Beryllium-10 surface exposure dating of offset moraines on one branch of the Karakorum Fault west of the Gar basin yields a long-term (140- to 20-thousand-year) right-lateral slip rate of ~10.7 ± 0.7 ...millimeters per year. This rate is 10 times larger than that inferred from recent InSAR analyses (~1 ± 3 millimeters per year) that span ~8 years and sample all branches of the fault. The difference in slip-rate determinations suggests that large rate fluctuations may exist over centennial or millennial time scales. Such fluctuations would be consistent with mechanical coupling between the seismogenic, brittle-creep, and ductile shear sections of faults that reach deep into the crust.
A bispecific antibody (BsAb) targeting the epidermal growth factor receptor (EGFR) and mesenchymal–epithelial transition factor (MET) pathways represents a novel approach to overcome resistance to ...targeted therapies in patients with non–small cell lung cancer. In this study, we sequentially screened a panel of BsAbs in a combinatorial approach to select the optimal bispecific molecule. The BsAbs were derived from different EGFR and MET parental monoclonal antibodies. Initially, molecules were screened for EGFR and MET binding on tumor cell lines and lack of agonistic activity toward MET. Hits were identified and further screened based on their potential to induce untoward cell proliferation and cross-phosphorylation of EGFR by MET via receptor colocalization in the absence of ligand. After the final step, we selected the EGFR and MET arms for the lead BsAb and added low fucose Fc engineering to generate amivantamab (JNJ-61186372). The crystal structure of the anti-MET Fab of amivantamab bound to MET was solved, and the interaction between the two molecules in atomic details was elucidated. Amivantamab antagonized the hepatocyte growth factor (HGF)-induced signaling by binding to MET Sema domain and thereby blocking HGF β-chain—Sema engagement. The amivantamab EGFR epitope was mapped to EGFR domain III and residues K443, K465, I467, and S468. Furthermore, amivantamab showed superior antitumor activity over small molecule EGFR and MET inhibitors in the HCC827-HGF in vivo model. Based on its unique mode of action, amivantamab may provide benefit to patients with malignancies associated with aberrant EGFR and MET signaling.
Thrusting implication in the crustal thickening history of eastern Tibet is highly debated. The ∼250 km‐long Muli thrust of the Yalong thrust belt in SE Tibet is a major Miocene structure with a ...pronounced topographic step (∼2,000 m). Using thermo‐kinematic modeling based on thermochronology data, we constrain the crustal geometry of the thrust as being steep (>70°) at the surface, in agreement with field observations, and flattening at depth (≥20 km) on an intra‐crustal décollement. Thrusting motion on the fault shows a velocity of 0.2 ± 0.06 km/Ma since 50 Ma, followed by an acceleration at a rate of 0.6 ± 0.08 km/Ma starting at 12.5 ± 1 Ma, yielding a total of ∼15 km of exhumed crust. Deeper, deformation may be localized through a ductile shear zone, and be related to the ∼15 km Moho step and shear wave velocity contrast imaged by tomography beneath the Yalong thrust belt.
Plain Language Summary
The India‐Eurasia collision (∼50 million years ago Ma) led to the formation of the Tibetan Plateau, the world's largest and highest orogenic plateau. The formation and evolution of such a unique geological feature has been one of the main controversies in Earth Sciences for decades, especially regarding the role of faulting in the thickening of the crust. Here, we present 3D thermo‐kinematic models of thermochronology data allowing to constrain the exhumation history of the Muli thrust fault, a ∼250 km‐long major structure of the SE Tibetan margin, linked to significant steps in surface topography and in crustal boundary at depth (Moho). We constrain a steep fault (>70°) within the upper crust, consistent with field observations, that flattens at depth (≥20 km). The Muli thrust presents rapid thrusting motion (0.6 ± 0.08 km/Ma) that initiated at ∼12.5 Ma, following a slower phase (0.2 ± 0.06 km/Ma) since 50 Ma, with total rock exhumation of ∼15 km. This underlines the important role of thrust faulting in the thickening of the SE Tibetan crust.
Key Points
Thermo‐kinematic modeling of Muli thrust, a major thrust fault of SE Tibetan Plateau
15 km crust exhumation in 50 Ma on a high‐angle (>70°) ramp—décollement fault linked to thickening of SE Tibetan crust
Fault related to significant Moho step and shear wave velocity contrast in deep crust suggests entire crust implication
The presence of ~NS‐trending rifts within the Tibetan Plateau attests that it is undergoing ~EW extension. In southern Tibet, the total extension rate, distributed across seven main rifts over a ...distance of ~1,000 km, has been inferred to amount to about half of the shortening rate across the Himalayas. Quantifying the late Quaternary extension rates across the largest rift (Yadong‐Gulu rift YGR) is important to understand Tibetan deformation and to discuss the high plateau evolution during the later stages of continental collision. We performed 10Be surface‐exposure cosmogenic nuclide dating of 57 samples from three fluvial surfaces and two moraines that are vertically offset by the normal faults bounding the northern YGR. After carefully assessing individual ages at each site, to elucidate scatter in the age distributions, we obtained ~EW extension rates of up to 3–6 mm/yr near the northern end of the rift (Gulu) and of only 1.3 ± 0.3 mm/yr in the south (Yangbajing). The fast rates in the north may be influenced by dextral slip along the Beng Co fault, whose rate ought to be at least 6.0 ± 1.8 mm/yr. The total late Quaternary extension rate of 9 ± 2 mm/yr we infer across southern Tibet between ~81°E and 92°E, assuming similar rates across each rift, is similar to earlier, qualitative inferences and consistent with recent geodetic results. Distinct deformation rates north and south of the Bangong‐Nujiang suture may reflect significant differences between the extensional kinematics and mechanisms across the Qiangtang and Lhasa blocks.
Key Points
Extension rates along Yadong‐Gulu rift decrease from north (3–6 mm/yr) to south (~1.3 mm/yr) due to Beng Co dextral faulting
The post‐250 ka extension rate across the ~1,000 km stretch of South Tibet north of Nepal is 9 ± 2 mm/yr, consistent with geodetic rates
The causes and mechanisms of eastward extension south and north of the Bangong‐Nujiang suture are different
Little is known about the genotypic make-up of HIV-1 DNA genomes during the earliest stages of HIV-1 infection. Here, we use near-full-length, single genome next-generation sequencing to ...longitudinally genotype and quantify subtype C HIV-1 DNA in four women identified during acute HIV-1 infection in Durban, South Africa, through twice-weekly screening of high-risk participants. In contrast to chronically HIV-1-infected patients, we found that at the earliest phases of infection in these four participants, the majority of viral DNA genomes are intact, lack APOBEC-3G/F-associated hypermutations, have limited genome truncations, and over one year show little indication of cytotoxic T cell-driven immune selections. Viral sequence divergence during acute infection is predominantly fueled by single-base substitutions and is limited by treatment initiation during the earliest stages of disease. Our observations provide rare longitudinal insights of HIV-1 DNA sequence profiles during the first year of infection to inform future HIV cure research.
It has been well documented that IQ scores calculated using Canadian norms are generally 2-5 points lower than those calculated using American norms on the Wechsler IQ scales. However, recent ...findings have demonstrated that the difference may be significantly larger for individuals with certain demographic characteristics, and this has prompted discussion about the appropriateness of using the Canadian normative system with a clinical population in Canada. This study compared the interpretive effects of applying the American and Canadian normative systems in a clinical sample. We used a multivariate analysis of variance (ANOVA) to calculate differences between IQ and Index scores in a clinical sample, and mixed model ANOVAs to assess the pattern of differences across age and ability level. As expected, Full Scale IQ scores calculated using Canadian norms were systematically lower than those calculated using American norms, but differences were significantly larger for individuals classified as having extremely low or borderline intellectual functioning when compared with those who scored in the average range. Implications of clinically different conclusions for up to 52.8% of patients based on these discrepancies highlight a unique dilemma facing Canadian clinicians, and underscore the need for caution when choosing a normative system with which to interpret WAIS-IV results in the context of a neuropsychological test battery in Canada. Based on these findings, we offer guidelines for best practice for Canadian clinicians when interpreting data from neuropsychological test batteries that include different normative systems, and suggestions to assist with future test development.
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