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Introduction: The heterocyclic compound 4‐hydroxy‐(2,2,6,6‐Tetramethylpiperidin‐1‐yl)oxyl (TEMPOL) has a protective effect on neurological function in brain tissues damaged by ischemia and hypoxia. This study explored the effects of TEMPOL pretreatment on postoperative cognitive function in aged rats under sevoflurane anesthesia, focusing on inflammatory response and oxidative stress. Methods: Sixty male rats were divided into normal control (C), sevoflurane anesthesia (S), TEMPOL pretreatment (T), and sevoflurane anesthesia + TEMPOL pretreatment (ST) groups (15 per group). Groups T and ST rats received continuous intraperitoneal TEMPOL (100 mg/kg) for 3 days, while groups C and S rats were injected with 0.9% saline. After pretreatment, groups S and ST received 3% sevoflurane anesthesia. Results: Rats in group S exhibited a longer swimming distance, longer escape latency, lower frequency of platform crossing, and shorter dwell time in the targeted quadrant than those in groups C and T. Rats in group ST exhibited a shorter swimming distance, shorter escape latency, higher frequency of platform crossing, and longer dwell time in the targeted quadrant than those in group S. The expressions of interleukin‐6, tumor necrosis factor‐α, inducible nitric oxide synthase, and Ym1/2 messenger ribonucleic acid were higher in groups S and ST rats than in groups C and T rats and lower in group ST rats than in group S rat (p <.05). Superoxide dismutase (SOD), total antioxidant capacity (T‐AOC), and glutathione peroxidase (GSH‐Px) were lower, while malondialdehyde (MDA) was higher in groups S and ST rats than in groups C and T rats (p <.05). Group ST showed higher SOD, T‐AOC, and GSH‐Px, and lower MDA than group S (p <.05). Conclusions: TEMPOL pretreatment attenuated postoperative cognitive impairment induced by sevoflurane anesthesia in aged rats. This may be attributed to the downregulation of NR2B‐CREB‐BDNF pathway, reducing the inflammatory response and oxidative stress damage in hippocampal tissue. [ABSTRACT FROM AUTHOR]

Oceanic transform faults connect spreading centers and are imprinted with previous tectonic events. However, their tectonic interactions are not well understood due to limited observations. The Discovery transform fault system at 4°S, East Pacific Rise (EPR), represents a young transform system, offering a unique opportunity to study the interplay between faulting and other tectonic events at an early phases of an oceanic transform system. Discovery regularly hosts M5–6 characteristic earthquakes, and the seafloor north of Discovery includes a 35 km‐long rift zone that records a complex history of rifting, faulting and volcanism, suggesting that the transform faults likely interact with regional tectonic activity. We apply a machine‐learning enabled workflow to locate 21,391 earthquakes recorded during a 1‐year ocean bottom seismometer experiment in 2008. Our results indicate that seismicity on the western Discovery fault is separated into seven patches with distinct aseismic and seismic slip modes. Additionally, we observe a patch of off‐fault seismicity near where seafloor abyssal hills intersect the rift zone. This seismicity may have been caused by varying opening rates as spreading rate decreases from north to south in the rift zone. Our findings suggest that the Discovery system is still evolving, and that system equilibrium has not been reached between rifting and faulting. These results reflect the complex yet rarely observed interactions between fault slip, plate rotation, and rifting which are likely ubiquitous at oceanic transform systems. Plain Language Summary: Oceanic transform faults are major plate boundaries connecting mid‐ocean ridges. Despite their important role in plate tectonics, their interactions with adjacent mid‐ocean ridges and surrounding oceanic plates are not well understood. The Discovery transform fault system at 4°S, East Pacific Rise, is a young oceanic transform system formed approximately 1 My ago, offering a unique opportunity to study the interplay between faulting and other tectonic events at an early phase of an OTF. Discovery faults have quasi‐periodical magnitude (M) 5–6 earthquakes. Using ocean bottom seismometer data recorded over 1 year, we find that seismicity of the western Discovery fault can be grouped into seven patches, indicating division of alternating slip modes that either releases tectonic strain by M > 5 earthquakes or creep steadily. North of the western Discovery fault, a ∼10 km wide rift zone, abundant seamounts, and abyssal hills form an interactive tectonic complex. We observe a patch of off‐fault seismicity coinciding with seafloor abyssal hills near their intersection with the rift zone. This off‐fault seismicity indicates ongoing deformation within the oceanic plate and possible spatial variations in rifting rates. Our results suggest that the Discovery system is still evolving with rifting and faulting accommodating plate spreading simultaneously. Key Points: The western Discovery transform fault has seven patches that are likely dominated by alternating seismic and aseismic slip modesMachine‐learning method helps to identify off‐fault seismicity along abyssal hills, indicating ongoing deformation within the oceanic plateThe Discovery transform system is young and still evolving, forming an interactive system with faulting, rifting, and plate rotation [ABSTRACT FROM AUTHOR]

Ocean transform faults often generate characteristic earthquakes that repeatedly rupture the same fault patches. The westernmost Gofar transform fault quasi‐periodically hosts ∼M6 earthquakes every ∼5 years, and microseismicity suggests that the fault is segmented into five distinct zones, including a rupture barrier zone that may have modulated the rupture of adjacent M6 earthquakes. However, the relationship between the systematic slip behavior of the Gofar fault and the fault material properties is still poorly known. Specifically, the role of pore fluids in regulating the slip of the Gofar fault is unclear. Here, we use differential travel times between nearby earthquakes to estimate the in‐situ Vp/Vs of the fault‐zone materials. We apply this technique to the dataset collected by an ocean‐bottom‐seismometer network deployed around the Gofar fault in 2008, which recorded abundant microearthquakes, and find a moderate Vp/Vs of 1.75–1.80 in the rupture barrier zone and a low Vp/Vs of 1.61–1.69 in the down‐dip edge of the 2008 M6 rupture zone. This lateral variation in Vp/Vs may be caused by both pore fluids and chemical alteration. We also find a 5%–10% increase in Vp/Vs in the barrier zone during the 9 months before the mainshock. This increase may have been caused by fluid migrations or slip transients in the barrier zone. Plain Language Summary: Oceanic transform faults are ideal natural laboratories for studying earthquake physics due to their regular behaviors. The westernmost Gofar transform fault near the East Pacific Rise generates magnitude six earthquakes every 5–6 years on two rupture zones, respectively, which are separated by a barrier zone repeatedly stopping ruptures on the adjacent segments. The distinct behavior of the barrier zone might be due to differences in material properties from the rupture zones. To explore this hypothesis, we analyze thousands of small earthquakes in 2008 and find that the barrier zone has a higher ratio between P and S velocities than the rupture zone. This difference indicates that the barrier and rupture zones differ in their fluid content and chemical composition, which may have regulated their distinct slip behaviors. We also find an increase in the ratio between P and S velocities in the barrier zone during the 9 months before the magnitude six earthquake in 2008, which may reflect fluid flows or aseismic fault slips. Our findings suggest that pore fluids and the chemical composition of fault‐zone materials likely play a crucial role in regulating the slip behaviors of oceanic transform faults. Key Points: Rupture barrier zone has a moderate Vp/Vs of 1.75–1.80Down‐dip edge of the 2008 M6 mainshock has a low Vp/Vs of 1.61–1.69Vp/Vs in the rupture barrier zone increased in the 9 months before the mainshock [ABSTRACT FROM AUTHOR]

Oceanic transform faults accommodate plate motions through both seismic and aseismic slips. However, deformation partition and slip mode interaction at these faults remain elusive mainly limited by rare observations. We use 1‐year ocean bottom seismometer data collected in 2008 to detect and locate earthquakes at the westernmost Gofar transform fault. The ultra‐fast slipping rate of Gofar results in ∼30,000 earthquakes during the observational period, providing an excellent opportunity to investigate interrelations between the slip mode, seismicity, and fault architecture at an unprecedented resolution. Earthquake distribution indicates that the ∼100‐km‐long Gofar transform fault is distinctly segmented into five zones, including one zone contouring a M6 earthquake that was captured by the experiment. Further, a barrier zone east of the M6 earthquake hosted abundant foreshocks preceding the M6 event and halted its active seismicity afterward. The barrier zone has two layers of earthquakes at depth, and they responded to the M6 earthquake differently. Additionally, a zone connecting to the East Pacific Rise had quasi‐periodic earthquake swarms. The seismicity segmentation suggests that the Gofar fault has multiple slip modes occurring in adjacent fault patches. Spatiotemporal characteristics of the earthquakes suggest that complex fault architecture and fluid–rock interaction play primary roles in modulating the slip modes at Gofar, possibly involving multiple concurrent physical processes. Plain Language Summary: Oceanic transform faults are apparently simple tectonic plate boundaries. However, their structures are surprisingly complex as manifested through various seismic and aseismic slip modes. The deformation partition mechanism is not well understood due to a lack of near‐field observations. Here, we use 1‐year ocean bottom seismometer data to study earthquakes at the westernmost Gofar transform fault and use these earthquakes to infer the fault slip modes. Spatiotemporal evolution of the earthquakes suggests that the fault has five distinctive zones along strike, including one zone hosted a magnitude (M) 6 earthquake captured by the experiment. The remaining zones are dominated by either seismic or aseismic slip. Such distinct variations of slip mode along strike likely originated from the complex, heterogeneous fault structure, and extensive fluid–rock interactions. Key Points: The westernmost Gofar transform fault is composed of distinct seismic and aseismic zonesThese fault zones are controlled by different slip modes and they possibly interact with each other via multiple mechanismsThe slip mode variations may result from the complex fault architecture and fluid–rock interactions at multiple scales [ABSTRACT FROM AUTHOR]

Autism spectrum disorder (ASD) is associated with altered gut microbiota. However, there has been little consensus on the altered bacterial species and studies have had small sample sizes. We aimed to identify the taxonomic composition and evaluate the changes in the fecal microbiota in Chinese children with ASD by using a relatively large sample size. We conducted a case–control study of 101 children with ASD and 103 healthy controls in China. Demographic information and fecal samples were collected, and the V3‐V4 hypervariable regions of the bacterial 16S ribosomal RNA (rRNA) gene were sequenced. The alpha and beta diversities between the two groups were significantly different. After correcting for multiple comparisons, at the phylum level the relative abundances of Actinobacteria and Proteobacteria in the case group were significantly higher than those in the control group. The relative abundance of the Escherichia‐Shigella genus in the case group was significantly higher than that of the control group, and the relative abundance of Blautia and unclassified_f__Lachnospiraceae in the control group were higher than that of the case group. Phylogenetic Investigation of Communities by Reconstruction of Unobserved States analysis showed that children with ASD may have disturbed functional pathways, such as amino acid metabolism, cofactor and vitamin metabolism, and the AMP‐activated protein kinase signaling pathway. This study revealed the characteristics of the intestinal flora of Chinese children with ASD and provided further evidence of gut microbial dysbiosis in ASD. Lay Summary: This study characterized the gut microbiota composition of 101 children with ASD and 103 healthy controls in China. The altered gut microbiota may contribute significantly to the risk of ASD, including significant increases in the relative abundances of Actinobacteria, Proteobacteria and Escherichia‐Shigella and significant decrease of Blautia and unclassified_f__Lachnospiraceae. This study provided further evidence of gut microbial dysbiosis in ASD. [ABSTRACT FROM AUTHOR]

IMB5036 is a novel pyridazinone compound with potent cytotoxicity. In this study, we reported its antitumour activity against pancreatic cancer and the underlying mechanism. We found that IMB5036 induced rapid cell swelling and increased membrane permeability in pancreatic cancer cells. IMB5036 increased the ratio of PI+ cells, which could be rescued by necroptosis inhibitor. Furthermore, MLKL inhibitor NSA attenuated the killing effect of IMB5036 on pancreatic cancer cells. IMB5036 stimulated translocation of MLKL and p‐MLKL from cytoplasm to cell membrane. IMB5036 upregulated the level of p‐RIPK1, p‐RIPK3, and p‐MLKL. At the same time, IMB5036 also partially activated apoptosis and pyroptosis. IMB5036 inhibited tumour growth in pancreatic xenograft. IMB5036 induced larger necrosis area, increased p‐MLKL level, and inhibited Ki67 expression in tumour mass. The study indicates that IMB5036 inhibits human pancreatic cancer growth primarily activating necroptosis. [ABSTRACT FROM AUTHOR]

Closely spaced, multi‐strand ridge transform faults (RTFs) accommodate relative motions along fast spreading mid‐ocean ridges. However, the relations between RTFs and plate spreading dynamics are poorly understood. The Quebrada system is one of the most unique RTF systems at the East Pacific Rise, consisting of four transform faults connected by three short intra‐transform spreading centers (ITSCs). We use seven‐months of ocean bottom seismograph data to study the Quebrada system, and find abundant earthquakes unevenly distributed among three active faults. We identify two deep, diffuse seismicity clouds at the inside corners of the ITSC‐transform fault intersections, and one seismically active fracture zone. The observations suggest a complex regional plate‐motion pattern, including possible heterogeneous rotations within the Quebrada system. Evolution of multi‐strand RTFs may have resulted from a strong three‐dimensional local thermal and fluid effects, while the RTFs may have also regulated regional tectonics, forming an intricate feedback system. Plain Language Summary: Mid‐ocean ridge transform faults (RTFs) are plate boundaries that offset adjacent mid‐ocean ridges. At fast spreading mid‐ocean ridges, such as the East Pacific Rise (EPR), closely spaced, multi‐strand RTFs are often connected by two or more short intra‐transform spreading centers (ITSCs). However, physical processes accommodating plate spreading along such multi‐strand RTF systems and the inter‐relations between the fault system and the tectonic dynamics are not well understood. Quebrada is one of such multi‐strand RTFs at the EPR. We utilize seven‐month seismic data from ocean bottom seismographs of a 2008 experiment to investigate the seismotectonics of the region. We find intriguing, abundant seismicity on one of the fracture zones, contradicting the traditional view that fracture zones are seismically quiescent. Further, we identify two diffuse seismicity clouds penetrating the uppermost mantle at the inside corners of the ITSC‐transform fault intersections, implying complex interactions among ITSCs, transform faults, and their surrounding structure. From these observations, we infer that there are rotational motions within the Quebrada fault system, which have caused slip along the fracture zone and facilitated fluid circulations to produce deep, diffuse seismicity. We speculate that there is a complex feedback system between the multi‐strand RTFs and local three‐dimensional tectonic processes. Key Points: Four segments of Quebrada transform system show significantly different seismic intensitiesOne fracture zone segment appears to be seismogenic indicating local plate rotationDeep clouds of seismicity extend into the uppermost mantle at spreading center‐ transform fault intersections [ABSTRACT FROM AUTHOR]

Although recent genome‐wide association studies have identified risk loci that strongly associates with autism spectrum disorder (ASD), how to pinpoint the causal genes remains a challenge. We aimed to pinpoint the potential causal genes and explore the possible susceptibility and mechanism. A convergent functional genomics (CFG) method was used to prioritize the candidate genes by combining lines of evidence, including Sherlock analysis, spatio‐temporal expression patterns, expression analysis, protein–protein interactions, co‐expression and association with brain structure. A higher score in the CFG approach suggested that more evidence supported this gene as an ASD risk gene. We screened genes with higher CFG scores for candidate functional single nucleotide polymorphisms (SNPs). A genotyping experiment (602 ASD children and 604 healthy sex‐matched children) and the dual‐luciferase reporter gene assay were followed to validate the effects of SNPs. We identified three genes (MAPT, ZNF285, and TIGD5) as candidate causal genes using the CFG approach. The genotyping experiment showed that TIGD5 rs75547282 was associated with an increased risk of ASD under the dominant model (OR = 1.37, 95% CI = 1.09–1.72, P = 0.006) though the statistical power was limited (5.2%). The T allele of rs75547282 activated the expression of TIGD5 compared with the C allele in the dual‐luciferase reporter assay. Our study indicates that such comprehensive integrative analyses may be an effective way to explore promising ASD susceptibility variants and needs to be further investigated in future research. Genotyping experiments should, however, be based on a larger population sample to increase statistical power. Lay Summary: We set out to pinpoint the potential causal genes of ASD and explore the possible susceptibility and mechanism by combining lines of evidence from different analyses. Our results show that TIGD5 rs75547282 is associated with the risk of ASD in the Han Chinese population. In addition, a similar framework to seek promising ASD risk variants could be further investigated in future research Autism Res 2021, 14: 631–644. © 2021 International Society for Autism Research and Wiley Periodicals LLC [ABSTRACT FROM AUTHOR]

The largest slip in great megathrust earthquakes often occurs in the 10–30 km depth range, yet seismic imaging of the material properties in this region has proven difficult. We utilize a dense onshore‐offshore passive seismic dataset from the southernmost Cascadia subduction zone where seismicity in the mantle of the subducted Gorda Plate produces S‐to‐P and P‐to‐S conversions generated within a few km of the plate interface. These conversions typically occur in the 10–20 km depth range at either the top or bottom of a ∼5 km thick layer with a high Vp/Vs that we infer to be primarily the subducted crust. We use their arrival times and amplitudes to infer the location of the top and bottom of the subducted crust as well as the velocity contrasts across these discontinuities. Comparing with both the Slab1.0 and the updated Slab2 interface models, the Slab2 model is generally consistent with the converted phases, while the Slab1.0 model is 1–2 km deeper in the 2–20 km depth range and ∼6–8 km too deep in the 10–20 km depth range between 40.25°N and 40.4°N. Comparing the amplitudes of the converted phases to synthetics for simplified velocity structures, the amplitude of the converted phases requires models containing a ∼5 km thick zone with at least a ∼10%–20% reduction in S wave velocity. Thus, the plate boundary is likely contained within or at the top of this low velocity zone, which potentially indicates a significant porosity and fluid content within the seismogenic zone. Key Points: We observe clear Ps and SP converted phases generated from the top and bottom of the oceanic crust of the subducted Gorda PlatePs and SP converted phases are used to constrain the geometry of the interface of the subducted slabAmplitude of the converted phases indicates that the subduction plate interface is a low shear‐wave velocity zone at seismogenic depth [ABSTRACT FROM AUTHOR]

Summary: Seed aging tolerance and rapid seedling growth are important agronomic traits for crop production; however, how these traits are controlled at the molecular level remains largely unknown. The unaged seeds of two independent maize DEHYDRATION‐RESPONSIVE ELEMENT‐BINDING2A mutant (zmdreb2a) lines, with decreased expression of GRETCHEN HAGEN3.2 (ZmGH3.2, encoding indole‐3‐acetic acid [IAA] deactivating enzyme), and increased IAA in their embryo, produced longer seedling shoots and roots, than the null segregant (NS) controls. However, the zmdreb2a seeds, with decreased expression of RAFFINOSE SYNTHASE (ZmRAFS) and less raffinose in their embryo, exhibit decreased seed aging tolerance, than the NS controls. Overexpression of ZmDREB2A in maize protoplasts increased the expression of ZmGH3.2, ZmRAFS genes and that of a Rennila LUCIFERASE reporter (Rluc) gene, which was controlled by either the ZmGH3.2‐ or ZmRAFS‐promoter. Electrophoretic mobility shift assays and chromatin immunoprecipitation assay quantitative polymerase chain reaction showed that ZmDREB2A directly binds to the DRE motif of the promoters of both ZmGH3.2 and ZmRAFS. Exogenous supplementation of IAA to the unaged, germinating NS seeds increased subsequent seedling growth making them similar to the zmdreb2a seedlings from unaged seeds. These findings provide evidence that ZmDREB2A regulates the longevity of maize seed by stimulating the production of raffinose while simultaneously acting to limit auxin‐mediated cell expansion. [ABSTRACT FROM AUTHOR]

Gravity, magnetic, and bathymetry data collected along a continuous 1,400‐km‐long spreading‐parallel flow line across the Mid‐Atlantic Ridge indicate significant tectonic and magmatic fluctuations in the formation of oceanic crust over a range of time scales. The transect spans from 28 Ma on the African Plate to 74 Ma on the North American plate, crossing the Mid‐Atlantic Ridge at 35.8°N. Gravity‐derived crustal thicknesses vary from 3–9 km with a standard deviation of 1.0 km. Spectral analysis of bathymetry and residual mantle Bouguer anomaly show a diffuse power at >1 Myr and concurrent peaks at 390, 550, and 950 kyr. Large‐scale (>10 km) mantle thermal and compositional heterogeneities, variations in upper mantle flow, and detachment faulting likely generate the >1 Myr diffuse power. The 550‐ and 950‐kyr peaks may reflect the presence of magma solitons and/or regularly spaced ~7.7 and 13.3 km short‐wavelength mantle compositional heterogeneities. The 390‐kyr spectral peak corresponds to the characteristic spacing of faults along the flow line. Fault spacing also varies over longer periods (>10 Myr), which we interpret as reflecting long‐lived changes in the fraction of tectonically versus magmatically accommodated extensional strain. A newly discovered off‐axis oceanic core complex (Kafka Dome) found at 8 Ma on the African plate further suggests extended time periods of tectonically‐dominated plate separation. Fault spacing negatively correlates with gravity‐derived crustal thickness, supporting a strong link between magma input and fault style at mid‐ocean ridges. Key Points: We conducted one of the longest continuous geophysical surveys along a 74‐Myr spreading‐parallel flow line across the Mid‐Atlantic RidgeSpectral densities of bathymetry and gravity data show concurrent peaks at 390‐, 550‐, and 950‐kyr periods and diffuse power at >1 MyrA negative correlation between fault spacing and gravity‐derived crustal thickness suggests a link between magma input and fault style [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that abnormal synaptic function leads to neuronal developmental disorders and is an important component of the etiology of autism spectrum disorder (ASD). Neurexins are presynaptic cell‐adhesion molecules that affect the function of synapses and mediate the conduction of nerve signals. Thus, neurexins are attractive candidate genes for autism. Since gene families have greater power to reveal genetic association than single genes, we designed this case‐control study to investigate six genetic variants in three neurexin genes (NRXN1, NRXN2, and NRXN3) in a Chinese population including 529 ASD patients and 1,923 healthy controls. We found that two SNPs were significantly associated with ASD after false discovery rate (FDR) adjustment for multiple comparisons. The NRXN2 rs12273892 polymorphism T allele and AT genotype were significantly associated with increased risk of ASD (respectively: OR = 1.328, 95% CI = 1.133–1.557, P < 0.001; OR = 1.528; 95% CI = 1.249–1.868, P < 0.001). The dominant model showed the same association (OR = 1.495, 95% CI = 1.231–1.816, P < 0.001). The NRXN3 rs12879016 polymorphism played a significant role in ASD susceptibility under the dominant model (OR = 0.747, 95% CI= 0.615–0.908, P = 0.023), with the same trend detected for the G allele and GT genotype (respectively: OR = 0.811, 95% CI = 0.699–0.941, P = 0.036; OR = 0.755, 95% CI = 0.615–0.928, P = 0.035). In conclusion, this study supports the importance of two genetic variants in the neurexin gene family in ASD susceptibility in China. Autism Res2018, 11: 37–43. © 2017 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary: Autism spectrum disorder (ASD) is a neurodevelopmental disorder that is highly heritable, and studies have found a number of candidate genes that might contribute to ASD. Neurexins are presynaptic cell‐adhesion molecules that affect the function of synapses and mediate the conduction of nerve signals, and they play an important role in normal brain development and become candidate genes for autism. The purpose of our study is to explore the association between variants of the neurexins gene family and ASD in a Chinese population through a case‐control study. [ABSTRACT FROM AUTHOR]

Objective Sclerostin plays a major role in regulating skeletal bone mass, but its effects in articular cartilage are not known. The purpose of this study was to determine whether genetic loss or pharmacologic inhibition of sclerostin has an impact on knee joint articular cartilage. Methods Expression of sclerostin was determined in articular cartilage and bone tissue obtained from mice, rats, and human subjects, including patients with knee osteoarthritis (OA). Mice with genetic knockout (KO) of sclerostin and pharmacologic inhibition of sclerostin with a sclerostin-neutralizing monoclonal antibody (Scl-Ab) in aged male rats and ovariectomized (OVX) female rats were used to study the effects of sclerostin on pathologic processes in the knee joint. The rat medial meniscus tear (MMT) model of OA was used to investigate the pharmacologic efficacy of systemic Scl-Ab or intraarticular (IA) delivery of a sclerostin antibody-Fab (Scl-Fab) fragment. Results Sclerostin expression was detected in rodent and human articular chondrocytes. No difference was observed in the magnitude or distribution of sclerostin expression between normal and OA cartilage or bone. Sclerostin-KO mice showed no difference in histopathologic features of the knee joint compared to age-matched wild-type mice. Pharmacologic treatment of intact aged male rats or OVX female rats with Scl-Ab had no effect on morphologic characteristics of the articular cartilage. In the rat MMT model, pharmacologic treatment of animals with either systemic Scl-Ab or IA injection of Scl-Fab had no effect on lesion development or severity. Conclusion Genetic absence of sclerostin does not alter the normal development of age-dependent OA in mice, and pharmacologic inhibition of sclerostin with Scl-Ab has no impact on articular cartilage remodeling in rats with posttraumatic OA. [ABSTRACT FROM AUTHOR]

The article discusses a study which found that sclerostin antibody therapy promoted bone formation and increased bone mass and strength in a rat model of postmenopausal osteoporosis. The researchers identified a sclerostin neutralizing monoclonal antibody (Scl-AbII) via a cell culture model. Scl-AbII treatment in the animal model showed robust anabolic effects.

Parkinson's disease (PD) patients vary widely in their response to levodopa treatment, and this variation may be partially genetic in origin. We determined whether particular dopamine and opioid receptor polymorphisms were associated with risk of earlier onset of dyskinesia side effects during levodopa therapy. Smoking status was also examined. The 92 subjects were recruited from the movement disorders clinic of a neurology practice associated with a medical school. All were adult-onset PD patients who had been taking levodopa at least 5 years and/or had developed levodopa-induced dyskinesia. Carrying the G-allele of the A118G single nucleotide coding region polymorphism of the mu opioid receptor, as well as a history of never smoking, were independently associated with increased risk of earlier onset of dyskinesia ( P = 0.05 and 0.02, respectively). One genotype of the D2 dopamine receptor intronic dinucleotide repeat polymorphism (14 repeats/15 repeats, with frequency of 6%) was also associated with earlier dyskinesia ( P = 0.003). History of smoking has previously been associated with reduced risk of developing PD. Our results suggest that smoking history may also influence the response to levodopa, with contribution comparable to those of individual genes including the mu opioid receptor and D2 dopamine receptor. © 2006 Movement Disorder Society [ABSTRACT FROM AUTHOR]