Probing the core of the strong nuclear interaction.

The strong nuclear interaction between nucleons (protons and neutrons) is the effective force that holds the atomic nucleus together. This force stems from fundamental interactions between quarks and gluons (the constituents of nucleons) that are described by the equations of quantum chromodynamics. However, as these equations cannot be solved directly, nuclear interactions are described using simplified models, which are well constrained at typical inter-nucleon distances1-5 but not at shorter distances. This limits our ability to describe high-density nuclear matter such as that in the cores of neutron stars6. Here we use high-energy electron scattering measurements that isolate nucleon pairs in short-distance, high-momentum configurations7-9, accessing a kinematical regime that has not been previously explored by experiments, corresponding to relative momenta between the pair above 400 megaelectronvolts per c (c, speed of light in vacuum). As the relative momentum between two nucleons increases and their separation thereby decreases, we observe a transition from a spin-dependent tensor force to a predominantly spin-independent scalar force. These results demonstrate the usefulness of using such measurements to study the nuclear interaction at short distances and also support the use of point-like nucleon models with two- and three-body effective interactions to describe nuclear systems up to densities several times higher than the central density of the nucleus.

Preindustrial 14CH4 indicates greater anthropogenic fossil CH4 emissions.

Atmospheric methane (CH4) is a potent greenhouse gas, and its mole fraction has more than doubled since the preindustrial era1. Fossil fuel extraction and use are among the largest anthropogenic sources of CH4 emissions, but the precise magnitude of these contributions is a subject of debate2,3. Carbon-14 in CH4 (14CH4) can be used to distinguish between fossil (14C-free) CH4 emissions and contemporaneous biogenic sources; however, poorly constrained direct 14CH4 emissions from nuclear reactors have complicated this approach since the middle of the 20th century4,5. Moreover, the partitioning of total fossil CH4 emissions (presently 172 to 195 teragrams CH4 per year)2,3 between anthropogenic and natural geological sources (such as seeps and mud volcanoes) is under debate; emission inventories suggest that the latter account for about 40 to 60 teragrams CH4 per year6,7. Geological emissions were less than 15.4 teragrams CH4 per year at the end of the Pleistocene, about 11,600 years ago8, but that period is an imperfect analogue for present-day emissions owing to the large terrestrial ice sheet cover, lower sea level and extensive permafrost. Here we use preindustrial-era ice core 14CH4 measurements to show that natural geological CH4 emissions to the atmosphere were about 1.6 teragrams CH4 per year, with a maximum of 5.4 teragrams CH4 per year (95 per cent confidence limit)-an order of magnitude lower than the currently used estimates. This result indicates that anthropogenic fossil CH4 emissions are underestimated by about 38 to 58 teragrams CH4 per year, or about 25 to 40 per cent of recent estimates. Our record highlights the human impact on the atmosphere and climate, provides a firm target for inventories of the global CH4 budget, and will help to inform strategies for targeted emission reductions9,10.

Increase in CFC-11 emissions from eastern China based on atmospheric observations.

The recovery of the stratospheric ozone layer relies on the continued decline in the atmospheric concentrations of ozone-depleting gases such as chlorofluorocarbons1. The atmospheric concentration of trichlorofluoromethane (CFC-11), the second-most abundant chlorofluorocarbon, has declined substantially since the mid-1990s2. A recently reported slowdown in the decline of the atmospheric concentration of CFC-11 after 2012, however, suggests that global emissions have increased3,4. A concurrent increase in CFC-11 emissions from eastern Asia contributes to the global emission increase, but the location and magnitude of this regional source are unknown3. Here, using high-frequency atmospheric observations from Gosan, South Korea, and Hateruma, Japan, together with global monitoring data and atmospheric chemical transport model simulations, we investigate regional CFC-11 emissions from eastern Asia. We show that emissions from eastern mainland China are 7.0 ± 3.0 (±1 standard deviation) gigagrams per year higher in 2014-2017 than in 2008-2012, and that the increase in emissions arises primarily around the northeastern provinces of Shandong and Hebei. This increase accounts for a substantial fraction (at least 40 to 60 per cent) of the global rise in CFC-11 emissions. We find no evidence for a significant increase in CFC-11 emissions from any other eastern Asian countries or other regions of the world where there are available data for the detection of regional emissions. The attribution of any remaining fraction of the global CFC-11 emission rise to other regions is limited by the sparsity of long-term measurements of sufficient frequency near potentially emissive regions. Several considerations suggest that the increase in CFC-11 emissions from eastern mainland China is likely to be the result of new production and use, which is inconsistent with the Montreal Protocol agreement to phase out global chlorofluorocarbon production by 2010.

Relative free-energy calculations for scaffold hopping-type transformations with an automated RE-EDS sampling procedure.

The calculation of relative free-energy differences between different compounds plays an important role in drug design to identify potent binders for a given protein target. Most rigorous methods based on molecular dynamics simulations estimate the free-energy difference between pairs of ligands. Thus, the comparison of multiple ligands requires the construction of a "state graph", in which the compounds are connected by alchemical transformations. The computational cost can be optimized by reducing the state graph to a minimal set of transformations. However, this may require individual adaptation of the sampling strategy if a transformation process does not converge in a given simulation time. In contrast, path-free methods like replica-exchange enveloping distribution sampling (RE-EDS) allow the sampling of multiple states within a single simulation without the pre-definition of alchemical transition paths. To optimize sampling and convergence, a set of RE-EDS parameters needs to be estimated in a pre-processing step. Here, we present an automated procedure for this step that determines all required parameters, improving the robustness and ease of use of the methodology. To illustrate the performance, the relative binding free energies are calculated for a series of checkpoint kinase 1 inhibitors containing challenging transformations in ring size, opening/closing, and extension, which reflect changes observed in scaffold hopping. The simulation of such transformations with RE-EDS can be conducted with conventional force fields and, in particular, without soft bond-stretching terms.

Variational implicit-solvent predictions of the dry-wet transition pathways for ligand-receptor binding and unbinding kinetics.

Ligand-receptor binding and unbinding are fundamental biomolecular processes and particularly essential to drug efficacy. Environmental water fluctuations, however, impact the corresponding thermodynamics and kinetics and thereby challenge theoretical descriptions. Here, we devise a holistic, implicit-solvent, multimethod approach to predict the (un)binding kinetics for a generic ligand-pocket model. We use the variational implicit-solvent model (VISM) to calculate the solute-solvent interfacial structures and the corresponding free energies, and combine the VISM with the string method to obtain the minimum energy paths and transition states between the various metastable ("dry" and "wet") hydration states. The resulting dry-wet transition rates are then used in a spatially dependent multistate continuous-time Markov chain Brownian dynamics simulation and the related Fokker-Planck equation calculations of the ligand stochastic motion, providing the mean first-passage times for binding and unbinding. We find the hydration transitions to significantly slow down the binding process, in semiquantitative agreement with existing explicit-water simulations, but significantly accelerate the unbinding process. Moreover, our methods allow the characterization of nonequilibrium hydration states of pocket and ligand during the ligand movement, for which we find substantial memory and hysteresis effects for binding vs. unbinding. Our study thus provides a significant step forward toward efficient, physics-based interpretation and predictions of the complex kinetics in realistic ligand-receptor systems.

Post-operative hearing among patients with labyrinthine fistula as a complication of cholesteatoma using "under water technique".

INTRODUCTION: During surgery in patients with labyrinthine fistula the mandatory complete removal of the cholesteatoma while preserving inner ear and vestibular function is a challenge. Options so far have been either the complete removal of the cholesteatoma or leaving the matrix on the fistula. We evaluated an alternative "under water" surgical technique for complete cholesteatoma resection, in terms of preservation of postoperative inner ear and vestibular function. METHODS: From 2013 to 2019, 20 patients with labyrinthine fistula due to cholesteatoma were operated. We used the canal wall down approach and removal of matrix on the fistula was done as the last step during surgery using the "under water technique". The pre and postoperative hearing tests and the vestibular function were retrospectively examined. RESULTS: There was no significant difference between pre and post-operative bone conduction thresholds; 20% experienced an improvement of more than 10 dB, with none experiencing a postoperative worsening of sensorineural hearing loss. Among seven patients who presented with vertigo, two had transient vertigo postoperatively but eventually recovered. CONCLUSION: Our data show that the "under water technique" for cholesteatoma removal at the labyrinthine fistula is a viable option in the preservation of inner ear function and facilitating complete cholesteatoma removal.

Differential effects of abaloparatide and teriparatide on hip cortical volumetric BMD by DXA-based 3D modeling.

In postmenopausal osteoporotic women in ACTIVE, abaloparatide reduced fracture risk and increased areal bone mineral density (BMD) more than teriparatide at the hip and wrist. DXA-based 3D modeling showed significantly greater increases in hip cortical volumetric BMD with abaloparatide versus teriparatide. This may explain differences reported in aBMD by DXA. INTRODUCTION: In ACTIVE, abaloparatide (ABL) increased bone mineral density (BMD) shown by dual-energy X-ray absorptiometry (DXA) while reducing fracture incidence in postmenopausal osteoporotic women. Changes in DXA BMD with ABL, 80 µg, were significantly greater than with open-label teriparatide (TPTD), 20 µg, at cortical sites including total hip, femoral neck, and 1/3 distal radius. The purpose of this study was to better understand the relative effects of ABL and TPTD on cortical and cancellous compartments in the proximal femur. METHODS: Hip DXA images from a subset of randomly selected patients in the ACTIVE trial (n = 250/arm) were retrospectively analyzed using three-dimensional modeling methods (3D-SHAPER software) to evaluate changes from baseline at months 6 and 18. RESULTS: Similar significant increases in trabecular volumetric BMD (vBMD, + 9%) and cortical thickness (+ 1.5%) were observed with ABL and TPTD by 3D-DXA at 18 months. In contrast, only ABL significantly increased cortical vBMD versus baseline (+ 1.3%), and changes in both cortical vBMD and cortical surface BMD were significantly greater with ABL versus TPTD. In the TPTD group, changes in cortical vBMD were inversely correlated with changes in serum CTX (carboxy-terminal telopeptide of type I collagen) and PINP (procollagen type I N-terminal propeptide), suggesting that higher bone turnover may have attenuated cortical gains. CONCLUSION: These results suggest previously reported differences in areal BMD increases between ABL and TPTD may be due to differential effects on cortical vBMD. Further studies are warranted to investigate how these differences affect therapeutic impact on hip strength in postmenopausal women with osteoporosis.

Volume-scaled common nearest neighbor clustering algorithm with free-energy hierarchy.

The combination of Markov state modeling (MSM) and molecular dynamics (MD) simulations has been shown in recent years to be a valuable approach to unravel the slow processes of molecular systems with increasing complexity. While the algorithms for intermediate steps in the MSM workflow such as featurization and dimensionality reduction have been specifically adapted to MD datasets, conventional clustering methods are generally applied to the discretization step. This work adds to recent efforts to develop specialized density-based clustering algorithms for the Boltzmann-weighted data from MD simulations. We introduce the volume-scaled common nearest neighbor (vs-CNN) clustering that is an adapted version of the common nearest neighbor (CNN) algorithm. A major advantage of the proposed algorithm is that the introduced density-based criterion directly links to a free-energy notion via Boltzmann inversion. Such a free-energy perspective allows a straightforward hierarchical scheme to identify conformational clusters at different levels of a generally rugged free-energy landscape of complex molecular systems.

Audiological benefit and subjective satisfaction with the ADHEAR hearing system in children with unilateral conductive hearing loss.

OBJECTIVE: The ADHEAR system (MED-EL, Innsbruck, Austria) is a new adhesive bone conduction hearing aid. This study evaluates the audiological benefit and subjective satisfaction as well as the manageability in everyday life in children with unilateral conductive hearing loss. METHODS: Ten children with unilateral hearing loss of different origin were included in the study. The audiological assessment included sound field audiometry and speech intelligibility in quiet and in noise, which was tested unaided and after 4 weeks of wearing the hearing system. Subjective benefit and satisfaction with the system was assessed using the SSQ for parents. With a second system-specific questionnaire, suitability for everyday use and quality of life were queried. RESULTS: With ADHEAR, speech perception in quiet improved by 44%. The word recognition score in noise improved from 11.7% in the unaided situation to 46.7% with the ADHEAR system. The SSQ for parents demonstrates a subjective benefit and satisfaction with the system. CONCLUSION: ADHEAR is an effective treatment option for children with unilateral conductive hearing loss. Especially children who are not eligible for semi-implantable hearing systems or do not accept hearing devices on a softband can benefit from this device.

[Development of the publication activity at the German university hospitals for Otorhinolaryngology, Head and Neck Surgery during the SARS-CoV-2-pandemic in 2020]. / Entwicklung der Publikationsleistung der Universitätskliniken für Hals-Nasen-Ohrenheilkunde, Kopf- und Hals-Chirurgie während der SARS-CoV-2-Pandemie im Jahr 2020 in Deutschland.

INTRODUCTION: The SARS-CoV-2 pandemic has led to profound limitations in patient care and student teaching at the University Hospitals of Otorhinolaryngology (ORL). In contrast, the impact on research has been variable. To classify the pandemic-related effect on research, the development of the number of scientific publications of the German ORL university hospitals before and during the pandemic was analyzed. MATERIAL AND METHODS: The publication performance between 2015 and 2020 of the 39 current chairmen was surveyed using a literature search (Pubmed). All entries relating to the chairmen of the university hospital as first, last or co-author were included. The absolute and relative development of each author's publication performance was determined and evaluated using nonparametric statistical methods. RESULTS: A total of 2420 publications could be documented. From 2015 to 2019, an average of 368 publications were published per year. In 2020, this number increased by 57.9 % to 581 publications. While the number of monthly publications remained constant between 2015 and 2019, a significant increase was seen from May 2020 up to a maximum of 74 publications in September 2020. In 2020, 34 articles (5.9 %) had a thematic relation to the SARS-CoV-2 pandemic, with 7 of these papers (20.6 %) resulting from cross-site publications. CONCLUSION: In 2020, the number of scientific publications was raised to more than 1.5 times the usual annual publications. This increase was clearly related in time to the reduction of elective patient care during the SARS-CoV-2 pandemic starting in mid-March 2020. Probably, free time capacities enabled this increased publication output. Our results confirm the great scientific potential of the ORL university hospitals, which has been successfully implemented despite the pandemic.

Characterizing patients initiating abaloparatide, teriparatide, or denosumab in a real-world setting: a US linked claims and EMR database analysis.

We characterized patients initiating abaloparatide (ABL), teriparatide (TPTD), or denosumab (DMAB) in a real-world clinical setting from a large medical and pharmacy claims database. Differences were noted in sex, age, pathologic fractures, comorbidity index, and prior bisphosphonate use for patients initiating ABL and TPTD compared with those receiving DMAB. INTRODUCTION: To characterize patients initiating abaloparatide (ABL), teriparatide (TPTD), or denosumab (DMAB) treatment in a real-world clinical setting. METHODS: Patients aged ≥ 18 years initiating ABL, TPTD, or DMAB between May 1, 2017, and September 24, 2018 (without receiving the same drug in the previous 12 months), were identified using the OM1 Data Cloud, which contains medical and pharmacy claims from approximately 200 million US patients. The index date was the date of initial prescription or dispensing for ABL, TPTD, or DMAB during the study period. RESULTS: During the study period, 2666 patients initiated ABL, 9210 TPTD, and 116,718 DMAB. Mean age (standard deviation) was 69.2 (10.6) years for the ABL cohort, 68.6 (11.3) for TPTD, and 72.1 (10.2) for DMAB (P < 0.001; ABL vs DMAB). Proportionally more patients initiating ABL were female (95.2% ABL, 86.9% TPTD, and 91.3% DMAB, P < 0.001 ABL vs TPTD or DMAB). Nearly twice as many patients initiating ABL (19.1%) and TPTD (18.8%) had a previous pathologic/fragility fracture vs DMAB (9.6%; P < 0.001 ABL vs DMAB). Fewer patients initiating ABL (36.3%) or TPTD (39.7%) had Charlson comorbidity index of ≥ 2 vs DMAB (48.4%; P < 0.001 ABL vs DMAB). Before initiating ABL, TPTD, or DMAB, 44.3%, 33.8%, and 33.9% of patients had prior osteoporosis treatment, respectively. Bisphosphonate use was more common before initiating ABL (19.2%) or TPTD (19.6%), than before initiating DMAB (16.6%; P < 0.001 ABL vs DMAB). CONCLUSIONS: Patients initiating ABL and TPTD differed in sex, age, pathologic fractures, comorbidity index, and prior bisphosphonate use compared with those initiating DMAB.

Osteoporotic fracture trends in a population of US managed care enrollees from 2007 to 2017.

This study expands on previous findings that hip fracture rates may no longer be declining. We found that age- and sex-adjusted fracture rates in the US plateaued or increased through mid-2017 in a population of commercially insured and Medicare Advantage health plan enrollees, in contrast to a decline from 2007 to 2013. INTRODUCTION: The purpose of this study was to evaluate fracture trends in US commercial and Medicare Advantage health plan members aged ≥ 50 years between 2007 and 2017. METHODS: Retrospective analysis of the Optum Research Database from January 1, 2007, to May 31, 2017. RESULTS: Of 1,841,263 patients identified with an index fracture, 930,690 were case-qualifying and included in this analysis. The overall age- and sex-adjusted fracture rate decreased from 14.67/1000 person-years (py) in 2007 to 11.79/1000 py in 2013, followed by a plateau for the next 3 years and then an increase to 12.50/1000 py in mid-2017. In females aged ≥ 65 years, fracture rates declined from 27.49/1000 py in 2007 to 22.08/1000 py in 2013, then increased to 24.92/1000 py in mid-2017. Likewise, fracture rates in males aged ≥ 65 years declined from 2007 (12.00/1000 py) to 2013 (10.72/1000 py), then increased to 12.04/1000 py in mid-2017. The age- and sex-adjusted fracture rates for most fracture sites declined from 2007 to 2013 by 3.7% per year (P = 0.310). CONCLUSIONS: Following a consistent decline in fracture rate from 2007 to 2013, trends from 2014 to 2017 indicate fracture rates are no longer declining and, for some fracture types, rates are rising.

Observational evidence for interhemispheric hydroxyl-radical parity.

The hydroxyl radical (OH) is a key oxidant involved in the removal of air pollutants and greenhouse gases from the atmosphere. The ratio of Northern Hemispheric to Southern Hemispheric (NH/SH) OH concentration is important for our understanding of emission estimates of atmospheric species such as nitrogen oxides and methane. It remains poorly constrained, however, with a range of estimates from 0.85 to 1.4 (refs 4, 7-10). Here we determine the NH/SH ratio of OH with the help of methyl chloroform data (a proxy for OH concentrations) and an atmospheric transport model that accurately describes interhemispheric transport and modelled emissions. We find that for the years 2004-2011 the model predicts an annual mean NH-SH gradient of methyl chloroform that is a tight linear function of the modelled NH/SH ratio in annual mean OH. We estimate a NH/SH OH ratio of 0.97 ± 0.12 during this time period by optimizing global total emissions and mean OH abundance to fit methyl chloroform data from two surface-measurement networks and aircraft campaigns. Our findings suggest that top-down emission estimates of reactive species such as nitrogen oxides in key emitting countries in the NH that are based on a NH/SH OH ratio larger than 1 may be overestimated.

Connecting dynamic reweighting Algorithms: Derivation of the dynamic reweighting family tree.

Thermally driven processes of molecular systems include transitions of energy barriers on the microsecond timescales and higher. Sufficient sampling of such processes with molecular dynamics simulations is challenging and often requires accelerating slow transitions using external biasing potentials. Different dynamic reweighting algorithms have been proposed in the past few years to recover the unbiased kinetics from biased systems. However, it remains an open question if and how these dynamic reweighting approaches are connected. In this work, we establish the link between the two main reweighting types, i.e., path-based and energy-based reweighting. We derive a path-based correction factor for the energy-based dynamic histogram analysis method, thus connecting the previously separate reweighting types. We show that the correction factor can be used to combine the advantages of path-based and energy-based reweighting algorithms: it is integrator independent, more robust, and at the same time able to reweight time-dependent biases. We can furthermore demonstrate the relationship between two independently derived path-based reweighting algorithms. Our theoretical findings are verified on a one-dimensional four-well system. By connecting different dynamic reweighting algorithms, this work helps to clarify the strengths and limitations of the different methods and enables a more robust usage of the combined types.

Direct Observation of Proton-Neutron Short-Range Correlation Dominance in Heavy Nuclei.

We measured the triple coincidence A(e,e^{'}np) and A(e,e^{'}pp) reactions on carbon, aluminum, iron, and lead targets at Q^{2}>1.5 (GeV/c)^{2}, x_{B}>1.1 and missing momentum >400 MeV/c. This was the first direct measurement of both proton-proton (pp) and neutron-proton (np) short-range correlated (SRC) pair knockout from heavy asymmetric nuclei. For all measured nuclei, the average proton-proton (pp) to neutron-proton (np) reduced cross-section ratio is about 6%, in agreement with previous indirect measurements. Correcting for single-charge exchange effects decreased the SRC pairs ratio to ∼3%, which is lower than previous results. Comparisons to theoretical generalized contact formalism (GCF) cross-section calculations show good agreement using both phenomenological and chiral nucleon-nucleon potentials, favoring a lower pp to np pair ratio. The ability of the GCF calculation to describe the experimental data using either phenomenological or chiral potentials suggests possible reduction of scale and scheme dependence in cross-section ratios. Our results also support the high-resolution description of high-momentum states being predominantly due to nucleons in SRC pairs.

Strain rate dependent nanostructure of hydrogels with reversible hydrophobic associations during uniaxial extension.

An energy dissipation mechanism during deformation is required to impart toughness to hydrogels. Here we describe how in situ small angle X-ray scattering (SAXS) provides insight into possible energy dissipation mechanisms for a tough hydrogel based on an amphiphilic copolymer where nanoscale associations of the hydrophobic moieties act as effective crosslinks. The mechanical properties of the hydrogels are intimately coupled with the nanostructure that provides reversible crosslinks and evolves during deformation. As the extension rate increases, more mechanical energy is dissipated from rearrangements of the crosslinks. The scattering is consistent with hopping of hydrophobes between the nanoscale aggregates as the primary rearrangement mechanism. This rearrangement changes the network conformation that leads to non-affine deformation, where the change in the nanostructure dimension from SAXS is less than 15% of the total macroscopic strain. These nanostructure changes are rate dependent and correlated with the relaxation time of the hydrogel. At low strain rate (0.15% s-1), no significant change of the nanostructure was observed, whereas at higher strain rates (1.5% s-1 and 8.4% s-1) significant nanostructure anisotropy occurred during extension. These differences are attributed to the ability for the network chains to rearrange on the time scale of the deformation; when the characteristic time for extension is longer than the average segmental relaxation time, no significant change in nanostructure occurs on uniaxial extension. These results illustrate the importance of strain rate in the mechanical characterization and consideration of relaxation time in the design of tough hydrogels with reversible crosslinks.

Quantitative Rheometry of Thin Soft Materials Using the Quartz Crystal Microbalance with Dissipation.

In the inertial limit, the resonance frequency of the quartz crystal microbalance (QCM) is related to the coupled mass on the quartz sensor through the Sauerbrey expression that relates the mass to the change in resonance frequency. However, when the thickness of the film is sufficiently large, the relationship becomes more complicated and both the frequency and damping of the crystal resonance must be considered. In this regime, a rheological model of the material must be used to accurately extract the adhered film's thickness, shear modulus, and viscoelastic phase angle from the data. In the present work we examine the suitability of two viscoelastic models, a simple Voigt model ( Physica Scripta 1999, 59, 391-396) and a more realistic power-law model ( Langmuir 2015, 31, 4008-4017), to extract the rheological properties of a thermoresponsive hydrogel film. By changing temperature and initial dry film thickness of the gel, the operation of QCM was traversed from the Sauerbrey limit, where viscous losses do not impact the frequency, through the regime where the QCM response is sensitive to viscoelastic properties. The density-shear modulus and the viscoelastic phase angle from the two models are in good agreement when the shear wavelength ratio, d/λ n, is in the range of 0.05-0.20, where d is the film thickness and λ n is the wavelength of the mechanical shear wave at the nth harmonic. We further provide a framework for estimating the physical properties of soft materials in the megahertz regime by using the physical behavior of polyelectrolyte complexes. This provides the user with an approximate range of allowable film thicknesses for accurate viscoelastic analysis with either model, thus enabling better use of the QCM-D in soft materials research.

A novel mutation in the TG gene (G2322S) causing congenital hypothyroidism in a Sudanese family: a case report.

BACKGROUND: Congenital hypothyroidism (CH) has an incidence of approximately 1:3000, but only 15% have mutations in the thyroid hormone synthesis pathways. Genetic analysis allows for the precise diagnosis. CASE PRESENTATION: A 3-week old girl presented with a large goiter, serum TSH > 100 mIU/L (reference range: 0.7-5.9 mIU/L); free T4 < 3.2 pmol/L (reference range: 8.7-16 pmol/L); thyroglobulin (TG) 101 µg/L. Thyroid Tc-99 m scan showed increased radiotracer uptake. One brother had CH and both affected siblings have been clinically and biochemically euthyroid on levothyroxine replacement. Another sibling had normal thyroid function. Both Sudanese parents reported non-consanguinity. Peripheral blood DNA from the proposita was subjected to whole exome sequencing (WES). WES identified a novel homozygous missense mutation of the TG gene: c.7021G > A, p.Gly2322Ser, which was subsequently confirmed by Sanger sequencing and present in one allele of both parents. DNA samples from 354 alleles in four Sudanese ethnic groups (Nilotes, Darfurians, Nuba, and Halfawien) failed to demonstrate the presence of the mutant allele. Haplotyping showed a 1.71 centiMorgans stretch of homozygosity in the TG locus suggesting that this mutation occurred identical by descent and the possibility of common ancestry of the parents. The mutation is located in the cholinesterase-like (ChEL) domain of TG. CONCLUSIONS: A novel rare missense mutation in the TG gene was identified. The ChEL domain is critical for protein folding and patients with CH due to misfolded TG may present without low serum TG despite the TG gene mutations.

Continued Emissions of the Ozone-Depleting Substance Carbon Tetrachloride From Eastern Asia.

Carbon tetrachloride (CCl4) is an ozone-depleting substance, accounting for about 10% of the chlorine in the troposphere. Under the terms of the Montreal Protocol, its production for dispersive uses was banned from 2010. In this work we show that, despite the controls on production being introduced, CCl4 emissions from the eastern part of China did not decline between 2009 and 2016. This finding is in contrast to a recent bottom-up estimate, which predicted a significant decrease in emissions after the introduction of production controls. We find eastern Asian emissions of CCl4 to be 16 (9-24) Gg/year on average between 2009 and 2016, with the primary source regions being in eastern China. The spatial distribution of emissions that we derive suggests that the source distribution of CCl4 in China changed during the 8-year study period, indicating a new source or sources of emissions from China's Shandong province after 2012.

Affinity, kinetics, and pathways of anisotropic ligands binding to hydrophobic model pockets.

Using explicit-water molecular dynamics simulations of a generic pocket-ligand model, we investigate how chemical and shape anisotropy of small ligands influences the affinities, kinetic rates, and pathways for their association with hydrophobic binding sites. In particular, we investigate aromatic compounds, all of similar molecular size, but distinct by various hydrophilic or hydrophobic residues. We demonstrate that the most hydrophobic sections are in general desolvated primarily upon binding to the cavity, suggesting that specific hydration of the different chemical units can steer the orientation pathways via a "hydrophobic torque." Moreover, we find that ligands with bimodal orientation fluctuations have significantly increased kinetic barriers for binding compared to the kinetic barriers previously observed for spherical ligands due to translational fluctuations. We exemplify that these kinetic barriers, which are ligand specific, impact both binding and unbinding times for which we observe considerable differences between our studied ligands.