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Dose control of warfarin is a major complication in anticoagulation therapy and overdose is reversed by the vitamin K antidote. Improving the dosage management and antidotal efficacy requires mechanistic understanding. Here we find that effects of the major predictor of warfarin dosage, SNP −1639 G>A, follow a general correlation that warfarin 50% inhibitory concentration decreases with cellular level of vitamin K epoxide reductase (VKORC1), suggesting stoichiometric inhibition. Characterization of the inhibition kinetics required the use of microsomal VKORC1 with a native reductant, glutathione, that enables effective warfarin inhibition in vitro. The kinetics data can be fitted with the Morrison equation, giving a nanomolar inhibition constant and demonstrating that warfarin is a tight-binding inhibitor. However, warfarin is released from purified VKORC1-warfarin complex with increasing amount of vitamin K, indicating competitive inhibition. The competition occurs also in cells, resulting in rescued VKORC1 activity that augments the antidotal effects of vitamin K. Taken together, warfarin is a competitive inhibitor that binds VKORC1 tightly and inhibits at a stoichiometric (1:1) concentration, whereas exceeding the VKORC1 level results in warfarin overdose. Thus, warfarin dosage control should use VKORC1 level as a major indicator, and improved antidotes may be designed based on their competition with warfarin.

Jet lag is commonly experienced when travelers cross multiple time zones, leaving the wake–sleep cycle and intrinsic biological “clocks” out of synchrony with the current environment. The effect of jet lag on intrinsic cortical function remains unclear. Twenty‐two healthy individuals experiencing west‐to‐east jet lag flight were recruited. Brain structural and functional magnetic resonance studies, as well as psychological and neurohormonal tests, were carried out when participants returned from travel over six time zones and 50 days later when their jet lag symptoms had resolved. During jet lag, the functional brain network exhibited a small‐world topology that was shifted toward regularity. Alterations during jet lag relative to recovery included decreased basal ganglia‐thalamocortical network connections and increased functional connectivity between the medial temporal lobe subsystem and medial visual cortex. The lower melatonin and higher thyroid hormone levels during jet lag showed the same trend as brain activity in the right lingual gyrus. Although there was no significant difference between cortisol measurements during and after jet lag, cortisol levels were associated with temporal lobe activity in the jet lag condition. Brain and neuroendocrine changes during jet lag were related to jet lag symptoms. Further prospective studies are needed to explore the time course over which jet lag acts on the human brain.

Accurate diagnosis of Mild Cognitive Impairment (MCI) has gained much more attention in the past few years. It should be noted that, in many recent works, the brain connection estimated by fMRI data have been provided the effective and robust biomarker for several neurological-disorders diagnosis. However, the existing works only focus on the single connection pattern (e.g., Pearson’s Correlation) for diagnosis, which often ignores the information from other patterns for diagnosis. Consequently, such approaches may not be sufficient to reveal the underlying connection differences between the groups of disease-affected patients and normal controls (NC), which limited its performance. As a result, Multiple Connection Pattern Combination (MCPC) method from Single Modal Data is come into beings. Specifically, we propose to combine three patterns of connections including Pearson’s Correlation, Partial Correlation and Dynamic Casual Modelling to identify MCI from Normal Controls (NC), using a kernel combination trick. 68 MCI and 69 NC from ADNI dataset are used for development and validation of our proposed MCPC method. As a result, the proposed methods achieved 87.40 % classification accuracy, significantly outperformed the case of methods using the single connection pattern.

Structural biology is entering an exciting time where many new high-resolution structures of large complexes and membrane proteins (MPs) are determined regularly. These advances have been driven by over 15 years of technological improvements, first in macromolecular crystallography, and recently in cryo-electron microscopy. Obtaining information about MP higher order structure and interactions is also a frontier, important but challenging owing to their unique properties and the need to choose suitable detergents/lipids for their study. The development of mass spectrometry (MS), both instruments and methodology in the past 10 years, has also advanced it as a complementary method to study MP structure and interactions. In this review, we discuss advances in MS-based footprinting for MPs and highlight recent methodologies that offer new promise for MP study by chemical footprinting and mass spectrometry.

Membrane proteins play crucial roles in cell signaling and transport and, thus, are the targets of many small molecule drugs. The characterization of membrane protein structures poses challenges for the high-resolution biophysical tools because the transmembrane (TM) domain is hydrophobic, opening an opportunity for mass spectrometry (MS)-based footprinting. The hydrophobic reagent diethylpyrocarbonate (DEPC), a heavily studied footprinter for water-soluble proteins, can label up to 30% of surface residues via a straightforward protocol, streamlining the MS-based footprinting workflow. To test its applicability to membrane proteins, we footprinted vitamin K epoxide reductase (VKOR) membrane protein with DEPC. The results demonstrate that besides labeling the hydrophilic extracellular (extramembrane (EM)) domain, DEPC can also diffuse into the hydrophobic TM domain and subsequently label that region. The labeling process was facilitated by tip sonication to enhance reagent diffusion into micelles. We then analyzed the correlation between the residue modification extent and the theoretical accessible surface area percentage (%ASA); the data generally show good correlation with the residue location. Compared with conventional hydrophilic footprinters, the relatively hydrophobic DEPC can map a membrane protein's TM domain, suggesting that the reagent's hydrophobicity can be exploited to obtain structural information on the membrane-spanning region. This encouraging result should assist in the development of more efficient footprinters for membrane protein TM domain footprinting, enabled by further understanding the relationship between a reagent's hydrophobicity and its preferred labeling sites.

Here, we introduce carbocations (R3C+) as laser-initiated footprinting reagents for proteins. We screened seven candidates and selected trifluomethoxy benzyl bromide (TFBB) as an effective precursor for the electrophilic trifluomethoxy benzyl carbocation (TFB+) under laser (248 nm) irradiation on the fast photochemical oxidation of proteins (FPOP) platform. Initial results demonstrate that this electrophilic cation reagent affords residue coverage of nucleophilic amino acids including H, W, M, and S. Further, the addition of TFB+ increases the hydrophobicity of the peptides so that separation of isomeric peptide products by reversed-phase LC is improved, suggesting opportunities for subresidue footprinting. Comparison of apo- and holo-myoglobin footprints shows that the TFB+ footprinting is sensitive to protein conformational change and solvent accessibility. Interestingly, because the TFB+ is amphiphilic, the reagent can potentially footprint membrane proteins as demonstrated for vitamin K epoxide reductase (VKOR) stabilized in a micelle. Not only does footprinting of the extra-membrane domain occur, but also some footprinting of the hydrophobic transmembrane domain is achieved owing to the interaction of TFB+ with the micelle. Carbocation precursors are stable and amenable for tailoring their properties and those of the incipient carbocation, enabling targeting their soluble or membrane-associated or embedded regions and distinguishing between the extra- and trans-membrane domains of membrane proteins.

This year's Congress of the International Society of Thrombosis and Haemostasis (ISTH) was hosted virtually from Philadelphia July 17-21, 2021. The conference, now held annually, highlighted cutting-edge advances in basic, population and clinical sciences of relevance to the Society. Despite being held virtually, the 2021 congress was of the same scope and quality as an annual meeting held in person. An added feature of the program is that talks streamed at the designated times will then be available on-line for asynchronous viewing. The program included 77 State of the Art (SOA) talks, thematically grouped in 28 sessions, given by internationally recognized leaders in the field. The SOA speakers were invited to prepare brief illustrated reviews of their talks that were peer reviewed and are included in this article. The topics, across the main scientific themes of the congress, include Arterial Thromboembolism, Coagulation and Natural Anticoagulants, COVID-19 and Coagulation, Diagnostics and Omics, Fibrinogen, Fibrinolysis and Proteolysis, Hemophilia and Rare Bleeding Disorders, Hemostasis in Cancer, Inflammation and Immunity, Pediatrics, Platelet Disorders, von Willebrand Disease and Thrombotic Angiopathies, Platelets and Megakaryocytes, Vascular Biology, Venous Thromboembolism and Women's Health. These illustrated capsules highlight the major scientific advances with potential to impact clinical practice. Readers are invited to take advantage of the excellent educational resource provided by these illustrated capsules. They are also encouraged to use the image in social media to draw attention to the high quality and impact of the science presented at the congress. ispartof: RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS vol:5 issue:5 ispartof: location:United States status: published

Store-operated calcium entry (SOCE) modulates cytosolic calcium in multiple cells. Endoplasmic reticulum (ER) localized STIM1 and plasma membrane (PM)-localized ORAI1 are two main components of SOCE. STIM1:ORAI1 association requires STIM1 oligomerization, its re-distribution to ER-PM junctions, and puncta formation. However, little is known about the negative regulation of these steps to prevent calcium overload. Here, we identified Tmem178 as a negative modulator of STIM1 puncta formation in myeloid cells. Using site-directed mutagenesis, co-immunoprecipitation assays and FRET imaging, we determined that Tmem178:STIM1 association occurs via their transmembrane motifs. Mutants that increase Tmem178:STIM1 association reduce STIM1 puncta formation, SOCE activation, impair inflammatory cytokine production in macrophages and osteoclastogenesis. Mutants that reduce Tmem178:STIM1 association reverse these effects. Furthermore, exposure to plasma from arthritic patients decreases Tmem178 expression, enhances SOCE activation and cytoplasmic calcium. In conclusion, Tmem178 modulates the rate-limiting step of STIM1 puncta formation and therefore controls SOCE in inflammatory conditions.

Climate science finds that the trend towards higher global temperatures exacerbates the risks of droughts. We investigate whether the prices of food stocks efficiently discount these risks. Using data from thirty-one countries with publicly-traded food companies, we rank these countries each year based on their long-term trends toward droughts using the Palmer Drought Severity Index. A poor trend ranking for a country forecasts relatively poor profit growth for food companies in that country. It also forecasts relatively poor food stock returns in that country. This return predictability is consistent with food stock prices underreacting to climate change risks.

Objectives: Half of the patients who have tailored resection of the suspected epileptogenic zone for drug-resistant epilepsy have recurrent postoperative seizures. Although neuroimaging has become an indispensable part of delineating the epileptogenic zone, no validated method uses neuroimaging of presurgical target area to predict an individual’s post-surgery seizure outcome. We aimed to develop and validate a machine learning-powered approach incorporating multimodal neuroimaging of a presurgical target area to predict an individual’s post-surgery seizure outcome in patients with drug-resistant focal epilepsy.Materials and Methods: One hundred and forty-one patients with drug-resistant focal epilepsy were classified either as having seizure-free (Engel class I) or seizure-recurrence (Engel class II through IV) at least 1 year after surgery. The presurgical magnetic resonance imaging, positron emission tomography, computed tomography, and postsurgical magnetic resonance imaging were co-registered for surgical target volume of interest (VOI) segmentation; all VOIs were decomposed into nine fixed views, then were inputted into the deep residual network (DRN) that was pretrained on Tiny-ImageNet dataset to extract and transfer deep features. A multi-kernel support vector machine (MKSVM) was used to integrate multiple views of feature sets and to predict seizure outcomes of the targeted VOIs. Leave-one-out validation was applied to develop a model for verifying the prediction. In the end, performance using this approach was assessed by calculating accuracy, sensitivity, and specificity. Receiver operating characteristic curves were generated, and the optimal area under the receiver operating characteristic curve (AUC) was calculated as a metric for classifying outcomes.Results: Application of DRN–MKSVM model based on presurgical target area neuroimaging demonstrated good performance in predicting seizure outcomes. The AUC ranged from 0.799 to 0.952. Importantly, the classification performance DRN–MKSVM model using data from multiple neuroimaging showed an accuracy of 91.5%, a sensitivity of 96.2%, a specificity of 85.5%, and AUCs of 0.95, which were significantly better than any other single-modal neuroimaging (all p ˂ 0.05).Conclusion: DRN–MKSVM, using multimodal compared with unimodal neuroimaging from the surgical target area, accurately predicted postsurgical outcomes. The preoperative individualized prediction of seizure outcomes in patients who have been judged eligible for epilepsy surgery could be conveniently facilitated. This may aid epileptologists in presurgical evaluation by providing a tool to explore various surgical options, offering complementary information to existing clinical techniques.

We examine whether fund managers overestimate carbon risk when they are exposed to local air pollution. We find that air pollution causes managers to underweight stocks of high-emission firms. The effects are stronger for less salient scopes of carbon emissions, among managers located in pro-environmental states, and among those likely to be surprised by air pollution—consistent with the idea that managers revise their beliefs about climate-transition risk following their exposure to air pollution. Carbon-intensive stocks sold by managers who are exposed to air pollution subsequently outperform stocks that they buy, suggesting that such underweighting is costly to fund investors.

Prior research finds that online social media usage may lower self-control and encourage indulgent behavior in laboratory subjects. We find that corporate CEOs show similar tendencies: CEOs with online social media presence are more likely to succumb to lower self-control and abuse their information advantage to profit from unethical insider trades. Specifically, CEOs’ social media presence strongly predicts their insider trading activity in terms of incidence, intensity (amount and frequency), and profitability. We further find that the effect is driven by insider buys (not by sells) and is more pronounced for opportunistic buys which tend to contain more material non-public information.

Post-collisional ultrapotassic rocks (UPRs) in the Tibetan Plateau exhibit extreme enrichment in incompatible elements and radiogenic isotopes. Such enrichment is considered to be either inherited from a mantle source or developed during crustal evolution. In this study, to solve this debate we combined mineral textures and in situ geochemical composition of clinopyroxene phenocrysts in UPRs from southern Tibet to reveal their crustal evolution, enrichment cause and constrain metasomatism in their mantle source. Results show that the UPRs experienced an array of crustal processes, i.e., fractional crystallization, mixing, and assimilation. Fractional crystallization is indicated by decreases in Mg# and Ni and enrichment in incompatible elements (e.g. rare earth element (REE), Sr, Zr) toward the rims of normally zoned clinopyroxene phenocrysts (type-I). Magma mixing is evidenced by the presence of some clinopyroxene phenocrysts (type-II, -III) showing disequilibrium textures (e.g. reversed and overgrowth zoning), but in situ Sr isotope and trace element analysis of those disequilibrium zones indicate that late-stage recharged mafic magmas are depleted (87Sr/86Sr: 0.70659–0.71977) compared with the primitive ultrapotassic magmas (87Sr/86Sr: 0.70929–0.72553). Assimilation is revealed by the common presence of crustal xenoliths in southern Tibetan UPRs. Considering the much lower 87Sr/86Sr values (0.707759–0.709718) and incompatible element contents of these crustal xenoliths relative to their host UPRs, assimilation should have resulted in geochemical depletion of southern Tibetan UPRs rather than enrichment. The diluting impact of both assimilation and mixing is also supported by the modeling results based on the EC-E′RAχFC model combining the growth history of clinopyroxene. Trace elements ratios in clinopyroxenes also imply that the mantle source of southern Tibetan UPRs suffered an enriched and carbonatite-dominated metasomatism. Thus, we conclude that enrichment of southern Tibetan UPRs was inherited from the mantle source.

Anticoagulants take over In its fully reduced form, vitamin K helps to catalyze an oxidation reaction essential for blood coagulations, but it must be regenerated in each reaction through reduction. Liu et al. determined the structures of the enzyme responsible, vitamin K epoxide reductase, bound to an oxidized vitamin K substrate or with anticoagulants, including the widely prescribed drug warfarin. Understanding how these molecules bind and inhibit explains some variations in the therapeutic response as well as resistance for anticoagulants used in pest control. Science , this issue p. 43

Unsupervised domain adaptation (UDA) aims to transfer knowledge from a well-labeled source domain to a different but related unlabeled target domain with identical label space. Currently, the main workhorse for solving UDA is domain alignment, which has proven successful. However, it is often difficult to find an appropriate source domain with identical label space. A more practical scenario is so-called partial domain adaptation (PDA) in which the source label set or space subsumes the target one. Unfortunately, in PDA, due to the existence of the irrelevant categories in the source domain, it is quite hard to obtain a perfect alignment, thus resulting in mode collapse and negative transfer. Although several efforts have been made by down-weighting the irrelevant source categories, the strategies used tend to be burdensome and risky since exactly which irrelevant categories are unknown. These challenges motivate us to find a relatively simpler alternative to solve PDA. To achieve this, we first provide a thorough theoretical analysis, which illustrates that the target risk is bounded by both model smoothness and between-domain discrepancy. Considering the difficulty of perfect alignment in solving PDA, we turn to focus on the model smoothness while discard the riskier domain alignment to enhance the adaptability of the model. Specifically, we instantiate the model smoothness as a quite simple intra-domain structure preserving (IDSP). To our best knowledge, this is the first naive attempt to address the PDA without domain alignment. Finally, our empirical results on multiple benchmark datasets demonstrate that IDSP is not only superior to the PDA SOTAs by a significant margin on some benchmarks (e.g., +10% on Cl->Rw and +8% on Ar->Rw ), but also complementary to domain alignment in the standard UDA, 10 pages. IEEE Transactions on Pattern Analysis and Machine Intelligence,2022

Exploiting the unique financial reporting format in China, we document that stocks with the strongest past year-to-date earnings growth experience a significant price run-up of 1.2% during the five trading days before their quarterly earnings announcements and a significant return reversal of -1.35% in the five trading days afterward. This inverted V-shaped pattern on cumulative return spreads is more pronounced among smaller firms with lower institutional ownership and fewer analyst coverage, and it is less pronounced among foreign B-share. Consistent with investor excess demand driving the price run-up, we find retail investor sentiment and buy-sell order imbalance rise ahead of earnings announcements for firms with high past earnings growth. Our findings support models of fundamental extrapolation and suggest investors naively extrapolate the salient but not-so-informative year-to-date earnings growth when forming expectations about the upcoming earnings.

We use COVID-19 as an experiment to study the effects of childcare and household duties on sell-side analysts. We find that female analysts' forecast accuracy declined more than male analysts, especially when schools were closed and among analysts who were more likely to have young children, inexperienced, busier, and lived in southern states. Relative to male analysts, females also reduced forecast timeliness and resorted to more heuristic forecasts but did not reduce coverage or updating frequency. Overall, our results show that the pandemic impacted female analysts more than males through the quality of their forecasts but not the quantity.

A free-radical footprinting approach is described for integral membrane protein (IMP) that extends, significantly, the "fast photochemical oxidation of proteins" (FPOP) platform. This new approach exploits highly hydrophobic perfluoroisopropyl iodide (PFIPI) together with tip sonication to ensure efficient transport into the micelle interior, allowing laser dissociation and footprinting of the transmembrane domains. In contrast to water soluble footprinters, PFIPI footprints both the hydrophobic intramembrane and the hydrophilic extramembrane domains of the IMP vitamin K epoxide reductase (VKOR). The footprinting is fast, giving high coverage for Tyr (100 %) and Trp. The incorporation of the reagent with sonication does not significantly affect VKOR's enzymatic function, and tyrosine iodination does not compromise protease digestion and the subsequent analysis. The locations for the modifications are largely consistent with the corresponding solvent accessibilities, recommending this approach for future membrane protein footprinting.

Small membrane proteins are difficult targets for structural characterization. Here, we stabilize their folding by restraining their amino and carboxyl termini with associable protein entities, exemplified by the two halves of a superfolder GFP. The termini-restrained proteins are functional and show improved stability during overexpression and purification. The reassembled GFP provides a versatile scaffold for membrane protein crystallization, enables diffraction to atomic resolution, and facilitates crystal identification, phase determination, and density modification. This strategy gives rise to 14 new structures of five vertebrate proteins from distinct functional families, bringing a substantial expansion to the structural database of small membrane proteins. Moreover, a high-resolution structure of bacterial DsbB reveals that this thiol oxidoreductase is activated through a catalytic triad, similar to cysteine proteases. Overall, termini restraining proves exceptionally effective for stabilization and structure determination of small membrane proteins.

Migration and homing of B cells involves a myriad of adhesion molecules and chemokines that enable the movement of B cells from one part of the body to another. This tightly regulated process is important to facilitate maturation and optimize B cell function. Accordingly, loss of proper adhesive interactions leads to reduced immunoglobulin production and impaired immune function. As a family, tetraspanins regulate cellular growth, survival, and migration. Specifically, the tetraspanin CD53 has been implicated in early B cell development and immunoglobulin production; yet a role for CD53 in B cell trafficking has not been studied. Using a Cd53−/− mouse, we find that splenic B cells have significantly reduced transmigration when placed on a monolayer of human dermal microvascular endothelial cells, compared to WT B cells (1.7% vs 4.2% transmigration, p Supported by institutional funding from Washington University in St. Louis

Coagulation factor IX (FIX) is a vitamin K dependent protein and its deficiency causes hemophilia B, an X-linked recessive bleeding disorder. More than 1000 mutations in the F9 gene have been identified in hemophilia B patients. Here, we systematically summarize the structural and functional characteristics of FIX and the pathogenic mechanisms of the mutations that have been identified to date. The mechanisms of FIX deficiency are diverse in these mutations. Deletions, insertions, duplications, and indels generally lead to severe hemophilia B. Those in the exon regions generate either frame shift or inframe mutations, and those in the introns usually cause aberrant splicing. Regarding point mutations, the bleeding phenotypes vary from severe to mild in hemophilia B patients. Generally speaking, point mutations in the F9 promoter region result in hemophilia B Leyden, and those in the introns cause aberrant splicing. Point mutations in the coding sequence can be missense, nonsense, or silent mutations. Nonsense mutations generate truncated FIX that usually loses function, causing severe hemophilia B. Silent mutations may lead to aberrant splicing or affect FIX translation. The mechanisms of missense mutation, however, have not been fully understood. They lead to FIX deficiency, often by affecting FIX’s translation, protein folding, protein stability, posttranslational modifications, activation to FIXa, or the ability to form functional Xase complex. Understanding the molecular mechanisms of FIX deficiency will provide significant insight for patient diagnosis and treatment.

ObjectiveIncreasing pieces of evidence suggest that abnormal brain connectivity plays an important role in the pathophysiology of schizophrenia. As an essential strategy in psychiatric neuroscience, the research of brain connectivity-based neuroimaging biomarkers has gained increasing attention. Most of previous studies focused on a single modality of the brain connectomics. Multimodal evidence will not only depict the full profile of the brain abnormalities of patients but also contribute to our understanding of the neurobiological mechanisms of this disease.MethodsIn the current study, 99 schizophrenia patients, 69 sex- and education-matched healthy controls, and 42 unaffected first-degree relatives of patients were recruited and scanned. The brain was parcellated into 246 regions and multimodal network analyses were used to construct brain connectivity networks for each participant.ResultsUsing the brain connectomics from three modalities as the features, the multi-kernel support vector machine method yielded high discrimination accuracies for schizophrenia patients (94.86%) and for the first-degree relatives (95.33%) from healthy controls. Using an independent sample (49 patients and 122 healthy controls), we tested the model and achieved a classification accuracy of 64.57%. The convergent pattern within the basal ganglia and thalamus–cortex circuit exhibited high discriminative power during classification. Furthermore, substantial overlaps of the brain connectivity abnormality between patients and the unaffected first-degree relatives were observed compared to healthy controls.ConclusionThe current findings demonstrate that decreased functional communications between the basal ganglia, thalamus, and the prefrontal cortex could serve as biomarkers and endophenotypes for schizophrenia.

As the sole iron exporter in humans, ferroportin controls systemic iron homeostasis through exporting iron into the blood plasma. The molecular mechanism of how ferroportin exports iron under various physiological settings remains unclear. Here we found that purified ferroportin incorporated into liposomes preferentially transports Fe2+ and exhibits lower affinities of transporting other divalent metal ions. The iron transport by ferroportin is facilitated by downhill proton gradients at the same direction. Human ferroportin is also capable of transporting protons, and this activity is tightly coupled to the iron transport. Remarkably, ferroportin can conduct active transport uphill against the iron gradient, with favorable charge potential providing the driving force. Targeted mutagenesis suggests that the iron translocation site is located at the pore region of human ferroportin. Together, our studies enhance the mechanistic understanding by which human ferroportin transports iron and suggest that a combination of electrochemical gradients regulates iron export.

Unsupervised Domain Adaptation (UDA) aims to classify unlabeled target domain by transferring knowledge from labeled source domain with domain shift. Most of the existing UDA methods try to mitigate the adverse impact induced by the shift via reducing domain discrepancy. However, such approaches easily suffer a notorious mode collapse issue due to the lack of labels in target domain. Naturally, one of the effective ways to mitigate this issue is to reliably estimate the pseudo labels for target domain, which itself is hard. To overcome this, we propose a novel UDA method named Progressive Adaptation of Subspaces approach (PAS) in which we utilize such an intuition that appears much reasonable to gradually obtain reliable pseudo labels. Speci fically, we progressively and steadily refine the shared subspaces as bridge of knowledge transfer by adaptively anchoring/selecting and leveraging those target samples with reliable pseudo labels. Subsequently, the refined subspaces can in turn provide more reliable pseudo-labels of the target domain, making the mode collapse highly mitigated. Our thorough evaluation demonstrates that PAS is not only effective for common UDA, but also outperforms the state-of-the arts for more challenging Partial Domain Adaptation (PDA) situation, where the source label set subsumes the target one.

Many mutations in the signal peptide and propeptide of factor IX (FIX) cause hemophilia B. A FIX variants database reports 28 unique missense mutations in these regions that lead to FIX deficiency, but the underlying mechanism is known only for the mutations on R43 that interfere with propeptide cleavage. It remains unclear how other mutations result in FIX deficiency and why patients carrying the same mutation have different bleeding tendencies. Here, we modify a cell-based reporter assay to characterize the missense mutations in the signal peptide and propeptide of FIX. The results show that the level of secreted conformation-specific reporter (SCSR), which has a functional γ-carboxyglutamate (Gla) domain of FIX, decreases significantly in most mutations. The decreased SCSR level is consistent with FIX deficiency in hemophilia B patients. Moreover, we find that the decrease in the SCSR level is caused by several distinct mechanisms, including interfering with cotranslational translocation into the endoplasmic reticulum, protein secretion, γ-carboxylation of the Gla domain, and cleavage of the signal peptide or propeptide. Importantly, our results also show that the SCSR levels of most signal peptide and propeptide mutations increase with vitamin K concentration, suggesting that the heterogeneity of bleeding tendencies may be related to vitamin K levels in the body. Thus, oral administration of vitamin K may alleviate the severity of bleeding tendencies in patients with missense mutations in the FIX signal peptide and propeptide regions.

Schnyder corneal dystrophy (SCD) is an autosomal dominant disease characterized by abnormal deposition of cholesterol and lipid in the cornea. The molecular mechanism underlying this process, which involves the interaction between UBAID1 and HMGCR, remains unclear. Here we investigate these events within silicoapproaches. We built the homology models of UBIAD1 and HMGCR based on the existing crystal and cryo-EM structures. The UBIAD1 and HMGCR models are docked and their binding interactions are interrogated by MD simulation. We find that the transmembrane helices of UBIAD1 bind to sterol sensing domain of HMGCR. Upon binding of the GGPP substrate, UBIAD1 shows lower structural flexibility in the TM regions binding to HMGCR. The N102S and G177R mutations disrupts GGPP binding, thereby lowering the binding affinity of HMGCR. Overall, our modeling suggests that SCD mutations in UBIAD1 or lower GGPP concentration increase the structural flexibility of UBIAD1, thereby facilitating its association with HMGCR.

Methods, Tables S1–S7, and Figures S1–S8

Tetraspanins, including CD53 and CD81, regulate a multitude of cellular processes through organizing an interaction network on cell membranes. Here, we report the crystal structure of CD53 in an open conformation poised for partner interaction. The large extracellular domain (EC2) of CD53 protrudes away from the membrane surface and exposes a variable region, which is identified by hydrogen-deuterium exchange as the common interface for CD53 and CD81 to bind partners. The EC2 orientation in CD53 is supported by an extracellular loop (EC1). At the closed conformation of CD81, however, EC2 disengages from EC1 and rotates toward the membrane, thereby preventing partner interaction. Structural simulation shows that EC1-EC2 interaction also supports the open conformation of CD81. Disrupting this interaction in CD81 impairs the accurate glycosylation of its CD19 partner, the target for leukemia immunotherapies. Moreover, EC1 mutations in CD53 prevent the chemotaxis of pre-B cells toward a chemokine that supports B-cell trafficking and homing within the bone marrow, a major CD53 function identified here. Overall, an open conformation is required for tetraspanin-partner interactions to support myriad cellular processes.

Using detailed information on establishments owned by U.S. public firms, we construct a novel measure of geographic linkage between firms. We show that the returns of geography-linked firms have strong predictive power for focal firm returns and fundamentals. A long-short strategy based on this effect yields monthly value-weighted alpha of approximately 60 basis points. This effect is distinct from other cross-firm return predictability and is not easily attributable to risk-based explanations. It is more pronounced for focal firms that receive lower investor attention, are more costly to arbitrage, and during high sentiment periods. Sell-side analysts similarly underreact, as their forecast revisions of geography-linked firms predict their future revisions of focal firms. Further tests suggest that the lead-lag relation we document results from innovation spillover among geographic peers in addition to their common exposure to the local economy.

We examine short sellers’ use of textual information in annual reports for shorting activities. We find that more uncertainty and negative words in annual reports are associated with greater abnormal shorting volume. Short selling motivated by textual information negatively predicts stock price reaction around the filing date of 10-K reports. We further provide some evidence that textual information used by short sellers are related to revisions of analysts’ earnings forecasts, changes in firm fundamentals, and increasing crash risk subsequently. Our results suggest that textual information in annual reports forms an important part of short sellers’ information advantage.

Using detailed information on establishments owned by U.S. public firms from 1990 to 2012, we show that higher abnormal temperatures over the previous five years in a county lead to a significant reduction in local employment and the number of establishments. The decline in employment and establishments is larger for firms in non-tradable sectors and consumer services and retailing industries, and when managers are likely to care more about global warming. In addition, we find that establishments located in abnormally hot counties seek to hire new workers with greater education and IT skills. Our findings are consistent with the notion that it is the declining local consumer demand, rather than deteriorating employee productivity, that drives firms’ responses. Overall, we provide large-sample evidence on firms’ adaptation to climate change and the resultant impacts on the local economy.

This paper examines the pricing of a firm's carbon risk in the corporate bond market. Contrary to the "carbon risk premium" hypothesis, bonds of more carbon-intensive firms earn significantly lower returns. This effect cannot be explained by a comprehensive list of bond characteristics and exposure to known risk factors. Investigating sources of the low carbon alpha, we find the underperformance of bonds issued by carbon-intensive firms cannot be fully explained by divestment from institutional investors. Instead, our evidence is most consistent with investor underreaction to the predictability of carbon intensity for firm cash-flow news, creditworthiness, and environmental incidents.

We present evidence of investors underreacting to the absence of events in financial markets. Routine-based insiders strategically choose to be silent when they possess private information not yet reflected in stock prices. Consistent with our hypothesis, insider silence following a routine sell (buy) predicts positive (negative) future returns, as well as fundamentals. The return predictability of insider silence is stronger among firms with a poor information environment and facing higher arbitrage costs, and a large fraction of abnormal returns concentrates on future earnings announcements. A long–short strategy that exploits insiders’ strategic silence behavior generates abnormal returns of 6% to 10% annually.

The tetraspanin CD53 has been implicated in B cell development and function. CD53 is a transcriptional target of EBF1, a critical transcription factor for early B cell development. Further, human deficiency of CD53 results in recurrent infections and reduced serum Igs. Although prior studies have indicated a role for CD53 in regulating mature B cells, its role in early B cell development is not well understood. In this study, we show that CD53 expression, which is minimal on hematopoietic stem and progenitor cells, increases throughout bone marrow B cell maturation, and mice lacking CD53 have significantly decreased bone marrow, splenic, lymphatic, and peripheral B cells. Mixed bone marrow chimeras show that CD53 functions cell autonomously to promote B lymphopoiesis. Cd53−/− mice have reduced surface expression of IL-7Rα and diminished phosphatidylinositol 3 kinase and JAK/STAT signaling in prepro- and pro-B cells. Signaling through these pathways via IL-7R is essential for early B cell survival and transition from the pro-B to pre-B cell developmental stage. Indeed, we find increased apoptosis in developing B cells and an associated reduction in pre-B and immature B cell populations in the absence of CD53. Coimmunoprecipitation and proximity ligation studies demonstrate physical interaction between CD53 and IL-7R. Together, these data, to our knowledge, suggest a novel role for CD53 during IL-7 signaling to promote early B cell differentiation.

As at the end of 2012, more than 600 nonstate-owned Chinese firms were listed in overseas stock markets. We find that Chinese firms listed in the US have the lowest cost of capital when compared to...

Organizational capital is the accumulation and use of private information to enhance economic efficiency for a firm. Theory has argued that organizational capital is typically embodied in employees and the organizational structure, and is hard to transfer across organizations. In this paper, we study whether organizational capital is transferable across firms via mergers. The evidence shows that acquirers gain more from acquiring firms with higher organizational capital and acquirers are also willing to pay a higher premium for higher organizational capital targets. The evidence suggests that acquiring higher organizational capital targets creates synergies which are shared between acquirers and targets.

Warfarin is an oral anticoagulant taken by ~1% of the US population to treat and prevent deep vein thrombosis, pulmonary embolism, stroke, and myocardial infarction. Warfarin targets vitamin K epoxide reductase in the vitamin K cycle [1–3], which supports the activity of vitamin-K-dependent proteins including several coagulation factors. The cycle begins with the γ-carboxylation of selected glutamic acids in these proteins, a post-translational modification that allows their membrane association and activation. The γ-carboxylase activity is driven by the epoxidation of the vitamin K hydroquinone, which is regenerated by vitamin K epoxide reductases to complete the vitamin K cycle. The epoxide reductase activity has been identified for two paralogs found in the human genome, VKORC1 and VKORL1, which share ~74% similarity (48% identity) in their protein sequences [3–7] (Fig. 1). VKORC1 is highly expressed in liver where coagulation factors are produced, whereas VKORL1 is more abundant in extrahepatic tissues where other vitamin-K-dependent proteins, such as osteocalcin and matrix Gla protein, are made [8,9]. Compared to VKORC1, VKORL1 shows 30–50-fold more resistance to warfarin in an in vitro assay [8]. Thus, at a warfarin dose administered to inhibit VKORC1-supported blood coagulation, the VKORL1 activity is largely retained, possibly explaining the small effects that short-term warfarin administration usually has against the bone mineralization and the inhibition of vascular calcification [8,9]. The mechanism underlying the relative resistance of VKORL1 to warfarin inhibition, however, is unclear. Open in a separate window Figure 1. Mapping of WR mutations in VKORC1 with sequence alignment of VKORC1 (C1) and VKORL1 (L1). Identical residues (48%) are shadowed in dark grey, and similar residues (26%) in grey. Prediction of secondary structures (top) are based on the crystal structure of a bacterial VKOR homolog [22]. Regions I–IV are identified (bottom) based on the distribution of WR mutations in VKORC1. The underlying panels show the resistant level of WRs in VKORC1 [15], with a Y-axis break at NRwar = 5. Residues with NRwar > 5 mutations are shown in bold letters in the sequence alignment. The orange-colored WR mutations in VKORC1 are selected for mutagenesis analysis of the corresponding residues in VKORL1 (Fig. 3A–C). Matching mutations (Fig. 4B) and the human SNP (Fig. 6) that increase the warfarin sensitivity of VKORL1 are indicated by green and red dots, respectively.