bluuebunny/crossref_metadata_2025 huggingface dataset:
Four scenarios in which shadow competition should be prominent and factors affecting its strength
Authors: Scharf Inon , Ruxton Graeme D.
Published: October 2023

Shadow competition is the interception of moving prey by a predator closer to its arrival source, preventing its availability to predators downstream. Shadow competition is likely common in nature, and unlike some other competition types, has a strong spatial component (with the exception of competition for space, which clearly also has a spatial component). We used an individual‐based spatially‐explicit simulation model to examine whether shadow competition takes place and which factors affect it in four scenarios considering ambush predators and active prey. First, when prey capture is uncertain (‘the ricochet effect'). Here, the strength of shadow competition increases when it is harder to capture prey after the first unsuccessful capture attempt, whereas shadow competition is moderated if capture success is higher in successive attempts. Second, shadow competition becomes stronger when predators can capture prey arriving only from certain directions. Third, when prey tend to move along a barrier after encountering it. Here, predators located along this barrier may be more successful than those at random positions, but shadow competition in this scenario drastically decreases the capture success of predators in central positions along a barrier (i.e. having more than a single neighbor). Finally, in three‐level systems of plants in clusters, herbivores searching for plants, and predators ambushing herbivores inside plant patches, predators with ambush locations in the periphery of plant patches are more successful than those at the patch center, especially at high predator densities. Our simulation indicates that shadow competition is plausibly relevant in various scenarios of ambush predators and prey, and that it varies based on the habitat structure and capture probability of prey by predators as well as the change in capture probability with successive encounters.
Cement‐Augmented Screw Fixation with PHILOS Plating for Osteoporotic Proximal Humeral Fractures: An Observation of Mid‐ and Long‐Term Curative Efficacy
Authors: She Rongfeng , Zhang Bin , Jiang Kundou , Yang Shuaiqi , Zhang Yi
Published: October 2023

Objectives

The mid‐ and long‐term clinical outcomes of cement‐augmented screws in the treatment of osteoporotic proximal humeral fractures have rarely been reported. The aim of this study was to observe the mid‐ and long‐term efficacy of combined cement‐augmented screw fixation and PHILOS plating in the treatment of osteoporotic fractures of the proximal humerus.

Methods

This study retrospectively analyzed data from 19 patients with osteoporotic fractures of the proximal humerus who had undergone internal fixation at the Guizhou Provincial People's Hospital from February 2017 to May 2021. The cohort was comprised of six males and 13 females, aged 75–87 (mean age: 82.52 ± 1.24) years. According to the Neer classification, three, 12, and four patients had two‐part, three‐part, and four‐part fractures, respectively. All patients were treated with open reduction internal fixation with cement‐augmented screws and PHILOS plating. Time until fracture healing was recorded postoperatively. Patients were observed for postoperative complications, including humeral head necrosis, loosening or breaking of the augmented screws, screw perforation of the humeral head, and varus fracture displacement. Visual analog scale and Constant scores of the shoulder joint were compared 1, 3, 6, and 12 months after surgery. Scores at the most recent follow‐up were used to evaluate shoulder joint function. Measured data conforming to a normal distribution were expressed as mean ± SD. Analysis of variance or rank sum tests were used for intergroup comparisons. A value of p < 0.05 was considered significant.

Results

All 19 patients followed up for 1–4 (average: 2.13 ± 0.61) years. Fractures united in all cases, with a healing time of 8–14 (average: 10.25 ± 1.72) weeks. There were no cases of humeral head necrosis, screw loosening, fractures, or perforation of the humeral head. One patient had mild varus fracture displacement with a reduced neck‐shaft angle. There were significant differences in visual analog scale and Constant scores 1, 3, and 6 months after surgery (p < 0.05). The visual analog scale score was 0 at final follow‐up in all cases. The Constant score of the shoulder joint was excellent, good, fair, and poor in two, 12, four, and one case, respectively, yielding an excellent and good rate of 73.68%.

Conclusions

Cement‐augmented screw fixation combined with PHILOS plating of osteoporotic proximal humeral fractures had good mid‐ and long‐term clinical efficacy. It should be considered a new option for fracture treatment in such patients.
Genome editing in rice using CRISPR/Cas12i3
Authors: Lv Ping , Su Fei , Chen Fangyuan , Yan Chunxue , Xia Dandan , Sun Hui , Li Shanshan , Duan Zhiqiang , Ma Changle , Zhang Hui , Wang Mugui , Niu Xiaomu , Zhu Jian‐Kang , Zhang Jinshan
Published: October 2023

The CRISPR/Cas type V‐I is a family of programmable nuclease systems that prefers a T‐rich protospacer adjacent motif (PAM) and is guided by a short crRNA. In this study, the genome‐editing application of Cas12i3, a type V‐I family endonuclease, was characterized in rice. We developed a CRIPSR/Cas12i3‐based Multiplex direct repeats (DR)‐spacer Array Genome Editing (iMAGE) system that was efficient in editing various genes in rice. Interestingly, iMAGE produced chromosomal structural variations with a higher frequency than CRISPR/Cas9. In addition, we developed base editors using deactivated Cas12i3 and generated herbicide‐resistant rice plants using the base editors. These CRIPSR/Cas12i3‐based genome editing systems will facilitate precision molecular breeding in plants.
When old and new selves collide: Identity conflict and entrepreneurial nostalgia among ex‐entrepreneurs
Authors: Nielsen Jordan D. , Gish J. Jeffrey
Published: October 2023

People undergoing career transitions often bring aspects of old roles into their new work contexts, and this interface can create conflict between lingering aspects of one's work self and the newer aspects of one's work self. Yet, we know little about how this conflict between old and new selves shapes employee outcomes. We examine this issue among ex‐entrepreneurs—individuals who have transitioned from a business owner to a wage employee. Drawing from role identity theory, we develop a model of the consequences of conflict between a lingering entrepreneur identity and a current work role identity. We propose that ex‐entrepreneurs who experience higher levels of identity conflict will be more likely to experience burnout and less likely to engage in boosterism of their employer, and that these relationships are explained by lower levels of perceived professional identity growth (i.e., progressive identity). We further suggest that the negative effect of conflict on progressive identity is exacerbated by nostalgia for one's entrepreneurial past. In a three‐stage field survey of ex‐entrepreneurs and their romantic partners, we found support for these hypotheses using both partner‐rated outcomes and self‐rated outcomes. We discuss implications for the literature on entrepreneurship careers and work identity in organizations.
Desperate or desirable? Perceptions of individuals seeking dates online and offline
Authors: Johanis Trenton C. , Midgley Claire E. , Lockwood Penelope
Published: October 2023

Past research suggests that people who use the Internet to pursue romantic relationships have been stereotyped negatively—as unattractive, desperate, or creepy. It is possible, however, that as finding dates online has grown in popularity, individuals who have themselves used online methods to meet a partner are less likely to apply these negative stereotypes than non‐users. In addition, as options for dating online have proliferated, it is not clear that users of all online formats are viewed negatively, or how perceptions of users of online methods might differ from perceptions of daters using various offline methods. This study examined perceptions of those who use various online (algorithm‐based, profile‐browsing, or social media) and offline (meeting through family/friends, luck, groups, work, or going out) methods to meet a partner. Participants (N = 214), who were themselves users or non‐users of online methods of meeting partners, were recruited through Amazon's Mechanical Turk system to complete online questionnaires. Results indicated that participants viewed individuals who used online methods more negatively than those using offline methods; however, individuals who had themselves used online methods viewed other online users more positively than did non‐users.
Current management of symptomatic vesicoureteral reflux in pediatric kidney transplantation—A European survey among surgical transplant professionals
Authors: Zirngibl Matthias , Weitz Marcus , Luithle Tobias , Tönshoff Burkhard , Nadalin Silvio , Buder Kathrin ,   Collaborators
Published: October 2023

Background

Vesicoureteral reflux (VUR) is common in children and adolescents undergoing kidney transplantation (KTx) and may adversely affect allograft kidney function.

Methods

To explore the current management of symptomatic native and allograft VUR in pediatric KTx recipients, an online survey was distributed to European surgical transplant professionals.

Results

Surgeons from 40 pediatric KTx centers in 18 countries participated in this survey. Symptomatic native kidney VUR was treated before or during KTx by 68% of the centers (all/selected patients: 33%/67%; before/during KTx: 89%/11%), with a preference for endoscopic treatment (59%). At KTx, 90% favored an anti‐reflux ureteral reimplantation procedure (extravesical/transvesical approach: 92%/8%; preferred extravesical technique: Lich‐Gregoir [85%]). Management strategies for symptomatic allograft VUR included surgical repair (90%), continuous antibiotic prophylaxis (51%), bladder training (49%), or noninterventional surveillance (21%). Redo ureteral implantation and endoscopic intervention for allograft VUR were equally reported (51%/49%).

Conclusions

This survey shows uniformity in some surgical aspects of the pediatric KTx procedure. However, with regard to VUR, there is a significant variation in practice patterns that need to be addressed by future well‐designed and prospective studies. In this way, more robust data could be translated into consensus guidelines for a more standardized and evidence‐based management of this common condition in pediatric KTx.
Embracing self‐defeat in normative theory
Authors: Fullhart Samuel
Published: October 2023

Some normative theories are self‐defeating. They tell us to respond to our situations in ways that bring about outcomes that are bad, given the aims of the theories, and which could have been avoided. Across a wide range of debates in ethics, decision theory, political philosophy, and formal epistemology, many philosophers treat the fact that a normative theory is self‐defeating as sufficient grounds for rejecting it. I argue that this widespread and consequential assumption is false. In particular, I argue that a theory can be self‐defeating and still internally consistent, action‐guiding, and suitable as a standard for criticism.
Beyond lawfare: An analysis of law's temporality through Russian‐doll urbanization from Turkey
Authors: Civelek Cansu
Published: October 2023

This article opens a discussion about how temporalities in spatial and legal spheres are interlinked and shape both policymaking and governance mechanisms and resistance practices. Taking a case study from Eskişehir, Turkey, the research examines several urban renewal attempts of a municipality on the same urban lands over two decades that used different laws and policy tools in each case while all of which were annulled by court suits. From a perspective of legal anthropology, the analysis shows the limits of lawfare discussions that remain incapable of explaining cases that cannot be categorized with domination and resistance. Instead of focusing on detecting who wins or loses, the article claims that such complex cases could be understood better by scrutinizing temporal dynamics: how do legal, spatial, and social temporalities intertwine and impact policymaking? More specifically, how does the law's temporality (re)shape urbanization? Even further, what political work do temporalities generate? The article offers Russian‐doll urbanization as an analogy and ethnographic metaphor to examine several layers and endlessness of renewal initiatives within the broader process of urbanization. Studying the revelation of each layer unravels entangled temporalities of law and socio‐spatial dynamics and their consequences in policymaking and resistance.
p‐aminobenzoic acid and vitamin B9 enhance rice defence against sheath blight disease caused by Rhizoctonia solani
Authors: Yang Fang , Xu Xing , Xie Jialian , Yu Wenjuan , Zhang Shu , Wu Hanlin , Peng Yunliang , Ji Hongli
Published: October 2023

Sheath blight is one of the most important rice diseases and its control is generally achieved by the use of fungicides, but the economic and environmental costs involved have led to a search for alternative management approaches. In this study, we evaluated the efficacy of eight defence inducers against the rice sheath blight pathogen, Rhizoctonia solani AG1‐IA. The results showed that 10 mM p‐aminobenzoic acid (PABA) and 3 mM vitamin B9 (VB9)‐treated plants had significantly lower disease indices, at 2.56 and 3.49, respectively, compared to the control at 5.36 in growth room conditions. The direct effect studies showed that PABA significantly suppressed fungal mycelial growth, sclerotial formation and hyphal regeneration ability. However, VB9 showed no effect on mycelial growth but promoted sclerotial formation and hyphal regeneration. Histological observation showed a decreased lesion size and lower amount of hyphal DNA in inducer‐treated leaves. Reverse transcription‐quantitative PCR revealed that OsPR1b was significantly induced by VB9 and the expression of OsPR5 was potentiated by PABA, which indicates that the salicylic acid pathway is possibly involved in VB9‐induced resistance, and the antifungal protein OsPR5 probably contributes partially to PABA protection against R. solani. Immediate control effects of PABA and VB9 were also found after disease establishment. Under greenhouse conditions, the control effects of PABA and VB9 were 29.8% and 40.5%, respectively. These findings reveal that the application of PABA and VB9 to complement plant resistance to sheath blight appears to be an effective strategy.
Improvement of diluted semen from Muscovy (Cairina moschata) drakes by the addition of water‐soluble antioxidants
Authors: Gerzilov Vasko , Andreeva Madlena , Tsvetanova Elina , Georgieva Almira , Alexandrova Albena
Published: October 2023

The aim of this study was to evaluate the effect of antioxidant supplementation in diluted semen from Muscovy drakes after the induction of oxidative stress (OS) on the sperm motility, kinematic parameters and biochemical markers – lipid peroxidation (LPO) levels and total glutathione (tGSH) concentration. The pooled semen was distributed equally into three parts, diluted (1:3 v/v) with IMV Canadyl, HIA‐1 or AU, and stored at 4°C for 6 h. Later, the semen was equilibrated at 20–25°C for 15 min, and divided in Eppendorf tubes. The sperm samples (final concentration of 50 × 106 sperm cells/mL per sample) were incubated at 37°C for 30 min in the absence (−) or presence (+) of 0.1 mM FeSO4 + 0.5 mM H2O2 (Fenton system) and the following combinations of antioxidants: ascorbic acid + Trolox (A + T); ascorbic acid + Desferal (A + D); Trolox + Desferal (T + D) and ascorbic acid + Trolox + Desferal (A + T + D), all of them in a final concentration of 0.1 mM. Thus, the total number of samples was 30 and in each one, the sperm motility, velocity parameters, LPO and tGSH were determined. The motility and kinematic parameters of the diluted semen with added antioxidants were restored by up to 20% after inducing OS via the Fenton reaction. Dual combinations of antioxidants (A + T, A + D, and T + D) lowered LPO levels, but not equally across different extenders. After the induction of OS, the tGSH levels in diluted semen with IMV–Canadyl were not affected by the added antioxidants. Whereas antioxidant combinations in diluted semen with HIA‐1 or AU had a beneficial effect and partially restored tGSH levels. In conclusion, the results showed that the extender IMV–Canadyl is well balanced and protected the Muscovy semen under OS conditions, while the other two extenders HIA‐1 and AU can be improved by adding antioxidants.
Fine‐root turnover and leaf litterfall of Salsola passerina facilitate soil restoration in Alxa steppe desert of northwest China
Authors: Ma Xiong‐Zhong , Wang Xin‐Ping , Xiong Wei‐Hong
Published: October 2023

Nutrient cycling in desert ecosystems is heavily reliant on the fine root turnover and litter decomposition processes of dominant plant species. Based on field investigations and laboratory experiments, we explored fine root production (FRP) and turnover of Salsola passerina in Alxa steppe desert, and assessed fine root and leaf litter input and its correlation with soil C and N stocks, and then compared the variability of soil physicochemical properties at the site below and the interspace of S. passerina canopy. Results showed that fine root biomass dynamics of S. passerina were consistent with soil water content. Annual FRP of S. passerina was 243.3 g m−2 yr−1 and the turnover rate was 2.0 per year. S. passerina contributed 172.2 g C m−2 and 6.8 g N m−2 to soil from its fine root senescence and leaf litter input annually. Compared to the canopy interspace, the soil texture and fertility beneath the shrubs significantly improved, while the soil salinity decreased. The results indicated that the activities of desert shrub growth provided the degraded soil with abundant nutrients through fine root turnover and litter decomposition processes, which promoted soil texture and nutrition heterogeneity at the stand scale, and played an important role in degraded dryland restoration.
Haunting details: A mixed‐methods study on predictors of details recalled from a victim narrative
Authors: Groggel Anne
Published: October 2023

Narratives are used to make sense of traumatic experiences. However, little attention has been paid to the way one processes another's traumatic personal narrative that is often disorganized and contains emotional language. I examine the orientations a sample of 734 participants took when encountering a protection order court narrative. Participants who took a substantive orientation approached the narrative through the lens of human experience and recalled physical violence, threats, injuries, and emotions experienced by the victim. However, some participants had an analytic orientation, focusing on the clarity of the narrative or the victim's marital status. The extent to which participants cognitively took the victim's perspective shaped whether they adopted a substantive or analytic orientation. Those who cognitively placed themselves in the perspective of the victim were more likely to recall the violence the victim faced and were more likely to find the scenario concerning.
Redundant function of the Arabidopsis phosphatidylinositol 4‐phosphate 5‐kinase genes PIP5K4–6 is essential for pollen germination
Authors: Kato Mariko , Watari Machiko , Tsuge Tomohiko , Zhong Sheng , Gu Hongya , Qu Li‐Jia , Fujiwara Takashi , Aoyama Takashi
Published: October 2023

Phosphatidylinositol 4‐phosphate 5‐kinase (PIP5K) is a key enzyme producing the signaling lipid phosphatidylinositol 4,5‐bisphosphate [PtdIns(4,5)P2] in eukaryotes. Although PIP5K genes are reported to be involved in pollen tube germination and growth, the essential roles of PIP5K in these processes remain unclear. Here, we performed a comprehensive genetic analysis of the Arabidopsis thaliana PIP5K4, PIP5K5, and PIP5K6 genes and revealed that their redundant function is essential for pollen germination. Pollen with the pip5k4pip5k5pip5k6 triple mutation was sterile, while pollen germination efficiency and pollen tube growth were reduced in the pip5k6 single mutant and further reduced in the pip5k4pip5k6 and pip5k5pip5k6 double mutants. YFP‐fusion proteins, PIP5K4‐YFP, PIP5K5‐YFP, and PIP5K6‐YFP, which could rescue the sterility of the triple mutant pollen, preferentially localized to the tricolpate aperture area and the future germination site on the plasma membrane prior to germination. Triple mutant pollen grains under the germination condition, in which spatiotemporal localization of the PtdIns(4,5)P2 fluorescent marker protein 2xmCHERRY‐2xPHPLC as seen in the wild type was abolished, exhibited swelling and rupture of the pollen wall, but neither the conspicuous protruding site nor site‐specific deposition of cell wall materials for germination. These data indicate that PIP5K4–6 and their product PtdIns(4,5)P2 are essential for pollen germination, possibly through the establishment of the germination polarity in a pollen grain.
Ex vivo comparison of pin placement with patient‐specific drill guides or freehand technique in canine cadaveric spines
Authors: Guevara Francisco , Foss Kari D. , Harper Tisha A. M. , Moran Clara A. , Hague Devon W. , Hamel Philip E. S. , Schaeffer David J. , McCoy Annette M.
Published: October 2023

Objective

To compare vertebral implant placement in the canine thoracolumbar spine between 3D‐printed patient‐specific drill guides (3DPG) and the conventional freehand technique (FH).

Study design

Ex vivo study.

Animals

Cadaveric canine spines (n = 24).

Methods

Implant trajectories were established for the left and right sides of the T10 through L6 vertebrae based on computed tomography (CT) imaging. Customized drill guides were created for each vertebra of interest. Each cadaver was randomly assigned to one of six veterinarians with varying levels of experience placing vertebral implants. Vertebrae were randomly assigned a surgical order and technique (3DPG or FH) for both sides. Postoperative CT images were acquired. A single, blinded observer assessed pin placement using a modified Zdichavsky classification.

Results

A total of 480 implants were placed in 240 vertebrae. Three sites were excluded from the analysis; therefore, a total of 238 implants were evaluated using the FH technique and 239 implants using 3DPG. When evaluating implant placement, 152/239 (63.6%) of 3DPG implants were considered to have an acceptable placement in comparison with 115/248 (48.32%) with FH. Overall, pin placement using 3DPG was more likely to provide acceptable pin placement (p < .001) in comparison with the FH technique for surgeons at all levels of experience.

Conclusion

The use of 3DPG was shown to be better than the conventional freehand technique regarding acceptable placement of implants in the thoracolumbar spine of canine cadavers.

Clinical significance

Utilizing 3DPG can be considered better than the traditional FH technique when placing implants in the canine thoracolumbar spine.
Tapered Origami Tubes With Non-Planar Cross Sections
Authors: Lv Weilin , Nie Wansui , Zhang Jianjun , Wang Yutong , Guo Shijie
Published: October 2023

Rigidly foldable origami tubes are widely used in origami-inspired engineering designs. Here, using a mechanism construction process, we show that these tubes can be combined with tapered adding parts to form new tubes with different-sized cross sections that are rigidly foldable. A tapered tube is proposed, whose geometries are provided based on the kinematics of spherical 4R linkages. Several variations of the tapered tubes are presented, and the flat-foldability of these tubes is studied, leading to the right-angled and non-right-angled tubes which can be folded along their radial direction. The approach can be applied to both single and multilayered tubes. Moreover, the thick-panel form of the right-angled tubes is developed. Our work provides designers great flexibility in the design of tubular structures that require large shape changes. The results can be readily utilized to build new structures for engineering applications ranging from deployable structures, meta-materials to origami robots.
Numerical Analysis of the Thermal–Hydraulic Performance of Supercritical Liquefied Natural Gas in Airfoil Fin PCHEs
Authors: Meng Xiangfeng , Yuan Qiuyang , Li Yaning , Lin Xiaochen , Liu Na
Published: October 2023

As a novel, compact, and efficient plate-fin heat exchanger, the Printed Circuit Heat Exchanger (PCHE) is a prospective candidate for liquefied natural gas (LNG) vaporization at low-temperature and high pressure. Generally, the airfoil fin PCHE has better thermal–hydraulic performance than the zigzag channel PCHE. In this study, the thermal–hydraulic performance of supercritical LNG in PCHEs with different airfoil fin types and arrangements is investigated by numerical simulations. First, the effects of six different airfoil fin types, NACA0010, NACA0020, NACA0025, NACA0030, NACA 0040, and NACA 0050, on the thermal–hydraulic performances were studied. The results show that NACA0025 has the best comprehensive heat transfer performance. Then, the effects of the airfoil fin arrangement's staggered, vertical, and horizontal pitch on thermal–hydraulic performance were investigated. The results show that the optimal values of the dimensionless number for staggered and vertical arrangements are 1 and 4, respectively. The comprehensive performance does not change much when the dimensionless horizontal pitch number exceeds 3.0. Finally, the thermal–hydraulic performance of uniformly distributed, three front sparse and rear dense, and three front-dense and rear-sparse distributed airfoil fins was investigated. The results show that the front-dense and rear-sparse airfoil fins enhance and the front-sparse and rear-dense airfoil fins reduce the comprehensive performance compared to the uniform arrangement. The results show that a denser arrangement of airfoil fins near the quasi-critical point can improve the comprehensive performance while keeping the number of airfoil fins constant.
On the Use of Pressure-Sensitive Paint to Determine the Rim Sealing Effectiveness
Authors: Orsini L. , Picchi A. , Facchini B. , Bonini A. , Innocenti L.
Published: October 2023

The control of cavities sealing has been a challenging problem since early gas turbine development stages and several aspects regarding the flow physics and the modeling of rim seal flows, especially in terms of unsteady phenomena, still represent an open question. Fundamental test cases have been extensively used in the open literature to characterize the level of ingestion by varying the main flow parameters and the geometrical features. In most of them, the seal effectiveness is measured by using taps connected to a gas analyzer used to sample the concentration on the stator surface of a reference foreign gas (generally CO2) used to seed the purge flow. Consequently, the results are usually single-point measurements, and unsteady effects are inevitably neglected. Moreover, the intrusiveness of the approach must be carefully checked, and the application on the rotor side demands for complex slip-rings or telemetry. To overcome these limitations, the current work presents the application of the pressure-sensitive paint (PSP) technique to the study of hot gas ingestion phenomena on a single-stage rotating cold rig. By using an oxygen-free gas such as N2 as purge flow, the PSP was used to measure the partial pressure of oxygen at the wall through the wide optical accesses present in the rig. Then, the collected 2D distributions of pressure were related to the seal effectiveness inside the wheel space. The proposed methodology was first validated through a comparison with the data obtained from standard gas sampling and then applied as main experimental technique to characterize the seal ingestion. The analysis of the results highlighted the capabilities of the PSP technique to fast collect data on both stator and rotor sides, including the tip of the seal tooth where nonuniform efficiency distributions in the circumferential direction have been detected.
Acquired resistance to KRAS G12C small-molecule inhibitors via genetic/nongenetic mechanisms in lung cancer
Authors: Mohanty Atish , Nam Arin , Srivastava Saumya , Jones Jeff , Lomenick Brett , Singhal Sharad S. , Guo Linlin , Cho Hyejin , Li Aimin , Behal Amita , Mirzapoiazova Tamara , Massarelli Erminia , Koczywas Marianna , Arvanitis Leonidas D. , Walser Tonya , Villaflor Victoria , Hamilton Stanley , Mambetsariev Isa , Sattler Martin , Nasser Mohd W. , Jain Maneesh , Batra Surinder K. , Soldi Raffaella , Sharma Sunil , Fakih Marwan , Mohanty Saswat Kumar , Mainan Avijit , Wu Xiwei , Chen Yihong , He Yanan , Chou Tsui-Fen , Roy Susmita , Orban John , Kulkarni Prakash , Salgia Ravi
Published: October 2023

Inherent or acquired resistance to sotorasib poses a substantialt challenge for NSCLC treatment. Here, we demonstrate that acquired resistance to sotorasib in isogenic cells correlated with increased expression of integrin β4 (ITGB4), a component of the focal adhesion complex. Silencing ITGB4 in tolerant cells improved sotorasib sensitivity, while overexpressing ITGB4 enhanced tolerance to sotorasib by supporting AKT-mTOR bypass signaling. Chronic treatment with sotorasib induced WNT expression and activated the WNT/β-catenin signaling pathway. Thus, silencing both ITGB4 and β-catenin significantly improved sotorasib sensitivity in tolerant, acquired, and inherently resistant cells. In addition, the proteasome inhibitor carfilzomib (CFZ) exhibited synergism with sotorasib by down-regulating ITGB4 and β-catenin expression. Furthermore, adagrasib phenocopies the combination effect of sotorasib and CFZ by suppressing KRAS activity and inhibiting cell cycle progression in inherently resistant cells. Overall, our findings unveil previously unrecognized nongenetic mechanisms underlying resistance to sotorasib and propose a promising treatment strategy to overcome resistance.
Temporal disparity of action potentials triggered in axon initial segments and distal axons in the neocortex
Authors: Rózsa Márton , Tóth Martin , Oláh Gáspár , Baka Judith , Lákovics Rajmund , Barzó Pál , Tamás Gábor
Published: October 2023

Neural population activity determines the timing of synaptic inputs, which arrive to dendrites, cell bodies, and axon initial segments (AISs) of cortical neurons. Action potential initiation in the AIS (AIS-APs) is driven by input integration, and the phase preference of AIS-APs during network oscillations is characteristic to cell classes. Distal regions of cortical axons do not receive synaptic inputs, yet experimental induction protocols can trigger retroaxonal action potentials (RA-APs) in axons distal from the soma. We report spontaneously occurring RA-APs in human and rodent cortical interneurons that appear uncorrelated to inputs and population activity. Network-linked triggering of AIS-APs versus input-independent timing of RA-APs of the same interneurons results in disparate temporal contribution of a single cell to in vivo network operation through perisomatic and distal axonal firing.
Whole human-brain mapping of single cortical neurons for profiling morphological diversity and stereotypy
Authors: Han Xiaofeng , Guo Shuxia , Ji Nan , Li Tian , Liu Jian , Ye Xiangqiao , Wang Yi , Yun Zhixi , Xiong Feng , Rong Jing , Liu Di , Ma Hui , Wang Yujin , Huang Yue , Zhang Peng , Wu Wenhao , Ding Liya , Hawrylycz Michael , Lein Ed , Ascoli Giorgio A. , Xie Wei , Liu Lijuan , Zhang Liwei , Peng Hanchuan
Published: October 2023

Quantifying neuron morphology and distribution at the whole-brain scale is essential to understand the structure and diversity of cell types. It is exceedingly challenging to reuse recent technologies of single-cell labeling and whole-brain imaging to study human brains. We propose adaptive cell tomography (ACTomography), a low-cost, high-throughput, and high-efficacy tomography approach, based on adaptive targeting of individual cells. We established a platform to inject dyes into cortical neurons in surgical tissues of 18 patients with brain tumors or other conditions and one donated fresh postmortem brain. We collected three-dimensional images of 1746 cortical neurons, of which 852 neurons were reconstructed to quantify local dendritic morphology, and mapped to standard atlases. In our data, human neurons are more diverse across brain regions than by subject age or gender. The strong stereotypy within cohorts of brain regions allows generating a statistical tensor field of neuron morphology to characterize anatomical modularity of a human brain.
Oxidative stress biomarker triggered multiplexed tool for auxiliary diagnosis of atherosclerosis
Authors: Ma Yuan , Sun Wei , Ye Zhifei , Liu Liuhui , Li Menghuan , Shang Jinhui , Xu Xinyu , Cao Hui , Xu Li , Liu Yongchao , Kong Xiangqing , Song Guosheng , Zhang Xiao-Bing
Published: October 2023

Oxidative stress is integral in the development of atherosclerosis, but knowledge of how oxidative stress affects atherosclerosis remains insufficient. Here, we design a multiplexed diagnostic tool that includes two functions (photoacoustic imaging and urinalysis), for assessing intraplaque and urinary malondialdehyde (MDA), a well-recognized end-product of oxidative stress. Molecular design is conducted to develop the first near-infrared MDA-responsive molecule (MRM). Acid-unlocked ratiometric photoacoustic nanoprobe is designed to report intraplaque MDA, enabling it to reflect plaque burden. Furthermore, MRM is tailored for urinary MDA detection with excellent specificity in a blind study. Moreover, we found a significant difference in urinary MDA between healthy adults and atherosclerotic patients (more than 600 participants). Combining these two functions, such a multiplexed diagnostic tool can dynamically report intraplaque and systemic oxidative stress levels during atherosclerosis progression, pneumonia infection, and drug treatment in atherosclerotic mice, which is promising for the auxiliary diagnosis of atherosclerosis.
Direct observation of glycans bonded to proteins and lipids at the single-molecule level
Authors: Anggara Kelvin , Sršan Laura , Jaroentomeechai Thapakorn , Wu Xu , Rauschenbach Stephan , Narimatsu Yoshiki , Clausen Henrik , Ziegler Thomas , Miller Rebecca L. , Kern Klaus
Published: October 2023

Proteins and lipids decorated with glycans are found throughout biological entities, playing roles in biological functions and dysfunctions. Current analytical strategies for these glycan-decorated biomolecules, termed glycoconjugates, rely on ensemble-averaged methods that do not provide a full view of positions and structures of glycans attached at individual sites in a given molecule, especially for glycoproteins. We show single-molecule analysis of glycoconjugates by direct imaging of individual glycoconjugate molecules using low-temperature scanning tunneling microscopy. Intact glycoconjugate ions from electrospray are soft-landed on a surface for their direct single-molecule imaging. The submolecular imaging resolution corroborated by quantum mechanical modeling unveils whole structures and attachment sites of glycans in glycopeptides, glycolipids, N-glycoproteins, and O-glycoproteins densely decorated with glycans.
Freedom from free will
Determined: A Science of Life without Free Will
Robert M. Sapolsky
Penguin Press, 2023. 528 pp.
Authors: Maoz Uri
Published: October 2023

A scientist presents a case for a predetermined future
Sensitive and selective phenol sensing in denitrifying
Aromatoleum aromaticum
EbN1
T
Authors: Buschen Ramona , Lambertus Pia , Scheve Sabine , Horst Simon , Song Fei , Wöhlbrand Lars , Neidhardt John , Winklhofer Michael , Wagner Tristan , Rabus Ralf
Published: October 2023

Aromatoleum aromaticum
EbN1
T
anaerobically degrades phenol,
p
-cresol, and
p
-ethylphenol, each via a distinct peripheral pathway. The compound-specific regulation of each pathway is proposed to occur on the transcriptional level in the case of phenol supposedly mediated by the one-component system PheR. To confirm its predicted function, we generated an unmarked, in-frame deletion mutant (Δ
pheR
). This mutant did not express the
ppsA1
gene, which encodes the A1 subunit of phenol-activating phenylphosphate synthase. The expression of
ppsA1
was restored by
in trans
complementation of
pheR
into the Δ
pheR
background. The responsiveness to phenol was studied
in vivo
in benzoate-limited anaerobic cultures by adding, upon benzoate depletion, single defined pulses of phenol (from 100 µM down to 0.1 nM). Time-resolved, targeted transcript profiling by qRT-PCR revealed a response threshold for
ppsA1
expression of 30‒50 nM phenol. Notably,
ppsA1
expression could not be induced by
p
-cresol or
p
-ethylphenol. Conversely, lack of expression was also observed for the additional target genes
cmh
(
p
-cresol degradation) and
acsA1
(
p
-ethylphenol degradation) applying phenol or
p
-ethylphenol as well as phenol or
p
-cresol as stimuli. Thus, the sensory proteins PheR, PcrS, and EtpR should be highly selective for phenol,
p
-cresol, and
p
-ethylphenol, respectively. The implicated incapability of cross-stimulus binding was corroborated by comparing the predicted 3D structural models of the proteins’ sensory domains. While the ligand-binding pockets share the conserved hydroxy group-anchoring histidine and tryptophane, their distal faces in PcrS and EtpR are, compared to PheR, enlarged to accommodate the bulkier methyl (
p
-cresol) and ethyl group (
p
-ethylphenol), respectively.

IMPORTANCE

Aromatic compounds are globally abundant organic molecules with a multitude of natural and anthropogenic sources, underpinning the relevance of their biodegradation.
A. aromaticum
EbN1
T
is a well-studied environmental betaproteobacterium specialized on the anaerobic degradation of aromatic compounds. The here studied responsiveness toward phenol in conjunction with the apparent high ligand selectivity (non-promiscuity) of its PheR sensor and those of the related
p
-cresol (PcrS) and
p
-ethylphenol (EtpR) sensors are in accord with the substrate-specificity and biochemical distinctiveness of the associated degradation pathways. Furthermore, the present findings advance our general understanding of the substrate-specific regulation of the strain’s remarkable degradation network and of the concentration thresholds below which phenolic compounds become essentially undetectable and as a consequence should escape substantial biodegradation. Furthermore, the findings may inspire biomimetic sensor designs for detecting and quantifying phenolic contaminants in wastewater or environments.
Flagellin is essential for initial attachment to mucosal surfaces by
Clostridioides difficile
Authors: Sidner Ben , Lerma Armando , Biswas Baishakhi , Do Thi Van Thanh , Yu Yafan , Ronish Leslie A. , McCullough Hugh , Auchtung Jennifer M. , Piepenbrink Kurt H.
Published: October 2023

Mucins are glycoproteins which can be found in host cell membranes and as a gelatinous surface formed from secreted mucins. Mucosal surfaces in mammals form a barrier to invasive microbes, particularly bacteria, but are a point of attachment for others.
Clostridioides difficile
is an anaerobic bacterium, which colonizes the mammalian gastrointestinal (GI) tract and is a common cause of acute GI inflammation leading to a variety of negative outcomes. Although
C. difficile
toxicity stems from secreted toxins, colonization is a prerequisite for
C. difficile
disease. While
C. difficile
is known to associate with the mucous layer and underlying epithelium, the mechanisms underlying these interactions that facilitate colonization are less well understood. To understand the molecular mechanisms by which
C. difficile
interacts with mucins, we used
ex vivo
mucosal surfaces to test the ability of
C. difficile
to bind to mucins from different mammalian tissues. We found significant differences in
C. difficile
adhesion based upon the source of mucins, with highest levels of binding observed to mucins purified from the human colonic adenocarcinoma line LS174T and lowest levels of binding to porcine gastric mucin. We also observed defects in adhesion by mutants deficient in flagella but not type IV pili. These results imply that interactions between host mucins and
C. difficile
flagella facilitate the initial host attachment of
C. difficile
to host cells and secreted mucus.

IMPORTANCE

Clostridioides difficile
is one of the leading causes of hospital-acquired infections worldwide and presents challenges in treatment due to recurrent gastrointestinal disease after treatment with antimicrobials. The mechanisms by which
C. difficile
colonizes the gut represent a key gap in knowledge, including its association with host cells and mucosa. Our results show the importance of flagellin for specific adhesion to mucosal hydrogels and can help to explain prior observations of adhesive defects in flagellin and pilin mutants.
Immunogenicity, safety, usability and acceptability of microarray patches for vaccination: a systematic review and meta-analysis
Authors: Berger Matthew N , Mowbray Ellen S , Farag Marian W A , Mathieu Erin , Davies Cristyn , Thomas Claire , Booy Robert , Forster Angus H , Skinner S Rachel
Published: October 2023

Background

Microarray patches (MAPs) deliver vaccines to the epidermis and the upper dermis, where abundant immune cells reside. There are several potential benefits to using MAPs, including reduced sharps risk, thermostability, no need for reconstitution, tolerability and self-administration. We aimed to explore and evaluate the immunogenicity, safety, usability and acceptability of MAPs for vaccination.

Methods

We searched CINAHL, Cochrane Library, Ovid Embase, Ovid MEDLINE and Web of Science from inception to January 2023. Eligibility criteria included all research studies in any language, which examined microarrays or microneedles intended or used for vaccination and explored immunogenicity, safety, usability or acceptability in their findings. Two reviewers conducted title and abstract screening, full-text reviewing and data extraction.

Results

Twenty-two studies were included (quantitative=15, qualitative=2 and mixed methods=5). The risk of bias was mostly low, with two studies at high risk of bias. Four clinical trials were included, three using influenza antigens and one with Japanese encephalitis delivered by MAP. A meta-analysis indicated similar or higher immunogenicity in influenza MAPs compared with needle and syringe (N&S) (standardised mean difference=10.80, 95% CI: 3.51 to 18.08, p<0.00001). There were no significant differences in immune cell function between MAPs and N&S. No serious adverse events were reported in MAPs. Erythema was more common after MAP application than N&S but was brief and well tolerated. Lower pain scores were usually reported after MAP application than N&S. Most studies found MAPs easy to use and highly acceptable among healthcare professionals, laypeople and parents.

Conclusion

MAPs for vaccination were safe and well tolerated and evoked similar or enhanced immunogenicity than N&S, but further research is needed. Vaccine uptake may be increased using MAPs due to less pain, enhanced thermostability, layperson and self-administration. MAPs could benefit at-risk groups and low and middle-income countries.

PROSPERO registration number

CRD42022323026.
Polycystic ovary syndrome: pathophysiology and therapeutic opportunities
Authors: Dong Jiawen , Rees D Aled
Published: October 2023

Polycystic ovary syndrome is characterised by excessive levels of androgens and ovulatory dysfunction, and is a common endocrine disorder in women of reproductive age. Polycystic ovary syndrome arises as a result of polygenic susceptibility in combination with environmental influences that might include epigenetic alterations and in utero programming. In addition to the well recognised clinical manifestations of hyperandrogenism and ovulatory dysfunction, women with polycystic ovary syndrome have an increased risk of adverse mental health outcomes, pregnancy complications, and cardiometabolic disease. Unlicensed treatments have limited efficacy, mostly because drug development has been hampered by an incomplete understanding of the underlying pathophysiological processes. Advances in genetics, metabolomics, and adipocyte biology have improved our understanding of key changes in neuroendocrine, enteroendocrine, and steroidogenic pathways, including increased gonadotrophin releasing hormone pulsatility, androgen excess, insulin resistance, and changes in the gut microbiome. Many patients with polycystic ovary syndrome have high levels of 11-oxygenated androgens, with high androgenic potency, that might mediate metabolic risk. These advances have prompted the development of new treatments, including those that target the neurokinin-kisspeptin axis upstream of gonadotrophin releasing hormone, with the potential to lessen adverse clinical sequelae and improve patient outcomes.
Transforming growth factor-β and matrix metalloproteinases as potential biomarkers of fibrotic lesions induced by tuberculosis: a systematic review and meta-analysis
Authors: Santoso Arif , Rasiha Rasiha , Zainal Ahmad Taufik Fadillah , Khairunnisa Indah Nurul , Fais Muthia Kintan , Gunawan Andi Muh Aunul Khaliq
Published: October 2023

Objectives

Very few studies and limited information are available regarding the mechanism of fibrosis in tuberculosis (TB). This study aimed to identify, describe and synthesise potential biomarkers of the development of tissue fibrosis induced by TB through a systematic method and meta-analysis.

Methods

A literature search was performed using keywords according to the topic from electronic databases (ScienceDirect and PubMed) and other methods (websites, organisations and citations). Studies that matched predetermined eligibility criteria were included. The quality assessment tool used was the Quality Assessment of Diagnostic Accuracy Score 2, and the data obtained were processed using Review Manager V.5.3.

Results

Of the 305 studies, 7 met the eligibility criteria with a total sample of 365. The results of the meta-analysis showed that the post-TB group of patients with pulmonary parenchymal fibrosis had a higher transforming growth factor (TGF)-β level (6.09) than the control group (1.82), with a 4.27 (95% CI: 0.92 to 7.61) mean difference. Moreover, patients with residual pleural thickening post-TB had a higher mean of TGF-β (0.61) than the control group (0.56), with a 0.05 (95% CI: 0.04 to 0.06) mean difference. Besides TGF-β, our qualitative synthesis also found that matrix metalloproteinase-1 might have a role in forming and developing pulmonary tissue fibrosis, thus, could be used as a predictor marker in the formation of fibrotic lesions in patients with TB. In addition, several other biomarkers were assessed in the included studies, such as tumour necrosis factor-α, interleukin (IL)-4, IL-8, IL-10, plasminogen activator inhibitor-1 and platelet-derived growth factor. However, this study is not intended to examine these biomarkers.

Conclusions

There were differences in the results of TGF-β levels in patients with fibrotic lesions compared with controls. TGF-β might be a biomarker of fibrotic tissue formation or increased pulmonary tissue fibrosis in post-TB patients. However, further studies are needed on a larger scale.