Drug combinations have demonstrated great potential in cancer treatments. They alleviate drug resistance and improve therapeutic efficacy. The fast-growing number of anti-cancer drugs has caused the ...experimental investigation of all drug combinations to become costly and time-consuming. Computational techniques can improve the efficiency of drug combination screening. Despite recent advances in applying machine learning to synergistic drug combination prediction, several challenges remain. First, the performance of existing methods is suboptimal. There is still much space for improvement. Second, biological knowledge has not been fully incorporated into the model. Finally, many models are lack interpretability, limiting their clinical applications. To address these challenges, we have developed a knowledge-enabled and self-attention transformer boosted deep learning model, TranSynergy, which improves the performance and interpretability of synergistic drug combination prediction. TranSynergy is designed so that the cellular effect of drug actions can be explicitly modeled through cell-line gene dependency, gene-gene interaction, and genome-wide drug-target interaction. A novel Shapley Additive Gene Set Enrichment Analysis (SA-GSEA) method has been developed to deconvolute genes that contribute to the synergistic drug combination and improve model interpretability. Extensive benchmark studies demonstrate that TranSynergy outperforms the state-of-the-art method, suggesting the potential of mechanism-driven machine learning. Novel pathways that are associated with the synergistic combinations are revealed and supported by experimental evidences. They may provide new insights into identifying biomarkers for precision medicine and discovering new anti-cancer therapies. Several new synergistic drug combinations have been predicted with high confidence for ovarian cancer which has few treatment options. The code is available at https://github.com/qiaoliuhub/drug_combination.
Background To date, coronavirus disease 2019 (COVID-19) becomes increasingly fierce due to the emergence of variants. Rapid herd immunity through vaccination is needed to block the mutation and ...prevent the emergence of variants that can completely escape the immune surveillance. We aimed to systematically evaluate the effectiveness and safety of COVID-19 vaccines in the real world and to establish a reliable evidence-based basis for the actual protective effect of the COVID-19 vaccines, especially in the ensuing waves of infections dominated by variants. Methods We searched PubMed, Embase and Web of Science from inception to July 22, 2021. Observational studies that examined the effectiveness and safety of SARS-CoV-2 vaccines among people vaccinated were included. Random-effects or fixed-effects models were used to estimate the pooled vaccine effectiveness (VE) and incidence rate of adverse events after vaccination, and their 95% confidence intervals (CI). Results A total of 58 studies (32 studies for vaccine effectiveness and 26 studies for vaccine safety) were included. A single dose of vaccines was 41% (95% CI: 28-54%) effective at preventing SARS-CoV-2 infections, 52% (31-73%) for symptomatic COVID-19, 66% (50-81%) for hospitalization, 45% (42-49%) for Intensive Care Unit (ICU) admissions, and 53% (15-91%) for COVID-19-related death; and two doses were 85% (81-89%) effective at preventing SARS-CoV-2 infections, 97% (97-98%) for symptomatic COVID-19, 93% (89-96%) for hospitalization, 96% (93-98%) for ICU admissions, and 95% (92-98%) effective for COVID-19-related death, respectively. The pooled VE was 85% (80-91%) for the prevention of Alpha variant of SARS-CoV-2 infections, 75% (71-79%) for the Beta variant, 54% (35-74%) for the Gamma variant, and 74% (62-85%) for the Delta variant. The overall pooled incidence rate was 1.5% (1.4-1.6%) for adverse events, 0.4 (0.2-0.5) per 10 000 for severe adverse events, and 0.1 (0.1-0.2) per 10 000 for death after vaccination. Conclusions SARS-CoV-2 vaccines have reassuring safety and could effectively reduce the death, severe cases, symptomatic cases, and infections resulting from SARS-CoV-2 across the world. In the context of global pandemic and the continuous emergence of SARS-CoV-2 variants, accelerating vaccination and improving vaccination coverage is still the most important and urgent matter, and it is also the final means to end the pandemic. Graphical Keywords: SARS-CoV-2, Vaccine, Effectiveness, Safety, Meta-analysis
Due to its practicality, hybrid flowshop scheduling problem (HFSP) with productivity objective has been extensively explored. However, studies on HFSP considering green objective in distributed ...production environment are quite limited. Moreover, the current manufacturing mode is gradually evolving toward distributed co-production mode. Thus, this paper investigated a distributed hybrid flowshop scheduling problem (DHFSP) with objectives of minimization the makespan and total energy consumption (TEC). To address this problem, this paper designed a Pareto-based multi-objective hybrid iterated greedy algorithm (MOHIG) by integrating the merits of genetic operator and iterated greedy heuristic. In this MOHIG, firstly, one cooperative initialization strategy is proposed to boost initial solutions’ quality based on the previous experience and rules. Secondly, one knowledge-based multi-objective local search method is invented to enhance the exploitation capability according to characteristics of problem. Thirdly, an energy-saving technique is developed to decrease the idle energy consumption of machine tools. Furthermore, the effectiveness of each improvement component of MOHIG is assessed by three common indicators. Finally, the proposed MOHIG algorithm is compared with other multi-objective optimization algorithms, including SPEA2, MOEA/D, and NSGAII. Experimental results indicate that the proposed MOHIG outperforms its compared algorithms in solving this problem. In addition, this research can better guide practical production in some certain environments.
•Considering green scheduling in distributed hybrid flowshop environment.•Designing a new energy-saving strategy into this problem.•Proposing a Pareto-based multi-objective hybrid iterated greedy algorithm (MOHIG).•Evaluating performance of the proposed MOHIG by conducting comparison experiments.
Multiple sclerosis is characterized by inflammatory activity that results in destruction of the myelin sheaths that enwrap axons. The currently available medications for multiple sclerosis are ...predominantly immune-modulating and do not directly promote repair. White matter regeneration, or remyelination, is a new and exciting potential approach to treating multiple sclerosis, as remyelination repairs the damaged regions of the central nervous system. A wealth of new strategies in animal models that promote remyelination, including the repopulation of oligodendrocytes that produce myelin, has led to several clinical trials to test new reparative therapies. In this Review, we highlight the biology of, and obstacles to, remyelination. We address new strategies to improve remyelination in preclinical models, highlight the therapies that are currently undergoing clinical trials and discuss the challenges of objectively measuring remyelination in trials of repair in multiple sclerosis.
Identification of grain shape determining genes can facilitate breeding of rice cultivars with optimal grain shape and appearance quality. Here, we identify GS9 (Grain Shape Gene on Chromosome 9) ...gene by map-based cloning. The gs9 null mutant has slender grains, while overexpression GS9 results in round grains. GS9 encodes a protein without known conserved functional domain. It regulates grain shape by altering cell division. The interaction of GS9 and ovate family proteins OsOFP14 and OsOFP8 is modulated by OsGSK2 kinase, a key regulator of the brassinosteroids signaling pathway. Genetic interaction analysis reveals that GS9 functions independently from other previously identified grain size genes. Introducing the gs9 allele into elite rice cultivars significantly improves grain shape and appearance quality. It suggests potential application of gs9, alone or in combination with other grain size determining genes, in breeding of rice varieties with optimized grain shape.
The Himalaya, the world's highest mountain ranges, are home to a large group of glaciers and glacial lakes. Glacial lake outburst floods (GLOFs) in this region have resulted in catastrophic damages ...and fatalities in the past decades. The recent warming has caused dramatic glacial lake changes and increased potential GLOF risk in the Himalaya. However, our knowledge on the current state and change of glacial lakes in the entire Himalaya is limited. This study maps the current (2015) distribution of glacial lakes across the entire Himalaya and monitors the spatially-explicit evolution of glacial lakes over five time periods from 1990 to 2015 using a total of 348 Landsat images at 30m resolution. The results show that 4950 glacial lakes in 2015 cover a total area of 455.3±72.7km2, mainly located between 4000m and 5700m above sea level. Himalayan glacial lakes expanded by approximately 14.1% from 1990 to 2015. The changing patterns of supraglacial lakes and proglacial lakes are rather complex, involving both lake disappearance and emergence. Many emergent glacial lakes are found at higher elevations, especially the new proglacial lakes, which have formed as a result of glacier retreat. Spatially heterogeneous changes of Himalayan glacial lakes are observed, with the most significant expansion occurring in the southern slopes of the central Himalaya. Increasing glacier meltwater induced by the Himalayan atmospheric warming is a primary cause for the observed lake expansion. This study provides primary data for future GLOF risk assessments. A total of 118 rapidly expanded glacial lakes are identified as potential vulnerable lakes for the priority of risk assessment.
•Revealing the distribution of Himalayan glacial lakes using Landsat 8 images in 2015•Demonstrating the evolution and regional heterogeneity of Himalayan glacial lakes•Detecting the rapidly expanding glacial lakes with potential outburst risk
Glacial lake outburst flood (GLOF) is a serious hazard in high, mountainous regions. In the Himalayas, catastrophic risks of GLOFs have increased in recent years because most Himalayan glaciers have ...experienced remarkable downwasting under a warming climate. However, current knowledge about the distribution and recent changes in glacial lakes within the central Himalaya mountain range is still limited. Here, we conducted a systematic investigation of the glacial lakes within the entire central Himalaya range by using an object-oriented image processing method based on the Landsat Thematic Mapper (TM) or Enhanced Thematic Mapper (ETM) images from 1990 to 2010. We extracted the lake boundaries for four time points (1990, 2000, 2005 and 2010) and used a time series inspection method combined with a consistent spatial resolution of Landsat images that consistently revealed lake expansion. Our results show that the glacial lakes expanded rapidly by 17.11% from 1990 to 2010. The pre-existing, larger glacial lakes, rather than the newly formed lakes, contributed most to the areal expansion. The greatest expansions occurred at the altitudinal zones between 4800 m and 5600 m at the north side of the main Himalayan range and between 4500 m and 5600 m at the south side, respectively. Based on the expansion rate, area and type of glacial lakes, we identified 67 rapidly expanding glacial lakes in the central Himalayan region that need to be closely monitored in the future. The warming and increasing amounts of light-absorbing constituents of snow and ice could have accelerated the melting that directly affected the glacial lake expansion. Across the main central Himalayas, glacial lakes at the north side show more remarkable expansion than those at the south side. An effective monitoring and warning system for critical glacial lakes is urgently needed.
Glacial lake outburst floods (GLOFs) are a unique type of natural hazard in the cryosphere that may result in catastrophic fatalities and damages. The Himalayas are known as one of the world's most ...GLOF-vulnerable zones. Effective hazard assessments and risk management require a thorough inventory of historical GLOF events across the Himalayas, which is hitherto absent. Existing studies imply that numerous historical GLOF events are contentious because of discrepant geographic coordinates, names, or outburst time, requiring further verifications. This study reviews and verifies over 60 historical GLOF events across the Himalayas using a comprehensive method that combines literature documentations, archival remote sensing observations, geomorphological analysis, and field investigations. As a result, three unreported GLOF events were discovered from remote sensing images and geomorphological analysis. Eleven suspicious events were identified and suggested to be excluded. The properties of five outburst lakes, i.e., Degaco, Chongbaxia Tsho, Geiqu, Lemthang Tsho, and a lake on Tshojo Glacier, were corrected or updated. A total of 51 GLOF events were verified to be convincing, and these outburst lakes were classified into three categories according to their statuses in the past decades, namely disappeared (12), stable (30), and expanding (9). Statistics of the verified GLOF events show that GLOF tended to occur between April and October in the Himalayas. We suggest that more attention should be paid to rapidly expanding glacial lakes with high possibility of repetitive outbursts. This study also demonstrates the effectiveness of integrating remote sensing and geomorphic interpretations in identifying and verifying GLOF events in remote alpine environments. This inventory of GLOFs with a range of critical attributes (e.g., locations, time, and mechanisms) will benefit the continuous monitoring and prediction of potentially dangerous glacial lakes and contribute to outburst-induced risk assessments and hazard mitigations.
•Developed a comprehensive method to review and verify historical GLOF events•Verified the persuadability for over 60 Himalayan GLOF events•Revealed the statuses of Himalayan outburst lakes in the past decades•Constructed a GLOF inventory with many critical attributes for hazard assessments
The weak dominance relation between two binary operations was introduced as an extension of the dominance relation and the modularity equation. This paper continues the study of the weak dominance ...between t-norms and t-conorms. First, we present the characterization of the weak dominance of a nilpotent t-norm over a continuous Archimedean t-norm. Second, we establish the generalized sufficient and necessary conditions for the weak dominance of continuous t-norms over continuous t-norms. Finally, we obtain a generalized characterization of a continuous t-conorm weakly dominating a continuous t-norm by showing that SM weakly dominates any t-norm.
•Periodic accelerations of a lake-terminating glacier are linked to rapid frontal retreats.•Proglacial lake-ice interactions can greatly modify the ice flow regime.•Recent terminus acceleration has ...likely induced glacier upstream dynamic thinning.•In contrast, a neighboring land-terminating glacier shows on-going deceleration.
Most lake-terminating glaciers in the Himalaya retreat rapidly due to periodic frontal ice loss at their terminus, but long-term observations are still limited regarding their flow dynamics, which is crucial for understanding the processes of ice mass loss and proglacial lake growth. We present multi-decadal surface velocity dynamics of the Longbasaba Glacier, a rapid retreating lake-terminating glacier in the Chinese Himalaya, using an image feature tracking method applied on optical satellite images between 1989 and 2018. We show that, in companion with rapid retreat (−51.7 m a−1), its lower 5 km tongue experienced high interannual fluctuations in velocity, comprising periodic acceleration and slowdown in 1989-1995 and 2001-2010 and a recent remarkable acceleration since 2012. The temporal variation of longitudinal velocity distribution indicates an upward propagation of the lake-ward acceleration (namely a downglacier inversion of strain from compression to extension). This propagation is coupled to the retreat of the glacier front and occurs along the lowermost 1∼1.5 km lake-adjacent section as the proglacial lake expands. The most recent acceleration of the near-lake section since 2012 has likely facilitated a dynamic thinning on its upper sections, where flow acceleration started two years later in 2014. This pattern contrasts markedly with a nearby decelerating land-terminating glacier, which has experienced a much slower retreat rate (−7.8 m a−1) and the same magnitude of mean thinning rate at its lower part since 2000. Our results confirm the strong influence of the proglacial lake on ice flow dynamics and suggest that lake-ice interactions are important to consider when analyzing, interpreting or modeling dynamics of rapidly retreating lake-terminating glaciers in the Himalayas as well as around the world.
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