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The birth of a baby or the hatching of an egg are moments when the risk of predation is particularly high. In oviparous species where clutches contain many eggs, one strategy for limiting predation is based on mechanisms that synchronise hatching, which reduces the individual risk of being targeted and may allow hatchlings to emerge under parental protection. These mechanisms involve communication signals between eggs and between eggs and parents. While previous studies in various species have shown the importance of sound and vibration signals in these exchanges, how embryos integrate this information remains poorly understood. Here we show that crocodile embryos respond differently to calls emitted by siblings (hatching calls) and to vibrations mimicking parental intervention (rubbing and scratching the shell) or the presence of a predator, suggesting that these two stimuli carry different information. Through playback experiments, we confirm that hatching calls elicit vocal responses and synchronous hatching in mature embryos, while embryos hatch earlier when they perceive vibrations. Our study underlines that the control of hatching by external factors can rely on differential apprehension of multiple sensory inputs by embryos. [ABSTRACT FROM AUTHOR]

It is generally argued that distress vocalizations, a common modality for alerting conspecifics across a wide range of terrestrial vertebrates, share acoustic features that allow heterospecific communication. Yet studies suggest that the acoustic traits used to decode distress may vary between species, leading to decoding errors. Here we found through playback experiments that Nile crocodiles are attracted to infant hominid cries (bonobo, chimpanzee and human), and that the intensity of crocodile response depends critically on a set of specific acoustic features (mainly deterministic chaos, harmonicity and spectral prominences). Our results suggest that crocodiles are sensitive to the degree of distress encoded in the vocalizations of phylogenetically very distant vertebrates. A comparison of these results with those obtained with human subjects confronted with the same stimuli further indicates that crocodiles and humans use different acoustic criteria to assess the distress encoded in infant cries. Interestingly, the acoustic features driving crocodile reaction are likely to be more reliable markers of distress than those used by humans. These results highlight that the acoustic features encoding information in vertebrate sound signals are not necessarily identical across species. [ABSTRACT FROM AUTHOR]

Anthropogenic noise has the potential to alter community dynamics by modifying the strength of nested ecological interactions such as predation. Direct effects of noise on per capita predation rates have received much attention but the context in which predation occurs is often oversimplified. For instance, many animals interact with conspecifics while foraging and these nontrophic interactions can positively or negatively influence per capita predation rates. These effects are often referred to as multiple‐predator effects (MPEs). The extent to which noise can modulate MPEs and thereby indirectly alter per capita predation remains unknown. To address this question, we derived the relationship between per capita predation rate and prey density, namely the functional response (FR), of single and pairs of the invasive topmouth gudgeon Pseudorasbora parva when feeding on water fleas under two noise conditions: control ambient noise estimated at 95 dB re 1 μPa and ambient noise supplemented with motorboat sounds whose relative importance over ambient noise ranged from 4.81 to 27 dB. In addition, we used video recordings to track fish movements. To detect MPEs, we compared the observed group‐level FRs to predicted group‐level FRs inferred from the individual FRs and based on additive effects only. Regardless of the number of fish and the noise condition, the FR was always of type II, showing predation rate in a decelerating rise to an upper asymptote. Compared to the noiseless condition, the predation rate of single fish exposed to noise did not differ at high prey densities but was significantly lower at low prey densities, resulting in an FR with the same asymptote but a less steep initial slope. Noise also reduced fish mobility, which might explain the decrease in predation rate at low prey densities. Conspecific presence suppressed the individual response to noise, the FRs of two fish (observed group‐level FRs) being perfectly similar between the two noise conditions. Although observed and predicted group‐level FRs did not differ significantly, observed group‐level FRs tended to fall in the low range of predicted group‐level FRs, suggesting antagonism and a negative effect of nontrophic interactions on individual foraging performance. Interestingly, the difference between predicted and observed group‐level FRs was not greater with noise, which means that noise did not strengthen MPEs. Our results show that when considering the social context of foraging, here through the presence of a conspecific, anthropogenic noise does not compromise foraging in the invasive P. parva. [ABSTRACT FROM AUTHOR]

Laparoscopic cholecystectomy (LC) is one of the most commonly performed surgical procedures worldwide. A previous abdominal operation is not considered a significant risk factor for conversion to open cholecystectomy. We describe the case of an 80-year-old woman with a surgical history of a giant uncomplicated incisional midline hernia presenting at our department with choledocholithiasis and acute cholangitis. After an ERCP with extraction of common bile duct stones, a LC was planned. The first trocar was inserted in the right midclavicular line, using an open technique and a careful inspection of the abdominal cavity and the hernia sac content. An uncomplicated cholecystectomy was performed and the postoperative course was uneventful. [ABSTRACT FROM AUTHOR]

Tolerance to human‐induced environmental stressors is known to contribute to the spread and success of invasive species but their response to anthropogenic noise has still to be explored. Anthropogenic noise might modulate the trophic impact of invasive species and their competitiveness against native species.We used an ecological approach through the derivation of the functional response to test whether the strength of the trophic interaction between the invasive pumpkinseed sunfish and Chaoborus larvae was influenced by motorboat noise, with or without pre‐exposure.Boat noise decreased maximum feeding rate in the fish that never experienced boat noise before, resulting in a lower functional response compared to the ambient noise condition. We hypothesised that fish were distracted and reallocated a part of their finite attention to this new acoustic stimulus at the expense of prey processing.The distraction effect weakened with repeated exposure suggesting a habituation process. Although we cannot exclude persistent adjustments in behaviour, we did not find evidence for altered predation by fish pre‐exposed to boat noise.Pumpkinseed sunfish did not exhibit clear symptoms of a behavioural stress response. Chaoborus movements were more numerous under boat noise but this was unlikely to influence trophic interaction strength relative to fish behaviour. Local species might experience increased trophic competition if they are disturbed and do not habituate contrary to invasive species. [ABSTRACT FROM AUTHOR]

Interfacing standard optical fibers with high index-contrast photonic waveguides remains a substantial challenge restricting the cost-efficiency and scalability of silicon photonic devices. To address this, we have proposed a mechanically compliant polymer interface, formed of a standard fiber connection and a flexible ribbon with lithographically defined polymer waveguides. Self-aligned mechanical assembly and optical mode evolution designs are employed for low cost and large spectral bandwidth. In this paper, we review our progress leading to the full demonstration of this concept with −1.8 dB peak transmission from a plugged-in standard fiber connector to Si wire waveguides. This with 0.7 dB roll-off on a 100 nm bandwidth and all polarization. We present a comprehensive analysis of loss sources and discuss intermediate results, self-alignment accuracy, and reliability. [ABSTRACT FROM AUTHOR]

Anthropogenic noise can affect animals physically, physiologically, and behaviourally. Although individual responses to noise are well documented, the consequences in terms of community structure, species coexistence, and ecosystem functioning remain fairly unknown.The impact of noise on predation has received a growing interest and alterations in trophic links are observed when animals shift from foraging to stress‐related behaviours, are distracted by noise, or because of acoustic masking. However, the experimental procedures classically used to quantify predation do not inform on the potential demographic impact on prey.We derived the relationship between resource use and availability (the functional response) for European minnows (Phoxinus phoxinus) feeding on dipteran larvae (Chaoborus sp.) under two noise conditions: ambient noise and ambient noise supplemented with motorboat noise. The shape and magnitude of the functional response are powerful indicators of population outcomes and predator–prey dynamics. We also recorded fish behaviour to explore some proximate determinants of altered predation.For both noise conditions, fish displayed a saturating (type II) functional response whose shape depends on two parameters: attack rate and handling time. Boat noise did not affect handling time but significantly reduced attack rate, resulting in a functional response curve of the same height but with a less steep initial slope. Fish exhibited a stress‐related response to noise including increased swimming distance, more social interactions, and altered spatial distribution.Our study shows the usefulness of the functional response approach to study the ecological impacts of noise and illustrates how the behavioural responses of predators to noise can modify the demographic pressure on prey. It also suggests that prey availability might mediate the negative effect of noise on predation. Community outcomes are expected if the reduced consumption of the main food sources goes with the overconsumption of alternative food sources, changing the distribution pattern of interaction strengths. Predation release could also trigger a trophic cascade, propagating the effect of noise to lower trophic levels. [ABSTRACT FROM AUTHOR]

Improving the scalability and cost efficiency of photonic packaging is central to fulfilling the silicon photonic promise of low-cost devices with unprecedented optical complexity. A key enabler toward this goal is an efficient, large-mode, integrated fiber coupler and mode converter. Using standard fiber modes at fiber-to-chip junctions avoids expensive in-fiber mode conversion and relaxes alignment tolerances for low-cost assembly and improved reliability. Metamaterial waveguides, also called subwavelength gratings, are particularly useful for such structures. They provide unmatched design flexibility and, counter-intuitively, are more forgiving to fabrication tolerances than solid-core waveguides. Here, we summarize our work on interfacing self-aligned, standard cleaved fibers to rectangular Si routing waveguides. Fiber V-grooves are integrated on chip with metamaterial converters embedded in suspended oxide membranes to prevent coupler-mode leakage to the substrate. We show optical results from first integration of V-grooves with metamaterial converters to commercial structures fabricated in 300 mm CMOS production facilities. We demonstrate a peak transmission of −0.7 dB on the TE polarization and –1.4 dB on the TM polarization with a respective spectral roll-off of 0.3 and 0.4 dB over the 60 nm bandwidth measured. [ABSTRACT FROM AUTHOR]

Pelargonium genus contains about 280 species among which at least 30 species are odorant. Aromas produced by scented species are remarkably diverse such as rose, mint, lemon, nutmeg, ginger and many others scents. Amongst odorant species, rose-scented pelargoniums, also named pelargonium rosat, are the most famous hybrids for their production of essential oil (EO), widely used by perfume and cosmetic industries. Although EO composition has been extensively studied, the underlying biosynthetic pathways and their regulation, most notably of terpenes, are largely unknown. To gain a better understanding of the terpene metabolic pathways in pelargonium rosat, we generated a transcriptome dataset of pelargonium leaf and used a candidate gene approach to functionally characterise four terpene synthases (TPSs), including a geraniol synthase, a key enzyme responsible for the biosynthesis of the main rose-scented terpenes. We also report for the first time the characterisation of a novel sesquiterpene synthase catalysing the biosynthesis of 10-epi-γ-eudesmol. We found a strong correlation between expression of the four genes encoding the respective TPSs and accumulation of the corresponding products in several pelargonium cultivars and species. Finally, using publically available RNA-Seq data and de novo transcriptome assemblies, we inferred a maximum likelihood phylogeny from 270 pelargonium TPSs, including the four newly discovered enzymes, providing clues about TPS evolution in the Pelargonium genus. Notably, we show that, by contrast to other TPSs, geraniol synthases from the TPS-g subfamily conserved their molecular function throughout evolution. [ABSTRACT FROM AUTHOR]

Abstract: The tachykinin NK1 and NK3 receptors are a novel drug target for schizophrenia in order to treat not only the positive and cognitive symptoms, but also the associated co-morbid depression and sleep disturbances associated with the disease. A novel class of peptidomimetic derivatives based on a versatile phenylglycine central core was synthesized and tested in vitro as dual NK1/NK3 receptor antagonists. From this series emerged compounds with good NK1 receptor affinity, although only modest dual NK1/NK3 receptor affinity was observed with one of these analogs. [Copyright &y& Elsevier]

Median arcuate ligament syndrome (MALS) poses a rare challenge in diagnosis and management. We present a case of MALS in a 50-year-old male with recurrent epigastric pain, vomiting, and diarrhea. Diagnostic imaging revealed celiac artery stenosis and gastroduodenal artery collateral dilatation. Robotic-assisted median arcuate ligament release successfully alleviated symptoms. Utilizing the da Vinci X system (Intuitive Surgical, Inc.), the procedure involved meticulous dissection of the celiac artery and surrounding tissue. Postoperative duplex ultrasound confirmed improved arterial flow. Literature underscores the diagnostic hurdles of MALS and the advantages of minimally invasive approaches over conventional open surgery. The robotic approach may help smoothen the learning curve associated with this procedure, by providing improved operative flexibility. Patient outcomes are excellent, with long-term symptom relief in most cases.

It is generally argued that distress vocalizations, a common modality for alerting conspecifics across a wide range of terrestrial vertebrates, share acoustic features that allow heterospecific communication. Yet studies suggest that the acoustic traits used to decode distress may vary between species, leading to decoding errors. Here we found through playback experiments that Nile crocodiles are attracted to infant hominid cries (bonobo, chimpanzee and human), and that the intensity of crocodile response depends critically on a set of specific acoustic features (mainly deterministic chaos, harmonicity and spectral prominences). Our results suggest that crocodiles are sensitive to the degree of distress encoded in the vocalizations of phylogenetically very distant vertebrates. A comparison of these results with those obtained with human subjects confronted with the same stimuli further indicates that crocodiles and humans use different acoustic criteria to assess the distress encoded in infant cries. Interestingly, the acoustic features driving crocodile reaction are likely to be more reliable markers of distress than those used by humans. These results highlight that the acoustic features encoding information in vertebrate sound signals are not necessarily identical across species.

Macrocyclic peptides have the potential to address intracellular protein-protein interactions (PPIs) of high value therapeutic targets that have proven largely intractable to small molecules. Here, we report broadly applicable lessons for applying this modality to intracellular targets and specifically for advancing chemical matter to address KRAS, a protein that represents the most common oncogene in human lung, colorectal and pancreatic cancers yet is one of the most challenging targets in human disease. Specifically, we focused on KRpep-2d, an arginine-rich KRAS-binding peptide with a disulfide-mediated macrocyclic linkage and a protease-sensitive backbone. These latter redox and proteolytic labilities obviated cellular activity. Extensive structure-activity relationship studies involving macrocyclic linker replacement, stereochemical inversion, and backbone α-methylation, gave a peptide with on-target cellular activity. However, we uncovered an important generic insight - the arginine-dependent cell entry mechanism limited its therapeutic potential. In particular, we observed a strong correlation between net positive charge and histamine release in an ex vivo assay, thus making this series unsuitable for advancement due to the potentially fatal consequences of mast cell degranulation. This observation should signal to researchers that cationic-mediated cell entry - an approach that has yet to succeed in the clinic despite a long history of attempts - carries significant therapy-limiting safety liabilities. Nonetheless, the cell-active molecules identified here validate a unique inhibitory epitope on KRAS and thus provide valuable molecular templates for the development of therapeutics that are desperately needed to address KRAS-driven cancers - some of the most treatment-resistant human malignancies., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

Macrocyclic peptides open new opportunities to target intracellular protein-protein interactions (PPIs) that are often considered nondruggable by traditional small molecules. However, engineering sufficient membrane permeability into these molecules is a central challenge for identifying clinical candidates. Currently, there is a lack of high-throughput assays to assess peptide permeability, which limits our capacity to engineer this property into macrocyclic peptides for advancement through drug discovery pipelines. Accordingly, we developed a high throughput and target-agnostic cell permeability assay that measures the relative cumulative cytosolic exposure of a peptide in a concentration-dependent manner. The assay was named NanoClick as it combines in-cell Click chemistry with an intracellular NanoBRET signal. We validated the approach using known cell penetrating peptides and further demonstrated a correlation to cellular activity using a p53/MDM2 model system. With minimal change to the peptide sequence, NanoClick enables the ability to measure uptake of molecules that enter the cell via different mechanisms such as endocytosis, membrane translocation, or passive permeability. Overall, the NanoClick assay can serve as a screening tool to uncover predictive design rules to guide structure-activity-permeability relationships in the optimization of functionally active molecules.

Ni/photoredox (4DPAIPN) dual catalysis enabled challenging peptide C(sp 2 )-O coupling reactions. Successful cross-coupling reactions were demonstrated with highly functionalized alcohols including side chains of amino acids ( i.e. , serine, threonine, tyrosine), trans -4-hydroxy-l-proline, alkyl alcohols, alkynylated alcohols, and carbohydrates. Coupling reactions between bromobenzoyl-capped peptides containing various side chains and either a protected serine building block or a serine-containing dipeptide also proceeded efficiently. Chemoselective C-O coupling (over C-N) was achieved in intermolecular reactions in the presence of a C-terminal primary amide. Furthermore, by judicious structural design in combination with computational modeling, we demonstrated side chain-to-tail macrocyclization of peptides containing a β-turn motif via C-O coupling. The methodology developed in this work brings new opportunities for late-stage diversification of complex linear and macrocyclic peptides.

Communication is essential during social interactions including animal conflicts and it is often a complex process involving multiple sensory channels or modalities. To better understand how different modalities interact during communication, it is fundamental to study the behavioural responses to both the composite multimodal signal and each unimodal component with adequate experimental protocols. Here we test how an African cichlid, which communicates with multiple senses, responds to different sensory stimuli in a social relevant scenario. We tested Maylandia zebra males with isolated chemical (urine or holding water coming both from dominant males), visual (real opponent or video playback) and acoustic (agonistic sounds) cues during agonistic interactions. We showed that (1) these fish relied mostly on the visual modality, showing increased aggressiveness in response to the sight of a real contestant but no responses to urine or agonistic sounds presented separately, (2) video playback in our study did not appear appropriate to test the visual modality and needs more technical prospecting, (3) holding water provoked territorial behaviours and seems to be promising for the investigation into the role of the chemical channel in this species. Our findings suggest that unimodal signals are non-redundant but how different sensory modalities interplay during communication remains largely unknown in fish., Competing Interests: The authors declare there are no competing interests.

Animals routinely receive information through different sensory channels, and inputs from a modality may modulate the perception and behavioural reaction to others. In spite of their potential adaptive value, the behavioural correlates of this cross-sensory modulation have been poorly investigated. Due to their predator life, crocodilians deal with decisional conflicts emerging from concurrent stimuli. By testing young Crocodylus niloticus with sounds in the absence or presence of chemical stimuli, we show that (i) the prandial (feeding) state modulates the responsiveness of the animal to a congruent, i.e. food-related olfactory stimulus, (ii) the prandial state alters the responsiveness to an incongruent (independent of food) sound, (iii) fasted, but not sated, crocodiles display selective attention to socially relevant sounds over noise in presence of food odour. Cross-sensory modulation thus appears functional in young Nile crocodiles. It may contribute to decision making in the wild, when juveniles use it to interact acoustically when foraging., Competing Interests: We declare we have no competing interests.

In connection with a program directed at potent and balanced dual NK1/NK3 receptor ligands, a focused exploration of an original class of peptidomimetic derivatives was performed. The rational design and molecular hybridization of a novel phenylalanine core series was achieved to maximize the in vitro affinity and antagonism at both human NK1 and NK3 receptors. This study led to the identification of a new potent dual NK1/NK3 antagonist with pK i values of 8.6 and 8.1, respectively.

The epipolythiodiketopiperazine (ETP) alkaloids are a highly complex class of natural products with potent anticancer activity. Herein, we report the application of a flexible and scalable synthesis, allowing the construction of dozens of ETP derivatives. The evaluation of these compounds against cancer cell lines in culture allows for the first expansive structure-activity relationship (SAR) to be defined for monomeric and dimeric ETP-containing natural products and their synthetic cognates. Many ETP derivatives demonstrate potent anticancer activity across a broad range of cancer cell lines, and kill cancer cellsviainduction of apoptosis. Several traits thatbode well for the translational potential of the ETP class of natural products includeconcise and efficient synthetic access, potent induction of apoptotic cell death, activity against a wide range of cancer types, and a broad tolerance for modifications at multiple sitesthat should facilitate small-molecule drug development, mechanistic studies, and evaluation in vivo .

The first total synthesis of (+)-gliocladin B is described. Our concise and enantioselective synthesis takes advantage of a new regioselective Friedel-Crafts-based strategy to provide an efficient multigram-scale access to the C3-(3'-indolyl)hexahydropyrroloindole substructure, a molecular foundation present in a significant subset of epipolythiodiketopiperazine natural alkaloids. Our first-generation solution to (+)-gliocladin B involved the stereoselective formation of (+)-12-deoxybionectin A, a plausible biosynthetic precursor. Our synthesis clarified the C15 stereochemistry of (+)-gliocladin B and allowed its full structure confirmation. Further studies of a versatile dihydroxylated diketopiperazine provided a concise and efficient synthesis of (+)-gliocladin B as well as access to (+)-gliocladin C.

An efficient, high-yielding strategy has been developed for the asymmetric total synthesis of seven norditerpenoid dilactones known for their diverse biological properties. The three key steps employed to obtain a tricyclic lactone intermediate involved a Morita-Baylis-Hillman reaction, the stereocontrolled construction of a gamma-lactone through bromolactonization, and an efficient catalytic Reformatsky-type reaction. Access to CJ-14,445, LL-Z1271gamma, oidiolactones A, B, C, and D, and nagilactone F was possible from a common intermediate. Structures and stereochemistry were determined by X-ray analysis.