Miracle-dz/UniFAR-FTUs huggingface dataset:
Comment: Entropy Learning for Dynamic Treatment Regimes

I congratulate Profs. Binyan Jiang, Rui Song, Jialiang Li, and Donglin Zeng (JSLZ) for an exciting development in conducting inferences on optimal dynamic treatment regimes (DTRs) learned via empirical risk minimization using the entropy loss as a surrogate. JSLZ's approach leverages a rejection-and-importance-sampling estimate of the value of a given decision rule based on inverse probability weighting (IPW) and its interpretation as a weighted (or cost-sensitive) classification. Their use of smooth classification surrogates enables their careful approach to analyzing asymptotic distributions. However, even for evaluation purposes, the IPW estimate is problematic as it leads to weights that discard most of the data and are extremely variable on whatever remains. In this comment, I discuss an optimization-based alternative to evaluating DTRs, review several connections, and suggest directions forward. This extends the balanced policy evaluation approach of Kallus (2018a) to the longitudinal setting.
Distinct senescence mechanisms restrain progression of dysplastic nevi

TERT promoter mutations (TPMs) are frequently found in different cancer types, including approximately 70% of sun-exposed skin melanomas. In melanoma, TPMs are among the earliest mutations and can be present during the transition from nevus to melanoma. However, the specific factors that contribute to the selection of TPMs in certain nevi subsets are not well understood. To investigate this, we analyzed a group of dysplastic nevi (DN) by sequencing genes commonly mutated in melanocytic neoplasms. We examined the relationship between the identified mutations, patient age, telomere length, histological features, and the expression of p16. Our findings reveal that TPMs are more prevalent in DN from older patients and are associated with shorter telomeres. Importantly, these TPMs were not found in nevi with BRAF V600E mutations. Conversely, DN with BRAF V600E mutations were observed in younger patients, had longer telomeres, and a higher proportion of p16-positive cells. This suggests that these nevi arrest growth independently of telomere shortening through a mechanism known as oncogene-induced senescence (OIS). These characteristics extend to melanoma sequencing data sets, where melanomas with BRAF V600E mutations were more likely to have CDKN2A inactivation, overriding OIS. In contrast, melanomas without BRAF V600E mutations showed a higher frequency of TPMs. Our data imply that TPMs are selected to bypass replicative senescence (RS) in cells that were not arrested by OIS. Overall, our results indicate that a subset of melanocytic neoplasms face constraints from RS, while others encounter OIS and RS. The order in which these barriers are overcome during progression to melanoma depends on the mutational context.
Worldwide synthetic gravity tide parameters available on Internet

This is to inform you that a set of synthetic (model) gravity tide parameters (amplitude factors and phase leads) for the waves MF, Q1, O1, P1, K1, N2, M2, S2, and K2 in a 1 o ×1 o worldwide grid has been computed in 26995 gridpoints located on land and is available to public domain on INTERNET electronic network together with program ETGTAB to compute gravity tides from tidal potential developments: . The files wload.dat and wparm.dat have been compressed under UNIX operation system (wload.dat.Z: 1681.930 kB and wparm.dat.Z: 1397.799 kB) in order to speed up the file transfer. They have to be uncompressed after transfer to your computer (uncompress wload.dat and uncompress wparm.dat)
Impact of antibody architecture and paratope valency on effector functions of bispecific NKp30 x EGFR natural killer cell engagers

ABSTRACT Natural killer (NK) cells emerged as a promising effector population that can be harnessed for anti-tumor therapy. In this work, we constructed NK cell engagers (NKCEs) based on NKp30-targeting single domain antibodies (sdAbs) that redirect the cytotoxic potential of NK cells toward epidermal growth factor receptor (EGFR)-expressing tumor cells. We investigated the impact of crucial parameters such as sdAb location, binding valencies, the targeted epitope on NKp30, and the overall antibody architecture on the redirection capacity. Our study exploited two NKp30-specific sdAbs, one of which binds a similar epitope on NKp30 as its natural ligand B7-H6, while the other sdAb addresses a non-competing epitope. For EGFR-positive tumor targeting, humanized antigen-binding domains of therapeutic antibody cetuximab were used. We demonstrate that NKCEs bivalently targeting EGFR and bivalently engaging NKp30 are superior to monovalent NKCEs in promoting NK cell-mediated tumor cell lysis and that the architecture of the NKCE can substantially influence killing capacities depending on the NKp30-targeting sdAb utilized. While having a pronounced impact on NK cell killing efficacy, the capabilities of triggering antibody-dependent cellular phagocytosis or complement-dependent cytotoxicity were not significantly affected comparing the bivalent IgG-like NKCEs with cetuximab. However, the fusion of sdAbs can have a slight impact on the NK cell release of immunomodulatory cytokines, as well as on the pharmacokinetic profile of the NKCE due to unfavorable spatial orientation within the molecule architecture. Ultimately, our findings reveal novel insights for the engineering of potent NKCEs triggering the NKp30 axis.
Sulfotransferase SULT2B1 facilitates colon cancer metastasis by promoting SCD1‐mediated lipid metabolism

Abstract Metastasis is responsible for at least 90% of colon cancer (CC)‐related deaths. Lipid metabolism is a critical factor in cancer metastasis, yet the underlying mechanism requires further investigation. Herein, through the utilisation of single‐cell sequencing and proteomics, we identified sulfotransferase SULT2B1 as a novel metastatic tumour marker of CC, which was associated with poor prognosis. CC orthotopic model and in vitro assays showed that SULT2B1 promoted lipid metabolism and metastasis. Moreover, SULT2B1 directly interacted with SCD1 to facilitate lipid metabolism and promoted metastasis of CC cells. And the combined application of SCD1 inhibitor CAY with SULT2B1‐ konockout (KO) demonstrated a more robust inhibitory effect on lipid metabolism and metastasis of CC cells in comparison to sole application of SULT2B1‐KO. Notably, we revealed that lovastatin can block the SULT2B1‐induced promotion of lipid metabolism and distant metastasis in vivo. Further evidence showed that SMC1A transcriptionally upregulated the expression of SULT2B1. Our findings unveiled the critical role of SULT2B1 in CC metastasis and provided a new perspective for the treatment of CC patients with distant metastasis.
The emerging perioperative treatment paradigm for non-small cell lung cancer: a narrative review.

BACKGROUND AND OBJECTIVE The management of resectable non-small cell lung cancer (NSCLC) has relied on surgery and adjuvant chemotherapy for the past two decades, but is now radically changing through the introduction of immunotherapy and targeted drugs. This review was conducted to summarize recent developments and highlight future directions. METHODS A literature search for randomized phase 2/3 trials on the treatment of early-stage NSCLC was performed based on PubMed and the content on major oncology congresses during the last 3 years. KEY CONTENT AND FINDINGS Perioperative strategies with 3-4 cycles of neoadjuvant chemoimmunotherapy and 1 year of adjuvant programmed cell death (ligand) 1 [PD-(L)1] blockade combine the efficacy of purely adjuvant [effective for both stage II and stage III tumors with event-free survival hazard ratios (HR) of approximately 0.70] and the purely neoadjuvant strategies (effective only for stage III with a lower EFS HR of approximately 0.50), show benefit across the entire spectrum of PD-L1 tumor expression levels, and significantly improve overall survival, as the NADIM-2 and Keynote-671 studies recently showed. Once approved, they will probably dominate the landscape of management for resectable NCSLC based on two main advantages: first, compared to purely adjuvant treatments, like those of the IMpower010 and Keynote-091 trials, they allow for evaluation of response in the surgical specimen and permit adjustment of the postoperative management accordingly; second, compared to the purely neoadjuvant treatment of Checkmate-816, their postoperative component appears to additionally improve the outcome of patients failing to achieve a pathologic complete remission (pCR). Further improvements in the near future will likely include intensified postoperative therapy for non-pCR patients, e.g., with addition of chemotherapy, antibody-drug conjugates, or next-generation immunotherapeutics; broader use of circulating tumor DNA assays for improved monitoring of minimal residual disease; as well as routine availability of further tyrosine kinase inhibitors (TKI) against oncogenic drivers beyond classic EGFR mutations, like adjuvant alectinib for tumors with ALK fusions, whose approval is expected soon based on the recent success of the ALINA trial, and adjuvant selpercatinib for tumors with RET fusions, if the ongoing LIBRETTO-432 trial is also positive. The availability of both TKI and neoadjuvant chemoimmunotherapy in the routine setting renders molecular tumor profiling imperative for potentially resectable tumors already at initial diagnosis. CONCLUSIONS Perioperative immunotherapy is becoming the dominant treatment paradigm for resectable NSCLC, while increasing use of targeted drugs for actionable alterations necessitates upfront molecular profiling of early tumors for patient selection.
Functional parcellation of the neonatal cortical surface.

The cerebral cortex is organized into distinct but interconnected cortical areas, which can be defined by abrupt differences in patterns of resting state functional connectivity (FC) across the cortical surface. Such parcellations of the cortex have been derived in adults and older infants, but there is no widely used surface parcellation available for the neonatal brain. Here, we first demonstrate that existing parcellations, including surface-based parcels derived from older samples as well as volume-based neonatal parcels, are a poor fit for neonatal surface data. We next derive a set of 283 cortical surface parcels from a sample of n = 261 neonates. These parcels have highly homogenous FC patterns and are validated using three external neonatal datasets. The Infomap algorithm is used to assign functional network identities to each parcel, and derived networks are consistent with prior work in neonates. The proposed parcellation may represent neonatal cortical areas and provides a powerful tool for neonatal neuroimaging studies.
Association of changes in expression of HDAC and SIRT genes after drug treatment with cancer cell line sensitivity to kinase inhibitors

ABSTRACT Histone deacetylases (HDACs) and sirtuins (SIRTs) are important epigenetic regulators of cancer pathways. There is a limited understanding of how transcriptional regulation of their genes is affected by chemotherapeutic agents, and how such transcriptional changes affect tumour sensitivity to drug treatment. We investigated the concerted transcriptional response of HDAC and SIRT genes to 15 approved antitumor agents in the NCI-60 cancer cell line panel. Antitumor agents with diverse mechanisms of action induced upregulation or downregulation of multiple HDAC and SIRT genes. HDAC5 was upregulated by dasatinib and erlotinib in the majority of the cell lines. Tumour cell line sensitivity to kinase inhibitors was associated with upregulation of HDAC5, HDAC1, and several SIRT genes. We confirmed changes in HDAC and SIRT expression in independent datasets. We also experimentally validated the upregulation of HDAC5 mRNA and protein expression by dasatinib in the highly sensitive IGROV1 cell line. HDAC5 was not upregulated in the UACC-257 cell line resistant to dasatinib. The effects of cancer drug treatment on expression of HDAC and SIRT genes may influence chemosensitivity and may need to be considered during chemotherapy.
The variations in anatomy of the sphenoid sinus and sellar floor to perform transsphenoidal endoscopy in adult age

A cirurgia transesfenoidal depende da habilidade de visualizar e identificar referências anatômicas chaves durante cada fase da operação. Um grau notável de variação anatômica existe no seio esfenoidal, sela túrcica e estruturas ao redor da base do crânio. Nosso objetivo é revisar as variações anatômicas no seio esfenoidal e assoalho selar que são importantes para realizar uma cirurgia endoscópica transesfenoidal de modo efetivo e seguro em pacientes adultos. Uma detalhada informação em relação a anatomia é o meio mais confiável e efetivo de evitar complicações de todos os tipos na cirurgia transesfenoidal.
Research on the performance improvement of a two-shaft gas turbine with a variable area nozzle power turbine

Both an increase in atmospheric temperature and a decrease in atmospheric pressure can lead to the degradation of the maximum allowable power output (MAPO) or the thermal efficiency of a gas turbine. In order to reduce these adverse effects, this paper provides a simulated study on the improvement of the MAPO and the variations of the thermal efficiency due to the fuel flow and variable area nozzle control under different atmospheric conditions. Simulation results indicate that the MAPO increases with the power turbine nozzle area, while the thermal efficiency shows a parabola trend. With the same increment of the power turbine nozzle area, the improvement of the MAPO goes up as the atmospheric temperature rises and the decrease of thermal efficiency is alleviated. Analyses show that the slow degradation of the compressor isentropic efficiency is a key factor that enables the MAPO to increase significantly and the thermal efficiency to remain almost constant.
Sex differences in immune function and disease risk are not easily explained by an evolutionary mismatch

The “Pregnancy Compensation Hypothesis” (PCH) posits that sex differences in the mammalian immune system reflect the effects of selection on female immunity during pregnancy, during which increased immunomodulation is required to reduce immune responses to the fetus, while maintaining the ability to respond to pathogens. In humans, fewer pathogens and lower parity in urban, industrialized environments has been suggested to leave female immune systems under-stimulated, creating an “evolutionary mismatch” which exacerbates sex differences in immunity and increases female autoimmune disease risk. Yet, robust tests of this mismatch hypothesis have not been conducted. Here, we first confirmed a sex-bias in autoimmune disease prevalence in a large dataset of individuals from the United Kingdom (UK Biobank). Second, we asked whether sex differences in immune function are affected by shifts toward urban, lower-parity lifestyles in a single population—the Turkana people of northwest Kenya. We found that lifestyle alters sex differences in immune cell type proportions, but not in gene expression levels. Contrary to expectations from the PCH, parity did not predict immune physiology. We then tested for generalizable trends across natural fertility mammalian populations versus urban humans (data from Turkana, NHANES, GTEx, Batwa and Bakiga, yellow baboons, and macaques). We did not find consistent relationships between lifestyle and sex-biases in immune biomarkers or between parity and the same immune outcomes. Indeed, we found that parity predicts autoimmune disease risk in the opposite direction than expected from the PCH, with higher parity associated with higher autoimmune disease risk while adjusting for relevant socioeconomic variables in the UK Biobank. Taken together, our work suggests that while sex clearly influences immune physiology and disease risk in urban settings, these effects are not easily explained by an evolutionary mismatch. Future work addressing how sex interacts with lifestyle change to generate disease is needed.
Molecular and computational studies of ADGRG6 reveal its extracellular CUB domain as a key regulator of cAMP signaling

ADGRG6 is a member of the adhesion G Protein-coupled receptor (aGPCR) family that regulates Schwann cell myelination among other developmental processes. ADGRG6 is associated with developmental diseases and cancers and ADGRG6 signaling activity is regulated by its multidomain extracellular region (ECR). Previous work shows that the ADGRG6 ECR adopts a compact conformation mediated by its Complement C1r/C1s, Uegf, Bmp1 (CUB) domain. An alternatively spliced form of ADGRG6 (+ss) has higher signaling levels and does not adopt the compact conformation, suggesting that the CUB domain regulates ADGRG6 signaling activity. However, mechanistic detail of how the CUB domain regulates ADGRG6 signaling is lacking. Here, we show that deletion of the ADGRG6 CUB domain decreases signaling levels of the receptor. Using microsecond-length molecular dynamics simulations, we demonstrate that a cancer-associated variant C94Y disrupts the compact conformation of ADGRG6. C94Y exposes the CUB ligand binding site to solvent without introducing any change to the binding site itself. In cell-based assays, C94Y signals significantly higher than the wild-type receptor. Another cancer associated variant, Y96A, removes a critical residue in the canonical CUB domain ligand binding site and this variant inhibits ADGRG6 signaling. Several CUB domains bind to collagen-like structures using the same surface which prominently features Y96. Taken together with the literature, our results strongly suggest that the CUB domain regulates ADGRG6 activity through its ligand binding surface, either through intramolecular binding to the ADGRG6 ECR, or to a putative ADGRG6 ligand.
The budding yeast Fkh1 Forkhead associated (FHA) domain promotes the G1-chromatin status and activity of chromosomal DNA replication origins

In Saccharomyces cerevisiae the forkhead (Fkh) transcription factor Fkh1 (forkhead homolog) enhances the activity of many DNA replication origins that act in early S-phase (early origins). Fkh1 binds directly to origin-adjacent Fkh1 binding sites (FKH sites), providing evidence that Fkh1 acts directly. However, the post-DNA binding functions that Fkh1 uses to promote early origin activity are undefined. Fkh1 contains a conserved FHA (forkhead associated) domain, a protein-binding module that binds phosphothreonine (pT)-containing partner proteins. At a small subset of yeast origins, the Fkh1-FHA domain enhances the ORC (origin recognition complex) -origin binding step, the G1-phase event that initiates the origin cycle. The relevance of the Fkh1-FHA to either chromosomal replication or ORC-origin interactions at genome scale has not been reported. Here, S-phase SortSeq experiments were used to assess genome replication in proliferating FKH1 and fkh1R80A mutant cells. The data provided evidence that the Fkh1-FHA domain promoted the activity of ≈ 100 origins that act in early S-phase, including the majority of centromere-associated origins, while simultaneously inhibiting ≈ 100 late origins. ORC ChIPSeq data provided evidence that the Fkh1-FHA domain promoted normal ORC-origin binding at FHA-stimulated origins. Origins are associated with a distinctive nucleosome organization that frames a nucleosome deplected region (NDR) over the origin, with ORC contributing to this architecture. To ask whether the Fkh1-FHA domain had an impact on the ORC and nucleosome protein-DNA interactions at origins, MNaseSeq data were generated from G1-arrested and proliferating FKH1 and fkh1R80A mutant cell populations. These data provided evidence that origin groups differentially regulated by the Fkh1-FHA domain were characterized by distinct G1-phase ORC and nucleosome configurations that were Fkh1FHA-dependent. Thus, the Fkh1-FHA domain performed an important post-DNA binding role of the Fkh1 protein in promoting hallmarks of origin-associated protein-DNA architecture in G1-phase and the activity of early origins in S-phase.
Bottlebrush polyethylene glycol nanocarriers translocate across human airway epithelium via molecular architecture enhanced endocytosis

Pulmonary drug delivery is critical to the treatment of respiratory diseases. However, the human airway surface presents multiscale barriers to efficient drug delivery. Here we report a bottlebrush polyethylene glycol (PEG-BB) nanocarrier that can translocate across all barriers within the human airway surface. Guided by the molecular theory, we design a PEG-BB molecule consisting of a linear backbone densely grafted by many (∼1,000) low molecular weight (∼1000 g/mol) PEG chains; this results in a highly anisotropic, wormlike nanocarrier featuring a contour length of ∼250 nm, a cross-section of ∼20 nm, and a hydrodynamic diameter of ∼40 nm. Using the classic air-liquid-interface culture system to recapitulate essential biological features of the human airway surface, we show that PEG-BB rapidly penetrates through endogenous airway mucus and periciliary brush layer (mesh size of 20-40 nm) to be internalized by cells across the whole epithelium. By quantifying the cellular uptake of polymeric carriers of various molecular architectures and manipulating cell proliferation and endocytosis pathways, we show that the translocation of PEG-BB across the epithelium is driven by bottlebrush architecture enhanced endocytosis. Our results demonstrate that large, wormlike bottlebrush PEG polymers, if properly designed, can be used as a novel carrier for pulmonary and mucosal drug delivery. Table of Contents
Genes required for the formation of virulence-provoking bacterial sphingolipids

Sphingolipids are ubiquitous in membranes of eukaryotes and are associated with important cellular functions. Although sphingolipids occur scarcely in bacteria, for some of them they are essential and, in other bacteria, they contribute to fitness and stability of the outer membrane, such as in the well-studied α-proteobacterium Caulobacter crescentus. We previously defined five structural genes for ceramide synthesis in C. crescentus. However, other mutants affected in genes of this same genomic region show cofitness with a mutant deficient in serine palmitoyltransferase. Here we show that at least two phospho-sphingolipids are produced in C. crescentus and that at least another six gene products are needed for the decoration of ceramide upon phospho-sphingolipid formation. All eleven genes participating in phospho-sphingolipid formation are also required in C. crescentus for membrane stability and for displaying sensitivity towards the antibiotic polymyxin B. The genes for the formation of complex phospho-sphingolipids are also required for C. crescentus virulence on Galleria mellonella insect larvae. Author Summary Sphingolipids participate in the formation of biological membranes and molecular signaling in higher organisms. Many bacteria also accommodate sphingolipids in their membranes. Here we report that eleven genes participate in the synthesis of complex bacterial phospho-sphingolipids. Our data show that these lipids contribute to membrane stability, but also confer sensitivity towards certain antibiotics. The bacterium Caulobacter crescentus is widely distributed in fresh water lakes and streams and was considered to be non-virulent. However, we demonstrate that complex phospho-sphingolipids are the main virulence contributors in this bacterium.