Multiple-Molecule Drug Design Based on Systems Biology Approaches and Deep Neural Network to Mitigate Human Skin Aging.

Human skin aging is affected by various biological signaling pathways, microenvironment factors and epigenetic regulations. With the increasing demand for cosmetics and pharmaceuticals to prevent or reverse skin aging year by year, designing multiple-molecule drugs for mitigating skin aging is indispensable. In this study, we developed strategies for systems medicine design based on systems biology methods and deep neural networks. We constructed the candidate genomewide genetic and epigenetic network (GWGEN) via big database mining. After doing systems modeling and applying system identification, system order detection and principle network projection methods with real time-profile microarray data, we could obtain core signaling pathways and identify essential biomarkers based on the skin aging molecular progression mechanisms. Afterwards, we trained a deep neural network of drug-target interaction in advance and applied it to predict the potential candidate drugs based on our identified biomarkers. To narrow down the candidate drugs, we designed two filters considering drug regulation ability and drug sensitivity. With the proposed systems medicine design procedure, we not only shed the light on the skin aging molecular progression mechanisms but also suggested two multiple-molecule drugs for mitigating human skin aging from young adulthood to middle age and middle age to old age, respectively.

Social implications of fission in wild Formosan macaques at Mount Longevity, Taiwan.

Group fission in non-human primates has long been proposed to result from interactions between ecological and social factors. Several studies have documented possible causes for group fission, but its proximate causes and ultimate adaptive values are not yet fully understood. We have examined the existing hypotheses on fission from long-term demographic data of Formosan macaques inhabiting the lowland rainforest at Mt Longevity, Taiwan. Five cases of fission occurred in four social groups. We have recorded two types of fission: one involving the separation of a high-ranking adult male and multiple adult females, the other initiated by adult females from main groups. Five adult females immigrated and emigrated a few times between the main and branch groups (oscillation) in three fission events. Data presented in this study are consistent with the prediction that low-ranking females split from main groups when their fitness costs increase due to ecological pressure or population growth. However, their reproductive success may decrease after fission due to a high rate of intra-group competition. Nevertheless, it is beneficial for males to be involved in fission since this increases reproductive benefits by decreasing the sex ratio in small newly formed groups.

Radiological Assessment of the Effect of Congenital C3-4 Synostosis on Adjacent Segments.

STUDY DESIGN: Retrospective case series. PURPOSE: To assess the effect of non-kyphotic aligned congenital C3-4 synostosis on the adjacent segment in 10 patients. OVERVIEW OF LITERATURE: In the cervical spine, fusion disease at the adjacent motion segments may be a risk factor for potential neurological compromise and death. METHODS: Radiograms of 10 patients 13 to 69 years of age presenting with neck/shoulder discomfort or pain with or without trauma history were examined. C3-4 synostosis was found incidentally in all patients on routine examination radiographs of cervical spine. RESULTS: Adjacent segment disease (ASD) was not found in the three patients younger than 39 years of age. Five of the 10 (50%) patients, including a 67-year-old man, did not develop spondylosis in any of the cervical mobile segments. Spondylosis was observed only in the caudal 1-2 mobile segments in the remaining five patients. The youngest was a 40-year-old male who had spondylosis in the two caudal mobile segments (C4-5 and C5-6). Spondylosis was limited to the two close caudal mobile segments and was not in the cranial segments. Flaring of the lower part of synostotic vertebra associated with advanced narrowed degenerate disc was evident in five patients. CONCLUSIONS: Mobile segment spondylosis in the individuals with congenital monosegment C3-4 synostosis over age of 40 years may be a natural manifestation of aging and is not solely an adjacent segment disease directly and fully related with congenital C3-4 synostosis.

Non-Maternal Infant Handling in Wild Formosan Macaques of Mount Longevity, Taiwan.

In this paper, we present quantitative data on how the social network and sex of infants influence allomothering behaviour among wild Formosan macaques, Macaca cyclopis. Using long-term field data collected from the Mount Longevity study site in Kaohsiung (Taiwan), we have tested relevant hypotheses incorporating data on age, rank and reproductive state of infant handlers, and the relationship between handlers and infants. The results support 2 major hypotheses, i.e. those of reciprocity and alliance formation. Nevertheless, neither could account for the observed occurrences of unrelated infant handling by dominant females.

Biomechanical comparison of three stand-alone lumbar cages--a three-dimensional finite element analysis.

BACKGROUND: For anterior lumbar interbody fusion (ALIF), stand-alone cages can be supplemented with vertebral plate, locking screws, or threaded cylinder to avoid the use of posterior fixation. Intuitively, the plate, screw, and cylinder aim to be embedded into the vertebral bodies to effectively immobilize the cage itself. The kinematic and mechanical effects of these integrated components on the lumbar construct have not been extensively studied. A nonlinearly lumbar finite-element model was developed and validated to investigate the biomechanical differences between three stand-alone (Latero, SynFix, and Stabilis) and SynCage-Open plus transpedicular fixation. All four cages were instrumented at the L3-4 level. METHODS: The lumbar models were subjected to the follower load along the lumbar column and the moment at the lumbar top to produce flexion (FL), extension (EX), left/right lateral bending (LLB, RLB), and left/right axial rotation (LAR, RAR). A 10 Nm moment was applied to obtain the six physiological motions in all models. The comparison indices included disc range of motion (ROM), facet contact force, and stresses of the annulus and implants. RESULTS: At the surgical level, the SynCage-open model supplemented with transpedicular fixation decreased ROM (>76%) greatly; while the SynFix model decreased ROM 56-72%, the Latero model decreased ROM 36-91%, in all motions as compared with the INT model. However, the Stabilis model decreased ROM slightly in extension (11%), lateral bending (21%), and axial rotation (34%). At the adjacent levels, there were no obvious differences in ROM and annulus stress among all instrumented models. CONCLUSIONS: ALIF instrumentation with the Latero or SynFix cage provides an acceptable stability for clinical use without the requirement of additional posterior fixation. However, the Stabilis cage is not favored in extension and lateral bending because of insufficient stabilization.

Radiographic assessment of congenital C2-3 synostosis.

PURPOSE: To evaluate the morphologies of congenital C2-3 synostosis in 25 patients. METHODS: Radiographs of 11 males and 14 females aged 5 to 74 years with congenital C2-3 synostosis were reviewed. All cases were found incidentally on radiographs when presenting with neck/shoulder discomfort/pain. RESULTS: 13 of the patients had spondylosis in 21 segments: C1-2 (n=1) and C3-4 (n=1), C4-5 (n=7), C5-6 (n=9), and C6-7 (n=3). Of whom 12 had normal sagittal alignment and one had kyphotic synostosis (who developed compensatory hyperlordosis of the caudal mobile segments and subsequent spondylosis at C3-4 and C5 retrolisthesis). The remaining 12 patients had no spondylosis and had normal sagittal alignment, but had other associated pathologies including disc herniation at C3-4, C1 ring hypoplasia, and calcification of the nuchal ligament. CONCLUSION: Normally aligned congenital synostosis of C2-3 is rarely associated with a junctional problem, whereas a kyphotic synostosis is associated with a caudal junctional problem. Spondylosis developing after age 40 years is not associated with C2-3 synostosis.

Instrumented ligamentotaxis and stabilization of compression and burst fractures of dorsolumbar and mid-lumbar spines.

BACKGROUND: Controversy continues regarding the best treatment for compression and burst fractures. The axial distraction reduction utilizing the technique employing the long straight rod or curved short rod without derotation to reduce fracture are practised together with short segment posterolateral fusion (PLF). Effects of the early postoperative mobilization without posterolateral fusion on reduction maintenance and fracture consolidation were not evaluated so far. The present prospective study is designed to assess the effectiveness of i) reduction and restoration of sagittal alignment, ii) no posterolateral fusion on the reduced, fractured vertebral body and injured disc, iii) fracture consolidation and iv) the fate of the unfused cephalad and caudal injured motion segments of the fractured vertebra. MATERIALS AND METHODS: The study includes 15 Denis burst and two Denis type D compression fractures between T(12) and L(3). The lordotic distraction technique was used for ligamentotaxis utilizing the contoured short rods and pedicle screw fixator. Three vertebrae including the fractured one were fixed. The patients after surgery were braced for ten weeks with activity restriction for 2-4 weeks. The patients were evaluated for change in vertebral body height, sagittal curve, reduction of retropulsion, improvement in neural deficit. The unfused motion segments, residual postoperative pain and bone and metal failure were also evaluated. RESULTS: The preoperative and postreduction percentile vertebral heights at, zero (immediate postoperative), at three, six and 12 months followup were 62.4, 94.8, 94.6, 94.5 and 94.5%, respectively. The percentages of the intracanal fragment retropulsion at preoperative, and postoperative at zero, 3, 6 and 12 months followup were 59.0, 36.2,, 36.0, 32.3, and 13.6% respectively. The preoperative and postreduction percentile loss of the canal dimension and at zero, three, six and 12 months were 52.1, 45.0, 44.0, 41.0 and 29% respectively suggesting that the under-reduced fragment was being resorbed gradually by a remodeling process. The mean initial kyphosis of 33° became mean 2° immediately after reduction and mean 3° at the final followup. The fractured vertebral bodies consolidated in an average period of ten weeks (range 8-14 weeks). The restored disc heights were relatively well maintained throughout the observation period. All paraparetic patients recovered neurologically. There were no postoperative complications. CONCLUSION: Instrument-aided ligamentotaxis for compression and burst fractures utilizing the short contoured rod derotation technique and the instrumented stabilization of the fractured spine are found to be effective procedures which contribute to the fractured vertebral body consolidation without recollapse and maintain the motion segment function.