bluuebunny/crossref_metadata_2025 huggingface dataset:
Swift 4D printing of thermoresponsive shape-memory polymers using vat photopolymerization
Authors: Alam Fahad , Ubaid Jabir , Butt Haider , El-Atab Nazek
Published: December 2023

Shape-memory polymers (SMPs) are smart materials that have gained significant attention in recent years owing to their widespread application in smart structures and devices. Digital light processing (DLP), a vat-photopolymerization-based technique, is a significantly faster technology for printing a complete layer in a single step. The current study reports a facile and fast method for the 3D printing of SMP-based smart structures using a DLP 3D printer and a customized resin. A liquid crystal (LC, RM257) was combined with the resin to introduce shape-memory properties. The combination of LCs in photocurable resin provides the opportunity to directly 3D-print thermoresponsive structures, avoiding the complexity of SMP resin preparation. The structures were printed with different geometries, and the shape-memory response was measured. Lattice structures were fabricated and programmed to obtain tunable mechanical properties. Furthermore, the strain-sensing response was measured to demonstrate the utility of these lattice structures as smart patches for joint-movement sensing. The SMPs can be prepared conveniently and can potentially be used for various applications, such as smart tools, toys, and meta-material sensors.
Spinal cord injury-induced gut dysbiosis influences neurological recovery partly through short-chain fatty acids
Authors: Jing Yingli , Yang Degang , Bai Fan , Wang Qiuying , Zhang Chao , Yan Yitong , Li Zihan , Li Yan , Chen Zhiguo , Li Jianjun , Yu Yan
Published: December 2023

Spinal cord injury (SCI) can reshape gut microbial composition, significantly affecting clinical outcomes in SCI patients. However, mechanisms regarding gut–brain interactions and their clinical implications have not been elucidated. We hypothesized that short-chain fatty acids (SCFAs), intestinal microbial bioactive metabolites, may significantly affect the gut–brain axis and enhance functional recovery in a mouse model of SCI. We enrolled 59 SCI patients and 27 healthy control subjects and collected samples. Thereafter, gut microbiota and SCFAs were analyzed using 16 S rDNA sequencing and gas chromatography–mass spectrometry, respectively. We observed an increase in Actinobacteriota abundance and a decrease in Firmicutes abundance. Particularly, the SCFA-producing genera, such as Faecalibacterium, Megamonas, and Agathobacter were significantly downregulated among SCI patients compared to healthy controls. Moreover, SCI induced downregulation of acetic acid (AA), propionic acid (PA), and butyric acid (BA) in the SCI group. Fecal SCFA contents were altered in SCI patients with different injury course and injury segments. Main SCFAs (AA, BA, and PA) were administered in combination to treat SCI mice. SCFA supplementation significantly improved locomotor recovery in SCI mice, enhanced neuronal survival, promoted axonal formation, reduced astrogliosis, and suppressed microglial activation. Furthermore, SCFA supplementation downregulated NF-κB signaling while upregulating neurotrophin-3 expression following SCI. Microbial sequencing and metabolomics analysis showed that SCI patients exhibited a lower level of certain SCFAs and related bacterial strains than healthy controls. SCFA supplementation can reduce inflammation and enhance nourishing elements, facilitating the restoration of neurological tissues and the improvement of functional recuperation. Trial registration: This study was registered in the China Clinical Trial Registry (www.chictr.org.cn) on February 13, 2017 (ChiCTR-RPC-17010621).
Effective protection of photoreceptors using an inflammation-responsive hydrogel to attenuate outer retinal degeneration
Authors: Kim Hyerim , Roh Hyeonhee , Kim Sang-Heon , Lee Kangwon , Im Maesoon , Oh Seung Ja
Published: December 2023

Retinitis pigmentosa (RP) is an outer retinal degenerative disease that can lead to photoreceptor cell death and profound vision loss. Although effective regulation of intraretinal inflammation can slow down the progression of the disease, an efficient anti-inflammatory treatment strategy is still lacking. This study reports the fabrication of a hyaluronic acid-based inflammation-responsive hydrogel (IRH) and its epigenetic regulation effects on retinal degeneration. The injectable IRH was designed to respond to cathepsin overexpression in an inflammatory environment. The epigenetic drug, the enhancer of zeste homolog 2 (EZH2) inhibitors, was loaded into the hydrogel to attenuate inflammatory factors. On-demand anti-inflammatory effects of microglia cells via the drug-loaded IRH were verified in vitro and in vivo retinal degeneration 10 (rd10) mice model. Therefore, our IRH not only reduced intraretinal inflammation but also protected photoreceptors morphologically and functionally. Our results suggest the IRH reported here can be used to considerably delay vision loss caused by RP.
Mathematical discoveries from program search with large language models
Authors: Romera-Paredes Bernardino , Barekatain Mohammadamin , Novikov Alexander , Balog Matej , Kumar M. Pawan , Dupont Emilien , Ruiz Francisco J. R. , Ellenberg Jordan S. , Wang Pengming , Fawzi Omar , Kohli Pushmeet , Fawzi Alhussein
Published: December 2023

Large language models (LLMs) have demonstrated tremendous capabilities in solving complex tasks, from quantitative reasoning to understanding natural language. However, LLMs sometimes suffer from confabulations (or hallucinations), which can result in them making plausible but incorrect statements1,2. This hinders the use of current large models in scientific discovery. Here we introduce FunSearch (short for searching in the function space), an evolutionary procedure based on pairing a pretrained LLM with a systematic evaluator. We demonstrate the effectiveness of this approach to surpass the best-known results in important problems, pushing the boundary of existing LLM-based approaches3. Applying FunSearch to a central problem in extremal combinatorics—the cap set problem—we discover new constructions of large cap sets going beyond the best-known ones, both in finite dimensional and asymptotic cases. This shows that it is possible to make discoveries for established open problems using LLMs. We showcase the generality of FunSearch by applying it to an algorithmic problem, online bin packing, finding new heuristics that improve on widely used baselines. In contrast to most computer search approaches, FunSearch searches for programs that describe how to solve a problem, rather than what the solution is. Beyond being an effective and scalable strategy, discovered programs tend to be more interpretable than raw solutions, enabling feedback loops between domain experts and FunSearch, and the deployment of such programs in real-world applications.
Template and target-site recognition by human LINE-1 in retrotransposition
Authors: Thawani Akanksha , Ariza Alfredo Jose Florez , Nogales Eva , Collins Kathleen
Published: December 2023

The long interspersed element-1 (LINE-1, hereafter L1) retrotransposon has generated nearly one-third of the human genome and serves as an active source of genetic diversity and human disease1. L1 spreads through a mechanism termed target-primed reverse transcription, in which the encoded enzyme (ORF2p) nicks the target DNA to prime reverse transcription of its own or non-self RNAs2. Here we purified full-length L1 ORF2p and biochemically reconstituted robust target-primed reverse transcription with template RNA and target-site DNA. We report cryo-electron microscopy structures of the complete human L1 ORF2p bound to structured template RNAs and initiating cDNA synthesis. The template polyadenosine tract is recognized in a sequence-specific manner by five distinct domains. Among them, an RNA-binding domain bends the template backbone to allow engagement of an RNA hairpin stem with the L1 ORF2p C-terminal segment. Moreover, structure and biochemical reconstitutions demonstrate an unexpected target-site requirement: L1 ORF2p relies on upstream single-stranded DNA to position the adjacent duplex in the endonuclease active site for nicking of the longer DNA strand, with a single nick generating a staggered DNA break. Our research provides insights into the mechanism of ongoing transposition in the human genome and informs the engineering of retrotransposon proteins for gene therapy.
Mucosal boosting enhances vaccine protection against SARS-CoV-2 in macaques
Authors: McMahan Katherine , Wegmann Frank , Aid Malika , Sciacca Michaela , Liu Jinyan , Hachmann Nicole P. , Miller Jessica , Jacob-Dolan Catherine , Powers Olivia , Hope David , Wu Cindy , Pereira Juliana , Murdza Tetyana , Mazurek Camille R. , Hoyt Amelia , Boon Adrianus C. M. , Davis-Gardner Meredith , Suthar Mehul S. , Martinot Amanda J. , Boursiquot Mona , Cook Anthony , Pessaint Laurent , Lewis Mark G. , Andersen Hanne , Tolboom Jeroen , Serroyen Jan , Solforosi Laura , Costes Lea M. M. , Zahn Roland C. , Barouch Dan H.
Published: December 2023

A limitation of current SARS-CoV-2 vaccines is that they provide minimal protection against infection with current Omicron subvariants1,2, although they still provide protection against severe disease. Enhanced mucosal immunity may be required to block infection and onward transmission. Intranasal administration of current vaccines has proven inconsistent3–7, suggesting that alternative immunization strategies may be required. Here we show that intratracheal boosting with a bivalent Ad26-based SARS-CoV-2 vaccine results in substantial induction of mucosal humoral and cellular immunity and near-complete protection against SARS-CoV-2 BQ.1.1 challenge. A total of 40 previously immunized rhesus macaques were boosted with a bivalent Ad26 vaccine by the intramuscular, intranasal and intratracheal routes, or with a bivalent mRNA vaccine by the intranasal route. Ad26 boosting by the intratracheal route led to a substantial expansion of mucosal neutralizing antibodies, IgG and IgA binding antibodies, and CD8+ and CD4+ T cell responses, which exceeded those induced by Ad26 boosting by the intramuscular and intranasal routes. Intratracheal Ad26 boosting also led to robust upregulation of cytokine, natural killer, and T and B cell pathways in the lungs. After challenge with a high dose of SARS-CoV-2 BQ.1.1, intratracheal Ad26 boosting provided near-complete protection, whereas the other boosting strategies proved less effective. Protective efficacy correlated best with mucosal humoral and cellular immune responses. These data demonstrate that these immunization strategies induce robust mucosal immunity, suggesting the feasibility of developing vaccines that block respiratory viral infections.
Proximity induced band gap opening in topological-magnetic heterostructure (Ni80Fe20/p-TlBiSe2/p-Si) under ambient condition
Authors: Singh Roshani , Maurya Gyanendra Kumar , Gautam Vidushi , Kumar Rachana , Kumar Mahesh , Suresh K. G. , Panigrahi Brahmaranjan , Murapaka Chandrasekhar , Haldar Arbinda , Kumar Pramod
Published: December 2023

The broken time reversal symmetry states may result in the opening of a band gap in TlBiSe2 leading to several interesting phenomena which are potentially relevant for spintronic applications. In this work, the quantum interference and magnetic proximity effects have been studied in Ni80Fe20/p-TlBiSe2/p-Si (Magnetic/TI) heterostructure using physical vapor deposition technique. Raman analysis shows the symmetry breaking with the appearance of A21u mode. The electrical characteristics are investigated under dark and illumination conditions in the absence as well as in the presence of a magnetic field. The outcomes of the examined device reveal excellent photo response in both forward and reverse bias regions. Interestingly, under a magnetic field, the device shows a reduction in electrical conductivity at ambient conditions due to the crossover of weak localization and separation of weak antilocalization, which are experimentally confirmed by magnetoresistance measurement. Further, the photo response has also been assessed by the transient absorption spectroscopy through analysis of charge transfer and carrier relaxation mechanisms. Our results can be beneficial for quantum computation and further study of topological insulator/ferromagnet heterostructure and topological material based spintronic devices due to high spin orbit coupling along with dissipationless conduction channels at the surface states.
The impact of difficult embryo transfer on the success of IVF: a systematic review and meta-analysis
Authors: Galati Giulia , Reschini Marco , Mensi Laura , Di Dio Camilla , Somigliana Edgardo , Muzii Ludovico
Published: December 2023

The procedure of embryo transfer (ET) must be as gentle as possible since any traumatism may cause uterine contractility that interferes with the implantation. However, this ideal conduct is not always possible, and additional measures may be necessary (difficult ET). Different studies have evaluated the impact of difficult ET on the clinical pregnancy rate (CPR), but results were not univocal. The present systematic review and meta-analysis was aimed to provide a precise estimate of the possible detrimental effects of difficult ET on CPR. The study protocol was registered online (PROSPERO number: CRD42023387197). An electronic database search was performed to identify articles published until September 2022. The primary outcome was CPR. Fifteen studies fulfilled the inclusion criteria. Difficult ET significantly reduced the CPR (OR 0.70; 95%CI: 0.64–0.76; p < 0.0001. All pre-planned subgroup analyses according to study design (retrospective vs prospective studies), historical period (studies published before and after 2010), type of catheter, frequency of difficult cases (> or < 19%) and pregnancy rate (> or < 38%) confirmed the significant association. Difficult ET is associated with a significant reduction of CPR. Further studies are warranted to understand how to prevent or manage this common clinical situation.
Filtering property of myelinated internode can change neural information representability and might trigger a compensatory action during demyelination
Authors: Das Sarbani , Maharatna Koushik
Published: December 2023

In this paper, for the first time, we showed that an Internode Segment (INS) of a myelinated axon acts as a lowpass filter, and its filter characteristics depend on the number of myelin turns. Consequently, we showed how the representability of a neural signal could be altered with myelin loss in pathological conditions involving demyelinating diseases. Contrary to the traditionally held viewpoint that myelin geometry of an INS is optimised for maximising Conduction Velocity (CV) of Action Potential (AP), our theory provides an alternative viewpoint that myelin geometry of an INS is optimised for maximizing representability of the stimuli a fibre is meant to carry. Subsequently, we show that this new viewpoint could explain hitherto unexplained experimentally observed phenomena such as, shortening of INS length during demyelination and remyelination, and non-uniform distribution of INS in the central nervous system fibres and associated changes in diameter of nodes of ranvier along an axon. Finally, our theory indicates that a compensatory action could take place during demyelination up to a certain number of loss of myelin turns to preserve the neural signal representability by simultaneous linear scaling of the length of an INS and the inner radius of the fibre.
The geodynamic origin of Los Humeros volcanic field in Mexico: insights from numerical simulations
Authors: Bayona A. , Manea V. C. , Manea M. , Yoshioka S. , Moreno E. , Suenaga N.
Published: December 2023

Compared to normal arc-related volcanic eruptions, the formation of a volcanic caldera is a relatively atypical event. During caldera formation a series of large volumes of magma are erupted, reducing the structural support for the rock above the magma chamber and creating a large depression at the surface called caldera. Los Humeros volcanic field (LHVF) represents one of the largest volcanic calderas in Mexico. It is located some 400 km from the trench at the eastern edge of the Trans Mexican Volcanic Belt where the depth to the Cocos slab is more than 300 km. In this study we employ high-resolution two-dimensional thermomechanical numerical simulations of magma intrusions and a horizontal tectonic strain rate to better understand the influence of crustal deformation for the formation of Los Humeros caldera. A minimum number of three thermal anomaly pulses of hydrated mantle material (with diameter of 15 km or more) and a regional strain rate of 7.927 × 10–16 s−1 are required for magma to reach the surface. Modeling results show that regional extension coupled with deep thermal anomalies (with a temperature excess of ΔT ≥ 100 °C) that come in a specific chain-type sequence produce surface deformation patterns similar to LHVF. We propose an asthenospheric sub-slab deep source (> 300 km depth) for the thermal anomalies where previous studies showed the existence of a gap or tear in the Cocos slab.
Risk assessment of hollow-bearing trees in urban forests
Authors: Suchocka Marzena , Jelonek Tomasz , Błaszczyk Magdalena , Wińska-Krysiak Marzena , Kubus Marcin , Ziemiański Maciej , Kalaji Hazem M.
Published: December 2023

The paper is a study of risk assessment posed by trees in selected urban woodlands (urban forests) of Warsaw. Two groups of trees were analysed and compared: exhibiting signs of maturity and ageing (hollow-bearing trees with open or hidden cavities and/or caries) and with no signs of decay. 373 individual trees growing near routes frequently or continuously used for recreational purposes were examined using Roloff's vitality classification, and tree risk assessment method, complemented by instrumental studies: a resistance resistograph, pulling tests, and sonic tomography (SoT). The collected data was analysed using the Chi-square test. The results indicate that it is not possible to conclude unequivocally that the presence of hollows in aged trees significantly increases the risk of falling. According to the safety factor results from the SoT and pulling tests, no correlation was demonstrated between the presence of hollow trees and an increase in risk class. The highest proportion of hollow trees (89.42%) was in the low risk group for trunk fracture and uprooting. The results also indicate the coherence of the diagnostic methods to be necessary for providing sufficient information to assess the statics and, ultimately, as our study showed, the protection of hollow trees.
Plasmodium sporozoite excystation involves local breakdown of the oocyst capsule
Authors: Saeed Sadia , Tremp Annie Z. , Dessens Johannes T.
Published: December 2023

Plasmodium oocysts develop on the abluminal side of the mosquito midgut in relatively small numbers. Oocysts possess an extracellular cell wall—the capsule—to protect them from the insect's haemolymph environment. To further maximise transmission, each oocyst generates hundreds of sporozoites through an asexual multiplication step called sporogony. Completion of transmission requires sporozoite egress from the capsule (excystation), but this process remains poorly understood. In this study, we fused the parasite-encoded capsule protein Cap380 with green fluorescent protein in a transgenic P. berghei line, allowing live fluorescence imaging of capsules throughout sporogony and sporozoite excystation. The results show that capsules progressively weaken during sporulation ultimately resulting in sporozoite exit through small holes. Prior to formation of the holes, local thinning of the capsule was observed. Our findings support an excystation model based on local, rather than global, weakening of the capsule likely facilitated by local re-orientation of sporozoites and apical secretion.
Cognitive impairment experienced by Chinese breast cancer survivors
Authors: Chen Dan , Mackenzie Lynette , Hossain Syeda Zakia , Wang Jing-Xin , Jiang Ping-Lan , Wang Yuanxiao , Qin Lanhui , Zhen Jun , Jia Jie
Published: December 2023

To identify cognitive function in Chinese breast cancer survivors. Research questions were: is cognitive function was associated with breast cancer and/or chemotherapy treatment and/or psychological functioning:? and did women with breast cancer experience more cognitive and psychological issues than age-matched women without cancer? Breast cancer survivors with chemotherapy (n = 106, mean age = 50.2 ± 9.5), breast cancer survivors without chemotherapy (n = 100, mean age = 50.5 ± 10.0) and matched healthy controls (n = 96, mean age = 47.9 ± 9.1) completed a battery of cognitive and psychosocial functioning. Demographic characteristics were also collected. The Perceived Cognitive Impairment score for cancer groups was significantly higher than for the healthy group (p = 0.04), but not between the cancer groups. Processing speed was significantly slower in the cancer groups than in the healthy group (both p < 0.001), but not between the cancer groups. Age, living status and education were significantly associated with the FACT-Cog (all p < 0.05). The correlations between the FACT-Cog score and BSI score were strong (r = 0.60 p < 0.01), and between the HADS anxiety and depression scales were strong (r = 0.53 and 0.50, p < 0.01) but correlations were weaker between performance based cognitive tests and measures of psychological functioning. Breast cancer groups indicated more cognitive impairment and reduced psychological functioning compared to the healthy group. However, there was no differences between the breast cancer groups. Chinese breast cancer survivors experienced excess cognitive impairment not associated with usual ageing. Assessment and intervention to address cognitive impairment should be made available to breast cancer survivors.
Granite dust application to hemp – variety-specific impacts on growth and cannabinoid production
Authors: Hillier N. K. , Voscort L. , Zamlynny L. , Hillier W. , Faraone N.
Published: December 2023

The hemp industry has grown exponentially with the recent legalization of Cannabis sativa in Canada. With this new market expansion, there is an increased need for hemp plants, particularly for production of cannabinoids. Growing concerns regarding pesticide residues in commodities for human consumption, as well as global demand for fertilizer has increased consumer demand for natural products as alternatives to synthetic agrochemicals and pest management strategies. The objective of this study was to investigate the potential for using different composite granite dusts applied as soil amendments in improving C. sativa growth, and cannabinoid production (specifically, cannabidiol and cannabidiolic acid). We selected three varieties of industrial hemp with low yield production of cannabidiol (Fibranova, CFX-2, and Katani) and one variety with high yield production of cannabidiol (Cherry Blossom). Varieties were planted in potting soil amended with zero, five or ten percent granite dust mixture, and assayed for growth characteristics, and cannabinoid composition. Among tested cannabis varieties, results suggest that improvements to flower growth (> 44% mass) and cannabinoid production (> 2.5 fold or > 145%) from application of granite dust were evident in one variety of fibre hemp, CFX-2. Overall, this work suggests there may be selective benefits to soil applications of granite dust composites to improve hemp propagation, and that degree of improvement to cannabinoid production vary between varieties of hemp.
PKM2 is a potential prognostic biomarker and related to immune infiltration in lung cancer
Authors: Yin Lan , Shi Jiaying , Zhang Jingfei , Lin Xinyu , Jiang Wenhao , Zhu Yingchuan , Song Yue , Lu Yilu , Ma Yongxin
Published: December 2023

Pyruvate kinase M2 (PKM2), a subtype of pyruvate kinase, plays a crucial role as a key enzyme in the final step of glycolysis. It is involved in regulating the tumor microenvironment and accelerating tumor progression. However, the relationship between PKM2 expression and the prognosis and immune infiltration remains unclear in lung cancer. In this study, we analyzed PKM2 expression in pan-cancer, and investigated its association with prognosis and immune cell infiltration of lung cancer by using multiple online databases, including Gent2, Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), PrognoScan, Kaplan–Meier plotter, and The Human Protein Atlas (HPA). The results showed that PKM2 expression is elevated in tumor tissues compared with the adjacent normal tissues of most cancers, including lung cancer. Prognostic analysis indicated that high expression of PKM2 was associated with poorer prognosis in overall lung cancer patients, especially in lung adenocarcinoma (LUAD). Notably, PKM2 exhibited a strong correlation with B cells and CD4+ T cells in LUAD; and with B cells, CD8+ T cells, CD4+ cells, and macrophages in lung squamous cell carcinoma (LUSC). Furthermore, PKM2 expression displayed a significant negative correlation with the expression of immune cell markers in both LUAD and LUSC. These findings suggested that PKM2 could serve as a promising prognostic biomarker for lung cancer and provided insights into its essential role in modulating the immune cell infiltration.
Tracking industry pollution sources and health risks in China
Authors: Sing Tien Foo , Wang Wenwen , Zhan Changwei
Published: December 2023

Agglomeration of firms significantly increases pollution emission intensity and brings unintended consequences to public health. We develop the pollution emission indices using the firm-level pollutant emission data in China to track pollution intensities at the source using the locally weighted regression approach. Our constant-quality pollutant emission indices for three pollutants (wastewater discharge, COD, and SO2) and the pollution emission heatmaps show decreasing trends for the three pollutants from 1998 to 2012. We also show significant spatial clustering and regional variations in pollution emission trends. Industrial pollution mitigations in China's Eastern and Central regions have been neglected for decades since 2021, when driving economic growth took priority. The regime shifts in pollution controls from the 10th (2000–2005) to the 11th (2006–2010) Five-Year Plan period show the effects of tightening pollution emission controls. Failure to cut pollution emissions at source causes health consequences to residents living and working in nearby polluting industries. The latent environmental hazard could be a ticking time bomb, which could not be delinked from the emergence of cancer villages in the regions. Therefore, enforcing strict and uniform pollution controls and setting clear emission limits at sources can eliminate free-rider problems by polluting firms.
The impact of perioperative fluid therapy on the short-term outcomes after laparoscopic colorectal cancer surgery with ERAS protocol: a prospective observational study
Authors: Pisarska-Adamczyk Magdalena , Torbicz Grzegorz , Gajewska Natalia , Małczak Piotr , Major Piotr , Pędziwiatr Michał , Wysocki Michał
Published: December 2023

The main goals of the Enhanced recovery after surgery (ERAS) protocol are focused on shortening the length of hospital stay (LOS), expediting convalescence, and reducing morbidity. A balanced perioperative fluid therapy is among the significant interventions incorporated by the ERAS protocol. The article contains extensive discussion surrounding the impact of this individual intervention on short-term outcomes. The aim of this study was to assess the impact of perioperative fluid therapy on short-term outcomes in patients after laparoscopic colorectal cancer surgery. The analysis included consecutive patients, who had undergone laparoscopic colorectal cancer operations between 2013 and 2020. Patients were divided into two groups: restricted (≤ 2500 ml) or excessive (> 2500 ml) perioperative fluid therapy. A standardized ERAS protocol was implemented in all patients. The study outcomes included recovery parameters and the morbidity rate, LOS and 30 days readmission rate. There were 361 and 80 patients in groups 1 and 2, respectively. There were no statistically significant differences between the groups in terms of demographic parameters and factors related to the surgical procedure. Logistic regression showed that restricted fluid therapy as a single intervention was associated with improvement in tolerance of diet on 1st postoperative day (OR 2.18, 95% CI 1.31–3.62, p = 0.003), accelerated mobilization on 1st postoperative day (OR 2.43, 95% CI 1.29–4.61, p = 0.006), lower risk of postoperative morbidity (OR 0.58, 95%CI 0.36–0.98, p = 0.046), shorter LOS (OR 0.49, 95% CI 0.29–0.81, p = 0.005) and reduced readmission rate (OR 0.48, 95% CI 0.23–0.98, p = 0.045). A balanced perioperative fluid therapy on the day of surgery may be associated with faster convalescence, lower morbidity rate, shorter LOS and lower 30 days readmission rate.
Unidirectional alignment and orientation pinning mechanism of h-BN nucleation on Ir(111) via reactive probe atomic force microscopy
Authors: Pan Jinliang , Wu Tongwei , Ma Chao , Wu Yangfan , Zheng Yi , Hu Kui , Sun Luye , Ma Sumei , Liu Mengxi , Zhang Yanning , Qiu Xiaohui
Published: December 2023

The epitaxial growth of wafer-scale single-crystalline two-dimensional materials requires precise control over the crystallographic orientation and morphology of clusters formed during the initial stages of nucleation. However, there is limited knowledge about the critical nucleus and its growth mechanism for h-BN on high-symmetry surfaces of transition metals. In this study, we provide atomic insights into h-BN nucleation on Ir(111) using scanning tunneling microscopy and noncontact atomic force microscopy, corraborated by density functional theory (DFT) calculations. The atomic-resolved structural characterization reveals that the smallest h-BN cluster, exhibiting a non-1:1 stoichiometric ratio of boron and nitrogen atoms, maintains a triangular shape with zigzag-type edges. Through force spectroscopy, individual B and N atoms within the cluster, as well as the N-termination edge, are clearly identified, indicating the atomic-scale elemental sensitivity of the chemical-reactive metallic tip. While DFT calculations suggest that the NtopBfcc configuration is thermodynamically favored for larger clusters, a predominant crystalline orientation is observed for nuclei of various sizes, unequivocally attributed to the NtopBhcp registry. This orientation pinning behavior presents opportunities for large-scale growth of binary and ternary materials by impeding rotational alignment of nuclei in the early stages of nucleation.
Artificial Neural Network Process Used in Global Drug Discovery and Development
Authors: Meena Grandhi Sai , Yetukuri Koushik
Published: December 2023

One of the branches of Artificial Intelligence (AI) that is most frequently employed in the advancement of medicine is artificial neural networks (ANN). An alternative name for neural networks is ANN. These are the computing systems inclined by the biological nervous system. It is built on a network of interconnected components known as artificial neurons. Similar to a biological neuron, the ANN is also having the interconnection nodes. The ANN is a simple mathematical function. This model has three sets of rules. Those are multiplication, summation and activation. In order to predict the properties of chemical compounds for drug discovery, ANNs are used. It has been demonstrated mathematically that an ANN may be used to roughly predict the link between any chemical property and its structure. To understand the significance of ANN in the drug discovery and development process is the primary goal of this article. Information was acquired from the USFDA’s official website as well as other research and review journals. ANN have been widely applied in a variety of key pharmacy-related fields, from clinical pharmacy to bio pharmacy to the interpretation of analytical data and the creation of drugs and dosage forms. It is commonly implemented in many areas of the pharmaceutical industry, including quantitative structure-activity relationships (QSAR) research and the analysis of chemicals used in drug discovery and development. ANN is useful for resolving nonlinear problems in multivariate and multi-response systems, including space analysis in QSAR in pharmacokinetic studies and structure prediction in drug development.
Screening of Some Novel Isoxazoles Against C. Albicans for their Potential Use as antifungals: A Computational Approach
Authors: Jays Judy , Parasuraman P , Saravanan J
Published: December 2023

Antifungal resistance represents a major challenge for treating invasive fungal infections due to the limited arsenal of systemic antifungal agents. Azole resistance among Candida and Aspergillus species and the spread of such species is alarming. Isoxazoles play a significant role in the field of medicinal chemistry. The great interest associated with this class of compounds is their versatility as synthetic intermediates. Isoxazole derivatives were found to possess anti-bacterial, anti-fungal, anti-inflammatory, pesticidal and herbicidal activities. This study focuses on screening some novel isoxazoles against essential enzymes of C. albicans using molecular docking and dynamic studies. Molecular docking studies were performed on twenty novel isoxazoles against N- methyl transferase and DNA gyrase of C. albicans using GLIDE. 2D and 3D dock poses were visualized. Molecular dynamic study was carried out by DESMOND. Docking study in the XP mode has given significant results with good GScores and Emodel for NMT. Compound 2D (2-hydroxy derivative) was ranked highest among the derivatives. The ligands bound tightly with the target protein, indicated by of hydrogen bond interactions and pi-pi stacking interactions at the active site. Molecular dynamic studies were carried out for two complexes. Complex was found to be stable during molecular dynamic simulation. Docking study suggests that compound 2D (2-hydroxy derivative) may be prospective inhibitors of N-methyl transferase as it are specific in binding to the active site of this enzyme. Hence it may be considered as lead molecule for the design of potential inhibitors of C. albicans.
Evaluation of In-Silico and In-Vitro Anthelmintic Activity of Heydotis Aspera (Heyne ex Roth) Using Pheretima Posthuma
Authors: Prasanth D S N B K , Jamullamudi Risy Namratha , Achanti Suneetha
Published: December 2023

Worm infections and their complications are serious problems affecting millions worldwide. Drug resistance has made alternative drug therapies desirable for worm infections owing to the failure of synthetic drugs. The ethnomedicinal plant Heydotis aspera (H. aspera) contains several secondary metabolites. Traditionally, its medicinal value has been attributed to plants. Methanol was extracted from whole H. aspera (MEHA) plants. Pheretima posthuma was used to assess anthelmintic activity in vitro, whereas AutoDock Vina was used for molecular docking using β-tubulin as the target. MEHA demonstrated the highest dose-dependent anthelmintic activity at various doses. It was found that Androsta-1,4-diene-3,17-dione, out of all the phytocompounds, had the most substantial docking rating of -7.4, which is more effective than the standard (-6.7), ensuring strong interactions between the ligand and β-tubulin. A potent anthelmintic effect of MEHA against P. posthuma was observed in in silico and in vitro studies. In addition, in vivo experiments must be performed to confirm the results obtained in vitro.
In Silico Screening, Analysis and Design of Potential Inhibitors Against RsmD for Treating Tuberculosis
Authors: Kadam Mangal S , Prasad Burra V L S
Published: December 2023

Mycobacterium tuberculosis (M.tb) causes TB and has ever since remained as a major global health burden because of increased rate of antibiotic resistance, an alert raised by WHO. RsmD is involved in the proper functioning of protein translation and protecting the organism (parasite) from drug action through methylation which is one of the most common epigenetic modifications adopted by the parasite referred to as drug resistance. Hence, targeting (RsmD) gives the opportunity to kill two-birds-with-one-stone: a) antibiotic role of drug and b) Anti-drug resistance. To discover the potential lead compounds against RsmD, a curated small molecule database of nucleoside mimetics from ASINEX were screened implementing Lipinski rule of five, further filtered to obtain compounds with molecular weights (MW) ranging between 350 Da - 450 Da. These compounds were docked with RsmD using CDOCKER of DS2022. Compounds with good CDOCKER score and favorable energies were further subjected to ADMET prediction, TOPKAT studies, molecular dynamics simulations and MM-PBSA binding energy calculations. Out of 4507 compounds 100 compounds were selected with CDOCKER energies ranging from -33 to -58 kcal/mol. On subjecting the 100 compounds to ADMET analysis and TOPKAT properties only 10 compounds were ensured as safe, non-toxic, non-carcinogenic and non-irritants. The top three leads, ASXNAID_3215, ASXNAID_3187 and ASXNAID_3182, are learnt to be easy to synthesize and are computationally verified and now demand for in vitro and in vivo evaluation and testing.
In Silico Pharmacokinetic and Pharmacodynamic Screening Methods of Phytol; An Antitubercular Lead Discovery Study
Authors: Asra Fathima , Thathapudi Daveedu , Ajra Fathima , Katari Sukeerthi , Dumala Naresh
Published: December 2023

Tuberculosis (TB) has become a serious global public health problem. There are very few new chemical entities being developed to manage this health concern. Hence, there is a need for developing new antitubercular drugs. Naturally occurring phytol is endowed with different types of biological applications. So the aim was to investigate in silico pharmacological and toxicological profile of Phytol using the mixed computational-based model. Physico-chemical parameters governing the bioactivity and antitubercular pharmacophore sites of Phytol were predicted. A molecular docking study was carried out to provide information about interactions of phytol in the binding site of the target proteins. In silico results indicated that Phytol has medium oral bioavailability, impermeable to the skin and blood-brain barrier, and is non-toxic. Phytol secured a low probability of binding with endocrine receptors. Phytol has some positive correlations among the molinspiration bioactivity score and docking score. The LD50 cut-off range would be 2000-5000 mg/kg body weight. Phytol has a less binding affinity with many antitargets and a good binding affinity with antitubercular target proteins. Hence, it may be a safe and efficacious antitubercular lead. Preclinical in vivo studies may suffice the in silico predictions and hence warranted.
Development and Validation of HPLC Method for Quantification of Parecoxib in Parecoxib Injection
Authors: Balanagu Haranatha Babu , Gopala Krishna Tatavarti SVS , Cheruvu Ramesh , Nalluri Buchi N.
Published: December 2023

The purpose of the present study was to evaluate and optimize lyophilization cycle time for the manufacturing of Parecoxib Injection than reported longer lyophilization cycle times. Optimization of lyophilization cycle time reduces the manufacturing costs since lyophilization process involves longer times which incurs cost to the finished product. Optimization of lyophilization cycle was done by using inputs from the results of Differential Scanning Calorimetry (DSC), Differential Thermal Analysis (DTA) and Impedance analysis. HPLC method was developed for quantification of Parecoxib Active Pharmaceutical Ingredient and Related Substances. Various stages involved in lyophilization cycle viz., freezing, extra-freezing, primary drying and secondary drying were evaluated and optimized. Results of drug excipient compatibility studies indicated no significant interaction between the drug and excipients. Optimization of developed lyophilization cycle resulted in reduced total lyophilization cycle time (29 hrs, 15 mins). Finished drug products were investigated by Powder X-ray Diffraction (PXRD) for evaluating complete conversion of crystalline API into amorphous solid and by Raman Spectroscopy to evaluate absence of hydrolytic conversion of Parecoxib to Valdecoxib. Reconstituted solutions are stable for 24 hrs. Residual moisture content was below 3.5%m/m. Results of chemical analysis are satisfactory. Optimized lyophilization cycle with reduced total lyophilization cycle time reduces the operational costs as well as improves productivity, and so can help manufacturers to sell the drug product at lower price which can be affordable to the common needy people.
A UV-Spectrophotometric Method for Simultaneous Estimation of Abacavir and Lamivudine in their Pharmaceutical Dosage Forms
Authors: Mohammed Jahasultana , Malothu Narender , Ganta Narayana Murthy , Mbilinyi Nestory , Uma Maheswari J , Idris Monzir
Published: December 2023

The combination of Abacavir (ABA) and lamivudine (LAM) is being used in the treatment of HIV. Though, there was several spectroscopic methods have been reported, it needs a simple, sensitive, and rapid analytical method for precise analysis. The objective of the current research was to establish a UV-spectrophotometric method for simultaneous estimation of in their bulk and tablet dosage form. In the current study, both drugs were estimated by simultaneous equation method. The method is characterized by measurement of absorbances at two wavelengths 218 nm and 274 nm, λmax of ABA and LAM, respectively. The analysis was carried by Acetonitrile: water (50:50 %v/v) using UV-Visible Spectrophotometer (Eppendorf Biospectrometer Basic) with a fixed 2 nm spectral bandwidth. The Beer’s law was compiled in the concentrations ranging from 2.5-15 μm/mL and 2.5-12.5 μm/mL for ABA and LAM, respectively. The linear regression was found with correlation coefficient (r2) of 0.9935, 0.9825 for ABA and LAM, respectively. This study was performed as per ICH guidelines and various parameters were validated. The % RSD for accuracy and precision were lies within the acceptance criteria. The percentage (%) recovery was within the potency range (99.6-101.8%). This statistical data analysis proved that the method followed was accurate, rigorous, and reproducible for ABA and LAM analysis in their tablet dosage forms. The wide linearity range, sensitivity and simple procedure imply that the proposed technique demonstrated to more appropriate for the testing and analysis of tablet dosage forms.
Development and Validation of A RP-HPLC Method for the Simultaneous Determination of Twenty Related Substances of Sulfamethoxazole and Trimethoprim in Injection Dosage Form
Authors: Rajasekhar K. , Naidu Ch. Gangu , Pavan Kumar Ch. Naga Sesha Sai , Varaprasada Rao K. , Srinivasa Rao Y.
Published: December 2023

A simple, robust and for the quantification of experimentally 20 related impurities of sulfamethoxazole (SM) and trimethoprim (TM) in liquid pharmaceutical dosage form, a novel RP-HPLC method was developed. Utilizing gradient elution on a Kromasil 100-5-C18; 5.0 m, (4.0x250) mm, column, chromatographic separation was accomplished. Solvent A (solution of 0.08% orthophosphoric acid in water) and Solvent B (mixture of acetonitrile and methanol, 80:20 v/v), given at a flow rate of 0.8 ml/min, respectively, make up the mobile phase. Using a photodiode array (PDA) detector, the analytes were identified and measured at 210 nm. Eight Sulfamethoxazole-related impurities and twelve Trimethoprim-related impurities can be quantified and evaluated using an organic impurities technique. According to the ingredients of the injection dosage form, the LOQ Standard solution concentration for Sulfamethoxazole Impurities is 0.0016 mg/mL and for Trimethoprim Impurities is 0.00032 mg/mL. For the OI process, the sample’s nominal concentrations of trimethoprim and sulfamethoxazole are 0.32 mg/mL and 1.6 mg/mL, respectively. The Validation range of the procedure was examined for test concentrations ranging from 0.1% to 1.0%. For all the stated contaminants, LOQ solution and LOQ spiked sample solution are stable for 24 hours at 5 °C sample temperature. At a sample temperature of 5°C, Trimethoprim EP Impurity-H is stable for up to 12 hours. According to ICH recommended guidelines, the method was validated, and it proved to be accurate and exact (repeatability and intermediate precision level) within the corresponding linear range of known SM and TM impurities.
Development and Validation of RP-HPLC-PDA Method for the Estimation of Fluoxetine Hydrochloride in Bulk, Mouth Dissolving Films and in Dissolution Samples
Authors: Mohammed Jahasultana , Nalluri Buchi N.
Published: December 2023

Selective serotonin reuptake inhibitor, fluoxetine hydrochloride (FLX) is a drug of choice for treating depression, obsessive-compulsive disorder (OCD), bulimia nervosa, etc. Even though FLX dosage forms such as tablets, capsules, oral solutions, and syrups are already available commercially, there is a considerable need for developing modified or immediate-release formulations with a quick onset of action and high bioavailability. The goal of this research is to provide a quick, practical, and cost-effective RP-HPLC-PDA approach for determining Fluoxetine hydrochloride (FLX) in bulk, mouth dissolving films (MDFs), and dissolution samples. A reverse-phase HPLC with chromatographic parameters like inertsil ODS3 column (150×4.6mm, 5µm), mobile phase composition of 10mM Ammonium acetate: Acetonitrile (58:42v/v), flow rate - 1.3mL/min, 20 μL injection volume in isocratic mode, wavelength at 226nm and a PDA detector is used to attain the peaks. Using the efficient liquid chromatographic conditions, FLX was eluted at retention time of 4.2min and a good linearity was seen over a concentration of 2-10µg/mL. The correlation coefficient (R2) was 0.999. The LOD and LOQ were 0.184μg/mL and 0.558μg/mL, respectively. The established technique was validated for method validation parameters like accuracy, precision, assay, linearity, specificity, robustness, LOD, and LOQ as per ICH Q2B recommendations. All the validation parameters were within acceptable limits. Hence, for the FLX estimation in bulk, MDFs and in-vitro dissolution samples the established technique can be utilized to produce reproducible results.
Formulation, Preparation, and Evaluation of Nebivolol Fast-Dissolving Tablets by Using 32 Factorial Design
Authors: Devi V. Rupa Sree , Sukanya M. , Shankar K. Ravi , Reddy G. Ramana , Lakshmi KNV. Chenchu
Published: December 2023

Nebivolol comes under BCS Class II Classification, so there is a need to improve the dissolution rate. The motive of the current work is to formulate the fast-dissolving tablets of Nebivolol from optimised solid dispersion by allowing complexation using solid dispersions of PEG 4000, Starch 1500, Poloxamer 188, and β-cyclodextrin (β CD). Nebivolol tablets with fast dissolution characteristics employing βCD were prepared using a 32 factorial study employing by direct compression technique. Dissolution of Nebivolol from the β-CD complexes was rapid and higher when seen with that of Pure Nebivolol and with different carriers like Poloxamer, PEG 4000, and Starch 1500. Hence β-CD (1:3 M) ratio was selected for the preparation of tablets by 32 factorial study. Nebivolol equivalent to 5mg tablets was prepared by immersing βCD (1:3 M) using Primojel and Crospovidone as super disintegrants through direct compression technique. Tablet powder blends in each case possess excellent flow characteristics suitable for direct compression. All prepared tablets satisfied the I.P disintegration time range of noncoated tablets. The factorial study was used in the formulation of nebivolol tablets in which all three levels of factor X1 (Primojel) and factor X2 (Crospovidone) are of concentration 3%, 4%, 5% (% calculated based on total tablet weight, i.e. 250 mg) were chosen as the hypothesis for the execution of the rapid dissolution of Nebivolol formulations. From the overview, it is evident that an enhancement in the portion of Superdisintegrant tends to decline in the disintegration time of the tablet and increase in drug dissolution.