bluuebunny/crossref_metadata_2025 huggingface dataset:
Stewardship-Guided T2Candida Testing Shortens Time to Antifungal Treatment and Reduces Antifungal Usage Among Medical Intensive Care Unit Patients With Septic Shock
Authors: O’Donnell Matthew , Shields Ryan K , Marini Rachel V , Groetzinger Lara M , Potoski Brian A , Falcione Bonnie A , Shah Sunish , McCreary Erin K , Clarke Lloyd , Brant Emily , McVerry Bryan J , Liegey Susan , Pasculle A William , Clancy Cornelius J , Nguyen M Hong
Published: November 2023

Background

Diagnosis of invasive candidiasis (IC) is limited by insensitivity and slow turnaround of cultures. Our objectives were to define the performance of T2Candida, a nonculture test, under guidance of a diagnostic stewardship program, and evaluate impact on time to antifungal initiation and antifungal utilization.

Methods

This was a retrospective study of adult medical intensive care unit (MICU) patients with septic shock for whom T2Candida testing was performed from March 2017 to March 2020. Patients with positive T2Candida results during this period were compared to MICU patients who did not undergo T2Candida testing but had septic shock and blood cultures positive for Candida from January 2016 through March 2020.

Results

Overall, 155 T2Candida tests from 143 patients were included. Nine percent of T2Candida tests were positive compared to 4.5% of blood cultures. Sensitivity, specificity, positive predictive value, and negative predictive value of T2Candida for proven and probable IC were 78%, 95%, 50%, and 99%, respectively. Patients who tested positive for T2Candida (n = 14) were diagnosed earlier and initiated on antifungal therapy sooner than patients with IC (n = 14) diagnosed by blood culture alone (median, 5.6 vs 60 hours; P < .0001). Median antifungal days of therapy/1000 patient-days were 23.3/month preimplementation and 15/month postimplementation (P  = .007). Following a negative T2Candida result, empiric antifungals were either not administered in 58% or discontinued within 72 hours in 96% of patients.

Conclusions

Diagnostic stewardship guided T2Candida testing resulted in reduced time to IC diagnosis, faster initiation of antifungal therapy, and lower antifungal usage among MICU patients with septic shock.
Central Nervous System Tuberculosis: Risk Factors for Mortality in a Propensity Score–Matched Case-Control Study
Authors: Asare-Baah Michael , Johnston Lori , Ramirez-Hiller Tatiana , Séraphin Marie Nancy , Lauzardo Michael
Published: November 2023

Background

Despite advancements in tuberculosis (TB) control and treatment in the United States (US), patients with central nervous system TB (CNS-TB) continue to experience significantly higher mortality rates than those without CNS-TB. This raises concerns regarding clinical management and the need for a deeper understanding of the risk factors contributing to these deaths. This study aimed to determine the predictors of mortality in patients with CNS-TB.

Methods

We conducted a retrospective 1:2 propensity score–matched case-control study. Cases were TB patients diagnosed with TB of the meninges, brain, spinal cord, or peripheral nerves, as documented in the Florida Department of Health (FDOH) TB registry, between 2009 and 2021. Controls were TB patients without CNS-TB, also reported in the FDOH TB registry during the same timeframe. We employed conditional logistic regression models to investigate the factors contributing to mortality in cases compared with controls.

Results

We analyzed data from 116 cases and 232 matched controls. Patients with CNS-TB had a 5.69-fold higher risk of death than those without CNS-TB (adjusted odds ratio [aOR], 5.69 [95% confidence interval {CI}, 2.91–11.6]). Increased risk of death was associated with human immunodeficiency virus (HIV) coinfection (aOR, 1.93 [95% CI, .82–4.37]) and diabetes (aOR, 3.13 [95% CI, 1.28–7.47]). Miliary TB and non-HIV immunosuppression were significantly associated with being a case, while cavitary TB was less likely to be associated with being a case.

Conclusions

Clinical management should prioritize screening and close monitoring of patients with HIV coinfection and diabetes to improve patient outcomes.
Evaluating the Goals of Personal Injury Law: Some Empirical Evidence
Authors: Harris Donald
Published: November 2023

A major justification put forward today for retaining tort liability for personal injuries is that the fear of incurring liability will lead potential defendants to take care to avoid causing accidents. Much of this paper will be devoted to examining, in the light of recent empirical data, both this goal, and that of compensating injured people. But something should be said about the view that tort law is a mode of corrective justice,2 which requires restoration of the previous balance between the wrongdoer and the victim. This goal is that the wrongdoer should be compelled to restore the victim’s previous position: he enjoys individual rights, and if they are violated the wrongdoer is required to reverse the wrong. In the case of unintended harm, corrective justice would require that losses caused by careless action should be shifted from the innocent victim to the careless person.
Emerging clinical relevance of microbiome in cancer: promising biomarkers and therapeutic targets
Authors: Dai Jia-Hao , Tan Xi-Rong , Qiao Han , Liu Na
Published: November 2023

The profound influence of microbiota in cancer initiation and progression has been under the spotlight for years, leading to numerous researches on cancer microbiome entering clinical evaluation. As promising biomarkers and therapeutic targets, the critical involvement of microbiota in cancer clinical practice has been increasingly appreciated. Here, recent progress in this field is reviewed. We describe the potential of tumor-associated microbiota as effective diagnostic and prognostic biomarkers, respectively. In addition, we highlight the relationship between microbiota and the therapeutic efficacy, toxicity, or side effects of commonly utilized treatments for cancer, including chemotherapy, radiotherapy, and immunotherapy. Given that microbial factors influence the cancer treatment outcome, we further summarize some dominating microbial interventions and discuss the hidden risks of these strategies. This review aims to provide an overview of the applications and advancements of microbes in cancer clinical relevance.
Lepton universality violation in the minimal flipped 331 model
Authors: Thu P N , Duy N T , Hernández A E Cárcamo , Huong D T
Published: November 2023

We perform a detailed study of the b → cτν and b → sl+l− processes in a minimal flipped 331 model based on the SU(3)C × SU(3)L × U(1)X gauge symmetry. The non-universal SU(3)L × U(1)X symmetry in the lepton sector gives rise to non-universal neutral and charged currents involving heavy non-SM gauge bosons and SM leptons that yield radiative contributions to the b → s, b → c, s → u, and d → u transitions arising from one-loop-level penguin and box diagrams. We find that the observables related to these transitions agree with their experimental values in a region of parameter space that includes TeV-scale exotic up-type quarks, within the reach of the Large Hadron Collider.
Development of a low-background HPGe detector at Kamioka Observatory
Authors: Ichimura K , Ikeda H , Kishimoto Y , Kurasawa M , Suzuki A A , Gando Y , Ikeda M , Hosokawa K , Sekiya H , Ito H , Minamino A , Suzuki S
Published: November 2023

A new ultra-low background high-purity germanium (HPGe) detector has been installed at the Kamioka underground experimental site. The background count rate in the energy range from 40 keV to 2700 keV is about 25% lower than that of the first HPGe detector installed in 2016, which has the same detector specification and similar shielding geometry. This paper describes the shielding configuration, including the cleaning of the material surface, the comparison of calibration data and simulation, the time variation of the background spectra, the sample measurement procedure, and some results of the radioactivity in the selected samples.
Screening, Identification, and Growth Promotion of Antagonistic Endophytes Associated with Chenopodium quinoa Against Quinoa Pathogens
Authors: Xie Tianyan , Shen Shuo , Hu Rong , Li Wei , Wang Jian
Published: November 2023

Fungal disease is one of the important reasons for crop yield reduction. Isolation of important endophytes with biocontrol and growth-promoting effects is of great significance for the exploitation of beneficial microbial resources and the biological control of crop fungal diseases. In this study, endophytes from roots, stems, and leaves of quinoa at different growth and development stages were isolated and purified; then the antagonistic activity and growth-promoting characteristics of antagonistic endophytes were determined. Finally, the antagonistic endophytes were identified by morphological characteristics and ITS/16S rRNA sequence analysis. Our results showed that 122 endophytic fungi and 371 endophytic bacteria were isolated from quinoa, of which three endophytic fungi and seven endophytic bacteria were screened that had inhibitory activity against quinoa pathogenic fungi. Most of the antagonistic strains could produce indole-3 acetic acid and had the ability to dissolve organic phosphorus. In addition, the bacterial suspension of endophytic bacteria had the ability to promote the seed germination and plant growth of quinoa. The endophytic fungi with antagonistic activity were identified as Penicillium raperi and P. pulvillorum; the endophytic bacteria were identified as Bacillus paralicheniformis, B. tequilensis, and B. velezensis, respectively. The strains of quinoa endophytes in this study can provide rich microbial resources and a theoretical basis for biological control of plant fungal diseases and agricultural production.
Full-Thickness Macular Hole Closure with Topical Medical Therapy
Authors: Wang Jessie , Rodriguez Sarah H , Xiao Jason , Luo Wendy , Gonnah Reem , Shaw Lincoln , Dao David , Schechet Sidney A , Mackin Anna G , Komati Rahul , Skondra Dimitra
Published: November 2023

Purpose:

To examine the efficacy and clinical characteristics of successful full-thickness macular hole (FTMH) closure with topical therapy.

Methods:

Retrospective case series of FTMHs managed by a single retinal physician (DS) diagnosed and treated from 2017-22.

Results:

Of 168 patients with FTMHs, 71 patients were started on steroid, carbonic anhydrase inhibitor (CAI), and non-steroidal anti-inflammatory (NSAID) drops. 49 patients (mean 67yrs, 59% women) were included in the analysis; 22 were excluded for poor follow-up. 7/49 were secondary post-PPV holes and 42/49 were idiopathic. 18/49 eyes (36.7%) achieved closure on topical therapy, of which 13 were idiopathic. Hole size was directly correlated with odds of closure: for every 10-micron decrease in size, odds of closure increased by 1.2x (p=0.001, CI 1.1-1.4). Average time to closure was 107.2 days (range 20-512 days), and was not correlated to hole size (p=0.217, CI -0.478–+1.938). The presence of VMT was found to be inversely related to successful closure (OR 6.1, p=0.029, CI 1.2-31.3). There was no significant difference in final BCVA for eyes undergoing primary PPV versus those trialing drops before undergoing PPV (p=0.318, CI -0.094–+0.112).

Conclusion:

In the first study to-date to report the overall efficacy and clinical characteristics of successful macular hole closure with topical therapy, drops achieved an overall closure rate of 36.7%, with higher efficacy in smaller holes and those without VMT. Rates of MH narrowing and reduction in CFT acted as predictors of effectiveness of drop therapy.
The Dissemination and Development of Chinese Medicine in Pakistan
Authors: Lin Jie , Saeed Saboor
Published: November 2023

This paper discusses the dissemination and development of Chinese medicine in Pakistan. Religious records show that Chinese medicine was introduced to Pakistanas early as 1400 years ago, while Hijama (Chinese cupping) was used by Prophet Hazrat Muhammad to cure different types of diseases. Exchanges and cooperations between China and Pakistan continue to the present day. Acupuncture and moxibustion therapy, cupping therapy and herbal medicine are practiced with significant merits in today’s Pakistan. In the future, with the proposal of the Belt and Road Initiative (BRI) and the landmark project of China-Pakistan Economic Corridor (CPEC),Chinese medicine can be strengthened through cooperations at the hebal medicine trade level, the research and development level, the educational level and the social association level. Chinese medicine will work together with Pakistani medicine to save people’s lives in Pakistan and help them stay healthy and improve their quality of life.
Comprehensive analysis of HDAC7 expression and its prognostic value in diffuse large B cell lymphoma: A review
Authors: Lu Weiguo , Zhuang Guangyan , Guan Youmin , Li Yongcong , Liu Liujun , Xiao Mingfeng
Published: November 2023

HDAC7 loss or dysregulation may lead to B cell-based hematological malignancies. This study aimed to explore the prognostic value of HDAC7 in patients with diffuse large B cell lymphoma (DLBCL). RNA sequencing data and clinical information for HDAC7 in DLBCL were collected from the cancer genome atlas database and analyzed using R software. Paired t and Mann–Whitney U tests were used to detect differences between DLBCL and adjacent normal tissues, and the pROC software package was used to generate receiver operator characteristic curves to detect cutoff values for HDAC7. Data from paraffin-embedded specimens from the 2 groups were used for validation of external immunohistochemical staining. The tumor immunity estimation resource and integrated repository portal for tumor immune system interactions databases were used to analyze the correlation between HDAC7 and DLBCL immune cell infiltration. Survival analysis of HDAC7 in patients with DLBCL was performed using the PrognoScan database. Compared with that in normal tissues, HDAC7 mRNA was overexpressed in DLBCL. The HDAC7 immunohistochemical staining scores of stage III and IV DLBCL patients were significantly lower than those of stage I and II DLBCL patients, which was associated with shorter overall survival and disease-specific survival. In addition, the higher expression of HDAC7 may play a role in the lower level of immune infiltration in DLBCL. Downregulation of HDAC7 expression was correlated with poor prognosis and immune infiltration in DLBCL patients.
Assessing the impact of COVID-19 on outpatient and inpatient revenues: A comparative analysis of large and small hospitals in Taiwan
Authors: Yan Yu-Hua , Ho Sam Yu-Chieh , Chien Tsair-Wei , Chou Willy
Published: November 2023

Background:

The COVID-19 pandemic has had profound effects on healthcare systems worldwide, not only by straining medical resources but also by significantly impacting hospital revenues. These economic repercussions have varied across different hospital departments and facility sizes. This study posits that outpatient (OPD) revenues experienced greater reductions than inpatient (IPD) revenues and that the financial impact was more profound in larger hospitals than in smaller hospitals.

Methods:

We collected data on patient case numbers and associated revenues for 468 hospitals from the Taiwan government-run National Health Insurance Administration website. We then employed Microsoft Excel to construct scatter plots using the trigonometric function (=DEGREES (Atan (growth rate))) for each hospital. Our analysis scrutinized 4 areas: the case numbers and the revenues (represented by medical fees) submitted to the Taiwan government-run National Health Insurance Administration in both March and April of 2019 and 2020 for OPD and IPD departments. The validity of our hypotheses was established through correlation coefficients (CCs) and chi-square tests. Moreover, to visualize and substantiate the hypothesis under study, we utilized the Kano diagram. A higher CC indicates consistent counts and revenues between 2019 and 2020.

Results:

Our findings indicated a higher impact on OPDs, with CCs of 0.79 and 0.83, than on IPDs, which had CCs of 0.40 and 0.18. Across all hospital types, there was a consistent impact on OPDs (P = .14 and 0.46). However, a significant variance was observed in the impact on IPDs (P < .001), demonstrating that larger hospitals faced greater revenue losses than smaller facilities, especially in their inpatient departments.

Conclusion:

The two hypotheses confirmed that the COVID-19 pandemic impacted outpatient departments more than inpatient departments. Larger hospitals in Taiwan faced greater financial challenges, especially in inpatient sectors, underscoring the pandemic’s varied economic effects. The COVID-19 pandemic disproportionately affected outpatient departments and larger hospitals in Taiwan. Policymakers must prioritize support for these areas to ensure healthcare resilience in future epidemics. The research approach used in this study can be utilized as a model for similar research in other countries affected by COVID-19.
Body Composition and Radiomics From 18F-FDG PET/CT Together Help Predict Prognosis for Patients With Stage IV Non–Small Cell Lung Cancer
Authors: Zhang Yi , Tan Weiyue , Zheng Zhonghang , Wang Jie , Xing Ligang , Sun Xiaorong
Published: November 2023

Purpose

To determine whether integration of data on body composition and radiomic features obtained using baseline 18F-FDG positron emission tomography/computed tomography (PET/CT) images can be used to predict the prognosis of patients with stage IV non–small cell lung cancer (NSCLC).

Methods

A total of 107 patients with stage IV NSCLC were retrospectively enrolled in this study. We used the 3D Slicer (The National Institutes of Health, Bethesda, Maryland) software to extract the features of PET and CT images. Body composition measurements were taken at the L3 level using the Fiji (Curtis Rueden, Laboratory for Optical and Computational Instrumentation, University of Wisconsin, Madison) software. Independent prognostic factors were defined by performing univariate and multivariate analyses for clinical factors, body composition features, and metabolic parameters. Data on body composition and radiomic features were used to build body composition, radiomics, and integrated (combination of body composition and radiomic features) nomograms. The models were evaluated to determine their prognostic prediction capabilities, calibration, discriminatory abilities, and clinical applicability.

Results

Eight radiomic features relevant to progression-free survival (PFS) were selected. Multivariate analysis showed that the visceral fat area/subcutaneous fat area ratio independently predicted PFS (P = 0.040). Using the data for body composition, radiomic features, and integrated features, nomograms were established for the training (areas under the curve = 0.647, 0.736, and 0.803, respectively) and the validation sets (areas under the receiver operating characteristic = 0.625, 0.723, and 0.866, respectively); the integrated model showed better prediction ability than that of the other 2 models. The calibration curves revealed that the integrated nomogram exhibited a better agreement between the estimation and the actual observation in terms of prediction of the probability of PFS than that of the other 2 models. Decision curve analysis revealed that the integrated nomogram was superior to the body composition and radiomics nomograms for predicting clinical benefit.

Conclusion

Integration of data on body composition and PET/CT radiomic features can help in prediction of outcomes in patients with stage IV NSCLC.
Machine Learning–based Prediction of Postoperative Pancreatic Fistula Following Pancreaticoduodenectomy
Authors: Verma Arjun , Balian Jeffrey , Hadaya Joseph , Premji Alykhan , Shimizu Takayuki , Donahue Timothy , Benharash Peyman
Published: November 2023

Objective:

The aim of this study was to develop a novel machine learning model to predict clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreaticoduodenectomy (PD).

Background:

Accurate prognostication of CR-POPF may allow for risk stratification and adaptive treatment strategies for potential PD candidates. However, antecedent models, such as the modified Fistula Risk Score (mFRS), are limited by poor discrimination and calibration.

Methods:

All records entailing PD within the 2014 to 2018 American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) were identified. In addition, patients undergoing PD at our institution between 2013 and 2021 were queried from our local data repository. An eXtreme Gradient Boosting (XGBoost) model was developed to estimate the risk of CR-POPF using data from the ACS NSQIP and evaluated using institutional data. Model discrimination was estimated using the area under the receiver operating characteristic (AUROC) and area under the precision recall curve (AUPRC).

Results:

Overall, 12,281 and 445 patients undergoing PD were identified within the 2014 to 2018 ACS NSQIP and our institutional registry, respectively. Application of the XGBoost and mFRS scores to the internal validation dataset revealed that the former model had significantly greater AUROC (0.72 vs 0.68, P<0.001) and AUPRC (0.22 vs 0.18, P<0.001). Within the external validation dataset, the XGBoost model remained superior to the mFRS with an AUROC of 0.79 (95% CI: 0.74–0.84) versus 0.75 (95% CI: 0.70–0.80, P<0.001). In addition, AUPRC was higher for the XGBoost model, compared with the mFRS.

Conclusion:

Our novel machine learning model consistently outperformed the previously validated mFRS within internal and external validation cohorts, thereby demonstrating its generalizability and utility for enhancing prediction of CR-POPF.
MTOR modulation induces selective perturbations in histone methylation which influence the anti-proliferative effects of mTOR inhibitors
Authors: Kim HaEun , Lebeau Benjamin , Papadopoli David , Jovanovic Predrag , Russo Mariana , Avizonis Daina , Morita Masahiro , Afzali Farzaneh , Ursini-Siegel Josie , Postovit Lynne-Marie , Witcher Michael , Topisirovic Ivan
Published: November 2023

Emerging data suggest a significant cross-talk between metabolic and epigenetic programs. However, the relationship between the mechanistic target of rapamycin (mTOR) which is a pivotal regulator of cellular metabolism, and epigenetic modifications remains poorly understood. We thus explored the impact of modulating mTOR signaling on histone methylation, a well-known epigenetic modification. Our results showed that mTORC1 activation caused by abrogation of TSC2 increased H3K27me3 but not H3K4me3 or H3K9me3. This appeared to be mediated via the induction of EZH2 protein synthesis, downstream of 4EBPs. Surprisingly, mTOR inhibition also induced H3K27me3 independently of TSC2. This coincided with reduced EZH2 and increased EZH1 protein levels. Notably, the ability of mTOR inhibitors to induce H3K27me3 levels was positively correlated with their anti-proliferative effects. Collectively, our findings demonstrate that both activation and inhibition of mTOR selectively increase H3K27me3 by distinct mechanisms, whereby the ability of mTOR inhibitors to induce H3K27me3 influences their anti-proliferative effects.

Highlights

Paradoxically, both mTOR activation and inhibition induce H3K27me3.

The effect of mTOR inhibitors on H3K27me3 are not secondary to cell cycle arrest.

H3K27me3 triggered by mTOR suppression coincides with perturbations in EZH1/2 ratio.

H3K27me3 impacts on the anti-proliferative effects of mTOR inhibitors.
Emergence and spread of feline infectious peritonitis due to a highly pathogenic canine/feline recombinant coronavirus
Authors: Attipa Charalampos , Warr Amanda S , Epaminondas Demetris , O’Shea Marie , Hanton Andrew J , Fletcher Sarah , Malbon Alexandra , Lyraki Maria , Hammond Rachael , Hardas Alexandros , Zanti Antria , Loukaidou Stavroula , Gentil Michaela , Gunn-Moore Danielle , Mazeri Stella , Tait-Burkard Christine
Published: November 2023

Cross-species transmission of coronaviruses (CoVs) poses a serious threat to both animal and human health1–3. Whilst the large RNA genome of CoVs shows relatively low mutation rates, recombination within genera is frequently observed and demonstrated4–7. Companion animals are often overlooked in the transmission cycle of viral diseases; however, the close relationship of feline (FCoV) and canine CoV (CCoV) to human hCoV-229E5,8, as well as their susceptibility to SARS-CoV-29highlight their importance in potential transmission cycles. Whilst recombination between CCoV and FCoV of a large fragment spanning orf1b to M has been previously described5,10, here we report the emergence of a novel, highly pathogenic FCoV-CCoV recombinant responsible for a rapidly spreading outbreak of feline infectious peritonitis (FIP), originating in Cyprus11. The minor recombinant region, spanning spike (S), shows 96.5% sequence identity to the pantropic canine coronavirus NA/09. Infection has rapidly spread, infecting cats of all ages. Development of FIP appears very frequent and sequence identities of samples from cats in different districts of the island is strongly supportive of direct transmission. A near cat-specific deletion in the domain 0 of S is present in >90% of FIP cats. It is unclear as yet whether this deletion is directly associated with disease development and may be linked to a biotype switch12. The domain 0 deletion and several amino acid changes in S, particularly the receptor binding domain, indicate potential changes to receptor binding and cell tropism.
The effect of temperature on the boundary conditions of West Nile virus circulation in Europe
Authors: de Freitas Eduardo Costa , Streng Kiki , de Souza Santos Mariana Avelino , Counotte Michel Jacques
Published: November 2023

West Nile virus (WNV) is a vector-borne flavivirus that causes an increasing number of human and equine West Nile fever cases in Europe. While the virus has been present in the Mediterranean basin and the Balkans since the 1960s, recent years have witnessed its northward expansion, with the first human cases reported in Germany in 2018 and the Netherlands in 2020. WNV transmission and amplification within mosquitoes are temperature-dependent. This study applies a mathematical modelling approach to assess the conditions under which WNV circulation occurs based on the proportion of mosquitoes’ bites on WNV-competent birds (dilution), vector-host ratios, mosquito season length and the observed daily temperature data in five distinct European regions where previous WNV circulation has been observed within the Netherlands, Germany, Spain, Italy, and Greece. We observed that the number of days in which the basic reproduction number (R0) is above one, increased over the last 40 years in all five regions. In the Netherlands, the number of days in which the R0is above one, is 70% lower than in Spain. The temperature in Greece, Spain and Italy allowed for circulation under low vector-host ratios, and at a high dilution. On the other hand in the Netherlands and Germany, given the observed daily temperature, the thresholds for circulation requires a lower dilution and higher vector-host ratios. For the Netherlands, a short window of introductions between late May and mid-June would result in detectable outbreaks. Our findings revealed that the temperate maritime climate of the Netherlands allows WNV circulation primarily during warmer summers, and only under high vector-host ratios. This research contributes valuable insights into the dynamic relationship between temperature, vector properties, and WNV transmission, offering guidance for proactive strategies in addressing this emerging health threat in Europe.
Neural network extrapolation to distant regions of the protein fitness landscape
Authors: Fahlberg Sarah A , Freschlin Chase R , Heinzelman Pete , Romero Philip A
Published: November 2023

Machine learning (ML) has transformed protein engineering by constructing models of the underlying sequence-function landscape to accelerate the discovery of new biomolecules. ML-guided protein design requires models, trained on local sequence-function information, to accurately predict distant fitness peaks. In this work, we evaluate neural networks’ capacity to extrapolate beyond their training data. We perform model-guided design using a panel of neural network architectures trained on protein G (GB1)-Immunoglobulin G (IgG) binding data and experimentally test thousands of GB1 designs to systematically evaluate the models’ extrapolation. We find each model architecture infers markedly different landscapes from the same data, which give rise to unique design preferences. We find simpler models excel in local extrapolation to design high fitness proteins, while more sophisticated convolutional models can venture deep into sequence space to design proteins that fold but are no longer functional. Our findings highlight how each architecture’s inductive biases prime them to learn different aspects of the protein fitness landscape.
Discovery of the sEH Inhibitor Epoxykynin as Potent Kynurenine Pathway Modulator
Authors: Dötsch Lara , Davies Caitlin , Hennes Elisabeth , Schönfeld Julia , Kumar Adarsh , Da Cruz Lopes Guita Celine , Ehrler Johanna H.M. , Hiesinger Kerstin , Thavam Sasikala , Janning Petra , Sievers Sonja , Knapp Stefan , Proschak Ewgenij , Ziegler Slava , Waldmann Herbert
Published: November 2023

Disease-related phenotypic assays enable unbiased discovery of novel bioactive small molecules and may provide novel insights into physiological systems and unprecedented molecular modes-of-action (MMOA). Herein we report the identification and characterization of epoxykynin, a potent inhibitor of the soluble epoxide hydrolase (sEH). Epoxykynin was discovered by means of a cellular assay monitoring modulation of kynurenine (Kyn) levels in BxPC-3 cells upon stimulation with the cytokine interferon-γ (IFN-γ) and subsequent target identification employing affinity-based chemical proteomics. Increased Kyn levels are associated with immune suppression in the tumor microenvironment and, thus, the Kyn pathway and its key player indoleamine 2,3-dioxygenase 1 (IDO1) are appealing targets in immuno-oncology. However, targeting IDO1 directly has led to limited success in clinical investigations, demonstrating that alternative approaches to reduce Kyn levels are in high demand. We uncover a cross-talk between sEH and the Kyn pathway that may provide new opportunities to revert cancer-induced immune tolerance.
Short internal open reading frames regulate the translation of N-terminally truncated proteoforms
Authors: Fettig Raphael , Gonda Zita , Walter Niklas , Sallmann Paul , Thanisch Christiane , Winter Markus , Bauer Susanne , Zhang Lei , Linden Greta , Litfin Margarethe , Etard Christelle , Armant Olivier , Vázquez Olalla , Kassel Olivier
Published: November 2023

Internal translation initiation sites, as revealed by ribosome profiling experiments can potentially drive the translation of many N-terminally truncated proteoforms. We have identified an mRNA cis-regulatory element which regulates their translation. nTRIP6 represents a short nuclear proteoform of the cytoplasmic protein TRIP6. We have previously reported that nTRIP6 regulates the dynamics of skeletal muscle progenitor differentiation. Here we show that nTRIP6 is generated by translation initiation at an internal AUG. Its translation is repressed by an internal short open reading frame (sORF) immediately upstream of the nTRIP6 AUG. Consistent with this representing a more general regulatory feature, we have identified other N-terminally truncated proteoforms which are repressed by internal sORFs. In anin vitromodel of myogenic differentiation, the translation of nTRIP6 is transiently de-repressed in a mechanistic Target of Rapamycin Complex 1-dependent manner. Thus, the translation of N-terminally truncated proteoforms can be regulated independently of the canonical ORF.
Structure and position-specific interactions of prion-like domains in transcription factor Efg1 phase separation
Authors: Wang Szu-Huan , Zheng Tongyin , Fawzi Nicolas L.
Published: November 2023

Candida albicans, a prominent member of the human microbiome, can make an opportunistic switch from commensal coexistence to pathogenicity accompanied by an epigenetic shift between the white and opaque cell states. This transcriptional switch is under precise regulation by a set of transcription factors (TFs), with Enhanced Filamentous Growth Protein 1 (Efg1) playing a central role. Previous research has emphasized the importance of Egf1’s prion-like domain (PrLD) and the protein’s ability to undergo phase separation for the white-to-opaque transition ofC. albicans. However, the underlying molecular mechanisms of Efg1 phase separation have remained underexplored. In this study, we delved into the biophysical basis of Efg1 phase separation, revealing the significant contribution of both N-terminal (N) and C-terminal (C) PrLDs. Through NMR structural analysis, we found that Efg1 N-PrLD and C-PrLD are mostly disordered though have prominent partial α-helical secondary structures in both domains. NMR titration experiments suggest that the partially helical structures in N-PrLD act as hubs for self-interaction as well as Efg1 interaction with RNA. Using condensed-phase NMR spectroscopy, we uncovered diverse amino acid interactions underlying Efg1 phase separation. Particularly, we highlight the indispensable role of tyrosine residues within the transient α-helical structures of PrLDs particularly in the N-PrLD compared to the C-PrLD in stabilizing phase separation. Our study provides evidence that the transient α-helical structure is present in the phase separated state and highlights the particular importance of aromatic residues within these structures for phase separation. Together, these results enhance the understanding ofC. albicansTF interactions that lead to virulence and provide a crucial foundation for potential antifungal therapies targeting the transcriptional switch.

Statement of Significance

Phase separated condensates have been found across the domains of life and many types of cells. To understand their varied functions, seeing the residue-by-residue details of the structure and interactions of component protein constituents is essential. A set of transcription factors that phase-separate controls cell fate of the pathogenic yeast Candida albicans. Here, we examine the structural and interaction details of a main regulator of this process, Efg1, using NMR spectroscopy and biochemical assays. We find Efg1’s phase-separating domains are not entirely disordered as often assumed but in fact contain helical regions that persist upon phase separation. We also reveal the balance of contacts formed in the condensed phase and the importance of specific residues and regions in phase separation.
A negative feedback loop is critical for recovery of RpoS after stress inEscherichia coli
Authors: Bouillet Sophie , Hamdallah Issam , Majdalani Nadim , Tripathi Arti , Gottesman Susan
Published: November 2023

RpoS is an alternative sigma factor needed for the induction of the general stress response in many gammaproteobacteria. Tight regulation of RpoS levels and activity is required for bacterial growth and survival under stress. InEscherichia coli, various stresses lead to higher levels of RpoS due to increased translation and decreased degradation. During non-stress conditions, RpoS is unstable, because the adaptor protein RssB delivers RpoS to the ClpXP protease. RpoS degradation is prevented during stress by the sequestration of RssB by anti-adaptors, each of which is induced in response to specific stresses. Here, we examined how the stabilization of RpoS is reversed during recovery of the cell from stress. We found that RpoS degradation quickly resumes after recovery from phosphate starvation, carbon starvation, and when transitioning from stationary phase back to exponential phase. This process is in part mediated by the anti-adaptor IraP, known to promote RpoS stabilization during phosphate starvation via the sequestration of adaptor RssB. The rapid recovery from phosphate starvation is dependent upon a feedback loop in which RpoS transcription ofrssB, encoding the adaptor protein, plays a critical role. Crl, an activator of RpoS that specifically binds to and stabilizes the complex between the RNA polymerase and RpoS, is also required for the feedback loop to function efficiently, highlighting a critical role for Crl in restoring RpoS basal levels.

Author summary

In their native environments, bacteria are exposed to constant changes in nutrient availability, as well as other biotic and abiotic stressors. To adjust to these changes, bacteria must rewire gene expression to adapt to or avoid stress-induced damage. A key player in the global response to general stresses is the alternative sigma factor RpoS, a promoter-specificity determining subunit of RNA polymerase. RpoS levels increase with stress, due to increased translation and stabilization of the otherwise unstable RpoS protein. Here, we examine how the cell restores homeostasis after the stress has passed. We show that a negative feedback loop in which RpoS regulates the transcription of an adaptor for proteolysis poises the cell to rapidly resume RpoS degradation upon the exit from stress.
Key morphological features of human pyramidal neurons
Authors: Benavides-Piccione Ruth , Blazquez-Llorca  , Kastanauskaite Asta , Fernaud Isabel , Gonzalez-Tapia Silvia , DeFelipe Javier
Published: November 2023

The basic building block of the cerebral cortex, the pyramidal cell, has been shown to be characterized by a markedly different dendritic structure among layers, cortical areas, and species. Functionally, differences in the structure of their dendrites and axons are critical in determining how neurons integrate information. However, within the human cortex, these neurons have not been quantified in detail. In the present work, we performed intracellular injections of Lucifer Yellow and 3D reconstructed over 200 pyramidal neurons, including apical and basal dendritic and local axonal arbors and dendritic spines, from human occipital primary visual area and associative temporal cortex. We found that human pyramidal neurons from temporal cortex were larger, displayed more complex apical and basal structural organization and had more spines compared to those in primary sensory cortex. Moreover, these human neocortical neurons displayed specific shared and distinct characteristics in comparison to previously published human hippocampal pyramidal neurons. Additionally, we identified distinct morphological features in human neurons that set them apart from mouse neurons. Lastly, we observed certain consistent organizational patterns shared across species. This study emphasizes the existing diversity within pyramidal cell structures across different cortical areas and species, suggesting substantial species-specific variations in their computational properties.
Crystal structure and Hirshfeld surface analysis of 10-hydroxy-2-(4-methoxyphenyl)-3-oxo-2,3,3a,4,10,10a-hexahydro-1H-9-thia-2-azacyclopenta[b]fluorene-4-carboxylic acid dimethyl sulfoxide-d
6 monosolvate
Authors: Mammadova Gunay Z. , Yakovleva Elizaveta D. , Erokhin Pavel P. , Grigoriev Mikhail S. , Atioğlu Zeliha , Azizova Asmet N. , Akkurt Mehmet , Bhattarai Ajaya
Published: November 2023

In the title compound, C22H19NO5S·C2D6OS, the central six-membered ring has a slightly distorted boat conformation, while the fused pyrrolidine ring adopts an envelope conformation. These conformations are stabilized by O—H...O hydrogen bonds between the main compound and solvent molecules. In addition, intramolecular C—H...O hydrogen bonds in the main molecule form two S(6) rings. Molecules are connected by pairs of intermolecular C—H...O hydrogen bonds, forming dimers with a R
2
2(8) motif. These dimers form a three-dimensional network through O—H...O, O—H...S and C—H...O hydrogen bonds with each other directly and through solvent molecules. In addition, weak π–π stacking interactions [centroid-to-centroid distances = 3.9937 (10) and 3.9936 (10) Å, slippages of 2.034 and 1.681 Å] are observed. The intermolecular contacts were quantified using Hirshfeld surface analysis and two-dimensional fingerprint plots, revealing the relative contributions of the contacts to the crystal packing to be H...H 41.7%, O...H/H...O 27.7%, C...H/H...C 17.0%, and S...H/H...S 7.5%.
Impact of project risk allocation on PPP housing project delivery in Nigeria: partial least square structural equation modeling approach
Authors: Arijeloye Bamidele Temitope
Published: November 2023

Purpose

This paper aims to help understand how adopting risk allocation criteria impacts the delivery of public–private partnership (PPP) mass housing in Nigeria with the view of promoting the adoption of PPP housing scheme in Nigeria.

Design/methodology/approach

The research design adopts the census sampling approach by using well-structured questionnaires distributed to stakeholders involved in PPP-procured mass housing projects, i.e. consultants, in-house professionals, contractors and the organized private sector, registered with PPP departments in the Federal Capital Territory Development Authority, Abuja, Nigeria. Sixty-three risk factors, nine risk allocation criteria and nine project delivery indices were submitted for the respondents to rank on a Likert scale of 7. Two hypotheses were formulated to test whether the risk allocation criteria impacted PPP mass housing delivery or otherwise. The study adopts partial least square-structural equation modeling to model the effect of risk on risk allocation criteria on project delivery indices and risk severity.

Findings

The finding shows that project risk allocation criteria have less effect on project delivery indices than on risk severity. The study concludes that risk allocation principles do not directly affect the delivery of PPP-procured mass housing projects. This is evident by the path coefficient of 0.724 values, which is not statistically significant at a 5% alpha protection value. The study concludes that allocating critical risk factors influences the performance of PPP-procured mass housing projects, as the path coefficient of 0.360 is also not significantly far from 0 and at a 5% alpha protection value.

Originality/value

The study is one of the recent studies conducted in PPP-procured mass housing projects in Nigeria owing to the novelty of procurement option in the sector. It highlights the risk factors that can jeopardize the PPP-procured mass housing project objectives. The study is of immense value to PPP actors in the sector by providing the necessary information required to formulate risk response methods to minimize the impact of the risk factors in PPP mass housing projects.
The ontogenetic dimension of plant functional ecology
Authors: Barton Kasey E.
Published: November 2023

Plant functional strategies change considerably as plants develop, driven by intraindividual variability in anatomical, morphological, physiological and architectural traits.

Developmental trait variation arises through the complex interplay among genetically regulated phase change (i.e. ontogeny), increases in plant age and size, and phenotypic plasticity to changing environmental conditions. Although spatial drivers of intraspecific trait variation have received extensive research attention, developmentally driven intraspecific trait variation is largely overlooked, despite widespread occurrence.

Ontogenetic trait variation is genetically regulated, leads to dramatic changes in plant phenotypes and evolves in response to predictable changes in environmental conditions as plants develop.

Evidence has accumulated to support a general shift from fast to slow relative growth rates and from shade to sun leaves as plants develop from the highly competitive but shady juvenile niche to the stressful adult niche in the systems studied to date.

Nonetheless, there are major gaps in our knowledge due to examination of only a few environmental factors selecting for the evolution of ontogenetic trajectories, variability in how ontogeny is assigned, biogeographic sampling biases on trees in temperate biomes, dependencies on a few broadly sampled leaf morphological traits and a lack of longitudinal studies that track ontogeny within individuals. Filling these gaps will enhance our understanding of plant functional ecology and provide a framework for predicting the effects of global change threats that target specific ontogenetic stages.

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Structural validity of nursing diagnosis insomnia in older adults of a community center
Authors: Szpalher Adriana Souza , de Souza Priscilla Alfradique , Weiss Carleara , de Oliveira Lopes Marcos Venícios , Cardoso Rosane Barreto , Silva Natália Chantal Magalhães da
Published: November 2023

Purpose

Insomnia is an important sleep disorder in older persons. Conceptual analysis studies on this nursing diagnosis have been developed, but the diagnostic accuracy has not been verified. This study aimed to verify the diagnostic accuracy of the nursing diagnosis of Insomnia (00095) in older adults in a community center in Brazil.

Methods

A validation study for diagnostic accuracy of the defining characteristics of the nursing diagnosis Insomnia. Data were collected through telephone interviews with 90 participants. Latent class analysis was used to verify the sensitivity and specificity of the defining characteristics. Poisson regression was used to assess the prevalence of the association of factors related to the nursing diagnosis of insomnia.

Findings

A 47.42% prevalence of insomnia in the sample was identified. Defining characteristics such as expresses dissatisfaction with sleep and nonrestorative sleep–wake cycle showed the best accuracy values for insomnia, with a specificity of 0.92 (0.78–1.00) and 0.89 (0.74–1.00), respectively. Related factors such as stressors and frequent naps during the day were more likely to develop insomnia in individuals.

Conclusions

This study indicates diagnostic accuracy of nursing diagnosis of insomnia in community‐dwelling older people from a community center. The findings highlighted the importance of the defining characteristics of nursing diagnosis insomnia and its main related factors contributing to accurate diagnostic identification.

Implications for nursing practice

This study can contribute to providing objective clinical indicators of insomnia in the older population to guide nurses in early diagnostic confirmation for the selection of health interventions. In addition, it can be a consistent contribution to theoretical and conceptual reviews of this diagnosis.