The need for calcium imaging in nonhuman primates: New motor neuroscience and brain-machine interfaces

A central goal of neuroscience is to understand how populations of neurons coordinate and cooperate in order to give rise to perception, cognition, and action. Nonhuman primates (NHPs) are an attractive model with which to understand these mechanisms in humans, primarily due to the strong homology of their brains and the cognitively sophisticated behaviors they can be trained to perform. Using electrode recordings, the activity of one to a few hundred individual neurons may be measured electrically, which has enabled many scientific findings and the development of brain-machine interfaces. Despite these successes, electrophysiology samples sparsely from neural populations and provides little information about the genetic identity and spatial micro-organization of recorded neurons. These limitations have spurred the development of all-optical methods for neural circuit interrogation. Fluorescent calcium signals serve as a reporter of neuronal responses, and when combined with post-mortem optical clearing techniques such as CLARITY, provide dense recordings of neuronal populations, spatially organized and annotated with genetic and anatomical information. Here, we advocate that this methodology, which has been of tremendous utility in smaller animal models, can and should be developed for use with NHPs. We review here several of the key opportunities and challenges for calcium-based optical imaging in NHPs. We focus on motor neuroscience and brain-machine interface design as representative domains of opportunity within the larger field of NHP neuroscience

A population-based analysis of germline BAP1 mutations in melanoma

Germline mutation of the BRCA1 associated protein-1 (BAP1) gene has been linked to uveal melanoma, mesothelioma, meningioma, renal cell carcinoma and basal cell carcinoma. Germline variants have also been found in familial cutaneous melanoma pedigrees, but their contribution to sporadic melanoma has not been fully assessed. We sequenced BAP1 in 1,977 melanoma cases and 754 controls and used deubiquitinase assays, a pedigree analysis, and a histopathological review to assess the consequences of the mutations found. Sequencing revealed 30 BAP1 variants in total, of which 27 were rare (ExAc allele frequency <0.002). Of the 27 rare variants, 22 were present in cases (18 missense, one splice acceptor, one frameshift and two near splice regions) and 5 in controls (all missense). A missense change (S98R) in a case that completely abolished BAP1 deubiquitinase activity was identified. Analysis of cancers in the pedigree of the proband carrying the S98R variant and in two other pedigrees carrying clear loss-of-function alleles showed the presence of BAP1-associated cancers such as renal cell carcinoma, mesothelioma and meningioma, but not uveal melanoma. Two of these three probands carrying BAP1 loss-of-function variants also had melanomas with histopathological features suggestive of a germline BAP1 mutation. The remaining cases with germline mutations, which were predominantly missense mutations, were associated with less typical pedigrees and tumours lacking a characteristic BAP1-associated histopathological appearances, but may still represent less penetrant variants. Germline BAP1 alleles defined as loss-of-function or predicted to be deleterious/damaging are rare in melanoma

Survival and major neurodevelopmental impairment in extremely low gestational age newborns born 1990–2000: a retrospective cohort study

<p>Abstract</p> <p>Background</p> <p>It is important to determine if rates of survival and major neurodevelopmental impairment in extremely low gestational age newborns (ELGANs; infants born at 23–27 weeks gestation) are changing over time.</p> <p>Methods</p> <p>Study infants were born at 23 to 27 weeks of gestation without congenital anomalies at a tertiary medical center between July 1, 1990 and June 30, 2000, to mothers residing in a thirteen-county region in North Carolina. Outcomes at one year adjusted age were compared for two epochs of birth: epoch 1, July 1, 1990 to June 30, 1995; epoch 2, July 1, 1995 to June 30, 2000. Major neurodevelopmental impairment was defined as cerebral palsy, Bayley Scales of Infant Development Mental Developmental Index more than two standard deviations below the mean, or blindness.</p> <p>Results</p> <p>Survival of ELGANs, as a percentage of live births, was 67% [95% confidence interval: (61, 72)] in epoch 1 and 71% (65, 75) in epoch 2. Major neurodevelopmental impairment was present in 20% (15, 27) of survivors in epoch 1 and 14% (10, 20) in epoch 2. When adjusted for gestational age, survival increased [odds ratio 1.5 (1.0, 2.2), p = .03] and major neurodevelopmental impairment decreased [odds ratio 0.54 (0.31, 0.93), p = .02] from epoch 1 to epoch 2.</p> <p>Conclusion</p> <p>The probability of survival increased while that of major neurodevelopmental impairment decreased during the 1990's in this regionally based sample of ELGANs.</p

Direct glia-to-neuron transdifferentiation gives rise to a pair of male-specific neurons that ensure nimble male mating

Sexually dimorphic behaviours require underlying differences in the nervous system between males and females. The extent to which nervous systems are sexually dimorphic and the cellular and molecular mechanisms that regulate these differences are only beginning to be understood. We reveal here a novel mechanism by which male-specific neurons are generated in Caenorhabditis elegans through the direct transdifferentiation of sex-shared glial cells. This glia-to-neuron cell fate switch occurs during male sexual maturation under the cell-autonomous control of the sex-determination pathway. We show that the neurons generated are cholinergic, peptidergic, and ciliated putative proprioceptors which integrate into male-specific circuits for copulation. These neurons ensure coordinated backward movement along the mate’s body during mating. One step of the mating sequence regulated by these neurons is an alternative readjustment movement performed when intromission becomes difficult to achieve. Our findings reveal programmed transdifferentiation as a developmental mechanism underlying flexibility in innate behaviour

MUTYH-Associated Polyposis: The Irish Experience>.

MUTYH is involved in DNA damage repair. Bi-allelic MUTYH mutations predispose to polyposis and gastrointestinal malignancies, distinct genetically from autosomal dominant familial adenomatous polyposis coli. Two common European MUTYH mutations account for 90% of MUTYH-associated polyposis (MAP). We aimed to examine the incidence of MAP in Ireland. A retrospective cohort study was undertaken. Patients undergoing MUTYH testing from 2003-2016 were identified by searching electronic databases using terms "MUTYH" and "MYH". Phenotypic and genotypic details were obtained by chart review. Bi-allelic mutations were confirmed in 26 individuals (17 families), of whom 16 (62%) developed colorectal malignancies, and 22(85%) polyposis. Eleven families had bi-allelic status for one/both common European mutations. Regional variation was noted, with over-representation of bi-allelic mutation carriers in the South-west of Ireland. MAP is under-diagnosed in Ireland. Increased awareness is required to facilitate appropriate identification and surveillance of bi-allelic mutation carriers for colorectal pathology

New directions in cellular therapy of cancer: a summary of the summit on cellular therapy for cancer

A summit on cellular therapy for cancer discussed and presented advances related to the use of adoptive cellular therapy for melanoma and other cancers. The summit revealed that this field is advancing rapidly. Conventional cellular therapies, such as tumor infiltrating lymphocytes (TIL), are becoming more effective and more available. Gene therapy is becoming an important tool in adoptive cell therapy. Lymphocytes are being engineered to express high affinity T cell receptors (TCRs), chimeric antibody-T cell receptors (CARs) and cytokines. T cell subsets with more naïve and stem cell-like characteristics have been shown in pre-clinical models to be more effective than unselected populations and it is now possible to reprogram T cells and to produce T cells with stem cell characteristics. In the future, combinations of adoptive transfer of T cells and specific vaccination against the cognate antigen can be envisaged to further enhance the effectiveness of these therapies

Dendritic calcium signals in rhesus macaque motor cortex drive an optical brain-computer interface

Calcium imaging is a powerful tool for recording from large populations of neurons in vivo. Imaging in rhesus macaque motor cortex can enable the discovery of fundamental principles of motor cortical function and can inform the design of next generation brain-computer interfaces (BCIs). Surface two-photon imaging, however, cannot presently access somatic calcium signals of neurons from all layers of macaque motor cortex due to photon scattering. Here, we demonstrate an implant and imaging system capable of chronic, motion-stabilized two-photon imaging of neuronal calcium signals from macaques engaged in a motor task. By imaging apical dendrites, we achieved optical access to large populations of deep and superficial cortical neurons across dorsal premotor (PMd) and gyral primary motor (M1) cortices. Dendritic signals from individual neurons displayed tuning for different directions of arm movement. Combining several technical advances, we developed an optical BCI (oBCI) driven by these dendritic signalswhich successfully decoded movement direction online. By fusing two-photon functional imaging with CLARITY volumetric imaging, we verified that many imaged dendrites which contributed to oBCI decoding originated from layer 5 output neurons, including a putative Betz cell. This approach establishes new opportunities for studying motor control and designing BCIs via two photon imaging

Cerebral palsy and placental infection: a case-cohort study

BACKGROUND: The association between cerebral palsy in very preterm infants and clinical, histopathologic and microbiological indicators of chorioamnionitis, including the identification of specific micro-organisms in the placenta, was evaluated in a case-cohort study. METHODS: Children with a diagnosis of cerebral palsy at five years of age were identified from amongst participants in a long-term follow-up program of preterm infants. The comparison group was a subcohort of infants randomly selected from all infants enrolled in the program. The placentas were examined histopathologically for chorioamnionitis and funisitis, and the chorioamnionic interface was aseptically swabbed and comprehensively cultured for aerobic and anaerobic bacteria, yeast and genital mycoplasmas. Associations between obstetric and demographic variables, indicators of chorioamnionitis and cerebral palsy status were examined by univariate analysis. RESULTS: Eighty-two infants with cerebral palsy were compared with the subcohort of 207 infants. Threatened preterm labor was nearly twice as common among the cases as in the subcohort (p < 0.01). Recorded clinical choroamnionitis was similar in the two groups and there was no difference in histopathologic evidence of infection between the two groups. E. coli was cultured from the placenta in 6/30 (20%) of cases as compared with 4/85 (5%) of subcohort (p = 0.01). Group B Streptococcus was more frequent among the cases, but the difference was not statistically significant. CONCLUSIONS: The association between E. coli in the chorioamnion and cerebral palsy in preterm infants identified in this study requires confirmation in larger multicenter studies which include microbiological study of placentas

Human neutrophil clearance of bacterial pathogens triggers anti-microbial gamma delta T cell responses in early infection

Human blood Vc9/Vd2 T cells, monocytes and neutrophils share a responsiveness toward inflammatory chemokines and are rapidly recruited to sites of infection. Studying their interaction in vitro and relating these findings to in vivo observations in patients may therefore provide crucial insight into inflammatory events. Our present data demonstrate that Vc9/Vd2 T cells provide potent survival signals resulting in neutrophil activation and the release of the neutrophil chemoattractant CXCL8 (IL-8). In turn, Vc9/Vd2 T cells readily respond to neutrophils harboring phagocytosed bacteria, as evidenced by expression of CD69, interferon (IFN)-c and tumor necrosis factor (TNF)-a. This response is dependent on the ability of these bacteria to produce the microbial metabolite (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP), requires cell-cell contact of Vc9/Vd2 T cells with accessory monocytes through lymphocyte function-associated antigen-1 (LFA-1), and results in a TNF-a dependent proliferation of Vc9/Vd2 T cells. The antibiotic fosmidomycin, which targets the HMB-PP biosynthesis pathway, not only has a direct antibacterial effect on most HMB-PP producing bacteria but also possesses rapid anti-inflammatory properties by inhibiting cd T cell responses in vitro. Patients with acute peritoneal-dialysis (PD)-associated bacterial peritonitis – characterized by an excessive influx of neutrophils and monocytes into the peritoneal cavity – show a selective activation of local Vc9/Vd2 T cells by HMB-PP producing but not by HMB-PP deficient bacterial pathogens. The cd T celldriven perpetuation of inflammatory responses during acute peritonitis is associated with elevated peritoneal levels of cd T cells and TNF-a and detrimental clinical outcomes in infections caused by HMB-PP positive microorganisms. Taken together, our findings indicate a direct link between invading pathogens, neutrophils, monocytes and microbe-responsive cd T cells in early infection and suggest novel diagnostic and therapeutic approaches.Martin S. Davey, Chan-Yu Lin, Gareth W. Roberts, Sinéad Heuston, Amanda C. Brown, James A. Chess, Mark A. Toleman, Cormac G.M. Gahan, Colin Hill, Tanya Parish, John D. Williams, Simon J. Davies, David W. Johnson, Nicholas Topley, Bernhard Moser and Matthias Eber

Effect of pre-milking teat preparation procedures on the microbial count on teats prior to cluster application

A study was carried out to investigate the effect of six pre-milking teat preparation procedures on lowering the staphylococal, streptococcal and coliform microbial count on teat skin prior to cluster application. The teat preparations included 'Iodine', 'Chlorhexidine' teat foam, 'Washing and drying' with paper, 'No preparation', 'Chlorine' teat foam, and disinfectant 'Wipes'. Teat preparations were applied for five days to 10 cows for each treatment during two herd management periods (indoors and outdoors). Teats were swabbed on day four and five before teat preparation and repeated after teat preparation. The swabs were plated on three selective agars: Baird Parker (Staphylococcus spp.), Edwards (Streptococcus spp.), and MacConkey (coliform). Following incubation, microbial counts for each pathogen type were manually counted and assigned to one of six categories depending on the microbial counts measured. The results were analysed by logistic regression using SAS [28]. The main analysis was conducted on binary improvement scores for the swabbing outcomes. There were no differences for staphylococcal, streptococcal and coliform bacterial counts between treatments, measured 'before' teat preparation. Treatments containing 'Chlorhexidine' teat foam (OR = 4.46) and 'Wipes' (OR = 4.46) resulted in a significant reduction (P < 0.01) in the staphylococcal count on teats compared to 'Washing and drying' or 'No preparation'. 'Chlorine' teat foam (OR = 3.45) and 'Wipes' (3.45) had the highest probability (P < 0.01) of reducing streptococcal counts compared to 'Washing and drying' or 'No preparation'. There was no statistical difference between any of the disinfectant treatments applied in reducing coliforms. Thus, the use of some disinfectant products for pre-milking teat preparation can have beneficial effects on reducing the levels of staphylococcal and streptococcal pathogens on teat skin