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Abstract Intratumoral cellular heterogeneity necessitates multi-targeting therapies for improved clinical benefits in advanced malignancies. However, systematic identification of patient-specific treatments that selectively co-inhibit cancerous cell populations poses a combinatorial challenge, since the number of possible drug-dose combinations vastly exceeds what could be tested in patient cells. Here, we describe a machine learning approach, scTherapy, which leverages single-cell transcriptomic profiles to prioritize multi-targeting treatment options for individual patients with hematological cancers or solid tumors. Patient-specific treatments reveal a wide spectrum of co-inhibitors of multiple biological pathways predicted for primary cells from heterogenous cohorts of patients with acute myeloid leukemia and high-grade serous ovarian carcinoma, each with unique resistance patterns and synergy mechanisms. Experimental validations confirm that 96% of the multi-targeting treatments exhibit selective efficacy or synergy, and 83% demonstrate low toxicity to normal cells, highlighting their potential for therapeutic efficacy and safety. In a pan-cancer analysis across five cancer types, 25% of the predicted treatments are shared among the patients of the same tumor type, while 19% of the treatments are patient-specific. Our approach provides a widely-applicable strategy to identify personalized treatment regimens that selectively co-inhibit malignant cells and avoid inhibition of non-cancerous cells, thereby increasing their likelihood for clinical success.

Abstract Background Downy mildew is a plant disease that affects all cultivated European grapevine varieties. The disease is caused by the oomycete Plasmopara viticola. The current strategy to control this threat relies on repeated applications of fungicides. The most eco-friendly and sustainable alternative solution would be to use bred-resistant varieties. During breeding programs, some wild Vitis species have been used as resistance sources to introduce resistance loci in Vitis vinifera varieties. To ensure the durability of resistance, resistant varieties are built on combinations of these loci, some of which are unfortunately already overcome by virulent pathogen strains. The development of a high-throughput machine learning phenotyping method is now essential for identifying new resistance loci. Results Images of grapevine leaf discs infected with P. viticola were annotated with OIV 452–1 values, a standard scale, traditionally used by experts to assess resistance visually. This descriptor takes two variables into account the complete phenotype of the symptom: sporulation and necrosis. This annotated dataset was used to train neural networks. Various encoders were used to incorporate prior knowledge of the scale’s ordinality. The best results were obtained with the Swin transformer encoder which achieved an accuracy of 81.7%. Finally, from a biological point of view, the model described the studied trait and identified differences between genotypes in agreement with human observers, with an accuracy of 97% but at a high-throughput 650% faster than that of humans. Conclusion This work provides a fast, full pipeline for image processing, including machine learning, to describe the symptoms of grapevine leaf discs infected with P. viticola using the OIV 452–1, a two-symptom standard scale that considers sporulation and necrosis. If symptoms are frequently assessed by visual observation, which is time-consuming, low-throughput, tedious, and expert dependent, the method developed sweeps away all these constraints. This method could be extended to other pathosystems studied on leaf discs where disease symptoms are scored with ordinal scales.

Abstract The Summer Olympic Games in 2024 will take place during the apex of the temperature seasonal cycle in the Paris Area. The mid-latitudes of the Northern hemisphere have witnessed a few intense heatwaves since the 2003 event. Those heatwaves have had environmental and health impacts, which often came as surprises. In this paper, we search for the most extreme heatwaves in Ile-de-France that are physically plausible, under climate change scenarios, for the decades around 2024. We circumvent the sampling limitation by applying a rare event algorithm on CMIP6 data to evaluate the range of such extremes. We find that the 2003 record can be exceeded by more than 4 °C in Ile-de-France before 2050, with a combination of prevailing anticyclonic conditions and cut-off lows. This study intends to raise awareness of those unprecedented events, against which our societies are ill-prepared, in spite of adaptation measures designed from previous events. Those results could be extended to other areas of the world.

Abstract Since the first applications of nanohoops in organic electronics appear promising, the time has come to go deeper into their rational design in order to reach high‐efficiency materials. To do so, systematic studies dealing with the incorporation of electron‐rich and/or electron‐poor functional units on nanohoops have to be performed. Herein, the synthesis, the electrochemical, photophysical, thermal, and structural properties of two [4]cyclo‐2,7‐carbazoles, [4]C‐Py‐Cbz, and [4]C‐Pm‐Cbz, possessing electron‐withdrawing units on their nitrogen atoms (pyridine or pyrimidine) are reported. The synthesis of these nanohoops is first optimized and a high yield above 50% is reached. Through a structure‐properties relationship study, it is shown that the substituent has a significant impact on some physicochemical properties (eg HOMO/LUMO levels) while others are kept unchanged (eg fluorescence). Incorporation in electronic devices shows that the most electrically efficient Organic Field‐Effect transistors are obtained with [4]C‐Py‐Cbz although this compound does not present the best‐organized semiconductor layer. These experimental data are finally confronted with the electronic couplings between the nanohoops determined at the DFT level and have highlighted the origin in the difference of charge transport properties. [4]C‐Py‐Cbz has the advantage of a more 2D‐like transport character than [4]C‐Pm‐Cbz, which alleviates the impact of defects and structural organization.

Abstract Chiral molecules are known to behave as spin filters due to the chiral induced spin selectivity (CISS) effect. Chirality can be implemented in molecular semiconductors in order to study the role of the CISS effect in charge transport and to find new materials for spintronic applications. In this study, the design and synthesis of a new class of enantiopure chiral organic semiconductors based on the well‐known dinaphtho[2,3‐b:2,3‐f]thieno[3,2‐b]thiophene (DNTT) core functionalized with chiral alkyl side chains is presented. When introduced in an organic field‐effect transistor (OFET) with magnetic contacts, the two enantiomers, (R)‐DNTT and (S)‐DNTT, show an opposite behavior with respect to the relative direction of the magnetization of the contacts, oriented by an external magnetic field. Each enantiomer displays an unexpectedly high magnetoresistance over one preferred orientation of the spin current injected from the magnetic contacts. The result is the first reported OFET in which the current can be switched on and off upon inversion of the direction of the applied external magnetic field. This work contributes to the general understanding of the CISS effect and opens new avenues for the introduction of organic materials in spintronic devices.

BackgroundProlapse is one of the sub-types of pelvic floor dysfunction (PFD) which occurs due to abnormal fall of the pelvic organs from their normal anatomic positions. Although the cause of prolapse is multifactorial, it primarily occurs due to pregnancy and vaginal delivery. Hence, the present study aimed to identify risk factors of prolapse among women who undergo gynecological surgery.Materials and methodsFacility-based-unmatched case–control design was employed. Cases were all gynecological women who were diagnosed with pelvic organ prolapse (POP) at Asella teaching referral hospital (ATRH) while controls were all charts of gynecological women who were diagnosed with other gynecological problems rather than POP at ATRH. For each case, two controls were selected using a simple random sampling technique. The data were entered into Epidata version 4.3.1 and finally exported to SPSS version 25 for further analysis. Then variables that had an association in the bivariate model (p < 0.25) were entered and analyzed by a multivariable conditional logistic regression model to identify the independent effect of different factors. Statistical significance was declared at p < 0.05.ResultsA total of 147 cases and 293 controls were included in this study. Women who had a history of chronic cough, previous pelvic floor surgery, constipation, and vaginal tear during delivery, history of pelvic trauma, age of the women, rural resident, and maternal gravidity were strongly associated with prolapse at p-value of < 0.05. Multigravida [adjusted odds ratio (AOR) 2.987 (95% CI 1.237–6.853), p = 0.014], age >50 years [AOR: 2.496 (95% CI 1.372–4.539), p = 0.003], women with a history of pelvic floor surgery [AOR: 0.3.666 (95% CI 1.328–10.124), p = 0.012], women who had diabetes mellitus [AOR: 4.676 (95% CI 0.908–24.075), p = 0.065], and resided in rural areas [AOR = 1.878; (95% CI: 0.984–3.585), I2 = 47.5%, p = 0.056] were the independent predictors were of prolapse.ConclusionsIn this study, women with diabetes mellitus, previous pelvic floor surgery, rural residents, being multigravida, and age >40 were independent predictors of prolapse. Therefore, delivering health education by focusing on the identified risk factors was strongly recommended.

Abstract The charge transport of crystalline organic semiconductors is limited by dynamic disorder that tends to localize charges. It is the main hurdle to overcome in order to significantly increase charge carrier mobility. An innovative design that combines a chemical structure based on sulfur‐rich thienoacene with a solid‐state herringbone (HB) packing is proposed and the synthesis, physicochemical characterization, and charge transport properties of two new thienoacenes bearing a central tetrathienyl core fused with two external naphthyl rings: naphtho[2,3‐b]thieno‐[2′′′,3′′′:4′′,5′′]thieno[2″,3″:4′,5′]thieno[3′,2′‐b]naphtho[2,3‐b]thiophene (DN4T) and naphtho[1,2‐b]thieno‐[2′′′,3′′′:4′′,5′′]thieno[2′′,3′′:4′,5′]thieno[3′,2′‐b]naphtho[1,2‐b]thiophene are presented. Both compounds crystallize with a HB pattern structure and present transfer integrals ranging from 33 to 99 meV (for the former) within the HB plane of charge transport. Molecular dynamics simulations point toward an efficient resilience of the transfer integrals to the intermolecular sliding motion commonly responsible for strong variations of the electronic coupling in the crystal. Best device performances are reached with DN4T with hole mobility up to μ = 2.1 cm2 V−1s−1 in polycrystalline organic field effect transistors, showing the effectiveness of the electronic coupling enabled by the new aromatic core. These promising results pave the way to the design of high‐performing materials based on this new thienoacene, notably through the introduction of alkyl side‐chains.

Estimation methods are continuously being adapted to obtain better and clearer estimations needed to achieve development goals. Some estimation methods were invented before the modern mobile application technology that is currently available. Thus, these methods are unable to cater to the requirements for estimating modern mobile application features. The objective of this paper is to propose a web-based system as a method to estimate the effort and cost of developing a mobile application. The key idea behind this study is to identify cost drivers that can be applied in mobile application development through literature review. From the analysis, 19 cost drivers are found to fit the vision of this study. In addition, this study also seeks to investigate the price range of cost drivers acquired from existing similar systems. The total price range is accumulated, and the mean value of each cost driver is obtained, which is then inserted further into the new estimation metric. The proposed system is then evaluated by comparing the obtained results with six similar systems according to basic user needs requirements in an application. The results demonstrate that the proposed system is a more enhanced cost estimation software that contains more cost driver options, which users can utilize to estimate mobile application development costs.

Abstract Background PTI and ETI are the two major defence mechanisms in plants. ETI is triggered by the detection of pathogen effectors, or their activity, in the plant cell and most of the time involves internal receptors known as resistance (R) genes. An increasing number of R genes responsible for recognition of specific effectors have been characterised over the years; however, methods to identify R genes are often challenging and cannot always be translated to crop plants. Results We present a novel method to identify R genes responsible for the recognition of specific effectors that trigger a hypersensitive response (HR) in Nicotiana benthamiana. This method is based on the genome-wide identification of most of the potential R genes of N. benthamiana and a systematic silencing of these potential R genes in a simple transient expression assay. A hairpin-RNAi library was constructed covering 345 R gene candidates of N. benthamiana. This library was then validated using several previously described R genes. Our approach indeed confirmed that Prf, NRC2a/b and NRC3 are required for the HR that is mediated in N. benthamiana by Pto/avrPto (prf, NRC2a/b and NRC3) and by Cf4/avr4 (NRC2a/b and NRC3). We also confirmed that NRG1, in association with N, is required for the Tobacco Mosaic Virus (TMV)-mediated HR in N. benthamiana. Conclusion We present a novel approach combining bioinformatics, multiple-gene silencing and transient expression assay screening to rapidly identify one-to-one relationships between pathogen effectors and host R genes in N. benthamiana. This approach allowed the identification of previously described R genes responsible for detection of avirulence determinants from Pseudomonas, Cladosporium and TMV, demonstrating that the method could be applied to any effectors/proteins originating from a broad range of plant pathogens that trigger an HR in N. benthamiana. Moreover, with the increasing availability of genome sequences from model and crop plants and pathogens, this approach could be implemented in other plants, accelerating the process of identification and characterization of novel resistance genes.

The remote viewing research conducted at Stanford Research Institute (SRI) and later at Science Applications International Corporation (SAIC) was covered in The Star Gate Archives Volumes 1 and 2, both reviewed in this journal (see Mörck, 2018, 2019). Less well-known is the fact that much psychokinesis (PK) research was also carried out. This research “ . . . was never intended to be an academic exercise typical of most laboratories. Rather, the only interest was to determine the degree to which PK might be used as part of a defensive or even offensive weapon system” (p. 12). This sounds dramatic. To U.S. intelligence agencies, a proper threat assessment was deemed necessary due to research conducted in the Soviet Union. The research in America, at SRI, was initially directed by Harold Puthoff from 1972 on, and later, for about ten years, by one of the volume’s editors, Edwin May. In addition to research reports and reviews, Volume 3, like its predecessor volumes, includes nine appendixes, a list of abbreviations, an extensive glossary, an author index, and a subject index. The papers are arranged chronologically, but it is not necessarily a good idea to read them in that order.

Background The bacterial plant pathogenic Ralstonia species belong to the beta-proteobacteria class and are soil-borne pathogens causing vascular bacterial wilt disease, affecting a wide range of plant hosts. These bacteria form a heterogeneous group considered as a “species complex” gathering three newly defined species. Like many other Gram negative plant pathogens, Ralstonia pathogenicity relies on a type III secretion system, enabling bacteria to secrete/inject a large repertoire of type III effectors into their plant host cells. Type III-secreted effectors (T3Es) are thought to participate in generating a favorable environment for the pathogen (countering plant immunity and modifying the host metabolism and physiology). Methods Expert genome annotation, followed by specific type III-dependent secretion, allowed us to improve our Hidden-Markov-Model and Blast profiles for the prediction of type III effectors. Results We curated the T3E repertoires of 12 plant pathogenic Ralstonia strains, representing a total of 12 strains spread over the different groups of the species complex. This generated a pangenome repertoire of 102 T3E genes and 16 hypothetical T3E genes. Using this database, we scanned for the presence of T3Es in the 155 available genomes representing 140 distinct plant pathogenic Ralstonia strains isolated from different host plants in different areas of the globe. All this information is presented in a searchable database. A presence/absence analysis, modulated by a strain sequence/gene annotation quality score, enabled us to redefine core and accessory T3E repertoires.

Much has been written about the Global Consciousness Project (GCP), including in this Journal. Parapsychology: A Handbook for the 21st Century included a chapter about the GCP (Nelson 2015). The author of this book has been involved in the GCP since its onset in 1998. . . . the way to get on with the research is to listen to the whispers of serendipity. Approach new experiments with a fully open mind and the intention to take hints and surprising suggestions. Coincidence is your friend. The GCP had its beginnings in a long series of coincidences . . . (p. 39) Nelson knows the origin story better than anyone else and relates it in the book. In the late 1960s, Helmut Schmidt (1928–2011), a physicist at Boeing Science Research Laboratories, developed quantum-based random number generators (RNGs) which he used in experiments; the participants were supposed to predict or influence their output: “. . . Schmidt never sought credit or glory. Years after Schmidt’s devices were in use in numerous labs, his design was patented by others who cited his work in the patent document but did not acknowledge him as the key inventor” (Schlitz 2011:353). Schmidt was aware of the possible influence of the experimenter and gave a presentation about it (Schmidt 1974) before parapsychologists started to review their extensive literature about experimenter effects. Schmidt’s (2009) worries about the GCP concerned the possible influence of the experimenter.

The parapsychological research by Harold Puthoff, Russell Targ, and their colleagues at SRI International during the 1970s and early 1980s was covered in my review of The Star Gate Archives Volume 1 (Mörck 2018). This was an explorative period during which focus was on applications. Targ had to leave in 1982, and Puthoff, the director of research, left in 1985; one of the Editors, Edwin May, became the new director of research. During the 1980s and early 1990s much basic research was conducted and oversight increased. Among the members of the oversight committees were Daryl Bem, Robert Morris, Melvin Schwartz, and Philip Zimbardo. Comments from the Scientific Oversight Committee are attached to some of the reproduced documents. The names used for the program between 1985 and 1995 were Dragoon Absorb, Sun Streak, and Star Gate. Volume 2 consists of a collection of unclassified reports and declassified documents. The anthology also includes nine appendixes, a list of abbreviations, an extensive glossary, an author index, and a subject index. Brief comments about all reproduced documents can be found in the volume’s Introduction.