO), as well as the value of the dead space volume and the tidal volume ratio (VD/VT) and the calculated shunt (QS/QT). TNA infusion appears to cause only a slight decrease in PaO2 and DLCO and a similar increase in VC and QS/QT, whereas VD/VT decreased significantly. The latter effect was abolished by filtration of TNA. There were no significant differences between the two groups. We therefore conclude that short-term preoperative administration of TNA at the rate of 4-5 g lipid/h in patients without preexisting lung disease does not jeopardize lung functions. Filtration of the TNA is, however, recommended to avoid the potential hazardous effects of long-term treatment of TNA on lung function.

Secretion of two different flowing masses by lymphokine-activated killer cells.

When grown on mesenchyme-fibroblastoid monolayers made of 16-day-old embryos, lymphokine-activated killer (LAK) cells in clones derived from nude mouse lymph node cells are signaled to synthesize and secrete two mucoid masses. The first is made of chondroitin sulfate, as determined by the degradation of 35S- and [3H]glucosamine-labeled macromolecules in the extracellular matrix, by hyaluronidase, and by chondroitin sulfate lyase AC. This determination correlates with the distinctive blue staining by periodic acid-Schiff/alcian blue (PAS-Ab) at pH 1.0. In the present study, two different masses were identified when methanol-fixed and dried LAK cells and their secretions were examined prior to staining. The chondroitin-sulfate-containing mass appeared as an optically bright structure. It also produced a positive fluorescence with rabbit anti-mouse perforin. The second structure, which appeared as a flowing material or as filling holes in the first, could be identified by its high optical density. However, it was not stained by PAS-Ab and was not blackened by osmium tetroxide. The biochemical nature of the second mass has yet to be determined. Both masses seemed eventually to mix, producing pools, in lacunae, or to spread into the culture space.