bluuebunny/crossref_metadata_2025 huggingface dataset:
Prognostic Value of Differential Expression of Polymerase Eta Gene in Nonresponding Patients With Diffuse Large B-cell Lymphoma
Authors: Sharma Aditi , Das Ashim , Bal Amanjit , Srinivasan Radhika , Malhotra Pankaj , Prakash Gaurav , Kumar Rajendar
Published: October 2023

Diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkins lymphoma. After the introduction of rituximab therapy like rituximab, cyclophosphamide, doxorubicin vincristine, prednisolone, there has been considerable improvement in the 5-year overall survival in this group of patients, but the nonresponding patients are a challenge to the clinician. The translesion polymerases are unique polymerases that make cells tolerant to DNA damage. Many point mutations are introduced owing to their inherent property of bypassing the points of lesions, preventing the cell from stalling replication. However, the impaired activity of these polymerases can lead to the development of tumors with aggressive clinical course. In this study, the gene expression levels of polymerase eta (POLE) were compared in 2 cohorts of patients with DLBCL: the first cohort, patients who had achieved complete response, and the second cohort, patients who were refractory to the treatment or had relapse within 2 years of treatment. There was a significantly upregulated expression in the refractory/relapse cohort compared with the complete remission cohort (P = 0.0001). The high POLE expression levels correlated significantly with advanced disease stages (III and IV) and poor disease-free survival in the Kaplan-Meier curve. The high POLE expression levels were correlated with poor disease-free survival in nonresponder patients with DLBCL. The results concluded that patients with DLBCL with a high polymerase gene expression may show nonresponsiveness to chemotherapy; hence the functional impact of upregulated expression of POLE in DLBCL requires an in-depth assessment.
Efficacy of rehabilitation after provision of ICRC lower limb prostheses in low-income and middle-income countries: A quantitative assessment from Myanmar
Authors: Weerasinghe Stephney , Aranceta-Garza Alejandra , Murray Laura
Published: October 2023

Background:

Low-income and middle-income countries (LMICs) have poorly resourced health services. Lack of access to assistive devices, such as prosthetics, may limit the functional outcomes of persons with amputation and affect quality of life (QoL).

Objective:

The objective of this study was to assess the functional level and QoL of prosthetic users in LMICs when prescribed a prosthesis made from International Committee for Red Cross (ICRC) components.

Study design:

The study design included a quantitative descriptive methodology assessing functional outcomes and QoL after prosthetic provision.

Methods:

Participants were identified from the prosthetic service in Mandalay, Myanmar. Included participants were those with unilateral, traumatic, lower limb amputations, with ICRC devices delivered at least 6 months earlier. Participants attended the prosthetic service and were assessed using the Amputee Mobility Predictor with Prosthesis tool and the World Health Organization Quality of Life Brief and Disability modules.

Results:

Thirty-five participants completed the study; of them, 63% were persons with transtibial level amputation and 37% were with transfemoral level amputation. Approximately 83% achieved a score of more than 37 using the Amputee Mobility Predictor with Prosthesis. There is a strong positive correlation between QoL and physical health (r = 0.55; p < 0.001), social relationships (r = 0.66; p < 0.001), and inclusion (r = 0.53; p < 0.001). Participants had a better QoL and overall health when they had better psychological health.

Conclusion:

The patient-based results presented within this study could be considered as a contribution to the evidence base and importance of provision of prosthetic services in LMICs. It was observed that participants with an amputation were able to achieve a high level of physical function with the ICRC prostheses while also reporting a high QoL.
ASSOCIATION BETWEEN PLASMA TRANSFUSION AND IN-HOSPITAL MORTALITY IN CRITICALLY ILL PATIENTS WITH SEPSIS-INDUCED COAGULOPATHY
Authors: Wang Renli , Liu Rongjun , Xu Zhaojun
Published: October 2023

Background: Plasma is commonly used in patients with coagulopathy; however, its role in patients with sepsis-induced coagulopathy (SIC) is unclear. This study aimed to evaluate the effect of plasma transfusion on the prognosis of patients with SIC. Methods: Data were collected from the Medical Information Mart for Intensive Care IV database. Multivariable logistic regression analysis was used to determine the association between plasma transfusion and the incidence of in-hospital mortality, pulmonary embolism, and lower extremity deep vein thrombosis in critically ill patients with SIC. Propensity score matching (PSM) and propensity score–based inverse probability of treatment weighting (IPTW) models were used to ensure the robustness of our findings. Furthermore, the nonparametric relationship between in-hospital mortality and plasma transfusion volume was analyzed using restricted cubic spline. Subgroups analyses were performed for age, sex, Charlson score, Sequential Organ Failure Assessment score, SIC score, and with hemorrhage. Results: A total of 8,747 patients with SIC were enrolled: of them, 1874 were in the plasma infusion group, and 6,873 were in the no plasma infusion group. Compared with the no plasma infusion group, the plasma infusion group had higher in-hospital mortality (odds ratio [OR], 1.4411; 95% confidence interval [CI], 1.2280–1.6897, P < 0.05), and the results were robust after PSM (OR, 1.3227; 95% CI, 1.1152–1.5697; P < 0.05) and IPTW (OR, 1.1541; 95% CI, 1.0738–1.2404; P < 0.05). Similar results were also observed in different subgroups. However, because of conflicting results after PSM and IPTW, we were unable to definitively link plasma transfusion with pulmonary embolism and deep vein thrombosis. Compared with the no early plasma transfusion group (≥12 h), the in-hospital mortality rate was lower in the early plasma transfusion group (<12 h) (OR, 0.5426; 95% CI, 0.4398–0.6844; P < 0.05). The restricted cubic spline analysis indicated that increased plasma transfusion was associated with increased in-hospital mortality in patients with SIC. Conclusion: Plasma transfusion increases in-hospital mortality in patients with SIC, and the mortality rate increases with the amount of plasma transfusion. Patients with SIC who received early plasma infusion had lower in-hospital mortality than those who received no early plasma transfusion.
Improving the Access of Highly Sensitized Patients to Kidney Transplantation From Deceased Donors: The Spanish PATHI Program With Allocation Based on the Virtual Crossmatch
Authors: Valentin Maria O. , Crespo Marta , Fernandez Constantino , Muro Manuel , Vega Rocio , Palou Eduard , Ruiz Juan Carlos , Diekman Fritz , Padilla Maria , Mancebo Esther , Perez Isabel , Andres Amado , Ontañon Jesus , Dominguez-Gil Beatriz ,   on behalf of the Working Group PATHI
Published: October 2023

Background.

In 2015, the Spanish National Transplant Organization developed a prioritization system (Program for Access to Transplantation for Highly Sensitized Patients [PATHI]) to increase transplant options for patients with calculated panel-reactive antibodies (cPRAs) ≥98%, based on virtual crossmatch. We describe the experience with the implementation of PATHI and assess its efficacy.

Methods.

PATHI registry was used to collect characteristics of donors and patients between June 15, 2015, and March 1, 2018. One-year graft and patient survival and acute rejection were also measured. A Cox model was used to identify factors related to patient death and graft loss and logistical regression for those associated with rejection.

Results.

One thousand eighty-nine patients were included, and 272 (25%) were transplanted. Transplant rate by cPRA was 54.9%, 40.5%, and 12.8% in patients with cPRA98%, cPRA99%, and cPRA100%, respectively. One-year patient survival was 92.5%. Recipient age ≥60, time under dialysis >7 y, and delayed graft function were mortality risk factors. One-year graft survival was 88.7%. The factor related to graft loss was delayed graft function. The rejection rate was 22%. Factors related to rejection were sex, older recipients, and posttransplant donor-specific antibodies.

Conclusions.

A prioritization approach increases transplant options for highly sensitized patients with appropriate short-term postransplant outcomes. Along with other programs, PATHI may inspire other countries to adopt strategies to meet transplant needs of these patients.
Long-Term Outcomes and Predictors of Response in Breast Cancer Patients with Advanced Nodal Involvement
Authors: Sun Susie X , Piotrowski Matthew J , Adesoye Taiwo , Mitchell Melissa P , Garber Haven R , Teshome Mediget , Kuerer Henry M , Tamirisa Nina , Singh Puneet
Published: October 2023

BACKGROUND:

Advanced nodal disease is associated with poor prognosis. However, modern neoadjuvant systemic therapy (NST) regimens have resulted in higher pathologic complete response (pCR) rates, which are associated with improved survival. We sought to assess contemporary outcomes in patients with advanced nodal involvement and response to NST.

STUDY DESIGN:

We conducted a single-institution, retrospective study of 521 patients with cN2–3 primary nonmetastatic breast cancer treated with NST followed by surgery and radiation from 2012 to 2018. Descriptive statistics, multivariate Cox regression, and Kaplan–Meier analyses were performed.

RESULTS:

The mean age was 50.5 years, and median follow-up was 61 (4.7 to 197) months. The majority of patients had hormone receptor–positive (HR+)/HER2-negative tumors (HER2−; n = 242, 47.8%). Most were cT2 (n = 243; 46.6%) or cT3 (n = 139; 26.7%) and 73.3% (n = 382) had cN3 disease. Rate of axillary pCR was 34.2%, and breast and axillary pCR was 19.4% (n = 101). Event-free survival (EFS) at 5 years was 75.1% (95% CI, 0.71 to 0.79). Rate of locoregional recurrence was 6.7%; distant metastatic rate was 29.4%. Axillary pCR with or without breast pCR was significantly associated with longer EFS (p = 0.001). Achieving breast/axillary pCR was an independent predictor of improved EFS (hazard ratio 0.22, p < 0.0001). Having triple-negative disease was associated with worse EFS (hazard ratio 1.74, p = 0.008).

CONCLUSIONS:

In a high-risk cohort of patients with cN2–3 disease, trimodality therapy was effective in achieving durable EFS. Approximately one-third of patients achieved axillary pCR, which was associated with improved survival. Further studies are needed to accurately determine axillary response in cN2–3 breast cancer after NST in order to develop de-escalation strategies to reduce morbidity associated with axillary surgery.
Biofilm destruction activity of alpha-tocopherol against Staphylococcus aureus, Proteus mirabilis and Pseudomonas aeruginosa
Authors: Leong Pui Yee , Choo Wee Sim
Published: October 2023

Antibiotic resistance and the persistence of sessile cells within biofilms complicate the eradication of biofilm-related infections using conventional antibiotics. This highlights the need for alternative forms of therapeutics. The objective of this study was to investigate the biofilm destruction activity of alpha-tocopherol against Staphylococcus aureus,Proteus mirabilis and Pseudomonas aeruginosa on polystyrene. Alpha-tocopherol showed significant biofilm destruction activity on the pre-formed biofilms of S. aureus (45 - 46%), P. mirabilis (42 - 54%) and P. aeruginosa (28%). Resazurin assay demonstrated that alpha-tocopherol disrupted the bacteria biofilms without interfering with the microbial cell viability. Scanning electron microscope images showed lower cell density and less compacted cell aggregates on polystyrene surfaces after treatment with alpha-tocopherol. This study demonstrated the biofilm destruction activity of alpha-tocopherol against S. aureus, P. mirabilis and P. aeruginosa. Alpha-tocopherol could potentially be used to decrease biofilm-associated infections of these bacteria.
Genetic diversity of clinical isolates of Mycobacterium tuberculosis complex circulating in Western Kenya
Authors: Chelimo Charles Komen , Angienda Paul Oyieng , Olwal Charles Ochieng , Nyamogoba Henry
Published: October 2023

Tuberculosis (TB) remains a burden in many countries, including Kenya, especially, Western Kenya. Mycobacterium tuberculosis complex (MTBC) is the etiological agent of tuberculosis. TB burden is majorly linked to development of drug resistant strains. For treatment of TB, there is need for close surveillance of MTBC circulating in a given region. Hence, this study aimed to determine the proportion of MTBC species, strains and genetic diversity in circulation in an HIV prevalent region, western Kenya. Clinical isolates archived between 2013 and 2014 at Moi Teaching and Referral Hospital, Eldoret, Kenya with confirmed tuberculosis following Lowenstein-Jensen medium cultures were used. A 12-loci MIRU-VNTR genotyping was performed to determine the circulating species and strains of MTBC using www.MIRU-VNTRplus web platform. Allelic diversity was calculated using Hunters-Gaston diversity index (HGDI). The species identified in this population were M. tuberculosis, M. bovis and M. africanum, M. pinnipedii, M. microti, M. caprae and M. canetti. The  strains were Beijing, Latin American Mediterranean (LAM), Uganda 1 and 2, East African Indian (EAI), Ilama, West African 1 and 2, Haelem, URAL, Ghana, Seal, Cameroon, Vole etc. Notably, some isolates had unknown (new/unassigned) species. The strains were grouped into nine clusters with clustering rate of 31.18%. The study revealed that there are multiple species and strains of Mycobacterium circulating in Western Kenya. These strains were moderately diverse as seen in the high allelic diversity index of 0.53. The present findings suggest that there is need for more awareness among healthcare and other stakeholders on the existence of foreign MTBC species and strains in Kenya. Furthermore, 12-loci MIRU-VNTR may not be suitable for surveillance of MTBC strains in circulation. High resolution techniques such as Whole Genome Sequencing need to be adopted to resolve the genetic diversityand establish evolutionary trends for future and archived samples. The knowledge will be crucial in curbing TB, giving insights into new drug development, TB prevention, control and treatment strategies.
The impact of light and thioredoxins on the plant thiol-disulfide proteome
Authors: Hou Liang-Yu , Sommer Frederik , Poeker Louis , Dziubek Dejan , Schroda Michael , Geigenberger Peter
Published: October 2023

Thiol-based redox regulation is a crucial post-translational mechanism to acclimate plants to changing light availability. Here, we conduct a biotin-switch-based redox proteomics study to systematically investigate dynamics of the thiol-redox network in response to temporal changes in light availability and across genotypes lacking parts of the thioredoxin (Trx) or NADPH-Trx-reductase C (NTRC) systems in the chloroplast. Time-resolved dynamics revealed light leading to marked decreases in the oxidation states of many chloroplast proteins with photosynthetic functions during the first 10 min, followed by their partial re-oxidation after 2-6 hours into the photoperiod. This involvedf,mandx-type Trx proteins showing similar light-induced reduction-oxidation dynamics, while NTRC, 2-Cys-Prx and Trxy2 showed an opposing pattern, being more oxidized in the light than the dark. In Arabidopsistrxf1f2,trxm1m2orntrcmutants, in the light most proteins showed increased oxidation states than wild type, suggesting their light-dependent dynamics being related to the NTRC/Trx networks. While NTRC deficiency had a strong influence in all light conditions, deficiencies inf- orm-type Trxs showed differential impacts on the thiol-redox proteome depending on the light environment, being higher in constant or fluctuating light, respectively. Results indicate plant redox proteomes to be subject to dynamic changes in reductive and oxidative pathways to cooperatively fine-tune photosynthetic and metabolic processes in the light. This involvesf-type Trxs and NTRC to play a role in constant medium light, while bothm-type Trxs and NTRC being important to balance changes in protein redox-pattern during dynamic alterations in fluctuating light intensities.

One sentence summary

The plant protein redoxome shows light-dependent reduction and reoxidation dynamics linked to Trxsf1/f2,m1/m2 and NTRC, being of different importance depending on the extent of light variability.
Dissolved gases from pressure changes in the lungs elicit an immune response in human peripheral blood
Authors: Harrell Abigail G. , Thom Stephen R. , Shields C. Wyatt
Published: October 2023

Conventional dogma suggests that decompression sickness (DCS) is caused by nitrogen bubble nucleation in the blood vessels and/or tissues; however, the abundance of bubbles does not correlate with DCS severity. Since immune cells respond to chemical and environmental cues, we hypothesized that the elevated partial pressures of dissolved gases drive aberrant immune cell phenotypes in the alveolar vasculature. To test this hypothesis, we measured immune responses within human lung-on–a-chip devices established with primary alveolar cells and microvascular cells. Devices were pressurized to 1.0 or 3.5 atm and surrounded by normal alveolar air or oxygen-reduced air. Phenotyping of neutrophils, monocytes, and dendritic cells as well as multiplexed ELISA revealed that immune responses occur within 1 hour and that normal alveolar air (i.e., hyperbaric oxygen and nitrogen) confer greater immune activation. This work strongly suggests innate immune cell reactions initiated at elevated partial pressures contribute to the etiology of DCS.

Translational Impact Statement

Our work reveals that the elevated partial pressures of dissolved gases within the vasculature drives immune cell activation. These findings have broad implications in identifying novel biomarkers for high-risk individuals (e.g., divers, pilots) through screening differential immune markers across patients. Further, this work offers a lens through which novel strategies to mitigate DCS in clinical scenarios may be employed by the delivery of prophylactic drugs that temper immune reactions.
Co-existence ofblaKPC-2andblaVIM-2in highly carbapenem-resistantPseudomonas aeruginosaisolated in the ICU of a public hospital
Authors: Zheng Lin , Wang Zixian , Guo Jingyi , Guan Jiayao , Li Quanliang , Lu Gejin , Jing Jie , Sun Shiwen , Sun Yang , Ji Xue , Jiang Bowen , Chen Ping , Wang Yongjie , Yang Yanling , Zhu Lingwei , Guo Xuejun
Published: October 2023

In this study, highly carbapenem-resistantPseudomonas aeruginosa(h-CRPA) 18102011 [the minimum inhibitory concentration (MIC) value of carbapenem antimicrobial imipenem (IP) for h-CRPA is 4,096 μg/mL] was isolated from the bile of an intensive care unit (ICU) burn patient in China, and genomic sequencing revealed a complete genome. The genome’s molecular characteristics were analyzed to assess the genetic environment ofblaKPC-2andblaVIM-2. Average nucleotide identity (ANI) comparisons were used for precise species-level identification, while serotyping, multi-locus sequence typing, and the identification of acquired resistance genes, and virulence genes were also carried out. The h-CRPA 18102011 strain carryingblaKPC-2andblaVIM-2was identified as strain ST2374 and the O4 serotype. Virulence genes (plcH,exoST) and resistance genes (aph(3’)-IIb,aac(6’)-Ib-cr,ant(2’’)-Ia,blaOXA-396,blaPAO,blaKPC-2,blaVIM-2,blaPER-1,sul1,catB7,qnrVC6,fosA) were both identified in the genome. In addition, the IncpRBL16type mega-plasmid pP2011-1 carryingblaVIM-2and the IncP6 type plasmid pP2011-2 carryingblaKPC-2were identified in the strain. The genetic environment ofblaVIM-2andblaKPC-2was specifically evaluated to assess their origins.blaVIM-2was located in the region of In2075 (a novel type 1 integron) that was inserted into plasmid pP2011-1, this plasmid contained 3 novel recombination sites, as well as the typical recombination site 2 (umuC) observed for IncpRBL16type plasmids. However, the core module Tn3-ISKpn27-blaKPC-ΔISKpn6was identified as theblaKPC-2platform in plasmid pP2011-2. Conjugation experiments revealed that the plasmids pP2011-1 and pP2011-2 of the h-CRPA 18102011 strain could be transferred intoEscherichia coliwith a conjugation transfer efficiency of 10-6. TheE. colitransconjugant carriedblaKPC-2andblaVIM-2from the donor and the MIC value of IP to theE. colitransconjugant was 4,096 μg/mL, which was the same as observed for the donor. Overall, this study revealed the molecular characteristics of a VIM-2 and KPC-2-co-producing strain that was typed as O4 and ST2374. The continuous monitoring of bacteria, such as the strain investigated here, that co-harbor different types of carbapenemase genes is critical for preventing the spread of these genes.
Bacterial vitamin B6 required for post-embryonic development inC. elegans
Authors: Feng Min , Gao Baizhen , Ruiz Daniela , Garcia L. Rene , Sun Qing
Published: October 2023

Nutritional intake influences animal growth, reproductive capacity, and survival of animals. Under nutrition deficiency, animal developmental arrest occurs as an adaptive strategy to survive. However, the nutritional basis and the underlying nutrient sensing mechanism essential for initiating animal regrowth after developmental arrest remain to be explored. InCaenorhabditis elegans, larvae undergo early developmental arrest are stress resistant, and they require certain nutrients to initiate postembryonic development. Here, we investigated the developmental arrest inC. elegansfeeding onLactobacillus plantarum, and the rescue of the diapause state with trace supplementation ofEscherichia coli. We performed a genome-wide screen using 3983 individual gene deletionE. colimutants and identifiedE. coligenes that are indispensable forC. eleganslarval growth on original not nutritionally sufficient bacteriaL. plantarum. Among these crucial genes, we confirmedE. coli pdxH, and the downstream metabolite pyridoxal 5-P (PLP, Vitamin B6) as essential nutritional factors initiatingC. eleganspostembryonic development. Transcriptome results suggest that bacterialpdxHaffects host development by coordinating host metabolic processes and PLP binding. Additionally, bacterial PLP may act as a cofactor for host tyrosine aminotransferase, thereby promoting the translocation of daf-16 to nucleus. Altogether, these results highlight the role of microbial metabolite PLP as a crucial micronutrient to recover postembryonic development inC. elegans.
ALCAM-mediated synapses between DC1 and CD8 T cells are inhibited in advanced lung tumors
Authors: Morosi Luciano G. , Piperno Giulia M. , Joshi Sonal , Amadio Roberto , Vodret Simone , López-Rodríguez Lucía , Benvenuti Federica
Published: October 2023

Conventional type 1 dendritic cells (DC1) control anti-tumoral CD8 T responses, in lymph nodes and tumor tissues. T-cell activation depends on the establishment of a tight physical interaction with antigen-presenting cell, the immunological synapse (IS). The molecular determinants of DC1-CD8 IS in tumor tissues and how they are regulated during cancer progression remain poorly investigated. Using a reporter for DC1 in a genetic model of non-small cell lung cancer (KP-XCR1venus) we show that IS in lung tissues are abundant and productive at early stages of tumor development but progressively diminish in advanced tumors. Transcriptional profiling and flow cytometry of lung resident DC1 identified a module of adhesion molecules downregulated in advanced tumors. We focused on ALCAM and LFA-1, ligands for CD6 and ICAM-1 on T cells, to investigate their role and functional impact. By immobilizing single receptor agonists on artificial cell surfaces, we demonstrate that ALCAM and LFA-1 are sufficient to trigger cytoskeletal remodeling in early tumor DC1, whereas late tumors DC1 are not responsive. Blocking ALCAM-CD6 interactions in functional assays impairs the acquisition of effector functions in CD8 T cells. Together these data highlight that adhesion molecules required to establish IS in early, immune-reactive, tumors are targeted during tumor progression blunting cross-talk within the IS.
Shoot-to-root mobile CEPD proteins regulate TGA transcription factors to allow nitrate root-to-shoot transport inArabidopsis thaliana
Authors: Pelizaeus Anja Maren , Thurow Corinna , Oskam Lisa , Hoßbach Ben Moritz , Budimir Jelena , Pierik Ronald , Gatz Christiane
Published: October 2023

InArabidopsis thaliana, nitrogen (N) starvation leads to increased synthesis of CEPD (C-TERMINALLY ENCODED PEPTIDE DOWNSTREAM) proteins in the shoot. CEPDs travel to the roots, where they activate expression of genes required for high affinity nitrate transport. CEPDs belong to a plant-specific class of glutaredoxin-like proteins that interact with TGACG-binding transcription factors (TGAs). Here we identified the redundant clade-I TGAs TGA1 and TGA4 as the link between CEPDs and target promoters. In the absence of CEPDs, TGA1/4 have a strong negative effect on N starvation-induced gene expression leading to reduced translocation of N from the root to the shoot and to reduced shoot fresh weight. Basal levels of CEPDs were sufficient to completely release TGA1/4-mediated repression of nitrate acquisition. The antagonism between CEPDs and TGA1/4 was also detected in shoots, where CEPDs dampened the activating function of TGA1/4 on hyponasty and defense. CEPDs encode the conserved putative active site motif CxxC/S that was suggested to mediate redox regulation of target proteins. Complementation of thetga1 tga4mutant with a TGA1 variant containing amino acid substitutions of all four potentially redox-active cysteines showed that CEPDs do not regulate TGA1/4 by modulating their redox state.
Constraints on Lanthanide Separation by Selective Biosorption
Authors: Anderson Carter , Medin Sean , Adair James , Demopoulos Bryce , Eneli Emeka , Kuelbs Chloe , Lee Joseph , Sheppard Timothy J. , Şinar Deniz , Thurston Zacharia , Xu Mingyang , Zhang Kang , Barstow Buz
Published: October 2023

Rare Earth Elements (REE) are essential ingredients of sustainable energy technologies1-5, but separation of lanthanides is considered one of the hardest problems in chemistry today6. Biosorption, where molecules adsorb to the surface of biological materials, offers a sustainable alternative to environmentally harmful solvent extractions currently used for REE separations. The REE-biosorption capabilities of some microorganisms already allow for REE separations that under specialized conditions are competitive with solvent extractions7. Our recent work has discovered the genetic basis for REE biosorption selectivity8. However, it is unclear if the small changes to selectivity produced by changes to single genetic loci could allow biosorption to leapfrog existing REE separation technologies. In this article we present three models of lanthanide separation by biosorption and desorption. The first model shows that if a biosorbing microbe behaves as it if has a single type of binding site with small preference for one lanthanide, then the small changes in selectivity produced by changes to a single genetic locus could reduce the length of a separation process by ≈ 25%. Large multi-locus gene edits could reduce a separation process length by almost 90%. On the other hand, if the microbe contains multiple sites each with a distinct preference for an individual lanthanide, then separations become challenging and larger genetic edits would be needed to enable high purity. However, even if these large genetic edits are not possible, high purity separations could still be possible by combining multiple microbes, each with small increases in selectivity, with the first designed to enrich for the target lanthanide, while subsequent microbes are designed to remove contaminants.
Brain Functional Connectivity Correlates of Anomalous Interaction Between Sensorily Isolated Monozygotic Twins
Authors: Silberstein Richard B. , Bigelow Felicity J.
Published: October 2023

This study examined brain functional connectivity (FC) changes associated with possible anomalous interactions between sensorily isolated monozygotic twins. Brain FC was estimated using the Steady State Visual Evoked Potential-Event Related Partial Coherence (SSVEP-ERPC) methodology. Five twin pairs served twice as participants with an average interval between sessions of 67 days. In each recording session, one twin, the sender, viewed a randomized set of 50 general images and 50 personally relevant images, whilst the other twin, the Receiver, viewed a static personally relevant image for the entire duration of the session. Images appeared on the sender screen for 1.0 sec with the interval between successive images varied randomly between 4.0 and 8.0 sec. Receiver FC changes were calculated from the appearance times of the images as viewed by the Sender. It was hypothesized that anomalous interactions would be indicated by statistically significant Receiver FC changes when those changes are determined using the sender image appearance times. For each twin serving as Receiver, FC components were separately analysed for the 50 general and the 50 personal images, yielding 38 observations (19 twin pairs by 2 conditions). The hypothesis was confirmed in that 12 of the 38 observations, yielded statistically significant receiver FC increases or decreases at the p<0.01 level only when trials were synchronized to the Sender image appearance times. Overall, this effect was significant at the p=4X10-8Df=175. To the best of our knowledge, this is the first study reporting statistically significant FC changes indicative of anomalous interactions between two sensorily isolated individuals.
Bnip3 expression is strongly associated with reelin-positive entorhinal cortex layer II neurons
Authors: Omholt Stig W. , Lejneva Raissa , Lagartos Donate Maria Jose , Fang Evandro Fei , Kobro-Flatmoen Asgeir
Published: October 2023

In layer II of the entorhinal cortex, the principal neurons that project to the dentate gyrus and the CA3/2 hippocampal fields express the large glycoprotein reelin (Re+ ECLII-neurons). In rodents, neurons located at the dorsal extreme of the entorhinal cortex that thus border the rhinal fissure, express the highest levels, and the expression gradually decreases at levels successively further away from the rhinal fissure. Here we test two predictions following from the hypothesis that reelin expression is strongly correlated with neuronal metabolic rate. Since mitochondrial turnover rate serves as a proxy for energy expenditure, we predicted that the expression of the canonical promitophagic BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (Bnip3) would be upregulated in Re+ ECLII-neurons, and that the degree of upregulation would strongly correlate with the expression level of reelin in these neurons. We confirm both predictions, which implies that the energy requirement of Re+ ECLII-neurons is generally high, and that there is a systematic decrease in metabolic rate in these neurons as one moves successively away from the rhinal fissure. We tentatively suggest that the reasons for the high energy requirement of these neurons are their high rate of synaptic transmission and the high frequency by which they remold their synaptic contacts. This implies that the systematic variation in energy requirement of the neurons manifesting the observed reelin gradient ties in with the level of spatial and temporal detail by which they encode information about the external environment.
Spies of the deep: an animal-borne active sonar and bioluminescence tag to characterise mesopelagic prey size and behaviour in distinct oceanographic domains
Authors: Chevallay Mathilde , Jeanniard du Dot Tiphaine , Goulet Pauline , Fonvieille Nadège , Craig Cassandra , Picard Baptiste , Guinet Christophe
Published: October 2023

Mesopelagic fish, a central component of marine trophic networks, play a fundamental role in marine ecosystems. However, as they live in highly inaccessible environments, little information is currently available on their ecology, especially on the influence of oceanographic parameters on their distribution. The emergence of biologging technologies has made it possible to use deep-diving predators as bio-samplers of their environment in under-sampled regions. In this work, we deployed an innovati ve miniaturised sonar tag that combines active acoustics with high-resolution GPS, pressure, movement and light sensors on Southern elephant seals, a deep-diving predator feeding on mesopelagic prey. Seals were also equipped with oceanographic tags, allowing us to explore the functional relationships between oceanographic parameters, distribution and ecology of mesopelagic prey targeted by seals and the seals’ foraging behaviour. We highlighted strong vertical differences in prey characteristics and behaviour, with larger, more evasive and less bioluminescent prey in deeper waters. Moreover, prey encountered in warmer waters were found deeper, were more evasive and displayed a more marked diel vertical migration behaviour compared to prey encountered in colder waters, suggesting that prey accessibility and characteristics differ according to oceanographic domains. This study highlights the usefulness of the sonar-bioluminescence tag to infer mesopelagic prey distribution and habitat when deployed on deep-diving predators such as elephant seals.
Enhancing Open-World Bacterial Raman Spectra Identification by Feature Regularization for Improved Resilience against Unknown Classes
Authors: Balytskyi Yaroslav , Kalashnyk Nataliia , Hubenko Inna , Balytska Alina , McNear Kelly
Published: October 2023

The combination of Deep Learning techniques and Raman spectroscopy shows great potential offering precise and prompt identification of pathogenic bacteria in clinical settings. However, the traditional closed-set classification approaches assume that all test samples belong to one of the known pathogens, and their applicability is limited since the clinical environment is inherently unpredictable and dynamic, unknown or emerging pathogens may not be included in the available catalogs. We demonstrate that the current state-of-the-art Neural Networks identifying pathogens through Raman spectra are vulnerable to unknown inputs, resulting in an uncontrollable false positive rate. To address this issue, first, we developed a novel ensemble of ResNet architectures combined with the attention mechanism which outperforms existing closed-world methods, achieving an accuracy of 87.8±0.1% compared to the best available model’s accuracy of 86.7±0.4%. Second, through the integration of feature regularization by the Objectosphere loss function, our model achieves both high accuracy in identifying known pathogens from the catalog and effectively separates unknown samples drastically reducing the false positive rate. Finally, the proposed feature regularization method during training significantly enhances the performance of out-of-distribution detectors during the inference phase improving the reliability of the detection of unknown classes. Our novel algorithm for Raman spectroscopy enables the detection of unknown, uncatalogued, and emerging pathogens providing the flexibility to adapt to future pathogens that may emerge, and has the potential to improve the reliability of Raman-based solutions in dynamic operating environments where accuracy is critical, such as public safety applications.

Our model is publicly available:https://github.com/BalytskyiJaroslaw/PathogensRamanOpenSet.git
Detection of Blood Volume Reduction and Vasoconstriction Following Focused Ultrasound Blood-Brain Barrier Opening Using Ultrasound Flow Imaging
Authors: Bae Sua , Lee Stephen A. , Konofagou Elisa E.
Published: October 2023

Microbubble-mediated focused ultrasound (FUS) offers a non-invasive treatment for transient and localized blood-brain barrier (BBB) opening for drug delivery or immunostimulation. It is known that FUS-induced BBB opening is accompanied by blood flow changes, vasoconstriction, and vasodilation, as validated by optical microscopy through a cranial window. In this study, we introduce a novel method for quantifying vascular changes after FUS-induced BBB opening by employing ultrasound flow imaging in mice. We acquired pre-FUS and post-FUS ultrasound flow images with the same microbubble concentration in the brain. Contrast-enhanced power Doppler (CEPD) images and ultrasound localization microscopy images were obtained to evaluate changes in cerebral blood volume and vessel diameter at the sonicated region of the brain. Our findings demonstrate that FUS leads to a reduction in blood volume at the treated region, with vasoconstriction being more dominant than vasodilation. Furthermore, we show that transcranial CEPD can detect local blood reduction following FUS, which spatially coincides with the edema region identified in T2-weighted MRI. Our findings suggest that ultrasound flow imaging has the potential to serve as a cost-effective and immediate monitoring tool for evaluating the safety and efficacy of FUS-induced BBB opening.
Synthesis of pyrazole-based macrocycles leads to a highly selective inhibitor for MST3
Authors: Amrhein Jennifer A. , Berger Lena M. , Balourdas Dimitrios-Ilias , Joerger Andreas C. , Menge Amelie , Krämer Andreas , Frischkorn Julia M. , Berger Benedict-Tilman , Elson Lewis , Kaiser Astrid , Schubert-Zsilavecz Manfred , Müller Susanne , Knapp Stefan , Hanke Thomas
Published: October 2023

MST1, MST2, MST3, MST4, and YSK1 are conserved members of the mammalian sterile 20 kinase (MST) family. MSTs regulate key cellular functions such as cell proliferation, cell migration, metabolic regulation, and cell polarity. The MST3 isozyme plays a role in regulation of cell growth, autophagy and apoptosis, and its dysregulation has been linked to the occurrence of high-grade tumors with poor survival prognosis. To date, there are no isoform-selective inhibitors available that could be used for validating the role of MST3 in tumorigenesis and to assess its potential as an anti-cancer target for drug development. To this end, we have designed a new series of 3-aminopyrazole-based macrocycles based on the structure of an acyclic promiscuous kinase inhibitor. By varying moieties targeting the solvent-exposed region and optimizing the linker, macrocycle JA310 (21c) was synthesized. JA310 exhibited high cellular potency for MST3 with an EC50= 106 nM and excellent kinome-wide selectivity with significantly lower cellular activity on the closely related kinase MST4 (EC50= 1.4 µM). The high-resolution crystal structure of the MST3-JA310 complex provided intriguing insights into the distinct binding mode of the macrocycle, which was associated with large-scale structural rearrangements, including concerted induced-fit movements of the glycine-rich loop, the αC helix, and the activation loop. In summary, the developed macrocyclic MST3 inhibitor, JA310, demonstrates the utility of macrocyclization for the design of highly selective inhibitors and presents a first chemical probe for MST3.
Systematic optimization of siRNA productive uptake into resting and activated T cellsex vivo
Authors: Kremer A , Ryaykenen T , Haraszti RA
Published: October 2023

RNA-based medicines are ideally suited for precise modulation of T cell phenotypes in anti-cancer immunity, in autoimmune diseases and forex vivomodulation of T-cell-based therapies. Therefore, understanding productive siRNA uptake to T cells is of particular importance.

Most studies used unmodified siRNAs or commercially available siRNA with undisclosed chemical modifications patterns to show functionality in T cells. Despite being an active field of research, robust siRNA delivery to T cells still represents a formidable challenge. Therefore, a systematic approach is needed to further optimize and understand productive siRNA uptake pathways to T cells.

Here we compared conjugate-mediated and nanoparticle-mediated delivery of siRNAs to T cells in the context of fully chemically modified RNA constructs. We showed that lipid-conjugate-mediated delivery outperforms lipid-nanoparticle-mediated and extracellular-vesicle-mediated delivery in activated T cellsex vivo. Yet, ex vivo manipulation of T cells without the need of activation is of great therapeutic interest for CAR-T, engineered TCR-T and allogeneic donor lymphocyte applications. We are first to report productive siRNA uptake into resting T cells using lipid-conjugate mediated delivery. Interestingly, we observed strong dependence of silencing activity on lipid-conjugate-identity in resting T cells but not in activated T cells. This phenomenon is consistent with our early uptake kinetics data. Lipid-conjugates also enabled delivery of siRNA to all mononuclear immune cell types, including both lymphoid and myeloid lineages. These findings are expected to be broadly applicable forex vivomodulation of immune cell therapies.
Out of Place: Three Eurasian Taxa Shed Light on Origin of Thermopsideae in North America
Authors: Farmer Todd A. , Jansen Robert K.
Published: October 2023

The North American Thermopsideae, a monophyletic group comprising the North American endemicBaptisia, and the paraphyletic Eurasian–North American disjunctThermopsis, is nested within the Sophoreae (Fabaceae: Papilionoideae). Previous phylogenetic studies have identified two East Asian taxa within the North American Thermopsideae, suggesting two independent dispersal events between North America–East Asia. More recent studies have also placed a third taxon,Vuralia turcica, an endemic species from Turkey, among the North American Thermopsideae. The presence of three geographically distant Eurasian taxa within a relatively young clade of North American origin is perplexing, and the biogeographic implications of this observation are not clear. To investigate this matter, 1540 low-copy nuclear genes and complete plastomes were obtained from 36 taxa across the core genistoids, including 26 newly sequenced taxa. Nuclear and plastome based maximum likelihood (ML) and ASTRAL analyses were conducted based on varying degrees of taxon coverage and read mapping consensus threshold values. Additional analyses were performed to estimate divergence times and to reconstruct biogeographic history. The results strongly support a relictual Old World clade, presently composed ofV. turcicaandT. chinensis, which diverged from the ancestor of the North American lineage during the mid to late Miocene. A single and recent North America–East Asia dispersal involvingT. lupinoidesis reported. Furthermore, the traditional inclusion of the genusAmmopiptanthusamong Thermopsideae, and the recent recircumscription ofT. turcicato the monotypicVuralia, are not supported. A relatively high degree of cytonuclear discordance is reported within each sub-clade of the North American Thermopsideae. This finding is likely attributable to the high degree of interspecific hybridization reported within these groups and raises the need for more rigorous genome-scale testing to disentangle their complex phylogenies.

Subjects:Biodiversity, Biogeography, Evolutionary Studies, Genetics, Plant Science
GLP-1 enhances beta-cell response to protein ingestion independent of glycemia and bariatric surgery amplifies it
Authors: Rayas Maria , Gastaldelli Amalia , Honka Henri , Pezzica Samantha , Carli Fabrizia , Peterson Richard , DeFronzo Ralph , Salehi Marzieh
Published: October 2023

Background

The glycemic-independent actions of glucagon-like peptide 1 (GLP-1) in the prandial state in humans are largely unknown. Protein ingestion stimulates beta-cell secretion without changing plasma glucose concentration. We examined the contribution of endogenous GLP-1 to glucose metabolism and beta-cell response to protein ingestion under basal glucose concentrations, and whether these responses are affected by rerouted gut after gastric bypass (GB) or sleeve gastrectomy (SG).

Methods

Insulin secretion rate (ISR) and glucose fluxes during a 50-gram oral protein load were compared between 10 non-diabetic individuals with GB, 9 matched subjects with SG and 7 non-operated controls (CN) with and without intravenous infusion of exendin-(9–39) [Ex-9], a specific GLP-1 receptor (GLP-1R) antagonist.

Results

Blocking GLP-1R increased plasma glucose concentration before and after protein ingestion and decreased beta-cell sensitivity to glucose in the first 30 minutes of protein ingestion (p<0.05) in all 3 groups. However, reduction in the premeal ISR by Ex-9 infusion only was observed in CN (p<0.05 for interaction), whereas diminished prandial ISR3hby GLP-1R blockade was observed in GB and SG and not in controls (p<0.05 for interaction). Also, GLP-1R blockade enhanced post-protein insulin action in GB and SG, but not in CN. Endogenous glucose production (EGP) during the first hour after protein ingestion was increased in all 3 groups butEGP3hwas accentuated by Ex-9 infusion only in GB (p<0.05 for interaction).

Conclusion

These findings are consistent with both a glucose-independent pancreatic and extra-pancreatic role for GLP-1 during protein ingestion in humans that are exaggerated by bariatric surgery.

Trial registration

This study was registered at Clinical Trials.Gov:NCT02823665
Towards AI-designed genomes using a variational autoencoder
Authors: Dudek Natasha K , Precup Doina
Published: October 2023

Genomes encode elaborate networks of genes whose products must seamlessly interact to support living organisms. Humans' capacity to understand these biological systems is limited by their sheer size and complexity. In this work, we develop a proof of concept framework for training a machine learning algorithm to model bacterial genome composition. To achieve this, we create simplified representations of genomes in the form of binary vectors that indicate the encoded genes, henceforth referred to as genome vectors. A denoising variational autoencoder was trained to accept corrupted genome vectors, in which most genes had been masked, and reconstruct the original. The resulting model, DeepGenomeVector, effectively captures complex dependencies in genomic networks, as evaluated by both qualitative and quantitative metrics. An in-depth functional analysis of a generated genome vector shows that its encoded pathways are interconnected, near complete, and ecologically cohesive. On the test set, where the model's ability to reconstruct uncorrupted genome vectors was evaluated, AUC and F1 scores of 0.98 and 0.83, respectively, support the model's strong performance. This work showcases the power of machine learning approaches for synthetic biology and highlights the possibility that AI agents may one day be able to design genomes that animate carbon-based cells.