Mitochondrial outer membrane permeabilization and inner membrane permeabilization in regulating apoptosis and inflammation.

Recent studies delineate an intimate crosstalk between apoptosis and inflammation. However, the dynamic mechanism linking them by mitochondrial membrane permeabilization remains elusive. Here, we construct a mathematical model consisting of four functional modules. Bifurcation analysis reveals that bistability stems from Bcl-2 family member interaction and time series shows that the time difference between Cyt c and mtDNA release is around 30 min, which are consistent with previous works. The model predicts that Bax aggregation kinetic determines cells to undergo apoptosis or inflammation, and that modulating the inhibitory effect of caspase 3 on IFN-ß production allows the concurrent occurrence of apoptosis and inflammation. This work provides a theoretical framework for exploring the mechanism of mitochondrial membrane permeabilization in controlling cell fate.

Discovery of diverse diterpenoid scaffolds from Euphorbia antiquorum and their activity against RANKL-induced osteoclastogenesis.

Seven new diterpenoids, euphorantones A-D (1, 3, 6, and 10), 8,12,13-epi-3,7,12-O-triacetyl-8-O-(2-methylbutanoyl)-ingol (9), 8,12,13-epi-3,12-O-diacetyl-7-O-benzoyl-8-methoxyingol (11), 2,3-epi-7,12-diacetate-8-benzoate-ingol (12), together with eighteen known compounds (2, 4-5, 7-8, and 13-25), were isolated from the aerial parts of Euphorbia antiquorum L.. The structures of new compounds 1, 3, 6, and 9-12 were elucidated by extensive spectroscopic analyses. The absolute configurations of new compounds were assigned using X-ray diffraction, Rh2(OCOCF3)4-induced CD spectrum, and confirmed through comparison of the calculated and experimental 13C NMR and electronic circular dichroism (ECD) data. Compounds 1-25 were evaluated for their inhibition of RANKL-induced osteoclastogenesis. Compound 1 showed the most potent inhibition of RANKL-induced osteoclastogenesis with IC50 value of 0.3 µM. It inhibited NFAT transcript activity and osteoclast related genes TRAcP, CTSK, and NFATc1 expression.

Temperature reconstruction and volcanic eruption signal from tree-ring width and maximum latewood density over the past 304 years in the southeastern Tibetan Plateau.

This study presents a 304-year mean July-October maximum temperature reconstruction for the southeastern Tibetan Plateau based on both tree-ring width and maximum latewood density data. The reconstruction explained 58% of the variance in July-October maximum temperature during the calibration period (1958-2005). On the decadal scale, we identified two prominent cold periods during AD 1801-1833 and 1961-2003 and two prominent warm periods during AD 1730-1800 and 1928-1960, which are consistent with other reconstructions from the nearby region. Based on the reconstructed temperature series and volcanic eruption chronology, we found that most extreme cold years were in good agreement with major volcanic eruptions, such as 1816 after the Tambora eruption in 1815. Also, clusters of volcanic eruptions probably made the 1810s the coldest decade in the past 300 years. Our results indicated that fingerprints of major volcanic eruptions can be found in the reconstructed temperature records, while the responses of regional climate to these eruption events varied in space and time in the southeastern Tibetan Plateau.

Finite element simulation of lower limb injuries to the driver in minibus frontal collisions.

PURPOSE: This study aims to explore the biomechanical mechanism of lower limb injuries to the driver by establishing a finite element (FE) simulation model of collisions. METHODS: First a minibus FE model was integrated with a seat belt system. Then it was used to rebuild two collisions together with the total human model for safety (THUMS) provided by Toyota Motor Corporation: a rear-end collision between a minibus and a truck and a head-on collision of a minibus to a rigid wall. The impact velocities of both collisions were set at 56 km/h. The vehicle dynamic response, vehicle deceleration, and dashboard intrusion in the two collisions were compared. RESULTS: In the minibus rear-end truck collision, the peak values of the von Mises equivalent stress at the tibia and the femur were 133 MPa and 126 MPa respectively; while in the minibus head-on rigid wall collision, the data were 139 MPa and 99 MPa. Compared with the minibus head-on rigid wall collision, the vehicle deceleration was smaller and the dashboard intrusion was larger in the minibus rear-end truck collision. CONCLUSION: The results illustrate that a longer dashboard incursion distance corresponds to a higher von Mises equivalent stress at the femur. The simulation results are consistent with the driver's autopsy report on lower limbs injuries. These findings verify that FE simulation method is reliable and useful to analyze the mechanisms of lower limb injuries to the driver in minibus frontal collisions.

Expression of Hsp70 and Caspase-3 in rabbits after severe traumatic brain injury.

OBJECTIVE: To investigate the expression of Caspase-3 and Hsp70 in rabbits after severe traumatic brain injury (TBI) and to explore the feasibility of its application in estimation of injury time in forensic medicine. METHODS: A rabbit model of heavy TBI was developed by high velocity impact on the parietal bone with an iron stick. Totally 8 healthy adult New Zealand white rabbits were randomly divided into control group (n equal to 2) and injury group (n equal to 6). Four hours after injury, tissue specimens from the parietal lobe, temporal lobe, occipital lobe, cerebellum and brainstem were harvested to detect the expression of Hsp70 and Caspase-3 by immunohistochemistry. Besides, the gray values of cells positive for Hsp70 and Caspase-3 were analyzed with an image analyzer. RESULTS: Immunohistochemistry staining demonstrated a low level of Caspase-3 and Hsp70 expression in normal control group. While in injury group, both the Caspase-3 and Hsp70 expression was significantly elevated (P less than 0.05). Positive cells gathered around the lesion focus. Occipital lobe and cerebellum had fewer positive cells while temporal and brainstem had the fewest. CONCLUSION: The expression of Caspase-3 and Hsp70 at an early stage following severe TBI is characteristic and can be applied to estimate the time of injury.

Forensic medical study on morphology and formative mechanism of blunt head injury.

OBJECTIVE: To study the patterns and morphologic characteristics of blunt head injury and analyse its formative mechanism in attempt to provide references for medicolegal expertise. METHODS: The statistical analysis was done in terms of gender, age, as well as the nature, pattern, location, and feature of the injuries. RESULTS: Among the 202 cases of head injury-induced death, 124 were male and 78 female with the age ranging from 1-81 years. Death caused by homicide was dominant (106, 52.5%), followed by suicide (49, 24.3%) and accident (44, 21.8%). The majority of suicide-induced death were by falling from height, and traffic crash was responsible for majority of unexpected death cases. The morphology and pathogenesis of the injuries varied according to differences on the mode, magnitude, and orientation of the outside force giving rise to blunt injury as well as the character of vulnerants. CONCLUSION: Studies on the morphology and its formative rationale of blunt head injury will offer easy access to medicolegal expertise on the mode and character of the injury.

Establishment of a blunt impact-induced brain injury model in rabbits.

OBJECTIVE: To establish an animal model to replicate the blunt impact brain injury in forensic medicine. METHODS: Twenty-four New Zealand white rabbits were randomly divided into control group (n equal to 4), minor injury group (n equal to 10) and severe injury group (n equal to 10). Based on the BIM-II Horizontal Bio-impact Machine, self-designed iron bar was used to produce blunt brain injury. Two rabbits from each injury group were randomly selected to monitor the change of intracranial pressure (ICP) during the impacting process by pressure microsensors. Six hours after injury, all the rabbits were dissected to observe the injury morphology and underwent routine pathological examination. RESULTS: Varying degrees of nervous system positive signs were observed in all the injured rabbits. Within 6 hours, the mortality rate was 1/10 in the minor injury group and 6/10 in the severe injury group. Morphological changes consisted of different levels of scalp hematoma, skull fracture, epidural hematoma, subdural hematoma, subarachnoid hemo- rrhage and brain injury. At the moment of hitting, the ICP was greater in severe injury group than in mild injury group; and within the same group, the impact side showed positive pressure while the opposite side showed negative pressure. CONCLUSIONS: Under the rigidly-controlled experimental condition, this animal model has a good reproducibility and stable results. Meanwhile, it is able to simulate the morphology of iron strike-induced injury, thus can be used to study the mechanism of blunt head injury in forensic medicine.

Morphologic studies of high fall injuries.

OBJECTIVE: By studying the mode and morphologic character of high fall injuries on the scene, and exploring the injury situation of different heights, different fall ways and postures, to provide a reference for the forensic identification of high fall injury. METHODS: All the high fall cases were statistically analysed according to their gender, age, ground-touching posture, fall height, site and type of the injury. RESULTS: Among 134 high fall cases, 98 were male and 36 were female with the age ranging from 2-71 years (37.6+/-16.9 on average), in which, 10-60 years old group consisted of 110 cases (82%). Most cases fell from windows or roofs (73%) and the touching objects were cement ground or shaft bottom of elevators. Among these cases, head injury was generally serious, followed by chest and abdominal injuries. The morphologic changes depend upon the height, nature, as well as the posture at the point while the body touches the ground. CONCLUSION: Morphologic study of high fall injury assists medicolegal physicians to make correct identifications of the cause and nature of high fall injuries.

Analysis of 86 fatal motorcycle frontal crashes in Chongqing, China.

OBJECTIVE: To analyze the injuries of motorcyclists involved in fatal motorcycle frontal crashes. METHODS: A survey group involving multi-discipline experts was built to randomly collect data on fatal motorcycle frontal collision accidents that occurred in Chongqing during 2006-2010. The sampled information included medical or autopsy reports, blood alcohol concentration (BAC) level, helmet use, accident witness, field sketch as well as field photos. The motorcyclist injuries were scored according to the Abbreviated Injury Scale (AIS) 2005. The involved riders with a BAC level larger than or equal to 20 mg/ml were attributed to alcohol use. Data were processed statistically with nonparametric test via software SPSS 11.0. RESULTS: A total of 86 fatal motorcycle frontal crashes were sampled and further analyzed. The age of motorcyclists enrolled in this investigation showed nominal distribution and the middle-aged (30-39 years) occupied the highest percentage of fatalities. There were only 14 motorcyclists (16.3%) wearing helmets at the moment of collision. And 12.8% of these motorcyclist crashes were attributable to alcohol use. Impact injury was the main fatal cause, accounting for 72% of motorcyclist deaths, followed by tumbling injury (26%) and run-over (2%). Respectively 84%, 22% and 19% of motorcyclists who sustained head, chest and abdominal trauma died. Extremity injury was the most frequently observed injury type. CONCLUSIONS: This investigation is helpful to build accident prevention programs and develop protection devices which may effectively mitigate injuries and prevent deaths following motorcycle frontal collision accidents. Further investigations on motorcycle collision accidents are still needed.

A rabbit model of graded primary mechanical injury to brainstem.

OBJECTIVE: To introduce a new animal model of graded mechanical primary brainstem injury (BSI). METHODS: Altogether 45 rabbits were subjected to BSI by type II biological impact machine designed by the Third Military Medical University. The animals were divided into 4 experimental groups (n equal to 10) and 1 control group (n equal to 5) according to different magnitudes of impact pressure imposed on the occipital nodule: Group 1, 500-520 kPa; Group 2, 520-540 kPa; Group 3, 540-560 kPa; Group 4, 560-580 kPa and Group 5, 0 kPa with 20 kPa increase in each grade. The impact depth was a constant 0.5 cm. After injury, the clinical symptoms and signs as well as pathological changes were observed. RESULTS: Rabbits in Group 1 revealed mild physiological reaction of BSI. They had localized cerebral contusion with punctate hemorrhage and subarachnoid hemorrhage (SAH) was limited to the peripheral tissues at the impact area. In Group 2, obvious physiological reaction was observed. Local pathological lesions reached the superficial layer of brainstem tissues; focal hemorrhage and girdle-shaped SAH in basilar pon were observed under microscope. In Group 3, BSI was more severe with a long respiratory depression. Pathological lesions reached the inner portion of brainstem with massive hemorrhage and the whole brainstem was wrapped by subarachnoid hematoma. In Group 4, most rabbits died due to severe BSI. Pathological lesions deepened to the central brainstem with wide pathological change, rapture of the medulla oblongata central canal. Group 5 was the control group, with normal brainstem structure and no lesion observed. CONCLUSION: This model successfully simulates different levels of brainstem mechanical injury and clearly shows the subsequent pathological changes following injury. It takes two external parameters (impact pressure and depth) and has a similar injury mechanism to clinical accelerating BSI. Moreover it is reproducible and stable, thus being be- neficial for exploring pathophysiological mechanism, diagnosis and forensic identification of various degrees of BSI.

Model-based orbital-scale precipitation δ18O variations and distinct mechanisms in Asian monsoon and arid regions.

The past Asian precipitation δ18O (δ18Op) records from stalagmites and other deposits have shown significant orbital-scale variations, but their climatic implications and regional differences are still not fully understood. This study, as the first attempt of a 300-kyr transient stable isotope-enabled simulation, investigated the characteristics and mechanisms of the orbital-scale δ18Op variations in three representative regions of Asia: arid Central Asia (CA), monsoonal South Asia (SA) and monsoonal East Asia (EA). The modelling results showed that the variations in the CA, SA and EA annual δ18Op exhibited significant but asynchronous 23-kyr precession cycles. Further analyses revealed that although the precession-induced insolation variation was the ultimate cause of the δ18Op variation in all three regions, the dominant mechanisms and the involved physical processes were distinct among them. For the CA region, the rainy-season (November-March) temperature effect and water vapour transport by the westerly circulation were identified as the key precession-scale processes linking the October-February boreal mid-latitude insolation to the rainy-season or annual δ18Op. In the SA region, the rainy-season (June-September) precipitation amount effect and upstream depletion of the monsoonal water vapour δ18O served as the main mechanisms linking the rainy-season or annual δ18Op to the April-July insolation variation at the precession scale. For the EA region, however, the precession-scale annual δ18Op was mainly controlled by the late-monsoon (August-September) and pre-monsoon (April-May) water vapour transport patterns, which were driven by the July-August insolation and the global ice volume, respectively. These results suggest that the climatic implications of the orbital-scale Asia δ18Op variations are sensitive to their geographic locations as determined by the combined effects of insolation and regional circulation patterns associated with the respective rainy seasons. This study provides new insights into understanding the regional differences and formation mechanisms of the Asian orbital-scale δ18Op variations.

Juvenile Hormone Is an Important Factor in Regulating Aspongopus chinensis Dallas Diapause.

Aspongopus chinensis is a Chinese traditional edible and medicinal insect, which is in great demand in the society. This insect reproduces once a year which is caused by reproductive diapause resulting in insufficient production in wild resources. However, the mechanism of diapause in A. chinensis is still unclear. In this study, we focus on the relationship between juvenile hormones (JHs) and A. chinensis diapause. The results showed that JHIII concentration in diapause adult individuals was significantly lower than that in diapause termination adult individuals. When exogenous JHⅢ was injected into diapause adults, the rate of mating was increased significantly, development of the reproductive systems was accelerated, consumption of fat intensified, the expression of juvenile hormone acid o-methyl-transferase (JHAMT) was upregulated, and juvenile hormone epoxide hydrolase (JHEH) and fatty acid synthase (FAS) gene expressions were downregulated. In addition, RNAi of JHAMT decreased JH concentration, delayed the development of reproductive systems, slowed down fat consumption, and delayed the mean mating occurrence time significantly. Conversely, RNAi of JHEH resulted in an increased concentration of JH, development of reproductive systems was accelerated, consumption of fat was intensified, and mean mating occurrence time advanced significantly. Taken together, these findings uncovered that JH plays an important role in regulating reproductive diapause in A. chinensis and, thus, could provide a theoretical basis for further research on the diapause of A. chinensis.

12-Month clinical results of drug-coated balloons for de novo coronary lesion in vessels exceeding 3.0 mm.

The purpose of this observational study was to investigate the feasibility, initial safety, and efficacy of the SeQuent® Please DCB (B. Braun Melsungen, Germany) for patients with de novo coronary lesions in vessels exceeding 3.0 mm in a consecutive series of all comer percutaneous coronary intervention. A total of 120 patients (135 lesions) with de novo coronary lesions in vessels ≥ 3.0 mm treated with DCB were enrolled in this single-centre prospective observational study. The primary endpoint was target lesion failure (TLF), a composite endpoint of cardiac death, target vessel-myocardial infarction (TV-MI), and clinically driven target vessel revascularization (TLR) at 12 months. Safety endpoints included cardiac death, TV-MI, and definite target vessel thrombosis. 45.9% of the lesions were classified as complex (type B2/C). The reference vessel diameter was 3.09 ± 0.31 mm measured via quantitative coronary angiography analysis. Coronary dissections occurred in 42 patients (35.0%; Type A-B 14.1%; Type C 19.1%; Type D: 1.6%), two of which [1.6%; (type D dissection)] underwent bail-out stent implantation. 12-month follow-up was completed in 100% patients. The 12-month incidence of TLF was 3.4%. The clinically driven TLR occurred in four patients (3.4%). The incidence of TLR was low in patients without any detectable dissections, similar to those with dissections (3.8% vs. 2.5%; p = 0.146). No patient suffered cardiac death, TV-MI, or target vessel thrombosis. The study shows the feasibility, initial safety, and efficacy of coronary intervention using SeQuent® Please DCB for the treatment of patients with de novo lesion in vessels exceeding 3 mm. The study highlights that the coronary dissection (Type A-C) post DCB treatment occurs frequently but is safe at follow up.

Chemical constituents from Daphne tangutica and their cytotoxicity against nasopharyngeal carcinoma cells.

Two new sesquiterpenoids (1-2), together with 30 known compounds including one sesquiterpenoid (3), six diterpenoids (4-9), fourteen lignans (10-23), and nine other kinds of compounds (24-32), were isolated from the stems of Daphne tangutica Maxim. Their structures were determined through extensive spectroscopic analyses, and the absolute configuration of daphnoid A (1) and B (2) were determined by the experimental and calculated electron circular dichroism (ECD) spectra. All the isolates were evaluated against two human nasopharyngeal carcinoma cells (HONE-1 and SUNE-1). Compound 25 (daphnenone) showed potent cytotoxicity toward HONE-1 and SUNE-1with IC50 values of 2.23 and 1.43 µM, respectively. Further studies indicated that compound 25 exhibited cytotoxic effects by inducing tumor cell apoptosis and arresting the cell cycle at G2/M phases in HONE-1 cells.

Fluvirosaones A and B, Two Indolizidine Alkaloids with a Pentacyclic Skeleton from Flueggea virosa.

Fluvirosaones A (1) and B (2), together with virosecurinine (3), were isolated from Flueggea virosa. Their structures were determined by physical, spectroscopic, and X-ray analysis and confirmed through comparison of the calculated and experimental 13C NMR and electronic circular dichroism (ECD) data. Compounds 1 and 2 represent the first examples of a pentacyclic Securinega alkaloid containing a pentacyclic system and an α,ß-unsaturated ketone. Plausible biogenetic pathways of compounds 1 and 2 are proposed.

Cembrane-type diterpenoids from Macaranga pustulata.

Three new cembrane-type diterpenoids, deheiculatins M-O (1-3), together with five known analogues (4-8), were isolated from the twigs of Macaranga pustulata King ex Hook. The structures of new compounds 1-3 were elucidated by extensive spectroscopic analyses, modified Mosher's method, and the experimental and calculated electronic circular dichroism (ECD) experiments. All the isolates were evaluated for their cytotoxicity on three human cancer cell lines (CNE1, CNE2, and HCT 116), and all of them showed weak cytotoxicity (IC50 > 20 µM).

Continental drift and plateau uplift control origination and evolution of Asian and Australian monsoons.

Evolutions of Asian and Australian monsoons have important significance for understanding the past global change but are still a controversial subject. Here, we explore systematically the effects of plate movement and plateau uplift on the formation and evolution of the Asian and Australian monsoons by numerical simulations based on land-sea distributions and topographic conditions for five typical geological periods during the Cenozoic. Our results suggest that the timings and causes of formation of the monsoons in South Asia, East Asia and northern Australia are different. The Indian Subcontinent, which was located in the tropical Southern Hemisphere in the Paleocene, was influenced by the austral monsoon system simulated at that time. Once it moved to the tropical Northern Hemisphere in the Eocene, the South Asian monsoon established and remained persistently thereafter. However, the monsoons of East Asia and northern Australia did not appear until the Miocene. The establishment of the simulated low-latitude South Asian (northern Australian) monsoon appeared to have strongly depended on the location of mainland India (Australia), associated with northward plate motion, without much relation to the plateau uplift. On the contrary, the establishment of the mid-latitude East Asian monsoon was mainly controlled by the uplift of Tibetan plateau.

[Comparative study on physical parameters and biological effects of blast wave on plateau and on plain].

OBJECTIVE: To compare the physical parameters and biological effects of blast wave on plateau and on plain. METHODS: Twenty-five pigs were divided into two groups: plateau group (n=15) and plain group (n=10). They were placed either 5 meters or 6 meters away from the site of explosion. Ten kilogram of TNT was detonated to produce blast injury. Physical parameters were measured with pressure transducers. The survival rate and gross morphological changes were carefully observed 28 hours later. RESULTS: There was no significant difference in propagation speed of blast wave between the two groups. Compared with plain group, the over-pressure value measured in plateau group was a slightly lower, however, the duration of positive pressure was more lengthy and impulse stronger compared with that of plain group. The survival rate was 12/15 and 8/10 respectively for plateau and plain groups 28 hours after injury. The morphological changes were mainly lung hemorrhage and edema. Intestinal subserosal hemorrhage and subendocardial hemorrhage were found in some animals. The lung injury severity in plateau group was one scale severer than that of plain group. CONCLUSION: Plateau blast wave is characterized by slightly higher impulse, longer duration, and lower over-pressure value, although the propagation speed of the wave is not different from that of plain environment. The blast injury in plateau environment is also severer, its underlying mechanisms need to be further explored.

Tree-Ring Dating of the Reshui-1 Tomb in Dulan County, Qinghai Province, North-West China.

Tuyuhun and Tubo were two important states that thrived in north-western China during AD 311-900 in parallel with the Han Chinese dynasties of Sui and Tang periods. The Reshui Tomb Cluster located in Dulan County of the north-eastern Tibetan Plateau is an important cultural relic of the Tuyuhun-Tubo age. The official excavations of the Reshui tombs were regarded as top events in archaeology in the 1980s and 1990s in China. The Reshui-1 Tomb is the largest one among the tombs in the area. Since its excavation, there have been debates on whether the owner of the tomb belonged to the Tuyuhun or Tubo ethnicity. Therefore, accurately dating the Reshui-1 Tomb has a critical place in studying the Tubo and Tuyuhun histories. We collected 7 discs and 11 increment cores of Qilian juniper (Juniperus przewalskii Kom.) from the exposed and fallen beams of the roof of the Reshui-1Tomb. The lengths of the 16 tree-ring records are between 69 and 152 years. Based on a previously developed master dating chronology using Qilian juniper samples from the eastern Qaidam Basin, the calendar dates of the 16 specimens were determined by the COFECHA program and visual dating procedure. The average inter-series correlation among the dated sample series is 0.696, indicating good quality of cross-dating. The year of the outermost rings is AD 715 for the 7 discs and 4 out of the 9 increment cores. Moreover, the ring-width variations of the samples are consistent with the existing chronologies from the region. The presence of late-wood of AD 715 in the samples indicated that the Reshui-1 Tomb was completed in late AD 715 or early 716, which means that the Reshui-1 Tomb was finished in the Tubo age. This date provides direct evidence for archaeologists to determine the owner's ethnicity and identify of the Reshui-1 Tomb.

[Pathomorphological changes in abdominal viscerae in dogs subjected to underwater blast wave injury].

OBJECTIVE: To explore the pathomorphological changes in abdominal viscerae injuries produced by underwater blast waves. METHODS: Sixty-one adult mongrel dogs were used in this study. Underwater explosions in different intensity were produced by detonating 200 g, 500 g and 1,000 g TNT, respectively. The physical parameters of blast wave were measured by PCB dynamic pressure transducers specially designed for underwater explosion. The pathomorphological changes in abdominal viscerae were observed at 6 hours after injury. RESULTS: The physical features of underwater blast wave were characterized by high peak pressure, short positive action duration, and higher intensity of impulse. The pathomorphological observation revealed high incidence of injuries of gastrointestinal tract (62.30 percent), manifesting mainly various degrees of subserosal and submucous bleeding in gastrointestinal tract. Rupture of seromuscular layer, subserosal hematoma, and even, perforations of gastrointestinal tract occurred in some animals. Injuries of the liver, spleen, pancreas and other parenchymatous organs injuries, such as subcapsular bleeding, hematoma, and ruptures, appeared with low incidence. No obvious injuries were found in the gallbladder or urinary bladder and other fluid containing organs. CONCLUSION: Underwater blast wave can induce injuries to many abdominal viscerae. Gastrointestinal tract injuries, occurring in high incidence are usually severe, and they should be given early treatment in underwater blast injuries.