Extension Of Domain Research Articles

Extension domain of amyloid processor protein inhibits amyloidogenic cleavage and balances neural activity in a traumatic brain injury mouse model.

Mechanisms underlying cognitive dysfunction following traumatic brain injury (TBI) partially due to abnormal amyloid processor protein (APP) cleavage and neural hyperactivity. Binding of the extension domain of APP (ExD17) to the GABAbR1 receptor results in reduced neural activity, which might play a role in the mechanisms of cognitive dysfunction caused by TBI. Stretch-induced injury was utilized to establish a cell injury model in HT22 cells. The TBI model was created by striking the exposed brain tissue with a free-falling weight. Topical or intraperitoneal administration of ExD17 was performed. Cell viability was assessed through a cell counting kit-8 assay, while intracellular Ca2+ was measured using Fluo-4. Western blotting was used to investigate the expression of APP amyloidogenic cleavage proteins, GABAbR1, phospholipase C (PLC), PLCB3, and synaptic proteins. ELISA was performed to analyze the levels of Aβ42. Seizures were assessed using electroencephalography (EEG). Behaviors were evaluated through the novel object recognition test, open field test, elevated plus maze test, and nest-building test. ExD17 improved cell viability and reduced intracellular calcium in the cell injury model. The treatment also suppressed the increased expression of APP amyloidogenic cleavage proteins and Aβ42 in both cell injury and TBI models. ExD17 treatment reversed the abnormal expression of GABAbR1, GRIA2, p-PLCG1/PLCG1 ratio, and p-PLCB3/PLCB3 ratio. In addition, ExD17 treatment reduced neural activity, seizure events, and their duration in TBI. Intraperitoneal injection of ExD17 improved behavioral outcomes in the TBI mouse model. ExD17 treatment results in a reduction of amyloidogenic APP cleavage and neuroexcitotoxicity, ultimately leading to an improvement in the behavioral deficits observed in TBI mice.

Extracellular proteases from halophiles: diversity and application challenges.

Halophilic extracellular proteases offer promising application in various fields. Information on these prominent proteins including the synthesizing organisms, biochemical properties, domain organisation, purification, and application challenges has never been covered in recent reviews. Although extracellular proteases from bacteria pioneered the study of proteases in halophiles, progress is being made in proteases from halophilic archaea. Recent advances in extracellular proteases from archaea revealed that archaeal proteases are more robust and applicable. Extracellular proteases are composed of domains that determine their mechanisms of action. The intriguing domain structure of halophilic extracellular proteases consists of N-terminal domain, catalytic domain, and C-terminal extension. The role of C-terminal domains varies among different organisms. A high diversity of C-terminal domains would endow the proteases with diverse functions. With the development of genomics, culture-independent methods involving heterologous expression, affinity chromatography, and in vitro refolding are deployed with few challenges on purification and presenting novel research opportunities. Halophilic extracellular proteases have demonstrated remarkable potentials in industries such as detergent, leather, peptide synthesis, and biodegradation, with desirable properties and ability to withstand harsh industrial processes. KEY POINTS: • Halophilic extracellular proteases have robust properties suitable for applications. • A high diversity of C-terminal domains may endow proteases with diverse properties. • Novel protease extraction methods present novel application opportunities.

Locally uniform domains and extension of bmo functions

We prove that for a domain \(\Omega\subset\mathbb{R}^n\), being \((\epsilon,\delta)\) in the sense of Jones is equivalent to being an extension domain for bmo, the nonhonomogeneous version of the space of functions of bounded mean oscillation on \(\Omega\). Such domains, which can be identified as local versions of uniform domains (defined by requiring the presence of length cigars between nearby points), allow a definition of bmo\((\Omega)\) in terms of "small" and "large" cubes contained in \(\Omega\), where the scale is closely tied to the geometry of the domain.

Learning to Extrapolate Using Continued Fractions: Predicting the Critical Temperature of Superconductor Materials

In the field of Artificial Intelligence (AI) and Machine Learning (ML), a common objective is the approximation of unknown target functions y=f(x) using limited instances S=(x(i),y(i)), where x(i)∈D and D represents the domain of interest. We refer to S as the training set and aim to identify a low-complexity mathematical model that can effectively approximate this target function for new instances x. Consequently, the model’s generalization ability is evaluated on a separate set T={x(j)}⊂D, where T≠S, frequently with T∩S=∅, to assess its performance beyond the training set. However, certain applications require accurate approximation not only within the original domain D but in an extended domain D′ that encompasses D as well. This becomes particularly relevant in scenarios involving the design of new structures, where minimizing errors in approximations is crucial. For example, when developing new materials through data-driven approaches, the AI/ML system can provide valuable insights to guide the design process by serving as a surrogate function. Consequently, the learned model can be employed to facilitate the design of new laboratory experiments. In this paper, we propose a method for multivariate regression based on iterative fitting of a continued fraction, incorporating additive spline models. We compare the performance of our method with established techniques, including AdaBoost, Kernel Ridge, Linear Regression, Lasso Lars, Linear Support Vector Regression, Multi-Layer Perceptrons, Random Forest, Stochastic Gradient Descent, and XGBoost. To evaluate these methods, we focus on an important problem in the field, namely, predicting the critical temperature of superconductors based on their physical–chemical characteristics.

Similarity-Driven Topology Optimization for Statics and Crash via Energy Scaling Method

Abstract Topology optimization (TO) is used in the initial design phase to optimize certain objective functions under given boundary conditions by finding suitable material distributions in a specified design domain. Currently available methods in the industry work very efficiently to get topologically optimized design concepts under static and dynamic load cases. However, conventional methods do not address the designer’s preferences about the final material layout in the optimized design. In practice, the final design might be required to have a certain degree of local or global structural similarity with an already present good reference design because of economic, manufacturing, and assembly limitations or the desire to re-use parts in different systems. In this article, a heuristic energy scaling method (ESM) for similarity-driven TO under static as well as dynamic loading conditions is presented and thoroughly evaluated. A 2D cantilever beam under static point load is used to show that the proposed method can be coupled with gradient-based and also heuristic, nongradient methods to get designs of varying similarity with respect to a reference design. Further testing of the proposed method for similarity-driven TO on a 2D crash test case and a large-scale 3D hood model of a car body indicates the effectiveness of the method for a wide range of problems in the industry. Finally, the application of similarity-driven TO is further extended to show that ESM also has the potential for sensitivity analysis of performance with respect to the extension of design domain.

The Gating Domain ofMEF28 Is Essential forEditing Two Contiguous Cytidines innad2 mRNA inArabidopsis thaliana.

In plant organelles, each C-to-U RNA-editing site is specifically recognized by pentatricopeptide repeat (PPR) proteins with E1-E2, E1-E2-E+ or E1-E2-DYW domain extensions at the C-terminus. The distance between the PPR domain-binding site and the RNA-editing site is usually fixed at four bases, increasing the specificity of target-site recognition in this system. We here report, in contrast to the general case, on MEF28, which edits two adjacent mitochondrial sites, nad2-89 and nad2-90. When the sDYW domain of MEF28 was replaced with one derived from MEF11 or CRR22, the ability to edit downstream sites was lost, suggesting that the DYW domain of MEF28 provides unique target flexibility for two continuous cytidines. By contrast, substitutions of the entire E1-E2-DYW domains by MEF19E1-E2, SLO2E1-E2-E+ or CRR22E1-E2-E+ target both nad2 sites. In these cases, access to the contiguous sites in the chimeric PPR proteins is likely to be provided by the trans-associated DYW1-like proteins via the replaced E1-E2 or E1-E2-E+ domains. Furthermore, we demonstrated that the gating domain of MEF28 plays an important role in specific target-site recognition of the DYW domain. This finding suggests that the DYW domain and its internal gating domain fine-tune the specificity of the target site, which is valuable information for designing specific synthetic RNA-editing tools based on plant RNA-editing factors.

Solution structure of the N-terminal extension domain of a Schistosoma japonicum asparaginyl-tRNA synthetase

Several secreted proteins from helminths (parasitic worms) have been shown to have immunomodulatory activities. Asparaginyl-tRNA synthetases are abundantly secreted in the filarial nematode Brugia malayi (BmAsnRS) and the parasitic flatworm Schistosoma japonicum (SjAsnRS), indicating a possible immune function. The suggestion is supported by BmAsnRS alleviating disease symptoms in a T-cell transfer mouse model of colitis. This immunomodulatory function is potentially related to an N-terminal extension domain present in eukaryotic AsnRS proteins but few structure/function studies have been done on this domain. Here we have determined the three-dimensional solution structure of the N-terminal extension domain of SjAsnRS. A protein containing the 114 N-terminal amino acids of SjAsnRS was recombinantly expressed with isotopic labelling to allow structure determination using 3D NMR spectroscopy, and analysis of dynamics using NMR relaxation experiments. Structural comparisons of the N-terminal extension domain of SjAsnRS with filarial and human homologues highlight a high degree of variability in the β-hairpin region of these eukaryotic N-AsnRS proteins, but similarities in the disorder of the C-terminal regions. Limitations in PrDOS-based intrinsically disordered region (IDR) model predictions were also evident in this comparison. Empirical structural data such as that presented in our study for N-SjAsnRS will enhance the prediction of sequence-homology based structure modelling and prediction of IDRs in the future. Communicated by Ramaswamy H. Sarma

End-to-end Procedural Material Capture with Proxy-Free Mixed-Integer Optimization

Node-graph-based procedural materials are vital to 3D content creation within the computer graphics industry. Leveraging the expressive representation of procedural materials, artists can effortlessly generate diverse appearances by altering the graph structure or node parameters. However, manually reproducing a specific appearance is a challenging task that demands extensive domain knowledge and labor. Previous research has sought to automate this process by converting artist-created material graphs into differentiable programs and optimizing node parameters against a photographed material appearance using gradient descent. These methods involve implementing differentiable filter nodes [Shi et al. 2020] and training differentiable neural proxies for generator nodes to optimize continuous and discrete node parameters [Hu et al. 2022a] jointly. Nevertheless, Neural Proxies exhibits critical limitations, such as long training times, inaccuracies, fixed resolutions, and confined parameter ranges, which hinder their scalability towards the broad spectrum of production-grade material graphs. These constraints fundamentally stem from the absence of faithful and efficient implementations of generic noise and pattern generator nodes, both differentiable and non-differentiable. Such deficiency prevents the direct optimization of continuous and discrete generator node parameters without relying on surrogate models. We present Diffmat v2 , an improved differentiable procedural material library, along with a fully-automated, end-to-end procedural material capture framework that combines gradient-based optimization and gradient-free parameter search to match existing production-grade procedural materials against user-taken flash photos. Diffmat v2 expands the range of differentiable material graph nodes in Diffmat [Shi et al. 2020] by adding generic noise/pattern generator nodes and user-customizable per-pixel filter nodes. This allows for the complete translation and optimization of procedural materials across various categories without the need for external proprietary tools or pre-cached noise patterns. Consequently, our method can capture a considerably broader array of materials, encompassing those with highly regular or stochastic geometries. We demonstrate that our end-to-end approach yields a closer match to the target than MATch [Shi et al. 2020] and Neural Proxies [Hu et al. 2022a] when starting from initially unmatched continuous and discrete parameters.

Engineering of Affibody Molecules.

Affibody molecules are small, robust, and versatile affinity proteins currently being explored for therapeutic, diagnostic, and biotechnological applications. Surface-exposed residues on the affibody scaffold are randomized to create large affibody libraries from which novel binding specificities to virtually any protein target can be generated using combinatorial protein engineering. Affibody molecules have the potential to complement-or even surpass-current antibody-based technologies, exhibiting multiple desirable properties, such as high stability, affinity, and specificity, efficient tissue penetration, and straightforward modular extension of functional domains. It has been shown in both preclinical and clinical studies that affibody molecules are safe, efficacious, and valuable alternatives to antibodies for specific targeting in the context of in vivo diagnostics and therapy. Here, we provide a general background of affibody molecules, give examples of reported applications, and briefly summarize the methodology for affibody generation.

The effects of subsalt relief on gravity-driven salt tectonics: Results from analogue modelling

Gravity-driven salt-related deformation on passive margins is commonly interpreted as kinematically-linked domains of updip extension and downdip contraction with an intermediate, undeformed zone of translation. Our study uses analogue models to show how salt flow is affected by the subsalt geometry resulting in complex deformation and the alternation of extensional and contractional domains in space and time in translational salt provinces. In our work, the analogue models incorporate subsalt relief associated with half-graben and graben that are realistic geometries along passive margins and combine the effects of gravity spreading in which deformation is driven by differential sedimentary loading, and an early-stage of gravity gliding induced by basin tilt. This approach allows for analysis of how salt flow and overburden deformation are affected by: (1) smoothly dipping subsalt relief; (2) subsalt relief characterized by half-graben with a gently landward dipping extensional fault; (3) subsalt half-graben connected laterally with a distal symmetric graben. For each of these models, we evaluate: 1) the interplay between slipping deformation corresponding to gravity gliding, gravity spreading mechanisms, and subsalt geometry; 2) the spatial and temporal distribution of salt-related structural domains; and 3) the contrasting styles of salt tectonics for different subsalt geometries. In addition, some of the experiments have been repeated considering thicker salt and pre-kinematic overburden and different sedimentation rates. We show that the structures of the subsalt relief variably resist salt flow producing flow mismatch. This variable resistance controls the orientation of the extension and contraction supra-salt structures. Salt surplus and contraction occur over landward dipping base-salt ramps, and a zone of salt depletion and subsidence limited by extensional and contractional hinges occurs over the basinward dipping base-salt ramp. Variations in width and the dip of these base-salt ramps result in stronger flow mismatches and deformation complexity. We also discuss variations in salt flow profile in response to the gravitational forces that drive deformation, allowing a good first-order approximation of viscous salt flow at a regional scale that can be directly compared to examples from various salt-bearing continental margins, particularly the relatively less understood but extremely economically important distal domains of Brazil's Campos and Santos basins.

New biostratigraphic evidence of Upper Devonian deposits by metamorphosed conodonts from Sidi Bou Othmane area of central Jebilet, Morocco and their paleogeographic implications

This report is dedicated to the Sidi Bou Othmane limestones outcrops, which are exposed in the Central Jebilet. This area experienced strong Hercynian metamorphism and deformation. Strongly metamorphosed and recrystallized conodonts point to Frasnian-Famennian ages, which are reported from this region for the first time. Based on conodont data, we thus revise the age of the Sidi Bou Othmane limestones, which are definitely Late Devonian in age instead of Mississippian (late Viséan) as reported in previous publications. Six stratigraphic intervals from the Middle falsiovalis to marginifera utahensis Zones are identified. The colour alteration index of conodonts (CAI) is very high and varies from CAI 6 to CAI 8, indicating a thermal gradient from 360 °C to over 600 °C for the conodont bearing strata, which is consistent with the isograds obtained in previous publications. Transgressive Upper Devonian limestones discontinuously overlie Ordovician psammites, beginning with a variably thick polymict conglomerate. This unconformity provides evidence of a regional exhumation and erosional event of the Ordovician strata in the Central Jebilet, prior to Upper Devonian transgression. Together with the Koudiat Laabid limestones at Jebel Gueliz in the south, these Upper Devonian outcrops, locally covered by upper Viséan Sarhlef Schists, suggest that the upper Viséan basin of Central Jebilet was divided in a N–S elongated paleogeographical highland formed by the Ordovician and Devonian bedrock. The proposed paleogeographic configuration could explain the lithological differences between the slate deposits to the west and the flysch-like deposits to the east. The exhumation/erosion of Ordovician strata in the Sidi Bou Othmane area may be related to the Eovariscan block faulting and the preorogenic extension of the Meseta domain.

Molecular Architecture Effects on Bulk Nanostructure in Bis(Orthoborate) Ionic Liquids.

A series of 19 ionic liquids (ILs) based on phosphonium and imidazolium cations of varying alkyl-chain lengths with the orthoborate anions bis(oxalato)borate [BOB]- , bis(mandelato)borate, [BMB]- and bis(salicylato)borate, [BScB]- , are synthesized and studied using small-angle neutron scattering (SANS). All measured systems display nanostructuring, with 1-methyl-3-n-alkyl imidazolium-orthoborates forming clearly bicontinuous L3 spongelike phases when the alkyl chains are longer than C6 (hexyl). L3 phases are fitted using the Teubner and Strey model, and diffusely-nanostructured systems are primarily fitted using the Ornstein-Zernicke correlation length model. Strongly-nanostructured systems have a strong dependence on the cation, with molecular architecture variation explored to determine the driving forces for self-assembly. The ability to form well-defined complex phases is effectively extinguished in several ways: methylation of the most acidic imidazolium ring proton, replacing the imidazolium 3-methyl group with a longer hydrocarbon chain, substitution of [BOB]- by [BMB]- , or exchanging the imidazolium for phosphonium systems, irrespective of phosphonium architecture. The results suggest there is only a small window of opportunity, in terms of molecular amphiphilicity and cation:anion volume matching, for the formation of stable extensive bicontinuous domains in pure bulk orthoborate-based ILs. Particularly important for self-assembly processes appear to be the ability to form H-bonding networks, which offer additional versatility in imidazolium systems.

Rapid exhumation of young granites in an extensional domain: the example of the Giglio Island pluton (Tuscany)

AbstractThe presence of recently intruded granites at Earth’s surface suggests that their exhumation may have occurred rapidly. The Neogene granites of the Tuscan Magmatic Province (Italy) were emplaced during a period of extensional tectonics and are ideal for determining and quantifying the exhumation process. The peraluminous monzogranite of Giglio Island in the northern Tyrrhenian Sea is characterized by the presence of roof pendants, xenoliths and miarolitic cavities. The petrologic study of metamorphic xenoliths and new zircon U–Pb ages show that the granite was emplaced at 6.4–10 km depth at 5.7 ± 0.4 Ma. Exhumation, constrained by apatite (U–Th)/He ages, was essentially complete in 0.9 Myr at a minimum rate of 6 mm/year. This requires rapid tectonic unroofing, isostatic rebound and thermal softening activity, weakening the upper crust and favouring exhumation at a previously undocumented rate.

Origin and evolution of the main starch biosynthetic enzymes

Starch, a semi-crystalline energy storage form primarily found in plant plastids plays a crucial role in various food or no-food applications. Despite the starch biosynthetic pathway's main enzymes have been characterized, their origin and evolution remained a subject of debate. In this study, we conducted the comprehensive phylogenetic and structural analysis of three types of starch biosynthetic enzymes: starch synthase (SS), starch branching enzyme (SBE) and isoamylase-type debranching enzyme (ISA) from 51,151 annotated genomes. Our findings provide valuable insights into the possible scenario for the origin and evolution of the starch biosynthetic pathway. Initially, the ancestor of SBE can be traced back to an unidentified bacterium that existed before the formation of the last eukaryotic common ancestor (LECA) via horizontal gene transfer (HGT). This transfer event likely provided the eukaryote ancestor with the ability to synthesize glycogen. Furthermore, during the emergence of Archaeplastida, one clade of SS was transferred from Deltaproteobacteria by HGT, while ISA and the other clade of SS originated from Chlamydiae through endosymbiosis gene transfer (EGT). Both these transfer events collectively contributed to the establishment of the original starch biosynthetic pathway. Subsequently, after the divergence of Viridiplantae from Rhodophyta, all three enzymes underwent multiple duplications and N-terminus extension domain modifications, resulting in the formation of functionally specialized isoforms and ultimately leading to the complete starch biosynthetic pathway. By shedding light on the evolutionary origins of key enzymes involved in the starch biosynthetic pathway, this study provides important insights into the evolutionary events of plants.

Large‐scale blending in an hourly 4D‐Var framework for a numerical weather prediction model

AbstractThe Met Office limited‐area model (LAM) data assimilation (DA) system is based on an hourly 4D‐Var method with lateral boundary conditions (LBCs) provided by the Met Office global model (GM). This set‐up was introduced operationally in summer 2017. The work presented here improved the representation of large‐scale dynamics in the LAM DA, which is now integrated on an extended domain and therefore also needs to represent larger scales than were present in 2017. To improve the representation of the large‐scale motions in the convective‐scale system, we choose to take advantage of the better estimation of these scales from the host model. The method presented here is called large‐scale blending (LSB), a spectral nudging solution which is applied to the Met Office LAM (UKV). Spectral nudging allows the LAM evolution to be constrained by a host model with a better representation of the larger scales while preserving the smaller scales predicted by the LAM. In this article, we investigate different options for the implementation of LSB, such as cut‐off wavelength and update frequency. The LAM forecast is typically improved for various variables over a forecast range from about to by the introduction of LSB. We also see a reduction in the internal gravity‐wave activity generated when new lateral boundary conditions are introduced to the LAM from the latest GM forecast. This research proves the benefits of a better representation of large‐scale motions for LAM forecasts.

Structural and biophysical characterization of the secreted, β-helical adhesin EtpA of Enterotoxigenic Escherichia coli.

Enterotoxigenic Escherichia coli (ETEC) is a diarrhoeal pathogen associated with high morbidity and mortality especially among young children in developing countries. At present, there is no vaccine for ETEC. One candidate vaccine antigen, EtpA, is a conserved secreted adhesin that binds to the tips of flagellae to bridge ETEC to host intestinal glycans. EtpA is exported through a Gram-negative, two-partner secretion system (TPSS, type Vb) comprised of the secreted EtpA passenger (TpsA) protein and EtpB (TpsB) transporter that is integrated into the outer bacterial membrane. TpsA proteins share a conserved, N-terminal TPS domain followed by an extensive C-terminal domain with divergent sequence repeats. Two soluble, N-terminal constructs of EtpA were prepared and analysed respectively including residues 67 to 447 (EtpA67-447) and 1 to 606 (EtpA1-606). The crystal structure of EtpA67-447 solved at 1.76 Å resolution revealed a right-handed parallel β-helix with two extra-helical hairpins and an N-terminal β-strand cap. Analyses by circular dichroism spectroscopy confirmed the β-helical fold and indicated high resistance to chemical and thermal denaturation as well as rapid refolding. A theoretical AlphaFold model of full-length EtpA largely concurs with the crystal structure adding an extended β-helical C-terminal domain after an interdomain kink. We propose that robust folding of the TPS domain upon secretion provides a template to extend the N-terminal β-helix into the C-terminal domains of TpsA proteins.

A semantic 3D city model for underground land administration: Development and implementation of an ADE for CityGML 3.0

Current practices of managing and communicating underground physical and cadastral (legal) data are based on fragmented and silo-based 2D methods, which cannot provide unambiguous, coordinated, and reliable representations of assets and their rights, restrictions, and responsibilities (RRRs) in subterranean environments. There is also no link between underground physical and legal data in current practices, resulting in ineffective Underground Land Administration (ULA). A single 3D integrated model of underground assets associated with the cadastral data at a city-scale can improve understanding and interpretation of underground legal and physical aspects. Extending a 3D city model to include underground legal data requirements can potentially provide a viable approach for developing a 3D integrated model. This research aims to develop a new Application Domain Extensions (ADE) for CityGML 3.0 (called VicULA ADE) to manage underground data using a single 3D integrated legal-physical model at a city-scale. The VicULA ADE proposes semantic entities for underground legal spaces, enabling the model to define spatial and semantic relationships between different types of legal spaces. The proposed approach comprises identifying requirements based on the Victorian state of Australia, developing the conceptual and logical data models in UML, and implementing the XML schema as the physical data model. The viability of the VicULA ADE is tested in a complex real-world case study that has various underground legal and physical objects, shifting this data model from a conceptual level to the implementation level. The proposed ADE of the CityGML 3.0 standard revealed how underground legal data elements can be logically embedded in this 3D data model.

Dimension estimate for the two-sided points of planar Sobolev extension domains

In this paper we give an estimate for the Hausdorff dimension of the set of two-sided points of the boundary of bounded simply connected Sobolev W 1 , p W^{1,p} -extension domain for 1 > p > 2 1>p>2 . Sharpness of the estimate is shown by examples. We also prove the equivalence of different definitions of two-sided points.

The Spectrum of Extraglandular Manifestations in Primary Sjögren's Syndrome.

Extraglandular manifestations (EGMs) in primary Sjogren's syndrome (pSS) represent the clinical expression of the systemic involvement in this disease. EGMs are characterized by a wide heterogeneity; virtually any organ or system can be affected, with various degrees of dysfunction. The existing gaps of knowledge in this complex domain of extraglandular extension in pSS need to be overcome in order to increase the diagnostic accuracy of EGMs in pSS. The timely identification of EGMs, as early as from subclinical stages, can be facilitated using highly specific biomarkers, thus preventing decompensated disease and severe complications. To date, there is no general consensus on the diagnostic criteria for the wide range of extraglandular involvement in pSS, which associates important underdiagnosing of EGMs, subsequent undertreatment and progression to severe organ dysfunction in these patients. This review article presents the most recent basic and clinical science research conducted to investigate pathogenic mechanisms leading to EGMs in pSS patients. In addition, it presents the current diagnostic and treatment recommendations and the trends for future therapeutic strategies based on personalized treatment, as well as the latest research in the field of diagnostic and prognostic biomarkers for extraglandular involvement in pSS.

Synthesizing MILP Constraints for Efficient and Robust Optimization

While mixed integer linear programming (MILP) solvers are routinely used to solve a wide range of important science and engineering problems, it remains a challenging task for end users to write correct and efficient MILP constraints, especially for problems specified using the inherently non-linear Boolean logic operations. To overcome this challenge, we propose a syntax guided synthesis (SyGuS) method capable of generating high-quality MILP constraints from the specifications expressed using arbitrary combinations of Boolean logic operations. At the center of our method is an extensible domain specification language (DSL) whose expressiveness may be improved by adding new integer variables as decision variables, together with an iterative procedure for synthesizing linear constraints from non-linear Boolean logic operations using these integer variables. To make the synthesis method efficient, we also propose an over-approximation technique for soundly proving the correctness of the synthesized linear constraints, and an under-approximation technique for safely pruning away the incorrect constraints. We have implemented and evaluated the method on a wide range of benchmark specifications from statistics, machine learning, and data science applications. The experimental results show that the method is efficient in handling these benchmarks, and the quality of the synthesized MILP constraints is close to, or higher than, that of manually-written constraints in terms of both compactness and solving time.