A weighted network analysis framework for the hourglass effect-And its application in the C. elegans connectome.

Understanding hierarchy and modularity in natural as well as technological networks is of utmost importance. A major aspect of such analysis involves identifying the nodes that are crucial to the overall processing structure of the network. More recently, the approach of hourglass analysis has been developed for the purpose of quantitatively analyzing whether only a few intermediate nodes mediate the information processing between a large number of inputs and outputs of a network. We develop a new framework for hourglass analysis that takes network weights into account while identifying the core nodes and the extent of hourglass effect in a given weighted network. We use this framework to study the structural connectome of the C. elegans and identify intermediate neurons that form the core of sensori-motor pathways in the organism. Our results show that the neurons forming the core of the connectome show significant differences across the male and hermaphrodite sexes, with most core nodes in the male concentrated in sex-organs while they are located in the head for the hermaphrodite. Our work demonstrates that taking weights into account for network analysis framework leads to emergence of different network patterns in terms of identification of core nodes and hourglass structure in the network, which otherwise would be missed by unweighted approaches.

The hourglass organization of the Caenorhabditis elegans connectome.

We approach the C. elegans connectome as an information processing network that receives input from about 90 sensory neurons, processes that information through a highly recurrent network of about 80 interneurons, and it produces a coordinated output from about 120 motor neurons that control the nematode's muscles. We focus on the feedforward flow of information from sensory neurons to motor neurons, and apply a recently developed network analysis framework referred to as the "hourglass effect". The analysis reveals that this feedforward flow traverses a small core ("hourglass waist") that consists of 10-15 interneurons. These are mostly the same interneurons that were previously shown (using a different analytical approach) to constitute the "rich-club" of the C. elegans connectome. This result is robust to the methodology that separates the feedforward from the feedback flow of information. The set of core interneurons remains mostly the same when we consider only chemical synapses or the combination of chemical synapses and gap junctions. The hourglass organization of the connectome suggests that C. elegans has some similarities with encoder-decoder artificial neural networks in which the input is first compressed and integrated in a low-dimensional latent space that encodes the given data in a more efficient manner, followed by a decoding network through which intermediate-level sub-functions are combined in different ways to compute the correlated outputs of the network. The core neurons at the hourglass waist represent the information bottleneck of the system, balancing the representation accuracy and compactness (complexity) of the given sensory information.

A versatile robotic platform for the design of natural, three-dimensional reaching and grasping tasks in monkeys.

OBJECTIVE: Translational studies on motor control and neurological disorders require detailed monitoring of sensorimotor components of natural limb movements in relevant animal models. However, available experimental tools do not provide a sufficiently rich repertoire of behavioral signals. Here, we developed a robotic platform that enables the monitoring of kinematics, interaction forces, and neurophysiological signals during user-defined upper limb tasks for monkeys. APPROACH: We configured the platform to position instrumented objects in a three-dimensional workspace and provide an interactive dynamic force-field. MAIN RESULTS: We show the relevance of our platform for fundamental and translational studies with three example applications. First, we study the kinematics of natural grasp in response to variable interaction forces. We then show simultaneous and independent encoding of kinematic and forces in single unit intra-cortical recordings from sensorimotor cortical areas. Lastly, we demonstrate the relevance of our platform to develop clinically relevant brain computer interfaces in a kinematically unconstrained motor task. SIGNIFICANCE: Our versatile control structure does not depend on the specific robotic arm used and allows for the design and implementation of a variety of tasks that can support both fundamental and translational studies of motor control.

Asymmetric and Distant Effects of a Unilateral Lesion of the Primary Motor Cortex on the Bilateral Supplementary Motor Areas in Adult Macaque Monkeys.

A restricted lesion of the hand area in the primary motor cortex (M1) leads to a deficit of contralesional manual dexterity, followed by an incomplete functional recovery, accompanied by plastic changes in M1 itself and in other cortical areas on both hemispheres. Using the marker SMI-32 specific to pyramidal neurons in cortical layers III and V, we investigated the impact of a focal unilateral M1 lesion (hand representation) on the rostral part (F6) and caudal part (F3) of the supplementary motor area (SMA) in both hemispheres in nine adult macaque monkeys compared with four intact control monkeys. The M1 lesion induced a consistent interhemispheric asymmetry in density of SMI-32-positive neurons in F3 layer V (statistically significant in 8 of 9 lesioned monkeys), highly correlated with the lesion volume and with the duration of functional recovery, but not with the extent of functional recovery itself. Such interhemispheric asymmetry was neither present in the intact monkeys, as expected, nor in F6 in all monkeys. In addition, the M1 lesion also impacted on the basal dendritic arborization of F3 layer V neurons. Neuronal density was clearly less affected by the M1 lesion in F3 layer III compared with layer V. We interpret the remote effect of M1 lesion onto the density of SMI-32-positive neurons and dendritic arborization in the SMAs bilaterally as the consequence of multiple factors, such as changes of connectivity, diaschisis and various mechanisms involved in cortical plasticity underlying the functional recovery from the M1 lesion.SIGNIFICANCE STATEMENT The motor system of macaque monkeys, in addition to be similarly organized as in humans, is a good candidate to study the impact of a focal lesion of the main contributor to voluntary movements, the primary motor cortex (M1), on non-primary motor cortical areas also involved in manual dexterity, both at behavioral and structural levels. Our results show that a unilateral permanent lesion of M1 hand area in nine monkeys affects the interhemispheric balance of the number of SMI-32-positive pyramidal neurons in the cortical layer V of the supplementary motor area, in a way strongly correlated to the lesion volume and duration of the incomplete functional recovery.

Effects of dorsolateral prefrontal cortex lesion on motor habit and performance assessed with manual grasping and control of force in macaque monkeys.

In the context of an autologous adult neural cell ecosystem (ANCE) transplantation study, four intact adult female macaque monkeys underwent a unilateral biopsy of the dorsolateral prefrontal cortex (dlPFC) to provide the cellular material needed to obtain the ANCE. Monkeys were previously trained to perform quantitative motor (manual dexterity) tasks, namely, the "modified-Brinkman board" task and the "reach and grasp drawer" task. The aim of the present study was to extend preliminary data on the role of the prefrontal cortex in motor habit and test the hypothesis that dlPFC contributes to predict the grip force required when a precise level of force to be generated is known beforehand. As expected for a small dlPFC biopsy, neither the motor performance (score) nor the spatiotemporal motor sequences were affected in the "modified-Brinkman board" task, whereas significant changes (mainly decreases) in the maximal grip force (force applied on the drawer knob) were observed in the "reach and grasp drawer" task. The present data in the macaque monkey related to the prediction of grip force are well in line with the previous fMRI data reported for human subjects. Moreover, the ANCE transplantation strategy (in the case of stroke or Parkinson's disease) based on biopsy in dlPFC does not generate unwanted motor consequences, at least as far as motor habit and motor performance are concerned in the context of a sequential grasping a small objects, which does not require the development of significant force levels.

Chromatin immunoprecipitation analysis fails to support the latency model for regulation of p53 DNA binding activity in vivo.

p53 can adopt two forms in vitro, a latent form that binds naked DNA poorly and an active form that binds DNA well. Conversion of the latent form to the active form is thought to occur by an allosteric mechanism induced by phosphorylation and acetylation. Despite the large differences in affinity produced by regulatory modifications in vitro, mutation of putative regulatory sites has not produced correspondingly large effects on transcription of p53 target genes in vivo. To determine whether genotoxic stress regulates DNA binding by p53 in vivo, we have performed quantitative chromatin immunoprecipitation (ChIP) assays on tumor and normal cell lines containing wild-type p53. ChIP recovers several hundredfold more p21 and MDM2 promoter DNA from p53 wild-type than p53-null cells, indicating that the assay is specific for p53. Genotoxic stress induces much smaller increases in chromatin precipitation, which are matched by changes in the p53 protein level. Thus, in the experimental systems tested, allosteric regulation of DNA binding is not a major level of regulation of p53 activity. The p53 target genes tested can be divided into a group showing high promoter occupancy in vivo (p21, MDM2, and PUMA) and a group giving substantially weaker or background p53 binding (bax, AIP1, and PIG3). Neither group shows selective recruitment of p53 to the promoter in cells undergoing apoptosis, indicating that the decision to undergo apoptosis or cell cycle arrest depends on other changes in the cell.

Implementing recommendations for the early detection of breast and cervical cancer among low-income women.

SCOPE OF THE PROBLEM: Among U.S. women, breast cancer is the most commonly diagnosed cancer and remains second only to lung cancer as a cause of cancer-related mortality. The American Cancer Society (ACS) estimates that 182,800 new cases of female breast cancer and 41,200 deaths from breast cancer will occur in 2000. Since the 1950s, the incidence of invasive cervical cancer and mortality from this disease have decreased substantially; much of the decline is attributed to widespread use of the Papanicolaou (Pap) test. ACS estimates that 12,800 new cases of invasive cervical cancer will be diagnosed, and 4,600 deaths from this disease will occur in the United States in 2000. ETIOLOGIC FACTORS: The risk for breast cancer increases with advancing age; other risk factors include personal or family history of breast cancer, certain benign breast diseases, early age at menarche, late age at menopause, white race, nulliparity, and igher socioeconomic status. Risk factors for cervical cancer include certain human papilloma virus infections, early age at first intercourse, multiple male sex partners, a history of sexually transmitted diseases, and low socioeconomic status. Black, Hispanic, or American Indian racial/ethnic background is considered a risk factor because cervical cancer detection and death rates are higher among these women. RECOMMENDATIONS FOR PREVENTION: Because studies of the etiology of breast cancer have failed to identify feasible primary prevention strategies suitable for use in the general population, reducing mortality from breast cancer through early detection has become a high priority. The potential for reducing death rates from breast cancer is contingent on increasing mammography screening rates and subsequently detecting the disease at an early stage--when more treatment options are available and survival rates are higher. Effective control of cervical cancer depends primarily on early detection of precancerous lesions through use of the Papanicolaou test, followed by timely evaluation and treatment. Thus, the intended outcome of cervical cancer screening differs from that of breast cancer screening. In 1991, the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) was implemented to increase breast and cervical cancer screening among uninsured, low-income women. RESEARCH AGENDA: To support recommended priority activities for NBCCEDP, CDC has developed a research agenda comprising six priorities. These six priorities are a) determining effective strategies to communicate changes in NBCCEDP policy to cancer screening providers and women enrolled in the program; b) identifying effective strategies to increase the proportion of enrolled women who complete routine breast and cervical cancer rescreening according to NBCCEDP policy; c) identifying effective strategies to increase NBCCEDP enrollment among eligible women who have never received breast or cervical cancerscreening; d) evaluating variations in clinical practice patterns among providers of NBCCEDP screening services; e) determining optimal models for providing case-management services to women in NBCCEDP who have an abnormal screening result, precancerous breast or cervical lesion, or a diagnosis of cancer; and f) conducting economic analyses to determine costs of providing screening services in NBCCEDP. CONCLUSION: The NBCCEDP, through federal, state, territorial, and tribal governments, in collaboration with national and community-based organizations, has increased access to breast and cervical cancer screening among low-income and uninsured women. This initiative enabled the United States to make substantial progress toward achieving the Healthy People 2000 objectives for breast and cervical cancer control among racial/ethnic minorities and persons who are medically underserved. A continuing challenge for the future is to increase national commitment to providing screening services for all eligible uninsured women to ultimately reduce morbidity and mortality from breast and cervical cancer.