bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of melatonin supplementation upon parental care and nestling growth in arctic‐breeding songbirds
Authors: Pullum Keelee , Hodinka Brett , Ward Zoe , Morrissette Greta , Richter Melanie M. , Hunt Kathleen E. , Ashley Noah T.
Published: August 2024

Arctic‐breeding birds exhibit around‐the‐clock activity, and these activity cycles are postulated to maximize reproductive success during the short breeding season characteristic of high‐latitude regions. Two closely related species of arctic‐breeding songbirds, Lapland longspurs (Calcarius lapponicus; ground‐nesting) and snow buntings (Plectrophenax nivalis; cavity‐nesting) exhibit extended activity cycles throughout the polar day (71° N) except for 4–5 h of daily quiescence. Ground‐nesting Lapland longspurs experience higher levels of nest predation than cavity‐nesting snow buntings, and this difference is reflected in elevated nest vigilance in male longspurs compared with snow buntings. In this study, we examined the effect of melatonin supplementation upon male parental care, corresponding measures of nestling growth, and ability to reduce activity (and increase sleep). A pharmacological dose of melatonin in captive snow buntings dampened the amplitude of activity rhythms over the polar day with no detectable phase‐shifting compared with control‐implanted birds. Melatonin treatment reduced nest visits and overall time spent on the nest by male snow buntings compared with controls. There was no significant increase in time spent by female snow buntings on the nest to compensate for this, and there was no significant effect on offspring growth rates. There were no effects of melatonin supplementation on longspur adults or offspring, suggesting behavioral insensitivity to exogenous melatonin treatment. These differences in sensitivity underscore the importance of nest defense in ground‐nesting longspurs compared with cavity‐nesting snow buntings, which participate minimally in nest defense.
Implementation of the Acute Inpatient Medicine—High Reliability, Learning Environment, and Workforce Development Initiative (AIM‐HI) in rural Veterans Health Administration hospitals: A mixed methods evaluation protocol
Authors: Gilmartin Heather M. , Connelly Brigid , Daus Marguerite , Hess Edward , Leonard Chelsea , Morgan Brianne , Nolan John P. , Perry Paige , Sjoberg Heidi , Subramaniam Soumya , Anderson Melver L.
Published: August 2024

Introduction

Few rural hospital medicine programs include workforce development training that provides social and professional support for interdisciplinary teams. Even fewer include training that creates supportive learning environments that result in higher staff satisfaction, lower burnout, and reduced turnover. The Acute Inpatient Medicine—High Reliability, Learning Environment, and Workforce Development Initiative (AIM‐HI) aims to create supportive learning environments in Veterans Health Administration (VA) rural hospital medicine teams.

Methods

AIM‐HI is a type II hybrid implementation study utilizing a convergent mixed methods approach to evaluate the Relational Playbook, a workforce development intervention, and three implementation strategies: behavioral nudges, learning and leadership collaboratives, and leadership coaching. AIM‐HI implementation will occur in waves, enrolling additional hospitals every 12 months. In the first wave, AIM‐HI will be implemented at three tertiary VA hospitals that treat at least 1000 rural Veterans annually and have an active inpatient hospital medicine program. The primary outcomes in year 1 will be the acceptability, appropriateness, and feasibility of AIM‐HI assessed through participant surveys and interviews. In subsequent years, trends in the learning environment, job satisfaction, burnout, and turnover scores will be assessed using a linear mixed‐effect model.

Discussion

The anticipated impact of AIM‐HI is to evaluate the utility of the implementation strategies and assess trends in Playbook intervention outcomes. The Playbook has strong face validity; however, before large‐scale adoption across the VA enterprise, it is essential to establish the acceptability, appropriateness, and feasibility of the Playbook and implementation strategies, as well as to gather data on AIM‐HI effectiveness.
Lead‐212/Bismuth‐212 In Vivo Generator Based on Ultrasmall Silver Telluride Nanoparticles
Authors: Wang Runze , Wolterbeek Hubert Th. , Denkova Antonia G.
Published: August 2024

Radionuclide therapy employing alpha emitters holds great potential for personalized cancer treatment. However, certain challenges remain when designing alpha radiopharmaceuticals, including the lack of stability of used radioconjugates due to nuclear decay events. In this work, ultrasmall silver telluride nanoparticles with a core diameter of 2.1 nm were prepared and radiolabeled with lead‐212 using a chelator‐free method with a radiolabeling efficiency of 75%. The results from the in vitro radiochemical stability assay indicated a very high retention of bismuth‐212 despite the internal conversion effects originating from the decay of 212Pb. To further evaluate the potential of the nanoparticles, they were radiolabeled with indium‐111, and their cell uptake and subcellular distribution were determined in 2D U87 cells, showing accumulation in the nucleus. Although not intentional, it was observed that the indium‐111‐radiolabeled nanoparticles induced efficient tumor cell killing, which was attributed to the Auger electrons emitted by indium‐111. Combining the results obtained in this work with other favorable properties such as fast renal clearance and the possibility to attach targeting vectors on the surface of the nanoparticles, all well‐known from the literature, these ultra‐small silver telluride nanoparticles provide exciting opportunities for the design of theragnostic radiopharmaceuticals.
Gaucher disease type 3c: Expanding the clinical spectrum of an ultra‐rare disease
Authors: Wang John S. , Koch Rebecca L. , Kenney‐Jung Daniel , Huggins Erin , Sodhi Sirajbir S. , Landstrom Andrew P. , Grewal Dilraj S. , Kishnani Priya S.
Published: August 2024

Gaucher disease (GD) type 3 is an autosomal recessive lysosomal disease caused by deficiency of β‐glucocerebrosidase (GCase) and encompasses a spectrum of cardiac, neurological, and ophthalmological abnormalities. Although the clinical presentations can be diverse, a recognized clinical trajectory points to an early onset, predominantly before 18 years. GD type 3c is primarily caused by homozygosity for GBA pathogenic variant c.1342G>C (p.Asp448His; historically referred to as D409H) and includes visceral, hematological, skeletal, and cardiac abnormalities. Notably, GD type 3c is distinct from other GD types because it is primarily characterized by valvular heart disease. Yet, with less than 50 patients with GD type 3c reported to date, the phenotypic spectrum and extent of cardiac involvement remains ill‐defined. We present a 20‐year‐old female with an atypical presentation of GD type 3c consisting of chronic intermediate uveitis as the presenting feature and the presence of extensive polyneuropathy starting in adolescence which has been previously unreported in GD type 3c. Distinctively, she has maintained normal cardiac function. Moreover, we compare our case with those reported in the literature to broaden awareness of the varied initial presentations of this disease. The diverse presentations seen in GD type 3c, underscored by our case and those previously reported, demonstrate the need for standardized evaluation and management protocols.
Bacterial Extracellular Vesicles: Potential Therapeutic Applications, Challenges, and Future Prospects
Authors: Humaira  , Ahmad Irfan , Shakir Hafiz Abdullah , Khan Muhammad , Franco Marcelo , Irfan Muhammad
Published: August 2024

Almost all cell types naturally secret extracellular vesicles (EVs) in the extracellular space with variable metabolic cargo facilitating intracellular communication, posing immune‐modulation capacity. Thus, “bacterial extracellular vesicles” (BEVs), with their great immunoregulatory, immune response stimulation and disease condition‐altering potential, have gained importance in the medical and therapeutic industry. Various subtypes of BEVs were observed and reported in the literature, such as exosomes (30–150 nm), microvesicles (100–1000 nm), apoptotic bodies (1000–5000 nm), and oncosomes (1000–10,000 nm). As biological systems are complex entities, inserting BEVs requires extra high purity. Various techniques for BEV isolation have been employed alone or with other strategies, such as ultracentrifugation, precipitation, size‐exclusion chromatography, affinity‐based separation, ultrafiltration, and field‐flow fractionation. But to date, no BEV isolation method is considered perfect as the lack of standard protocols limits their scale‐up. Medical research has focused on BEVs to explore their diverse therapeutic potential. This review particularly focused on the recent advancements in the potential medical application of BEVs, current challenges, and prospects associated with their scale‐up.
The rental‐function effect: How does product acquisition mode affect consumer preference relating to product attributes?
Authors: Liu Wumei , Kang Na , Song Pengfei
Published: August 2024

Purchasing and renting are two basic modes for consumers to acquire a product. While prior research has investigated which factors affect consumers' choice of renting versus purchasing a product, very limited research studies the outcome of renting versus purchasing a product. Extending this line of research, this paper links product acquisition mode to product attribute preference. Specifically, through a series of eight multimethod studies, including secondary data study, field experiment, and lab experiments, we show that renting a product, as compared to purchasing a product, increases consumers' focus on the product's feasibility aspect rather than its desirability aspect, which in turn drives consumers to prefer the product option with superior function over the one with superior appearance. Furthermore, we show that this rental‐function effect amplifies (attenuates) when the product's brand image is positioned as a mass brand (a luxury brand). This paper uncovers a novel finding of renting products. It also provides practical guidelines for rental companies and marketing managers on how to effectively position their products and optimize advertising strategies.
Room‐Temperature Self‐Healing and Recyclable Self‐Crosslinked Isosorbide‐Based Adhesive Bioelastomer
Authors: Ouyang Qing , Du Ming‐Xuan , Xiao Yao‐Nan , Wu Shao‐Hua , Zhang Bo , Liu Jia‐Jian , Li Chun‐Cheng
Published: August 2024

Recently, renewable bio‐based materials have received more and more attention due to environmental issues such as global warming and ecosystem destruction. In the present work, a series of isosorbide‐based bioelastomers poly(isosorbide carbonate‐co‐butanediol aliphatic esters)s (PICBAs) are synthesized by a facile and economical two‐step melt polycondensation. Due to the slightly self‐crosslinking reaction of isosorbide, PICBAs exhibit excellent tensile strength and self‐healing ability, the mechanical properties of PICBAs can recover over 95% after 48 h under room temperature. In addition, PICBAs can stick different substances, such as glass, rubber, plastic, and stones, and show better adhesive performance than 3M commercially available double‐sided tape. Consequently, isosorbide‐based bioelastomers PICBAs are of great potential to be used as environmentally friendly pressure‐sensitive adhesives (PSA) in the future.
ROR2 promotes cell cycle progression and cell proliferation through the PI3K/AKT signaling pathway in gastric cancer
Authors: Liu Qi , Zhao Xin , Shao Xiaowen , Cheng Ping , Cui Jingyi , Han Shuyi
Published: August 2024

Proliferation is a critical characteristic of the progression of gastric cancer (GC). Receptor tyrosine kinase‐like orphan receptor 2 (ROR2), the orphan receptor tyrosine kinase‐like receptor, exhibits effects on tumor growth due to its abnormal expression in cancer. The goal of our study was to assess the potential regulatory role exerted by the ROR2 on GC cells. Through previous bioinformatics analysis, we discovered an association between ROR2 and the G2/M phase of the GC cell cycle. However, little is known about the link between ROR2 and the G2/M phase cell cycle in GC. Here, the findings of our study indicate that ROR2, after transcribed expression by Twist1, activates the PI3K/AKT/mTOR/S6K signal transduction pathway, thus leading to the acceleration of the G2/M phase and subsequent promotion of cell proliferation in GC. Furthermore, the functional link among ROR2, Twist1, and G2/M phase of cell cycle was also confirmed in mouse xenograft tissues and human tissues. ROR2 expression was correlated with Twist expression and lower survival in vivo. Notably, our suggestion is that focusing on ROR2 as a potential therapeutic approach could show potential for the management of GC.
Time‐of‐Day Adrenal Modulation of Corticosterone Synthesis is Affected by Sex and Diet but Not by Proanthocyanidins in Rat
Authors: Romero Maria‐del‐Mar , Martín‐González Miguel Z. , Aragonès Gerard , Muguerza Begoña , Remesar Xavier , Arola‐Arnal Anna , Fernández‐López José‐Antonio
Published: August 2024

Scope

The aim of this study is to investigate the effect of time‐of‐day on serum hormones and gene expression in adrenal glands, studying the impact of sex, obesogenic diet, and timing of proanthocyanidins administration, with a focus on glucocorticoids synthesis by this gland.

Methods and results

Female and male rats, assigned to a standard chow or a cafeteria diet‐fed group, receive a daily oral dose of a grape seed proanthocyanidin extract (GSPE), or a vehicle (when light is turned on, or when light is turned off). Corticosterone, estradiol, and testosterone serum levels, and the expression analysis of clock genes and genes related to corticosterone synthesis pathway, are assessed. Serum hormone levels exhibited a marked time‐of‐day effect also see in the expression of scavenger receptor class B member 1 (Scarb1) and cyp11b genes. The correlation between these two genes and period circadian regulator 2 (Per2) is also extended to other clock genes, although to a lesser extent: cryptochrome (Cry) and nuclear receptor subfamily 1 group D member 1 (Rev‐erba).

Conclusion

The strong correlations found suggest an important role of local Per2 (but also of Cry and Rev‐erbA) in regulating the expression of the enzymes involved in the corticosterone synthesis pathway. The expression of clock genes in adrenals is influenced by sex and diet but not by GSPE.
The SDF‐1/CXCR4 axis is involved in adipose‐derived stem cell migration
Authors: Li Jiang , Deng Tibin , Zhu Shaojie , Xie Pingbo , Wang Wei , Zhou Hongqing , Xu Chenxiang
Published: August 2024

Background

Intravenous injection of adipose‐derived stem cells (ADSCs) can improve the urinary function of stress urinary incontinence (SUI) model rats and C‐X‐C chemokine receptor type 4 (CXCR4)‐positive ADSCs are found in urethral tissues. The CXCR4 ligand stromal cell‐derived factor‐1 (SDF‐1) is highly expressed in urinary incontinence model rats. In this study, we investigated the involvement of the SDF‐1/CXCR4 axis in the homing of ADSCs.

Methods

ADSCs were isolated from rats and purified. The levels of CXCR4 and CXCR7 were determined by western blot analysis and immunofluorescence assays following stimulation with SDF‐1. Hypoxia conditioning was performed to treat the cells in vitro, following which the messenger RNA (mRNA) and protein level of SDF‐1, CXCR4, and CXCR7 were estimated.

Results

We found that CXCR4 and CXCR7 were expressed in ADSCs at passage zero (P0), P1, and P3, and the expression of both increased after SDF‐1 stimulation. The level of expression of the mRNAs and proteins of SDF‐1, CXCR4, and CXCR7 in ADSCs was higher after hypoxic conditioning. We then knocked down CXCR4 or CXCR7 using small interfering RNAs and found that the mRNA levels of CXCR4 and CXCR7 were considerably downregulated in the si‐CXCR4/7‐transfected cells. We also found that the SDF‐1/CXCR4 axis was required for the migration of ADSCs. The phosphorylation levels of Janus kinase (JAK), protein kinase B (AKT), and extracellular regulated protein kinase significantly increased in SDF‐1‐stimulated ADSCs. However, the migration of ADSCs was suppressed when the corresponding specific inhibitors were used to block JAK and AKT signaling or silence CXCR4, whereas no significant change was observed in the migratory ability of ADSCs when the ERK pathway was blocked or CXCR7 was silenced.

Conclusions

The SDF‐1/CXCR4 axis is involved in the migration of ADSCs and may play a role in the migrate of ADSCs in SUI.
Chemodenervation is Associated With Reduced Mental Health Disorders in Patients With Synkinesis
Authors: Lorenz Fred Jeffrey , Schopper Heather K. , Lighthall Jessyka G.
Published: August 2024

Objective

To compare the prevalence of mental health disorders in individuals with facial synkinesis, facial paralysis alone, and the general population.

Study Design

Retrospective cohort.

Setting

Eighty‐two health care organizations across the United States.

Methods

The TriNetX Research Network was queried from 2011 to 2021 for patients with facial paralysis without synkinesis, facial paralysis and documented synkinesis, and controls, matched for age, sex, race, and ethnicity. Cases included infectious, iatrogenic, or idiopathic facial paralysis. Patients with pre‐existing depression or anxiety were excluded. Two‐year rates of newly diagnosed depression, anxiety, and mental health prescriptions were compared.

Results

Among 127,573 patients with facial paralysis, 92.5% (n = 117,976) had facial paralysis alone, and 7.5% (n = 9597) also had documented synkinesis. Compared to controls, patients with facial paralysis alone had increased risks of new depression (8.9% vs 7.3%, P < .001) and anxiety (10.1% vs 9.6%, P < .001), with higher mental health medication rates (16.6% vs 13.1%, P < .001). Patients with documented synkinesis, in comparison to controls, had the highest risks of depression (19.8% vs 8.6%, P < .001), anxiety (20.5% vs 10.5%, P < .001), and prescriptions (28.1% vs 15.8%, P < .001). The 27.8% (n = 2669) of synkinetic patients treated with chemodenervation had lower rates of depression (8.5% vs 23.5%, P < .001), anxiety (9.0% vs 23.8%, P < .001), and prescriptions (21.6% vs 30.0%, P < .001) compared to synkinetic patients who were not.

Conclusion

Facial paralysis, particularly synkinesis, is linked to increased mental health disorders. Integrating mental health screening and treatment into a comprehensive approach is crucial. Chemodenervation is associated with decreased mental health disorders in synkinesis, highlighting its therapeutic potential.
Lingual Tonsillectomy as Part of a DISE‐Directed Multilevel Upper Airway Surgery to Treat Complex Pediatric OSA: A Safe and Appropriate Procedure
Authors: Trandafir Cornelia , Couloigner Vincent , Chatelet Florian , Fauroux Brigitte , Luscan Romain
Published: August 2024

Objective

To study the efficiency of lingual tonsillectomy (LT) as part of multilevel surgery in children with complex obstructive sleep apnea (OSA). To evaluate the safety and the outcomes of LT.

Study Design

Retrospective case series.

Setting

Pediatric tertiary care academic center.

Methods

We included all children operated for LT to treat complex OSA, from January 2018 to June 2022. All patients underwent a protocolized drug‐induced sleep endoscopy (DISE) followed by a coblation LT, associated with the treatment of all other obstructive sites. Patient demographics, medical history, surgery, and outcomes were reviewed. The efficiency of LT was analyzed exclusively in patients with a preoperative and postoperative sleep study.

Results

One hundred twenty‐three patients were included. Median age was 8 years (interquartile range, IQR [3‐12]). Sixty‐five (53%) patients had Down syndrome, 22 (18%) had a craniofacial malformation, and 8 (7%) were obese. LT was associated with adenoidectomy (n = 78, 63%), partial tonsillectomy (n = 70, 57%), inferior turbinoplasty/turbinectomy (n = 59, 48%), epiglottoplasty (n = 92, 75%), and/or expansion pharyngoplasty (n = 2, 2%). Eighty‐nine patients underwent a sleep study before and after surgery. The median apnea‐hypopnea index (AHI) decreased from 18 events/h (IQR [9‐36]) before surgery to 3 events/h (IQR [1‐5]) after surgery (P < .001) (patients with a postoperative AHI <1.5 events/h, n = 31, 35%, and an AHI <5 events/h, n = 32, 36%). Seventeen out of 30 (57%) patients could be weaned from continuous positive airway pressure after surgery. Two patients had a postoperative hemorrhage and 2 patients required a transient postoperative reintubation.

Conclusion

In children with complex OSA, LT as part of a DISE‐directed multilevel upper airway surgery, was a very efficient and safe procedure.
Effectiveness of marsupialization on the reduction of cystic jaw lesions in children: A scoping review
Authors: Tran Thao Phuong , Ngoc Vo Truong Nhu , Linh Le Ngoc Phuong , Le Anh Kha
Published: August 2024

This study aimed to review and critically appraise the available literature concerning marsupialization's effectiveness in reducing cystic jaw lesions in children. The study conducted a search strategy that involved combining the following keywords: (1) children, (2) marsupialization, (3) jaw, and (4) cyst. An electronic search on four critical databases—PubMed, The Cochrane Library, Science Direct, and ResearchGate—to review English‐language articles with no limitations in terms of time, sample size, or type of study design has been conducted. Based on the inclusion and exclusion criteria applied to the preliminary search, 46 studies were included in the final review. Among the 194 identified lesions, the majority were dentigerous cysts (93.8%), followed by radicular cysts (2.6%), odontogenic keratocysts (1.6%), juvenile paradental cysts (1%), and calcifying odontogenic cysts (1%). Postoperatively, permanent teeth involved in the cysts were reported to develop continuously in 40 studies, whereas bone neo‐formation after removal of cystic lesions was reported in 30 studies. Only one study reported postoperative recurrence. The complete healing time of the cysts after marsupialization ranged from 6 months to 5 years. Marsupialization was mainly considered a definite treatment. Because of the long follow‐up period, the cooperation of the patient and family plays an essential role in the success of treatment.
Cross‐sectional study on university students' mental health during the COVID‐19 pandemic: Exploring the influence of adverse and positive childhood experiences
Authors: Noda Tetsuro , Nagaura Hiromu , Fujita Yoshinobu , Tsutsumi Toshihiko
Published: August 2024

Aim

This study examined the psychological impact of the COVID‐19 pandemic on university students, focusing on how adverse childhood experiences (ACEs) and positive childhood experiences (PCEs) influence mental health.

Methods

A web‐based survey was administered to 3000 university students from October 26 to 31, 2022, following the peak of the COVID‐19 pandemic. Mental health assessments included the Japanese version of the Kessler Psychological Distress 6‐Item Scale (K6) for depressive/anxiety symptoms, the Impact of Event Scale‐Revised (IES‐R‐J) for distress, fear of COVID‐19, and a three‐item loneliness scale.

Results

Of the respondents, 46.9% reported depressive/anxiety symptoms, 55.4% reported distress, and 37.3% reported fear of COVID‐19. Factors such as current psychiatric treatment history and reduced income (either parental or personal) were predictive of worsening depressive/anxiety symptoms, distress, and loneliness. ACEs were found to exacerbate depressive/anxiety symptoms and distress, while PCEs mitigated these symptoms, and vice versa.

Conclusion

This study underscores the importance of considering both ACEs and PCEs in supporting the mental health of university students. PCEs were found to independently prevent mental health deterioration, including depressive/anxiety symptoms and distress, which may include post‐traumatic stress disorder symptoms, even in the presence of ACEs. Recognizing and fostering PCEs emerged as an effective strategy for mitigating mental health issues.
Impact of predictive selection of LbCas12a CRISPR RNAs upon on‐ and off‐target editing rates in soybean
Authors: Rymarquis Linda , Wu Chenxi , Hohorst Diane , Vega‐Sanchez Miguel , Mullen Thomas E. , Vemulapalli Vijetha , Smith Douglas R.
Published: August 2024

Clustered regularly interspaced short palindromic repeats (CRISPR) technology has revolutionized creating targeted genetic variation in crops. Although CRISPR enzymes have been reported to have high sequence‐specificity, careful design of the editing reagents can also reduce unintended edits at highly homologous sites. This work details the first large‐scale study of the heritability of on‐target edits and the rate of edits at off‐target sites in soybean (Glycine max), assaying ~700 T1 plants each resulting from transformation with LbCas12a constructs containing CRISPR RNAs (crRNAs) predicted to be either “unique” with no off‐target sites or “promiscuous” with >10 potential off‐targets in the soybean genome. Around 80% of the on‐target edits observed in T0 plants were inherited in the T1 generation, and ~49% of the total observed on‐target edits in T1 were not observed at T0, indicating continued activity of LbCas12a throughout the life cycle of the plant. In planta editing at off‐target sites was observed for the Promiscuous but not the Unique crRNA. Examination of the edited off‐target sites revealed that LbCas12a was highly tolerant to mismatches between the crRNA and target site in bases 21–23 relative to the start of the protospacer, but even a single mismatch in the first 20 nt drastically reduced the editing rate. In addition, edits at off‐target sites have lower inheritance rates than on‐target edits, suggesting that they occur later in the plant's lifecycle. Plants with a desired on‐target edit and no off‐target edits could be identified in the T1 generation for 100% of the T0 plants edited with the Unique crRNA compared with the 65% of T0 plants edited with the Promiscuous crRNA. This confirms that proper crRNA selection can reduce or eliminate off‐target editing. Even when potential off‐target sites are predicted, plants containing only the intended edits can still be identified and propagated.
Combining artificial intelligence and conventional statistics to predict bronchopulmonary dysplasia in very preterm infants using routinely collected clinical variables
Authors: Montagna Sara , Magno Dalila , Ferretti Stefano , Stelluti Michele , Gona Andrea , Dionisi Camilla , Simonazzi Giuliana , Martini Silvia , Corvaglia Luigi , Aceti Arianna
Published: August 2024

Background

Prematurity is the strongest predictor of bronchopulmonary dysplasia (BPD). Most previous studies investigated additional risk factors by conventional statistics, while the few studies applying artificial intelligence, and specifically machine learning (ML), for this purpose were mainly targeted to the predictive ability of specific interventions. This study aimed to apply ML to identify, among routinely collected data, variables predictive of BPD, and to compare these variables with those identified through conventional statistics.

Methods

Very preterm infants were recruited; antenatal, perinatal, and postnatal clinical data were collected. A BPD prediction model was built using conventional statistics, and nine supervised ML algorithms were applied for the same purpose: the results of the best‐performing model were described and compared with those of conventional statistics.

Results

Both conventional statistics and ML identified the degree of immaturity (low gestational age and/or birth weight), need for mechanical ventilation, and absent or reversed end diastolic flow (AREDF) in the umbilical arteries as risk factors for BPD. Each of the two approaches also identified additional potentially predictive clinical variables.

Conclusion

ML algorithms might be useful to integrate conventional statistics in identifying novel risk factors, in addition to prematurity, for the development of BPD in very preterm infants. Specifically, the identification of AREDF status as an independent risk factor for BPD by both conventional statistics and ML highlights the opportunity to include detailed antenatal information in clinical predictive models for neonatal diseases.
Mispacking of the F87 sidechain drives aggregation‐promoting conformational fluctuations in the subunit interfaces of the transthyretin tetramer
Authors: Sun Xun , Ferguson James A. , Yang Ke , Stanfield Robyn L. , Dyson H. Jane , Wright Peter E.
Published: August 2024

Aberrant formation and deposition of human transthyretin (TTR) aggregates causes transthyretin amyloidosis. To initialize aggregation, transthyretin tetramers must first dissociate into monomers that partially unfold to promote entry into the aggregation pathway. The native TTR tetramer (T) is stabilized by docking of the F87 sidechain into an interfacial cavity enclosed by several hydrophobic residues including A120. We have previously shown that an alternative tetramer (T*) with mispacked F87 sidechains is more prone to dissociation and aggregation than the native T state. However, the molecular basis for the reduced stability in T* remains unclear. Here we report characterization of the A120L mutant, where steric hindrance is introduced into the F87 binding site. The x‐ray structure of A120L shows that the F87 sidechain is displaced from its docking site across the subunit interface. In A120S, a naturally occurring pathogenic mutant that is less aggregation‐prone than A120L, the F87 sidechain is correctly docked, as in the native TTR tetramer. Nevertheless, 19F‐NMR aggregation assays show an elevated population of a monomeric aggregation intermediate in A120S relative to a control containing the native A120, due to accelerated tetramer dissociation and slowed monomer tetramerization. The mispacking of the F87 sidechain is associated with enhanced exchange dynamics for interfacial residues. At 298 K, the T* populations of various naturally occurring mutants fall between 4% and 7% (ΔG ~ 1.5–1.9 kcal/mol), consistent with the free energy change expected for undocking and solvent exposure of one of the four F87 sidechains in the tetramer (ΔG ~ 1.6 kcal/mol). Our data provide a molecular‐level picture of the likely universal F87 sidechain mispacking in tetrameric TTR that promotes interfacial conformational dynamics and increases aggregation propensity.
ARCIMBOLDO at low resolution: Verification for coiled coils and globular proteins
Authors: Caballero Iracema , Castellví Albert , Triviño Josep , Jiménez Elisabet , Soler Nicolas , Borges Rafael Junqueira , Usón Isabel
Published: August 2024

Crystallography at low resolution must determine the atomic model from less experimental observations, which is challenging in the absence of a model. In addition, model bias is more severe when independent experimental data are scarce. Our methods solve the phase problem by combining the location of accurate model fragments using Phaser with density modification and interpretation of the resulting maps using SHELXE. From a partial, correct structure, the density modification process and the stereochemical constraints draw the rest of the structure, validating the result. This same principle is now exploited at low resolution. Coiled coils are important, ubiquitous structures but notoriously difficult to phase and to predict. Both correct solutions and incorrect ones are poorly discriminated by the crystallographic figures of merit as long as helices are correctly oriented. We incorporate coiled‐coil verification, designed to set up competing, incompatible structural hypotheses to probe both the results and establish the power of the data to discriminate them. Efficiency of coiled‐coil phasing and validation in test cases from 3 to 4 Å is demonstrated in ARCIMBOLDO_LITE, placing single helices, and in ARCIMBOLDO_SHREDDER, with fragments derived from AlphaFold models. SHELXE tracing at low resolution has been enhanced, maintaining its local character but extending the environment assessment. For non‐helical structures, verification is demonstrated in the fragment location process. Its use is exemplified with the solution of the VSR1 structure at 3.5 Å, depending on LLG optimization and the emergence of new features in the electron density. Relying on verification, we have extended the use of the ARCIMBOLDO software to low resolution.
Structural basis for substrate flexibility of the O‐methyltransferase MpaG' involved in mycophenolic acid biosynthesis
Authors: You Cai , Pan Yunjun , Liu Ruxin , Li Shengying , Feng Yingang
Published: August 2024

MpaG' is an S‐adenosyl‐L‐methionine (SAM)‐dependent methyltransferase involved in the compartmentalized biosynthesis of mycophenolic acid (MPA), a first‐line immunosuppressive drug for organ transplantations and autoimmune diseases. MpaG' catalyzes the 5‐O‐methylation of three precursors in MPA biosynthesis including demethylmycophenolic acid (DMMPA), 4‐farnesyl‐3,5‐dihydroxy‐6‐methylphthalide (FDHMP), and an intermediate containing three fewer carbon atoms compared to FDHMP (FDHMP‐3C) with different catalytic efficiencies. Here, we report the crystal structures of S‐adenosyl‐L‐homocysteine (SAH)/DMMPA‐bound MpaG', SAH/FDHMP‐3C‐bound MpaG', and SAH/FDHMP‐bound MpaG' to understand the catalytic mechanism of MpaG' and structural basis for its substrate flexibility. Structural and biochemical analyses reveal that MpaG' utilizes the catalytic dyad H306‐E362 to deprotonate the C5 hydroxyl group of the substrates for the following methylation. The three substrates with differently modified farnesyl moieties are well accommodated in a large semi‐open substrate binding pocket with the orientation of their phthalide moiety almost identical. Based on the structure‐directed mutagenesis, a single mutant MpaG'Q267A is engineered with significantly improved catalytic efficiency for all three substrates. This study expands the mechanistic understanding and the pocket engineering strategy for O‐methyltransferases involved in fungal natural product biosynthesis. Our research also highlights the potential of O‐methyltransferases to modify diverse substrates by protein design and engineering.
Validation of candidate protein biomarkers previously identified by genetic instruments for prostate cancer risk: A prospective cohort analysis of directly measured protein levels in the ARIC study
Authors: Liu Tanxin , Joshu Corinne E. , Lu Jiayun , Prizment Anna , Chatterjee Nilanjan , Wu Lang , Platz Elizabeth A.
Published: August 2024

Background

Multiple novel protein biomarkers have been shown to be associated with prostate cancer risk using genetic instruments. This study aimed to externally validate the associations of 30 genetically predicted candidate proteins with prostate cancer risk using aptamer‐based levels in US Black and White men in the Atherosclerosis Risk in Communities (ARIC) study. Plasma protein levels were previously measured by SomaScan® using the blood collected in 1990–1992.

Methods

Among 4864 eligible participants, we ascertained 667 first primary prostate cancer cases through 2015. Hazard ratios (HRs) of prostate cancer and 95% confidence intervals (CIs) were estimated using Cox proportional hazards regression for tertiles of each protein. We adjusted for age, race, and other risk factors.

Results

Of the 30 proteins and considering a nominal p trend < 0.05, two were positively associated with prostate cancer risk—RF1ML (tertile 3 vs. 1: HR = 1.23; 95% CI 1.02–1.48; p trend = 0.037) and TPST1 (1.28, 95% CI 1.06–1.55; p trend = 0.0087); two were inversely associated—ATF6A (HR = 0.80, 95% CI 0.65–0.98; p trend = 0.028) and SPINT2 (HR = 0.74, 95% CI 0.61–0.90; p trend = 0.0025). One protein, KDEL2, which was nonlinearly associated (test‐for‐linearity: p < 0.01) showed a statistically significant lower risk in the second tertile (HR = 0.79, 95% CI 0.65–0.95). Of these five, four proteins—ATF6A, KDEL2, RF1ML, and TPST1—were consistent in the direction of association with the discovery studies.

Conclusion

This study validated some pre‐diagnostic protein biomarkers of the risk of prostate cancer.
Microstructures and Mechanical Properties of TiC/Al–Si–Fe Composite with Ti–C Powder Mixture Prepared by Contact Reaction Method
Authors: Xiao Peixin , Tang Peng , Li Li
Published: August 2024

This article investigates in situ TiC particle‐reinforcement Al–Si–Fe matrix composites prepared by the contact reaction method. The addition of Ti–C to alloys results in the formation of β‐Fe and significantly refined the eutectic Si phase. Meanwhile, the exothermic reaction of C accelerates generation velocity of TiC. The refinement of the Al3Ti phase is attributed to refinement of α‐Al, which expedites solidification speed and prevents the further diffusion of Si atom, resulting in the bulk of the primary Si phase is formed locally. The best refinement effect of microstructure is obtained when the mixing powder addition content is 1.0 wt% and the Al‐12Si‐1Fe alloy has maximum tensile strength. The appearance of TiC is regarded as underlying reason for the re‐enhancement of mechanical properties.
The role of gastrodin in the management of CNS‐related diseases: Underlying mechanisms to therapeutic perspectives
Authors: He Xirui , Chen Xufei , Yang Yan , Gu Jingyi , Xie Yulu , Liu Yujie , Hao Man , Heinrich Michael
Published: August 2024

Central nervous system (CNS)‐related diseases have a high mortality rate, are a serious threat to physical and mental health, and have always been an important area of research. Gastrodin, the main active metabolite of Gastrodia elata Blume, used in Chinese medicine and food, has a wide range of pharmacological effects, mostly related to CNS disorders. This review aims to systematically summarize and discuss the effects and underlying mechanisms of gastrodin in the treatment of CNS diseases, and to assess its potential for further development as a lead drug in both biomedicine and traditional Chinese medicine. Studies on the pharmacological effects of gastrodin on the CNS indicate that it may exert anti‐neurodegenerative, cerebrovascular protective, and ameliorative effects on diabetic encephalopathy, perioperative neurocognitive dysfunction, epilepsy, Tourette's syndrome, depression and anxiety, and sleep disorders through various mechanisms. To date, 110 gastrodin products have been approved for clinical use, but further multicenter clinical case–control studies are relatively scarce. Preclinical studies have confirmed that gastrodin can be used to treat CNS‐related disorders. However, important concerns need to be addressed in the context of likely non‐specific, assay interfering effects when gastrodin is studied using in vitro and in silico approaches, calling for a systematic assessment of the evidence to date. High‐quality clinical trials should have priority to evaluate the therapeutic safety and clinical efficacy of gastrodin. Further experimental research using appropriate in vivo models is also needed, focusing on neurodegenerative diseases, cerebral ischemic and hypoxic diseases, brain damage caused by methamphetamine or heavy metals, and epilepsy.
Synthesis of Novel Nanomaterials Based on FeIIICoII and FeIIINiII Mixed Oxides: Characterization and Tribological Performance
Authors: Dzhardimalieva Gulzhian I. , Kugabaeva Gulsara D. , Kydralieva Kamila A. , Drogan Ekaterina G. , Zabiyaka Igor Yu. , Burlakova Victoria E. , Uflyand Igor E.
Published: August 2024

In this work, nanomaterials based on FeIIICoII and FeIIINiII mixed oxides were obtained for the first time by thermal decomposition of polymer complexes of Fe and Co or Ni nitrates with acrylamide. During thermolysis, core‐shell nanomaterials are formed containing nanoparticles of FeCo and FeNi oxides uniformly distributed inside the carbon layer. These nanomaterials are characterized by high chemical and thermal stability. During thermolysis, nanoparticles of mixed oxides FeCo and FeNi were formed with an average crystallite size of 13–22 and 22–33 nm, respectively. Nanomaterials were tested as antifriction and antiwear additives to liquid industrial oil I‐20 A. The values of the friction coefficient decrease by more than 60 % when CoO⋅Fe2O3 with a concentration of 0.05 % is added to the industrial oil I‐20 A.
Synthesis, In Vitro Enzymatic Inhibition, and Molecular Modeling of Novel Piperazine‐Based Bis‐Schiff Base Derivatives as Promising Anti‐urease Agents
Authors: Masood Najat , Hussain Rafaqat , Khan Shoaib , Rahim Fazal , Mumtaz Sundas , Taha Muhammad , Ur Rahman Abid Obaid , Iqbal Tayyiaba , Adnan Ali Shah Syed , Omar Al Wesabi Esam , Magam Seami M.
Published: August 2024

The current study was aimed to synthesize piperazine‐based bis‐Schiff base derivatives (1–15) and were also screened in vitro for their inhibition against urease enzyme under the positive control of thiourea drug (IC50 value of 36.40±2.35 μM). Among the tested analogs, the maximum potency was shown by analog 2 with the lowest IC50 value of 2.10±1.10 μM, whereas the minimum activity was demonstrated by the scaffold 5 having an IC50 value of 49.60±6.10 μM. The experimental results of urease activity prompted us to investigate and propose a possible mechanism of how actives analogs of piperazine derivatives will interacts with the catalytic sites of targeted urease enzymes. For this purpose, molecular docking with Auto Dock Vina gave us an insight into the binding interactions of the active compounds to different amino acid residues of the targeted urease enzyme.
Machine Learning Aided De Novo Design Identifies Novel Benzimidazolone Based Inhibitor‐Modulators for Heat Shock Protein 90 (HSP90)
Authors: Bhowmick Shovonlal , Malhotra Jagriti , Choudhary Rinku , Dilip Shinde Omkar , Metwally Ahmed Sayed M. , Chunarkar Patil Pritee
Published: August 2024

The present study investigates the identification of novel heat shock protein‐90 (HSP90) inhibitors‐modulators employing de novo drug design methodologies. Precisely, a machine learning (ML) assisted de novo design tool, REINVENT4, was employed for generating novel molecules against a given set of known HSP90 inhibitors. Further, a series of cheminformatics analyses were undertaken to assess pharmacokinetic properties, evaluate binding affinity using docking, and predict absolute binding affinity using the KDeep tool to reduce the chemical space. Finally, three novel benzimidazole‐based drug‐like candidates viz. IM1, IM2, and IM3 were selected as potent inhibitors‐modulators for HSP90 protein. Docking‐based binding affinity of IM1, IM2, and IM3 was obtained as −11.30, −11.50, and −11.20 kcal/mol, respectively. Moreover, all identified protein‐ligand complex dynamic behavior has been extensively assessed through MD simulation for a 100 ns span, highlighting overall interaction stability and conformational rearrangements for protein bound with all selected compounds. The MM‐GBSA‐based binding free energy estimation for each complex demonstrated the superiority of identified compounds, as found to be −43.54, −38.34, and −25.50 kcal/mol for IM1, IM2, and IM3. Collectively, pharmacokinetics and drug‐like profile assessment of identified compounds, along with simulation trajectories, explained the potentiality of the compounds for modulating the activity of the HSP90.
Cdo‐Zno Nanocomposite for Efficient Dye Degradation, Sensitive Nitrite Detection, Potential Luminescence and Antioxidant Properties
Authors: Nethravathi P. C. , Gayathri Devi V. , Tejaswini K. C. , Suresh D.
Published: August 2024

Environmental remediation evinces sensitive detection and elimination of contaminants from the environment. Recent investigations delineate nanomaterials as potentially useful agents in environment remediation. In this investigation, we have developed multifunctional CdO‐ZnO nanocomposite (NCs) for efficient degradation of organic dyes and sensitive detection of nitrite ions which also exhibits excellent luminescence and antioxidant properties. The CdO‐ZnO NCs were developed through a facile method which improved the yield quantity by decreasing the energy consumption there by reducing the cost. Thus synthesized CdO‐ZnO NCs were characterized through X‐ray diffraction, FT‐IR, SEM, TEM, EDX studies. These studies confirmed the successful formation of CdO‐ZnO composite and the average particle size of the NCs was found to be ~50 nm. Selective reduction of harmful industrial organic dyes from the water bodies is one of the important aspects of water pollution. As prepared CdO‐ZnO NCs degraded the MB dye completely in 30 min under visible light irradiation. The effect of various parameters such as catalytic load, dye concentration and pH on the degradation of dye was assessed and the NCs exhibited maximum degradation efficiency at 25 mg of catalytic load and alkaline pH of 11. The photoluminescence studies reveal that the NCs have inherent excellent luminescence property by exhibiting the emission band at 277 and 282 nm. From electrochemical studies, the CdO‐ZnO NCs proclaimed magnificent nitrite sensing property with the LOD value of 9.8 μM. Additionally, antioxidant studies disclosed that NCs remarkably scavenged the DPPH free radicals with IC50 value of 249 μg/mL. Thus, this study establishes simple method for the development of efficient mixed oxide material CdO‐ZnO for multifunctional properties that could find industrial applications.
Nanoscale Mechanical Manipulation of Ultrathin SiN Membranes Enabling Infrared Near‐Field Microscopy of Liquid‐Immersed samples
Authors: Baù Enrico , Gölz Thorsten , Benoit Martin , Tittl Andreas , Keilmann Fritz
Published: August 2024

Scattering scanning near‐field optical microscopy (s‐SNOM) is a powerful technique for mid‐infrared spectroscopy at nanometer length scales. By investigating objects in aqueous environments through ultrathin membranes, s‐SNOM has recently been extended toward label‐free nanoscopy of the dynamics of living cells and nanoparticles, assessing both the optical and the mechanical interactions between the tip, the membrane and the liquid suspension underneath. Here, the study reports that the tapping AFM tip induces a reversible nanometric deformation of the membrane manifested as either an indentation or protrusion. This mechanism depends on the driving force of the tapping cantilever, which is exploited to minimize topographical deformations of the membrane to improve optical measurements. Furthermore, it is shown that the tapping phase delay between driving signal and tip oscillation is a highly sensitive observable to study the mechanics of adhering objects, exhibiting highest contrast at low tapping amplitudes where the membrane remains nearly flat. Mechanical responses are correlated with simultaneously recorded spectroscopy data to reveal the thickness of nanometric water layers between membrane and adhering objects. Besides a general applicability of depth profiling, the technique holds great promise for studying mechano‐active biopolymers and living cells, biomaterials that exhibit complex behaviors when under a mechanical load.