bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploiting pretrained biochemical language models for targeted drug design
Authors: Uludoğan Gökçe , Ozkirimli Elif , Ulgen Kutlu O , Karalı Nilgün , Özgür Arzucan
Published: September 2022

Motivation

The development of novel compounds targeting proteins of interest is one of the most important tasks in the pharmaceutical industry. Deep generative models have been applied to targeted molecular design and have shown promising results. Recently, target-specific molecule generation has been viewed as a translation between the protein language and the chemical language. However, such a model is limited by the availability of interacting protein–ligand pairs. On the other hand, large amounts of unlabelled protein sequences and chemical compounds are available and have been used to train language models that learn useful representations. In this study, we propose exploiting pretrained biochemical language models to initialize (i.e. warm start) targeted molecule generation models. We investigate two warm start strategies: (i) a one-stage strategy where the initialized model is trained on targeted molecule generation and (ii) a two-stage strategy containing a pre-finetuning on molecular generation followed by target-specific training. We also compare two decoding strategies to generate compounds: beam search and sampling.

Results

The results show that the warm-started models perform better than a baseline model trained from scratch. The two proposed warm-start strategies achieve similar results to each other with respect to widely used metrics from benchmarks. However, docking evaluation of the generated compounds for a number of novel proteins suggests that the one-stage strategy generalizes better than the two-stage strategy. Additionally, we observe that beam search outperforms sampling in both docking evaluation and benchmark metrics for assessing compound quality.

Availability and implementation

The source code is available at https://github.com/boun-tabi/biochemical-lms-for-drug-design and the materials (i.e., data, models, and outputs) are archived in Zenodo at https://doi.org/10.5281/zenodo.6832145.

Supplementary information

Supplementary data are available at Bioinformatics online.
Preoperative risk factors for early recurrence after resection of perihilar cholangiocarcinoma
Authors: Yamamoto Ryusei , Sugiura Teiichi , Ashida Ryo , Ohgi Katsuhisa , Yamada Mihoko , Otsuka Shimpei , Aramaki Takeshi , Asakura Koiku , Uesaka Katsuhiko
Published: September 2022

Background

Early recurrence after curative resection of perihilar cholangiocarcinoma (PHCC) often occurs within a year of surgery. Preoperative predictors of early recurrence remain unclear. The aim of this study was to define reliable preoperative predictors of early recurrence.

Methods

Medical records and preoperative multidetector-row CT of patients with PHCC who underwent resection between 2002 and 2018 were reviewed. Clinical findings, tumour markers, and radiological appearances including a ‘periductal enation sign’ (PES) where there was evidence of soft tissue enhancement appearing to arise from the extrahepatic bile duct, were analysed.

Results

Among 261 patients who underwent resection for PHCC, 67 (25.7 per cent) developed early recurrence. Multivariable analysis identified four preoperative risk factors for early recurrence, namely carbohydrate antigen 19–9 (CA19-9) 37 U/ml or higher (OR 2.19, 95 per cent confidence interval (c.i.) 1.08 to 4.46), positive PES (OR 7.37, 95 per cent c.i. 2.46 to 22.10), mass-forming tumour (OR 4.46, 95 per cent c.i. 1.83 to 10.90), and luminal-occlusion tumour (OR 4.52, 95 per cent c.i. 2.11 to 9.68). The OR of preoperative risk factors were used to define four risk subgroups for early recurrence. The early recurrence rates in the low, moderate, high, and very-high risk groups were 0, 9.4 , 39.7, and 65.0 per cent respectively.

Conclusion

CA19-9, PES, mass-forming tumour, and luminal-occlusion tumour identify patients at higher risk for early recurrence after resection of PHCC.
The reduction of astrocytic tau prevents amyloid-β-induced synaptotoxicity
Authors: Cisternas Pablo , Taylor Xavier , Martinez Pablo , Maldonado Orlando , Jury Nur , Lasagna-Reeves Cristian A
Published: September 2022

Alzheimer’s disease is a neurological disorder characterized by the overproduction and aggregation of amyloid-beta and the phosphorylation and intraneuronal accumulation of tau. These events promote synaptic dysfunction and loss, leading to neurodegeneration and cognitive deficits. Astrocytes are intimately associated with synapses and become activated under pathological conditions, becoming neurotoxic and detrimentally affecting synapses. Although it has been established that reducing neuronal tau expression prevents amyloid-beta-induced toxicity, the role of astrocytic tau in this setting remains understudied. Herein, we performed a series of astrocytic and neuronal primary cultures to evaluate the effects of decreasing astrocytic tau levels on astrocyte-mediated amyloid-beta-induced synaptic degeneration. Our results suggest that the downregulation of tau in astrocytes mitigates the loss of synapses triggered by their exposure to amyloid-beta. Additionally, the absence of tau from astrocytes promotes the upregulation of several synaptoprotective genes, followed by increased production of the neuroprotective factor Pentraxin 3. These results expand our understanding of the contribution of astrocytic tau to the neurodegenerative process induced by amyloid-beta-stimulation and how reducing astrocytic tau could improve astrocyte function by stimulating the expression of synaptoprotective factors. Reducing endogenous astrocytic tau expression could be a potential strategy to prevent synaptic damage in Alzheimer's disease and other neurological conditions.
Tofacitinib treatment modulates the levels of several inflammation-related plasma proteins in rheumatoid arthritis and baseline levels of soluble biomarkers associate with the treatment response
Authors: Valli Atte , Kuuliala Krista , Virtanen Anniina , Kuuliala Antti , Palmroth Maaria , Peltomaa Ritva , Vidqvist Krista-Liisa , Leirisalo-Repo Marjatta , Silvennoinen Olli , Isomäki Pia
Published: September 2022

The data on the effects of tofacitinib on soluble proteins in patients with rheumatoid arthritis (RA) is currently very limited. We analyzed how tofacitinib treatment and thus inhibition of the Janus kinase—signal transducer and activation of transcription pathway affects the in vivo levels of inflammation-related plasma proteins in RA patients. In this study, 16 patients with active RA [28-joint disease activity score (DAS28) >3.2] despite treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) started tofacitinib treatment 5 mg twice daily. Levels of 92 inflammation-related plasma proteins were determined by proximity extension assay at baseline and at 3 months. Tofacitinib treatment for 3 months, in csDMARD background, decreased the mean DAS28 from 4.4 to 2.6 (P < 0.001). Marked (>20%) and statistically significant (P < 0.05) changes were found in the levels of 21 proteins, 18 of which decreased and 3 increased. Of these proteins, 17 are directly involved in inflammatory responses or in the cellular response to cytokines. The highest (>50%) decrease was observed for interleukin-6 (IL-6), C-X-C motif chemokine ligand 1, matrix metalloproteinase-1, and AXIN1. Higher baseline levels of IL-6 and lower levels of C-C motif chemokine 11 and Delta and Notch-like epidermal growth factor-related receptors were associated with DAS28 improvement. Our results indicate that tofacitinib downregulates several proinflammatory plasma proteins that may contribute to the clinical efficacy of tofacitinib. In addition, soluble biomarkers may predict the treatment response to tofacitinib.
Visually induced γ band rhythm in spatial summation beyond the receptive field in mouse primary visual cortex
Authors: Hou BoJun , Chen Ke , Jia Ang , Liu Shanshan , Bao Xiaojing , Liao Baitao , Zhao Yi Lei , Guo Daqing , Xia Yang , Yao Dezhong
Published: September 2022

Recent studies in many kinds of mammals have established the existence of multiple γ rhythms in the cerebral cortex subserving different functions. In the primary visual cortex (V1), visually induced γ rhythms are dependent on stimulus features. However, experimental findings of γ power induced by varying the size of the drifting grating are inconsistent. Here, we reinvestigated the spatial summation properties of visually induced spike and γ rhythm activities in mouse V1. Our results show that drifting sinusoidal grating stimuli mainly induce 2 γ band rhythms, including a low-frequency band (25–45 Hz) and a high-frequency band (55–75 Hz). Unlike previous findings, we discovered that visually induced γ power could also exhibit extrareceptive field (ERF) modulatory properties. The modulation by ERF stimulation could be either suppressive, countersuppressive, or nonsuppressive, mostly similar to the local spike activity. Moreover, further analysis of the neuron group exhibiting surround suppression in both spike and γ activity revealed that the strength of the surround suppression and the receptive field size showed moderate correlations between measurements by spike and γ rhythm activity. Our findings improve the understanding of the characteristics and neural mechanisms of induced γ rhythms in visual spatial summation.
Age and the eGFR-dependent risk for adverse clinical outcomes
Authors: Liu Ping , Ravani Pietro
Published: September 2022

Although the relative risk of kidney failure increases with more severe chronic kidney disease (CKD) independent of age, with older age the absolute risk of kidney failure at a given time horizon becomes smaller. In this article, we first review some epidemiological measures of outcome occurrence (absolute rate or risk) and association (relative measures: difference or ratio of rates or risks). We emphasize that relative measures need to be presented along with absolute measures to be understood and absolute risk is more helpful than absolute rate when making treatment decisions. We then apply these principles to the discussion of the absolute and relative rates or risks of kidney failure and death across categories of estimated glomerular filtration rate and age. Lastly, we discuss the implications of existing studies on whether the definition of CKD should account for age.
A thelytokous predatory mite is more cannibalistic towards distant kin
Authors: Zhang Keshi , Zhang Zhi-Qiang
Published: September 2022

Kin recognition has been widely observed in various taxa. Cannibalism avoidance may be a strong driver for the evolution of kin recognition, as it may avoid a reduction in inclusive fitness. Kin recognition has recently been observed in a generalist phytoseiid, Amblyseius herbicolus (Acari: Phytoseiidae). This study experimentally examined the degree of relatedness needed between prey larvae and cannibal adults of A. herbicolus for the occurrence of kin discrimination. The adults were individually placed in enclosed arenas with two prey, a daughter and a more distant related larva, to observe their cannibalizing choice. The adults of A. herbicolus did not discriminate between close relatives (daughter versus niece) but preferably cannibalized more distant kin (i.e., first and second cousins once removed). Phenotype matching and familiarization seem prominent as recognition mechanisms used by A. herbicolus adults. The effect of learning on kin recognition through prior contact in A. herbicolus requires further investigation. Studies on other adaptive functions of kin recognition of A. herbicolus, such as cooperation and parental care, may provide meaningful insights.
The broad impact of functional lumen imaging probe panometry in addition to high-resolution manometry in an esophageal clinical practice
Authors: Ellison Ashton , Nguyen Anh D , Zhang Jesse , Mendoza Roseann , Davis Daniel , Podgaetz Eitan , Ward Marc , Reddy Chanakyaram , Souza Rhonda , Spechler Stuart J , Konda Vani J A
Published: September 2022

High-resolution manometry (HRM) with the Chicago Classification (CC) is the standard paradigm to define esophageal motility disorders. Functional lumen imaging probe (FLIP) panometry utilizes impedance planimetry to characterize esophageal compliance and secondary peristalsis. The aim of this study was to explore the clinical impact of FLIP panometry in addition to HRM. A retrospective chart review was performed on FLIP panometry cases utilizing the 322N catheter. Cases with prior foregut surgeries or botulinum injection within 6 months of FLIP panometry were excluded. EGJ-diameter and distensibility index (DI) and secondary contraction patterns at increasing balloon volumes were recorded. An EGJ-DI of ≥2.8 mm2/mm Hg at 60 mL was considered as a normal EGJ distensibility. CC diagnosis, Eckhardt score, Brief Esophageal Dysphagia Questionnaire, and clinical outcomes were obtained for each FLIP case. A total of 186 cases were included. Absent contractility and achalasia types 1 and 2 showed predominantly absent secondary contraction patterns, while type 3 had a variety of secondary contractile patterns on FLIP panometry. Among 77 cases with EGJ outflow obstruction (EGJOO), 60% had a low EGJ-DI. Among those with no motility disorder or ineffective esophageal motility on HRM, 27% had a low DI and 47% had sustained contractions on FLIP, raising concern for an esophageal dysmotility process along the achalasia and/or spastic spectrum. FLIP panometry often confirmed findings on HRM in achalasia and absent contractility. FLIP panometry is useful in characterizing EGJOO cases. Spastic features on FLIP panometry may raise concern for a motility disorder on the spastic spectrum not captured by HRM. Further studies are needed on FLIP panometry to determine how to proceed with discrepancy with HRM and explore diagnoses beyond the CC.
Randomized trial of cardiovascular prevention in Norway combining an in-hospital lifestyle course with primary care follow-up: the Hjerteløftet study
Authors: Bergum Hilde , Sandven Irene , Abdelnoor Michael , Anderssen Sigmund Alfred , Grimsmo Jostein , Rivrud Dag Elle , Myhr Nils Erling , Vold Mona Bekken , Stenbakken Cesilie , Lidfors Bengt , Dufseth Laila , Klemsdal Tor Ole
Published: September 2022

Aims

Cardiovascular risk factor control is suboptimal in Europe, including Norway. The present study examined the efficacy of a multimodal primary prevention intervention programme based on the existing Norwegian health care system.

Methods and results

In this open-label randomized controlled trial, adult patients with elevated cardiovascular risk were randomly assigned to an intervention programme including a hospital-based lifestyle course and primary care follow-up or to a control group (CG). The participants were recruited between 2011 and 2015. Primary outcome was change in validated cardiovascular risk scores, national and international (NORRISK, NORRISK 2, Framingham, PROCAM) between baseline and follow-up. Secondary outcomes included major cardiovascular risk factors. After 36 months the NORRISK score was significantly improved in patients assigned to the intervention group (IG) compared to patients assigned to the CG; absolute difference in mean delta score in the IG (n = 305) compared to mean delta score in the CG (n = 296): −0.92, 95% CI: −1.48 to −0.36, P = 0.001. The results for NORRISK 2, Framingham and PROCAM showed similar significant effects. The secondary endpoints including total cholesterol and blood pressure were only minimally, and non-significantly, reduced in the IG, but the proportion of smokers (P = 0.0028) and with metabolic syndrome (P < 0.0001) were significantly reduced. A limited number of cardiovascular events were observed, IG (n = 9), CG (n = 16).

Conclusion

In subjects with elevated cardiovascular risk, a newly developed prevention programme, combining a hospital-based lifestyle course and primary care follow-up, significantly reduced cardiovascular risk scores after 36 months. This benefit appeared achievable primarily through improvements in metabolic syndrome characteristics and smoking habits.

The study protocol was registered in ClinicalTrials.gov (NCT01741428).
The association between dairy intake and risk of cardiovascular disease and mortality in patients with stable angina pectoris
Authors: Van Parys Anthea , Sæle Jostein , Puaschitz Nathalie G , Anfinsen Åslaug Matre , Karlsson Therese , Olsen Thomas , Haugsgjerd Teresa R , Vinknes Kathrine J , Holven Kirsten B , Dierkes Jutta , Nygård Ottar K , Lysne Vegard
Published: September 2022

Aims

The association of dairy products with cardiovascular disease and mortality risk remains heavily debated. We aimed to investigate the association between intake of total dairy and dairy products and the risk of acute myocardial infarction (AMI), stroke, and cardiovascular and all-cause mortality.

Methods and results

We included 1929 patients (80% men, mean age 62 years) with stable angina pectoris from the Western Norway B-vitamin Intervention Trial. Dietary data were obtained via a 169-item food frequency questionnaire. Risk associations were estimated using Cox proportional hazard regression models adjusted for relevant covariates. Non-linear associations were explored visually. The mean (±SD) dairy intake in the study population was 169 ± 108 g/1000 kcal. Median follow-up times were 5.2, 7.8, and 14.1 years for stroke, AMI, and mortality, respectively. Higher intake of total dairy and milk were positively associated with stroke risk [HR (95% CI): 1.14 (1.02, 1.27) and 1.13 (1.02, 1.27), cardiovascular mortality 1.06 (1.00, 1.12) and 1.07 (1.01, 1.13)] and all-cause mortality [1.07 (1.03, 1.11) and 1.06 (1.03, 1.10)] per 50 g/1000 kcal. Higher cheese intake was inversely associated with AMI risk [0.92 (0.83, 1.02)] per 10 g/1000 kcal. Butter was associated with increased AMI risk [1.10 (0.97, 1.24)] and all-cause mortality [1.10 (1.00, 1.20) per 5 g/1000 kcal.

Conclusion

Higher dairy and milk consumption were associated with increased risk of mortality and stroke. Cheese was associated with decreased, and butter with increased, risk of AMI. Dairy is a heterogenous food group with divergent health effects and dairy products should therefore be investigated individually.
learnMET: an R package to apply machine learning methods for genomic prediction using multi-environment trial data
Authors: Westhues Cathy C , Simianer Henner , Beissinger Timothy M
Published: September 2022

We introduce the R-package learnMET, developed as a flexible framework to enable a collection of analyses on multi-environment trial breeding data with machine learning-based models. learnMET allows the combination of genomic information with environmental data such as climate and/or soil characteristics. Notably, the package offers the possibility of incorporating weather data from field weather stations, or to retrieve global meteorological datasets from a NASA database. Daily weather data can be aggregated over specific periods of time based on naive (for instance, nonoverlapping 10-day windows) or phenological approaches. Different machine learning methods for genomic prediction are implemented, including gradient-boosted decision trees, random forests, stacked ensemble models, and multilayer perceptrons. These prediction models can be evaluated via a collection of cross-validation schemes that mimic typical scenarios encountered by plant breeders working with multi-environment trial experimental data in a user-friendly way. The package is published under an MIT license and accessible on GitHub.
Seismically active structures of the Main Himalayan Thrust revealed before, during and after the 2015 Mw 7.9 Gorkha earthquake in Nepal
Authors: Adhikari L B , Laporte M , Bollinger L , Vergne J , Lambotte S , Koirala B P , Bhattarai M , Timsina C , Gupta R M , Wendling-Vazquez N , Batteux D , Lyon-Caen H , Gaudemer Y , Bernard P , Perrier F
Published: September 2022

The Mw 7.9 2015 April 25 Gorkha earthquake is the latest of a millenary-long series of large devastating Himalayan earthquakes. It is also the first time a large Himalayan earthquake and its aftershocks were recorded by a local network of seismic stations. In the 5 yr following the main shock, more than 31 000 aftershocks were located by this permanent network within the ruptured area, including 14 362 events with ML greater than 2.5, 7 events with ML > 6, including one large aftershock with Mw 7.2 on 2015 May 12. In 2020, 5 yr after the main shock, the seismicity rate along the ruptured fault segments was still about 5 times higher than the background seismicity before the Gorkha earthquake. Several bursts of earthquakes, sometimes organized in clusters, have been observed from a few days to several years after the main shock. Some of these clusters were located at the same place as the clusters that happened during the decades of interseismic stress build-up that preceded the large earthquake. They also happened in the vicinity of the high frequency seismic bursts that occurred during the main shock. These heterogeneities contribute to a persistent segmentation of the seismicity along strike, possibly controlled by geological structural complexities of the Main Himalayan Thrust fault. We suggest that these pre-2015 clusters revealed the seismo-geological segmentation that influences both the coseismic rupture and the post-seismic relaxation.
Acoustic-gravity waves generated by a point source on the ground in a stratified atmosphere-Earth structure
Authors: Gao Yongxin , Li Ting , Zhou Guanqun , Chen Chieh-Hung , Sun Yang-Yi , Zhang Xuemin , Liu Jann-Yenq , Wen Jian , Yao Cheng , Bai Xiaodong
Published: September 2022

An analytically based method is proposed to simulate the acoustic-gravity waves in the horizontally stratified atmosphere-Earth structure generated by a point force on the Earth's surface. The method solves the linear momentum, continuity and adiabaticity equations in the atmosphere and elastodynamic equations in the solid Earth in the frequency–wavenumber domain. The time-domain waveforms are obtained by wavenumber integration and fast Fourier transform with respect to the frequency. Numerical simulations are conducted to investigate the properties of the acoustic-gravity waves, including both the high-frequency acoustic-mode waves and low-frequency gravity-mode waves. Simulations of the high-frequency responses show that disturbances in the atmosphere with three apparent horizontal velocities can be identified. They are, namely, the direct acoustic-mode wave generated by source travelling with the sound speed, the head wave generated by the seismic P-wave travelling with apparent horizontal speed identical to the P velocity, and the head wave generated by the Rayleigh wave with a horizontal speed same to the Rayleigh wave velocity. Simulations of the low-frequency responses show that the gravity-mode wave and Lamb wave can be identified. The gravity-mode wave travels with a speed lower than the sound seed and does not reach everywhere, especially the area directly above the source. The Lamb wave travels along the Earth surface with a speed of about 310 m s–1 and its energy decays with the altitude. We also apply our method to explaining the Doppler sounding data observed in Taiwan area during the 2011 Tohoku M 9 earthquake, and find good agreement between the predicted signals and observed data in the arrival time and wave envelope associated with the Rayleigh wave.
The Implementation of Art. 17 DSM Directive in Germany – A Primer with Some Comparative Remarks
Authors: Leistner Matthias
Published: September 2022

The CJEU’s judgment in Case 401/19 (Poland v EU Parliament and Council) of April 2022 has unambiguously settled that, if it is to be in line with EU constitutional law, Art. 17 DSM Directive has to be implemented and applied in a balanced way to prevent the immediate ex ante blocking of contents which do not manifestly infringe copyright. Germany (and Austria) have implemented Art. 17 in their national laws in such a balanced way that provides for a delayed takedown for contents which can be presumed to be covered by exceptions to copyright law. This paper outlines the structure and workability of the German implementation law which now, after the CJEU judgment, in fact is a genuine (and perhaps the only reasonable) model for implementation in other Member States which have not yet implemented Art. 17.
Specific Associations Between Type of Childhood Abuse and Elevated C-Reactive Protein in Young Adult Psychiatric Rehabilitation Participants
Authors: Jabbi Mbemba M , Harvey Philip D , Kotwicki Raymond J , Nemeroff Charles B
Published: September 2022

Background

Early-life adversity such as childhood emotional, physical, and sexual trauma is associated with later-life psychiatric and chronic medical conditions, including elevated inflammatory markers. Although previous research suggests a role for chronic inflammatory dysfunctions in several disease etiologies, specific associations between childhood trauma types and later-life inflammation and health status are poorly understood.

Methods

We studied patients (n = 280) admitted to a psychiatric rehabilitation center. Self-reported histories of childhood emotional, physical, and sexual trauma were collected with a standard instrument. At the time of admission, we also assessed individuals’ body mass index and collected blood samples used to examine inflammatory marker C-reactive protein (CRP) levels.

Results

The prevalence of all 3 types of abuse was relatively high at 21% or more. Fifty percent of the sample had elevations in CRP, with clinically significant elevations in 26%. We found that compared with a history of emotional or physical abuse, a history of childhood sexual trauma was more specifically associated with elevated CRP. This result held up when using linear regressions to examine the contribution of body mass index.

Limitation

Our sample was relatively young, with an average age of 27.2 years and minimal representation of ethnic and racial minority participants.

Conclusion

Relative to childhood emotional and physical trauma, childhood sexual trauma may lead to elevated inflammatory responses, as confirmed in our finding of an association between CRP and sexual abuse. Future studies need to assess the causal link between childhood sexual trauma and poorer health outcomes later in life.
A fundamental change emerging in locally advanced rectal cancer management: a case report
Authors: Edwards-Murphy Amy , Earley Helen , Creavin Ben , McCullough Peter , Cooke Fiachra , Neary Peter
Published: September 2022

Treatment of locally advanced rectal cancer remains a challenge in colorectal surgery. It has had an evolving landscape over the past three decades. Implementation of total neoadjuvant therapy (TNT) as a novel approach to management has begun globally but long-term outcomes and data analysis to identify optimal schedules are eagerly awaited. We report a case of locally advanced rectal cancer management in a young male with a complete pathological response to TNT.
A rare case of azygous vein aneurysm with cotriatrium dextrum
Authors: Chandrakumanan Ashviini , Tee Sui Wu , Sylverster Melvin , Richards Avisha , Chew Loon Guan
Published: September 2022

Azygous vein aneurysm (AVA) is an infrequent entity for posterior mediastinal lesion and paratracheal mass. Usually asymptomatic, AVA is discovered during routine examination of a patient. The patho-etiology of the azygous vein aneurysm has not been fully understood till date, making it difficult to postulate the most common cause for its occurrence. Nonetheless, AVA has to be taken into consideration as a differential diagnosis for posterior mediastinal mass or right paratracheal lesion. The objective of this paper is to report a rare case of AVA and further discuss on its patho-etiology leading to the dilatation of azygous vein aneurysm.
Multiple plasma membrane SLC4s contribute to external HCO3– acquisition during CO2 starvation in the marine diatom Phaeodactylum tricornutum
Authors: Nawaly Hermanus , Matsui Hiroaki , Tsuji Yoshinori , Iwayama Kazufumi , Ohashi Hiroki , Nakajima Kensuke , Matsuda Yusuke
Published: September 2022

The availability of CO2 is one of the restrictions on aquatic photosynthesis. Solute carrier (SLC) 4-2, a plasma membrane HCO3– transporter has previously been identified in the marine diatom Phaeodactylum tricornutum. In this study, we discovered two paralogs, PtSLC4-1 and PtSLC4-4, that are both localized at the plasma membrane. Their overexpression stimulated HCO3– uptake, and this was inhibited by the anion channel blocker 4,4´-diisothiocyanostilbene-2,2´-disulfonic (DIDS). Similarly to SLC4-2, PtSLC4-1 specifically required Na+ of ~100 mM for its maximum HCO3– transport activity. Unlike PtSLC4-1 and PtSLC4-2, the HCO3– transport of PtSLC4-4 depended equally on Na+, K+, or Li+, suggesting its broad selectivity for cations. Transcript analyses indicated that PtSLC4-1 was the most abundant HCO3– transporter under CO2 concentrations below atmospheric levels, while PtSLC4-4 showed little transcript induction under atmospheric CO2 but transient induction to comparable levels to PtSLC4-1 during the initial acclimation stage from high CO2 (1%) to very low CO2 (<0.002%). Our results strongly suggest a major HCO3– transport role of PtSLC4-1 with a relatively minor role of PtSLC4-2, and that PtSLC4-4 operates under severe CO2 limitation unselectively to cations when the other SLC4s do not function to support HCO3– uptake.
AtHD2D, a plant-specific histone deacetylase involved in abscisic acid response and lateral root development
Authors: Zhang Zhaochen , Yang Weixia , Chu Yueyang , Yin Xiaotong , Liang Yueqi , Wang Qiuping , Wang Lei , Han Zhaofen
Published: September 2022

In eukaryotes, histone acetylation levels directly regulate downstream gene expression. As a plant-specific histone deacetylase (HDAC), HD2D is involved in plant development and abiotic stress. However, the response of HD2D to drought stress and its interacting proteins, is still unclear. In this study, we analysed HD2D gene expression patterns in Arabidopsis, revealing that HD2D gene was highly expressed in roots and rosette leaves, but poorly expressed in other tissues such as stems, flowers, and young siliques. The HD2D gene expression was induced by d-mannitol. We investigated the responses to drought stress in the wild-type plant, HD2D overexpression lines, and hd2d mutants. HD2D-overexpressing lines showed abscisic acid (ABA) hypersensitivity and drought tolerance, and these phenotypes were not present in hd2d mutants. RNA-seq analysis revealed the transcriptome changes caused by HD2D under drought stress, and showed that HD2D responded to drought stress via the ABA signalling pathway. In addition, we demonstrated that CASEIN KINASE II (CKA4) directly interacted with HD2D. The phosphorylation of Ser residues on HD2D by CKA4 enhanced HD2D enzymatic activity. Furthermore, the phosphorylation of HD2D was shown to contribute to lateral root development and ABA sensing in Arabidopsis, but, these phenotypes could not be reproduced by the overexpression of Ser-phospho-null HD2D lines. Collectively, this study suggests that HD2D responded to drought stress by regulating the ABA signalling pathway, and the expression of drought stress-related genes. The regulatory mechanism of HD2D mediated by CKII phosphorylation provides new insights into the ABA response and lateral root development in Arabidopsis.
P002 Antifungal activity of antimicrobial synthetic peptides against Candida species of public health importance
Authors: Torres Richar , Barreto-Santamaría Adriana , Arévalo-Pinzón PhD Gabriela , Escandón Patricia , Firacative Carolina , Gómez Beatriz L , Patarroyo Manuel A , Muñoz Phd Julian E
Published: September 2022

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PM

 

Background

Candidiasis is one of the most frequent opportunistic infections in immunosuppressed and/or hospitalized patients. In countries like Colombia, candidiasis is associated with a mortality rate of ∼ 46%. Growing pharmacological resistance of Candida spp., and the appearance of the emerging pathogen Candida auris, have turned candidiasis into a major public health problem. Different types of antimicrobial peptides have been investigated as a therapeutic alternative to control candidiasis effectively and safely.

Objective

This work aimed at evaluating the in vitro antifungal activity of three synthetic antimicrobial peptides (35 409, 1609, and 29 009) obtained from Plasmodium falciparum Rif1 protein against C. auris, C. albicans, C. glabrata, C. parapsilosis, C. krusei, and C. tropicalis, species with worldwide clinical importance.

Methods

The minimum inhibitory concentrations (MIC) of the three peptides against Candida species were determined by the plate microdilution method; the peptides’ effect on biofilm formation in C. auris and C. albicans species was also evaluated through the XTT metabolic activity assay. Additionally, the structural damages in C. auris and C. albicans caused by the action of the peptides were observed by transmission electron microscopy (TEM) and finally, the in vitro peptides’ cytotoxicity against L929 murine fibroblasts was verified.

Results

Our findings showed that the three peptides herein evaluated, displayed antifungal activity in both planktonic and sessile Candida cells. Likewise, the TEM evidenced morphological alterations induced by the peptides, both in the membrane and at the intracellular level of the yeasts. As well, total safety against the murine cell line L929 with 24 h of treatment was observed.

Conclusions

From these results, we conclude that the antimicrobial peptides 35 409, 1609, and 29 009 are potential therapeutic alternatives against the most important Candida species in Colombia and the world.
P011 Antifungal lock therapy
Authors: Koparkar Vidyullata , Soman Rajeev , Shetty Anjali , Purandare Bharat , Sunavala Ayesha , Doshi Aakash
Published: September 2022

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PM

 

Objective

Candida spp is the fourth leading cause of catheter-related blood stream infection (CRBSI). The standard treatment is prompt removal of the device (central venous catheter, CVC, or port or hemodialysis catheter) along with administration of systemic antifungal therapy. However, in patients with a lack of alternative intravenous access and in some critically ill patients, this standard of care is challenging. Our success with antibiotic lock solution in MDR GNB CRBSI, prompted us to consider similar therapy in Candida spp CRBSI.

Methods

Catheter salvage using antifungal lock therapy was tried in a total of 15 cases in two centers. In 10 cases echinocandin (9 anidulafungin, 1 micafungin) and in 5 cases amphotericin b deoxycholate (AmB-d) were used to obtain an antifungal concentration of ∼ 1000 mcg/ml in the lock solutions. All these formulations had additional NAC, heparin, and normal saline. Systemic antifungal therapy was also administered concurrently.

Success was defined as clearance of candidemia at 48 h and 14 days and/or till the use of the device was needed. Some of these patients had prior/co-infections with bacterial pathogens and they were managed with appropriate systemic antibiotics with antibiotic lock therapy.

Results

In 11/15 episodes of CRBSI due to Candida species, catheter salvage was achieved. One case could not be assessed at 14 days as a port was removed in view of megaprosthesis in situ. In two cases this therapy failed and one patient lost to follow-up.

See Figures 1 and 2 for details of all cases.

Conclusions

Antifungal lock therapy using echinocandins and AmB-d appears to be a promising therapy in patients where catheter removal is difficult. However, this success neither means that this can become standard practice, nor should it make clinicians and hospital staff complacent about infection control practices.
P025 A study on candiduria in neonates and infants from a tertiary care center, North India.
Authors: Yadav Renu , Xess Immaculata , Singh Gagandeep , Rana Bhaskar , CS Saumya
Published: September 2022

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PM

 

Objective

Candida albicans is the major cause of fungal UTI in neonates and infants but nowadays incidence of other species of Candida is also increasing, and these are mostly multidrug resistant. It is, therefore, important to determine the causative Candida species in fungal UTI for appropriate management. This study was undertaken to determine the Candida species distribution in UTI along with susceptibility patterns and outcomes in infants and neonates admitted to various wards and intensive care units (ICUs) of our hospital. The incidence rate of candiduria in ICUs was also assessed.

Method

Urine samples were collected from infants and neonates presented in pediatric and neonatal ICUs and clinical wards with a clinical suspicion of candiduria. Infants at risk of invasive candidiasis were also included in the study. Identification of Candida species was done by Gram's staining, germ tube test, chlamydospore formation on corn meal agar, color of colonies on CHROMagar, and confirmed by Matrix Assisted Laser Desorption-Time of Flight (MALDI-TOF). Antifungal susceptibility was performed by using the Broth microdilution method as per the latest CLSI guidelines (M27-A3/M27-S4).

Result

Urine samples were received from 219 infants, and Candida was isolated from samples from 52 infants (isolation rate 23.75%), of which 30 were admitted to pediatric or neonatal ICU and 22 in the wards. The incidence rate of candiduria in ICU was 3.25%. Candida albicans was the most frequently isolated species from the samples of infants in the wards (13/22 ie, 59%), while Candida tropicalis was most frequently isolated from samples of infants in the ICUs (13/30 ie, 43.34%). Candida glabrata was the least commonly isolated species and was only encountered in the ICU. The species distribution of isolates is given in Table 1. There was no discrepancy between the results of conventional methods of identification and MALDI-TOF.

Antifungal susceptibility was performed for 18 randomly selected isolates. All were found to be susceptible to caspofungin, micafungin, itraconazole, voriconazole, fluconazole, and amphotericin B. MIC distribution for various isolates is given in Table 2.

Conclusion

High index of suspicion of candiduria is necessary for early diagnosis of fungal UTI and initiation of antifungal treatment, especially in critically ill infants requiring intensive care. Species other than C. albicans are also encountered more frequently nowadays and these species often have higher MICs for commonly used antifungal drugs, which may lead to delayed or failed response to routine antifungal therapy and necessitate prolonged use and or higher doses of antifungals. Identification of Candida isolates at species level along with analysis of the susceptibility patterns is therefore important for successful outcomes in candiduria in neonates and infants.
P026 Antifungal activity of a novel triazole and comparators against a large collection of identified Aspergillus isolates
Authors: Abbasi Kiana , Ahangarkani Fatemeh , Badali Hamid
Published: September 2022

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PM

 

 

Aspergillus species are capable of causing both invasive disease and chronic infections in immunocompromised patients or those with preexisting lung conditions. Management of superficial aspergillosis is a significant challenge owing to the frequent relapses and treatment failure, which may pose a potential risk, thereby gradually developing resistant species. So, necessitating the development of new antifungals with higher potency should be considered alternative strategies for efficient management of aspergillosis. We investigated the susceptibility patterns of Aspergillus isolates toward efinaconazole compared with various antifungal drugs. Antifungal susceptibility testing was performed according to the CLSI (M38) guidelines. Efinaconazole exhibited poor activity against azole-resistant A. fumigatus strains, A. niger sensu stricto, and A. tubingensis with GM MIC values of 3.62, 1.62, and 2 mg/l, respectively; however, surprisingly, it efficiently inhibited the growth of A. terreus sensu stricto, followed by wild-type A. fumigatus and A. flavus with GM MIC values of 0.29, 0.42, and 0.52 mg/l, respectively. Presumably, efinaconazole is inefficient in aspergillosis treatment due to the low susceptibility of A. niger sensu stricto, A. tubingensis, and azole-resistant A. fumigatus; however, it may be effective in treating superficial aspergillosis caused by susceptible A. fumigatus, A. terreus sensu stricto, and A. flavus. Differences in susceptibility patterns were observed between the generA. Awareness of the epidemiology of Aspergillus isolates and differences in antifungal susceptibility patterns around the globe may aid clinicians in choosing antifungal treatment regimens. However, studies are warranted to correlate these findings with clinical outcomes. Therefore, further studies are needed to determine how these findings may translate into in vivo efficacy.
P029 Synergic effect of deferoxamine combined with fluconazole against fluconazole-resistant Candida Spp. through inhibited Cek1 MAPK signaling pathway
Authors: An Lulu , Tan Jingwen , Wang Yuanyuan , Liu Siyu , Li Yongyong , Yang Lianjuan
Published: September 2022

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PM

 

Objectives

The opportunistic fungal infections represent an increasing threat to humans with the increase of immunocompromised patients, in which Candida albicans is the most common fungal pathogen. Though fluconazole (FCA) is still the first line choice to treat C. albicans infections, several limitations such as an increase in drug resistance compromised its clinical application. This study proposes a combination therapy of deferoxamine (DFO) and FCA to overcome C. albicans resistance.

Methods

Checkerboard microdilution assay was used to determine the minimum inhibitory concentration (MIC) of DFO used alone and in combination with FCA against FCA-resistant Candida Spp. Spot assay and time-kill curves were used to investigate the cell viability and dynamic inhibitory effect. Hyphal formation was performed to investigate the underlying mechanism of DFO. Then, a murine model of cutaneous candidiasis was established to explore the in vivo synergistic activity of DFO and FCA.

Results

DFO combined with FCA showed synergistic antifungal activity against FCA-resistant C. albicans, with a fractional inhibitory concentration index (FICI) of 0.25. Moreover, DFO combined with FCA significantly inhibited the activity of C. glabrata cells, which is naturally insensitive to antifungal drugs. The spot assay and time-kill curve assay indicated that DFO can turn the fungistasis activity of FCA into fungicidal activity. Hyphal formation study showed the inhibition of hyphal induction of C. albicans. DFO combined with FCA also significantly inhibited the expression of Cek1 MAPK signaling pathway-related genes (CEK1 and CPH1) and adhesion-related genes (ALS1). In vivo data showed DFO combined with FCA significantly reduced the pustule, CFU numbers, and inflammatory cell infiltration of skin tissue.

Conclusion

Our results suggest that DFO combined with FCA inhibited the transformation of yeast-hyphae through Cek1 MAPK signaling pathway, resulting in reduced infectivity and resistance of C. albicans in vitro and in vivo, which may provide a new option for the treatment of cutaneous candidiasis.
P031 Post-antifungal effect of the combination of a nidulafungin with amphotericin B and fluconazole against fluconazole-susceptible and resistant Candida albicans
Authors: Aslani Narges
Published: September 2022

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PM

 

Objectives

Invasive Candidiasis is a life-threatening condition that kills a large number of immunocompromised patients each year around the world. We used post-antifungal effect studies to analyze the activities of anidulafungin, as a clinically crucial antifungal drug, amphotericin B, and fluconazole (alone and in combinations) against FLC-susceptible and -resistant Candida albicans isolates obtained from the cancer patients.

Methods

We tested the phenomenon of post-antifungal effects (PAFEs) of fluconazole (FLC), amphotericin B (AMB), anidulafungin (AFG), and combinations of FLC + AFG, AFG + AMB, and FLC + AMB against 17 C. albicans isolates obtained from the oral cavity of cancer patients. Isolates that had not been exposed to antifungals, served as a control group. Colony counts were performed at 0, 2, 4, 6, and 24 h after a brief (1 h) antifungal exposure.

Results

The FLC had no detectable post-antifungal effect independent of antifungal concentration and resembled drug-free FLC (control). When all AMB and AFG were compared with FLC, significant variations in the post-antifungal effect were observed. Combining AFG and AMB with FLC resulted in effective activity compared to FLC alone. Combination regimens were rated as indifferent in general. Interestingly, low dosages of the AFG displayed increasing fungistatic action as it neared a fungistatic endpoint against C. albicans isolates (n = 17).

Conclusion

Our findings suggest that brief exposure to AFG, in combination with FLC and AMB, at low concentrations of the medicines utilized, could be effective in the evaluation and optimization of new dosage regimens to manage candidiasis. However, future research will look at the clinical utility of our findings.
P047 Comparative evaluation of disc diffusion and E-test with broth micro-dilution in susceptibility testing of amphotericin B, posaconazole, isuvuconazole, itraconazole against Rhizopus isolates of post COVID mucormycosis
Authors: Gupta Prashant , Hasan Mohd Saqib
Published: September 2022

Poster session 1, September 21, 2022, 12:30 PM - 1:30 PM

 

Objectives

To investigate and compare susceptibility pattern of Rhizopus isolates in post-COVID mucormycosis by disc diffusion (DD), E-test, and broth micro-dilution for amphotericin B, posaconazole. DD and BMD for isavuconazole and itraconazole.

Methods

All the isolates were identified by MALDI-ToF (Vitek MS). A total of 72 isolates of R. oryzae complex and 48 isolates of R. microsporus complex were selected. AFS by DD and E-test was done on non-supplemented Mueller Hinton Agar (MHA) and was compared with the Clinical Laboratory Standard Institute (CLSI M 38 A2) broth micro-dilution (BMD) method of AFS.

Results

The disk diffusion method for amphotericin B showed 91.6% agreement while E-test showed 97.2% agreement with broth micro-dilution. Disk diffusion method for posaconazole showed 93% agreement while E-test showed 97.2% agreement with broth micro-dilution. Disk diffusion method for ITZ and ISC showed 94.4% and 100% agreement respectively with broth micro-dilution.

Conclusion

CLSI method of DD promises to be an easier, reproducible, and cost-effective method of susceptibility testing, but this method must be interpreted with caution in the case of amphotericin B susceptibility testing. E-test correlates better than DD with BMD.