bluuebunny/crossref_metadata_2025 huggingface dataset:
mRNA expression of vitamin D receptor, calcium-sensing receptor, cyclin D1, and PTH in symptomatic and asymptomatic primary hyperparathyroidism
Authors: Kaur Parjeet , Hegde Dwijraj , Singh Priyanka , Gautam Dheeraj , Sarin Deepak , Bhadada Sanjay , Mithal Ambrish
Published: October 2024

Background and objective

The exact underlying mechanism for the differential clinical profiles of symptomatic and asymptomatic primary hyperparathyroidism (PHPT) patients has not been fully elucidated, and efforts to define the molecular mechanisms underlying the phenotypic heterogeneity of PHPT have been limited. The aim of this study was to explore the underlying molecular mechanisms involved in the pathogenesis of symptomatic and asymptomatic sporadic PHPT in Asian Indians.

Methods

A prospective cohort study was conducted at a tertiary care hospital in North India. PHPT patients who underwent parathyroidectomy were included. The main outcome was the comparison of vitamin D receptor (VDR), calcium-sensing receptor (CaSR), cyclin D 1 (CD1), and parathyroid hormone (PTH) mRNA levels between symptomatic and asymptomatic PHPT patients and controls determined via quantitative real-time polymerase chain reaction (qRT-PCR).

Results

Forty-two PHPT patients were studied. The mean (SD) age was 49.7 (12.8) years. Twenty patients were asymptomatic. The median PTH levels were significantly greater in the symptomatic group than in the asymptomatic group (878 vs 653 pg/mL). CaSR and VDR mRNAs were significantly lower in both symptomatic and asymptomatic patients than in controls. CD1 and PTH mRNAs were significantly increased in symptomatic patients, but not in asymptomatic PHPT patients compared with controls. Symptomatic PHPT patients had significantly greater CD1 mRNA expression and reduced CaSR expression than asymptomatic patients.

Conclusion

Symptomatic PHPT patients had significantly greater CD1 mRNA expression and lower CaSR expression than asymptomatic patients, underscoring the importance of the molecular mechanisms underlying the phenotypic heterogeneity of PHPT.
Frequency of clinical signs in patients with Cushing's syndrome and mild autonomous cortisol secretion: overlap is common
Authors: Braun Leah T , Vogel Frederick , Nowak Elisabeth , Rubinstein German , Zopp Stephanie , Ritzel Katrin , Beuschlein Felix , Reincke Martin
Published: October 2024

Background

Cushing's syndrome (CS) can be difficult to diagnose. A timely diagnosis, however, is the cornerstone for targeted treatment, to reduce morbidity and mortality. One reason for the difficulties to identify early on patients with CS might be the presence of a mild phenotype. The aim of the study was to classify the phenotypic landscape of CS. We studied patients with overt CS and mild autonomous cortisol secretion (MACS).

Method

The study was part of the German Cushing's registry. Patients were prospectively included at time of diagnosis and the number of comorbidities and clinical signs and symptoms were assessed in a standardized fashion. One hundred twenty-nine patients with CS (pituitary CS, n = 85, adrenal CS, n = 32, ectopic CS, n = 12, respectively) and 48 patients with MACS were included. Patients with clinical signs and/or comorbidities typical for CS and at least 2 pathological screening tests were classified as having CS. Patients with a 1 mg low-dose-dexamethasone-suppression test above 1.8 µg/dL without being clinically overt CS were classified as having MACS.

Results

On average, patients with CS had 2 comorbidities (range 1-3) at time of diagnosis (pituitary CS: 2 [1-3], adrenal CS: 3 [2-4], ectopic CS: 3 [2-4]). Patients with MACS, however, had 3 comorbidities (range 2-3). Hypertension was the most common comorbidity in all subtypes of CS (78%-92%) and in patients with MACS (87%). Of a total of 11 clinical signs, patients with CS had on average 5 with 28% of patients having between 0 and 3 clinical signs, 50% 4-7 signs, and 22% more than 7 clinical signs. Patients with MACS had on average 2 clinical signs (range 1-3) at time of diagnosis.

Conclusion

The phenotypic landscape of CS is quite variable. The frequency of comorbidities is similar between patients with CS and MACS. A relevant number of patients with overt CS have just a few clinical signs. There is also an overlap in frequency of symptoms and clinical signs between patients with CS and MACS. According to the current guidelines, 96% of our patients with MACS fall into the category “consideration of adrenalectomy”. This should be kept in mind when making treatment decisions in the latter group of patients.
Ileoanal Pouch–Related Fistulas: A Narrative Review
Authors: Bronze Sergio , Kayal Maia , Estevinho Maria Manuela , Hahn Sue , Khaitov Sergey , Colombel Jean-Frederic , Wong Serre-Yu
Published: October 2024

Ileoanal pouch–related fistula (IAPRF) is a possible complication after ileal pouch-anal anastomosis that significantly impacts pouch prognosis and the patient’s quality of life. This study aimed to perform a comprehensive narrative review to better classify the epidemiology, risk factors, etiology, management, and outcomes of IAPRF, and to propose an algorithm for its systematic classification. Ten studies comprising 664 patients with IAPRF were identified, with a prevalence ranging from 4% to 45%. The reported fistula types were as follows: pouch-vaginal (n = 236, 35.5%), perineal (n = 139, 21%), enterocutaneous (n = 54, 8%), pouch-anal (n = 53, 8%), presacral (n = 18, 2%), and anastomotic (n = 15, 2%). Postsurgical pelvic sepsis occurred in 21%-37.2% of patients. Twenty additional studies regarding fistula classification divided them according to onset time and etiology, defining 5 categories: anastomotic-related, technical aspects of the surgery, Crohn’s disease–like pouch inflammation, cryptoglandular, and malignancy. Pouch excision was reported in up to 70% of patients. Fistulas associated with anastomotic complications, technical surgical issues, and cryptoglandular fistulas warrant surgical management. On the other hand, fistulas associated with inflammation are preferentially managed with biologics or small molecules.
Associations Between Histo-blood Group Antigen Status in Mother-Infant Dyads and Infant Oral Rotavirus Vaccine Immunogenicity in Rural Zimbabwe
Authors: Pun Joshua , Evans Ceri , Chasekwa Bernard , Church James A , Gough Ethan , Mutasa Kuda , Rukobo Sandra , Govha Margaret , Mushayanembwa Patience , Majo Florence D , Tavengwa Naume V , Humphrey Jean H , Kirkpatrick Beth D , Kosek Margaret , Ntozini Robert , Prendergast Andrew J
Published: October 2024

Background

Histo-blood group antigen (HBGA) phenotypes may contribute to poor oral rotavirus vaccine (RVV) immunogenicity, since rotavirus binds intestinal epithelial HBGA glycans, while maternal HBGA status shapes breastmilk composition, which influences the composition of the infant microbiome. We investigated associations between maternal/infant HBGA phenotypes and RVV immunogenicity in rural Zimbabwe.

Methods

We undertook salivary FUT2/FUT3 phenotyping in mother-infant pairs. Serum anti-rotavirus immunoglobulin A was measured by enzyme-linked immunosorbent assay. We explored adjusted associations between FUT2/FUT3 status and RVV seroconversion (primary outcome, n = 322) and seropositivity and geometric mean titer (secondary outcomes, n = 776).

Results

Infants of FUT2- or FUT3-positive women were less likely to seroconvert post-RVV than infants of FUT2- or FUT3-negative women (FUT2 positive [20.1%] vs FUT2 negative [27.5%]: adjusted relative risk [aRR], 0.47; 95% CI, .26–.82; P = .008; FUT3 positive [18.1%] vs FUT3 negative [30.0%]: aRR, 0.45; 95% CI, .25–.78; P = .005). When compared with FUT2-positive infants with FUT2-positive mothers, FUT2-positive infants with FUT2-negative mothers were twice as likely to seroconvert (36.8% vs 21.9%; aRR, 2.12; 95% CI, 1.23–3.63; P = .006). When compared with FUT3-positive infants with FUT3-positive mothers, FUT3-positive infants with FUT3-negative mothers were 3 times as likely to seroconvert (48.3% vs 18.2%; aRR, 2.99; 95% CI, 1.82–4.90; P < .001).

Conclusions

Maternal and infant FUT2 and FUT3 status influences infant RVV immunogenicity.
Anarchy and Empire: World-Conquerors and International Systems
Authors: Phillips Andrew , Sharman J C
Published: October 2024

Why are some international systems characterized by stable multipolarity while elsewhere conquest produces universal empires? We explain this variation through contrasting the conventional story of the consolidation of multipolar anarchy in Europe against the Ottoman conquest of the Near East and the Manchu conquest of greater China. Both the Ottomans and the Manchus developed the capacity for systemic conquest via hybridizing steppe and sedentary military techniques. Furthermore, both surmounted the legitimation gradient of conquest. The Ottomans and Manchus used cultural statecraft to prevent balancing coalitions and encourage bandwagoning and collaboration. Cultural statecraft comprised strategies of co-opting preexisting symbols of imperial rule and employing multivocal legitimacy strategies to sequentially appeal to multiple segmented audiences. In Europe, both military obstacles and religious confessional ideational divisions frustrated would-be conquerors. Multipolar anarchy is thus a contingent outcome in international politics rather than a constant, which can be extinguished by militarily powerful and culturally agile “world conquerors.”
Situatedness and distantiation: education in a time of ecological and climate crises
Authors: Kvamme Ole Andreas
Published: October 2024

In this article, I explore the significance of place in education. The historical context is expressed by the ecological and climate crises in a world distinguished by the unjust distribution of privileges and burdens. I elucidate the concept of place by entering the tradition of the pedagogy of place. Here, the significance of place is accentuated with a sensitivity to the local context, in contrast to other educational approaches that emphasize more generic, abstract knowledge. A central premise is the notion of place as a delimited unit that is distinguished from other places. This stable notion, I argue, needs to be reconsidered in the present. With reference to Massey, I accentuate relations as pivotal to a notion of place that accommodates both a sense of belonging and conflicts of power and interest. I hold that education at this time in history should be sensitive to our situatedness in everyday life’s web of relationships. Still, general knowledge is required to bring up perspectives that enable students to critically conceive the place in which they are situated. I make and discuss these claims with reference to and in critique of Young’s notion of powerful knowledge and Klafki’s reformulation of German Didaktik. A central concern is to clarify the mediation of situated knowledge and general knowledge in educational practice. In the final part of the article, I bring in elements from critical hermeneutics and utopian thinking, approaching Bildung as a process involving situatedness, distantiation, and refiguration.
Terminating bias: How Arnold Schwarzenegger showed us the importance of spelling names correctly
Authors: Lam Joseph
Published: October 2024

In his winning entry for our 2024 Statistical Excellence Award for Early Career Writing, Joseph Lam explores data linkage errors and biases and the implication for ethnically minoritised populations
Double distal corporal anchoring stitch for lateral penile implant cylinder extrusion
Authors: Raheem Omer A , Kalidoss Senthooran , Pomar Hector Alejandro , Suarez-Sarmiento Jr Alfredo , Perito Paul
Published: October 2024

Background

The ventral and distal aspects of the corpora cavernosa are the thinnest, increasing the likelihood of cylinder extrusion or crossover complications pertaining to inflatable penile prosthesis procedures. A double distal corporal anchoring double stitch can be used to robustly secure impending lateral extrusions and crossovers of implant cylinders. It is a novel, effective corrective measure for the uncommon complication of migrated cylinders in inflatable penile prosthesis placement.

Aim

To describe the surgical indications and technique for the double distal corporal anchoring fixation stitch for lateral penile implant cylinder extrusion.

Methods

We discuss a double-stitch technique that is performed following corporoplasty and capsulotomy. A lateral incision is made subcoronally on the affected side to identify the crossover or lateral extrusion. The cylinder is repositioned properly within the native corpora to prevent further cylinder migration. Two 2-0 Ethibond sutures are threaded through the distal cylinder eyelet, and each suture is delivered through the glans with a Keith needle and tied off. An incision is made in the glans, and 1 arm of each suture is tied with the other to create a bridge between the sutures that can be positioned deep within the skin of the glans.

Outcomes

Over the past 4 years, 66 patients with lateral cylinder extrusion underwent the double distal corporal anchoring fixation stitch procedure, with overall improved satisfaction (97%). Only 2 patients had surgical complications. One patient experienced repeated lateral extrusion of the penile implant cylinders 6 weeks following the double-anchoring stitches procedure. The second patient developed a painful suture granuloma that necessitated excision, which resolved this issue, and the penile implant cylinder remained in the proper position over a year later.

Clinical Implications

This technique ensures the secure fixation of the affected cylinders in the surgical capsule by creating a bridge between 2 sutures holding each repositioned cylinder in place, and the ensuing fibrotic reaction helps to fixate the extruded cylinder within the midglandular tissue.

Strength and Limitations

This surgical technique describes the double distal corporal anchoring stitch for lateral penile implant cylinder extrusion. Further studies are warranted to validate long-term outcomes and satisfaction.

Conclusion

The double distal corporal anchoring fixation stitch is a safe and efficacious method to secure cylinders in the proper surgical capsule during revision procedures to correct distal crossovers or laterally extruded penile prosthesis implants.
Quantitative assessment of residual tumor is a strong and independent predictor of survival in methylated glioblastoma following radiochemotherapy with lomustine/temozolomide
Authors: Zeyen Thomas , Böhm Laura , Paech Daniel , Schäfer Niklas , Tzaridis Theophilos , Duffy Cathrina , Nitsch Louisa , Schneider Matthias , Potthoff Anna-Laura , Schneider-Rothhaar Javen Lennard , Steinbach Joachim Peter , Hau Peter , Kowalski Thomas , Seidel Clemens , Krex Dietmar , Grauer Oliver , Goldbrunner Roland , Zeiner Pia Susan , Tabatabai Ghazaleh , Galldiks Norbert , Stummer Walter , Hattingen Elke , Glas Martin , Gkika Eleni , Vatter Hartmut , Radbruch Alexander , Herrlinger Ulrich , Weller Johannes , Schaub Christina
Published: October 2024

Background

Maximum tumor resection improves overall survival (OS) in patients with glioblastoma. The extent of resection (EOR) is historically dichotomized. The response assessment in neuro-oncology (RANO) resects group recently proposed criteria for volumetry-based EOR assessment in patients that were treated according to Stupp´s protocol. The purpose of this study was (1) to investigate the prognostic value of EOR in patients receiving combined chemotherapy with lomustine (CCNU)/temozolomide (TMZ), and (2) to analyze the prognostic performance of binary EOR assessment compared to volumetric assessment.

Methods

Seventy-eight patients with newly diagnosed MGMT-methylated GBM undergoing tumor resection followed by radiochemotherapy with CCNU/TMZ were included in this study. Residual contrast-enhancing (CE) tumor volume after the first resection was measured and its influence on OS and progression-free survival was analyzed using uni- and multivariable Cox regression analysis as well as two-sided log-rank test. Patients were divided into residual tumor volume (RTV) ≤1 cm³, >1–≤5 cm³, and >5 cm³ following the proposed criteria of the RANO resect group.

Results

Prolonged OS was associated with age <60 years, low RTV, and gross total resection. RTV had a superior prognostic value compared to binary EOR assessment. Patients with total or near total resection of CE tumor (≤ 1 cm³ RTV) showed prolonged OS (median 54.4 months, 95% CI: 46.94–not reached), with a 5-year survival rate of 49%.

Conclusions

Low RTV is associated with increased survival in glioblastoma patients undergoing radiochemotherapy with CCNU/TMZ. This study demonstrates the applicability of the recently proposed RANO resect criteria in this subgroup of patients.
Sonic restoration: acoustic stimulation enhances plant growth-promoting fungi activity
Authors: Robinson Jake M. , Annells Amy , Cando-Dumancela Christian , Breed Martin F.
Published: October 2024

Ecosystem restoration interventions often utilize visible elements to restore an ecosystem (e.g. replanting native plant communities and reintroducing lost species). However, using acoustic stimulation to help restore ecosystems and promote plant growth has received little attention. Our study aimed to assess the effect of acoustic stimulation on the growth rate and sporulation of the plant growth-promoting fungus
Trichoderma harzianum
Rifai, 1969. We played a monotone acoustic stimulus (80 dB sound pressure level (SPL) at a peak frequency of 8 kHz and a bandwidth at −10 dB from the peak of 6819 Hz—parameters determined via review and pilot research) over 5 days to
T. harzianum
to assess whether acoustic stimulation affected the growth rate and sporulation of this fungus (control samples received only ambient sound stimulation less than 30 dB). We show that the acoustic stimulation treatments resulted in increased fungal biomass and enhanced
T. harzianum
conidia (spore) activity compared to controls. These results indicate that acoustic stimulation influences plant growth-promoting fungal growth and potentially facilitates their functioning (e.g. stimulating sporulation). The mechanism responsible for this phenomenon may be fungal mechanoreceptor stimulation and/or potentially a piezoelectric effect; however, further research is required to confirm this hypothesis. Our novel study highlights the potential of acoustic stimulation to alter important fungal attributes, which could, with further development, be harnessed to aid ecosystem restoration and sustainable agriculture.
Host genetic diversity and body condition influence parasite resistance and clearance in a wild marine mammal population
Authors: Gutiérrez Josefina , Seguel Mauricio , Saenz-Agudelo Pablo , Acosta-Jamett Gerardo , Verdugo Claudio
Published: October 2024

Host genetic variability can modulate infection resistance, although its role in infection clearance remains unclear. Hookworm disease (
Uncinaria
sp.) is the leading cause of pup mortality in several otariid species, although the parasite can be cleared through immune-mediated processes. We evaluated the association of host genetic diversity, body condition and immune response with hookworm resistance and/or clearance in the South American fur seal (
Arctocephalus australis
). Uninfected pups had higher heterozygosity than parasitized individuals, indicating a negative relationship between heterozygosity and the chances of infection. Likewise, pups that died of hookworm infection had lower heterozygosity than those that died of non-infectious causes. Interestingly, once infected, pups that survived hookworm infection had heterozygosities similar to pups that died of hookworm disease. However, pups that cleared the infection had a higher body mass and parasite-specific immunoglobulin G levels than those that did not recover or died of hookworm disease. Thus, although heterozygosity predicted resistance to and mortality from hookworm infections, it did not affect parasite clearance, which was facilitated by better body condition and adaptive immune responses. This demonstrates that host genetic variability and host–environment interactions influence disease dynamics, acting at different, well-defined stages of infection.
Quantifying age-specific household contacts in Aotearoa New Zealand for infectious disease modelling
Authors: Sullivan Caleb , Senanayake Pubudu , Plank Michael J.
Published: October 2024

Accounting for population age structure and age-specific contact patterns is crucial for accurate modelling of human infectious disease dynamics and impact. A common approach is to use contact matrices, which estimate the number of contacts between individuals of different ages. These contact matrices are frequently based on data collected from populations with very different demographic and socio-economic characteristics from the population of interest. Here we use a comprehensive household composition dataset based on Aotearoa New Zealand census and administrative data to construct a household contact matrix and a synthetic population that can be used for modelling. We investigate the behaviour of a compartment-based and an agent-based epidemic model parametrized using these data, compared with a commonly used contact matrix that was constructed by projecting international data onto New Zealand’s population. We find that using the New Zealand household data, either in a compartment-based model or in an agent-based model, leads to lower attack rates in older age groups compared with using the projected contact matrix. This difference becomes larger when household transmission is more dominant relative to non-household transmission. We provide electronic versions of the synthetic population and household contact matrix for other researchers to use in infectious disease models.
Temporal Dynamics of Nucleus Accumbens Neurons in Male Mice During Reward Seeking
Authors: Schall Terra A. , Li King-Lun , Qi Xiguang , Lee Brian T. , Wright William J. , Alpaugh Erin E. , Zhao Rachel J. , Liu Jianwei , Li Qize , Zeng Bo , Wang Lirong , Huang Yanhua H. , Schlüter Oliver M. , Nestler Eric J. , Nieh Edward H. , Dong Yan
Published: October 2024

The nucleus accumbens (NAc) regulates reward-motivated behavior, but the temporal dynamics of NAc neurons that enable “free-willed” animals to obtain rewards remain elusive. Here, we recorded Ca2+activity from individual NAc neurons when mice performed self-paced lever-presses for sucrose. NAc neurons exhibited three temporally-sequenced clusters, defined by times at which they exhibited increased Ca2+activity: approximately 0, -2.5 or -5 sec relative to the lever-pressing. Dopamine D1 receptor (D1)-expressing neurons and D2-neurons formed the majority of the -5-sec versus -2.5-sec clusters, respectively, while both neuronal subtypes were represented in the 0-sec cluster. We found that pre-press activity patterns of D1- or D2-neurons could predict subsequent lever-presses. Inhibiting D1-neurons at -5 sec or D2-neurons at -2.5 sec, but not at other timepoints, reduced sucrose-motivated lever-pressing. We propose that the time-specific activity of D1- and D2-neurons mediate key temporal features of the NAc through which reward motivation initiates reward-seeking behavior.
Synchronized Chromatin Organization Serves as Potent Biomarker in Anaesthesia-based Plant Consciousness
Authors: Chandra Shilpa , Mukherjee Bodhidipra , Salam Abdul , Anjum Farhan , Nandi Chayan Kanti , Behera Laxmidhar
Published: October 2024

Anaesthesia has been used for centuries for medical purposes. With the application of anaesthesia, organisms lose their conscious awareness. It provides a temporary loss of sensation, which enables painless performance during surgery. However, the cellular mechanisms underlying the effects of anaesthesia are not clearly understood. It has been proposed that plant root function is analogous to the human brain. Here, using super-resolution imaging technique, we explored an organelle-level understanding of the effect of anaesthesia on plant roots and the stem connecting to the root. Our results showed that the nuclei organized themselves in an orchestrated manner upon treatment with both local and general anaesthesia without damaging their structure. Euchromatin within the nucleus was found to be reorganized in the nuclear periphery, and this process was found to be independent of ATP. In contrast, mitochondria, microtubules, endocytic vesicles, and chloroplasts, which are other important organelles in plant cells, were highly altered or damaged under the same experimental conditions. Eventually, the cellular homeostasis again maintained and process is reversible upon the removal of anaesthesia. Our results suggest that such orchestrated chromatin organization without disturbing the overall structure of the nucleus could be used as a potent biomarker for conscious awareness in plants.

Graphical Abstract
Damage-induced IL-18 stimulates thymic NK Cells limiting endogenous tissue regeneration
Authors: Granadier David , Cooper Kirsten , Kousa Anastasia , Acenas Dante , Lemarquis Andri , Hernandez Vanessa , Warren Makya , Iovino Lorenzo , deRoos Paul , Lederer Emma E. , Shannon-Sevillano Steve , Kinsella Sinéad , Evandy Cindy , Brink Marcel R.M. van den , Dudakov Jarrod A.
Published: October 2024

Interleukin-18 is an acute phase pro-inflammatory molecule crucial for mediating viral clearance by activating Th1 CD4+, cytotoxic CD8+T, and NK cells. Here, we show that mature IL-18 is generated in the thymus following numerous distinct forms of tissue damage, all of which cause caspase-1-mediated immunogenic cell death. We report that IL-18 stimulated cytotoxic NK cells limit endogenous thymic regeneration, a critical process that ensures restoration of immune competence after acute insults like stress, infection, chemotherapy, and radiation. NK cells suppressed thymus recovery by aberrantly targeting thymic epithelial cells (TECs), which act as the master regulators of organ function and regeneration. Together these studies reveal a novel pathway regulating tissue regeneration in the thymus and offer IL-18 as a potential therapeutic target to boost thymic function. Moreover, given the enthusiasm for IL-18 as a cancer immunotherapy for its capacity to elicit a type-1 immune response, these findings also offer insight into potential off-target effects.
Redox Signaling Mediates Differentiation of Adipose Progenitors in Response to Inflammatory Cytokines in the Adipose Tissue Secretome
Authors: Wager Jessica L. , Baker Larissa G. , Scheidl Taylor B. , Yonan Sophie Z. , Colarusso Pina , Dufour Antoine , Thompson Jennifer A.
Published: October 2024

Adipogenesis, the terminal differentiation of adipose progenitor cells (APCs), is critical in maintaining the functional integrity of adipose depots under obesogenic conditions. It is thought that a signal arising from the adipose microenvironment triggers APC differentiation; yet the identity and source of the signal remains unknown. This study sought to uncover the signal responsible for activating adipogenesis. Redox signaling was shown to influence adipogenesis in primary murine APCs treated with pharmacologic agents to manipulate the levels of reactive oxygen species (ROS). Increased generation of superoxide (O2-) and hydrogen peroxide (H2O2)viaredox cyclers amplified both early and late APC differentiation, while ROS scavengers and antioxidants blunted differentiation. The impact of specifically targeting H2O2with the antioxidant, catalase, or a catalase inhibitor, was restricted to lipid accumulation in late adipogenesis. Protein was concentrated from conditioned media of adipose tissue explants culturedex vivoto capture signals within the adipose secretome. Differentiation was enhanced in APCs cultured in the presence of the adipose secretome, an effect that was diminished with scavenging of ROS and amplified when the secretome was collected from mice fed a high fat diet for 8 weeks. Proteomic analysis revealed that the adipose secretome from animals on a high fat diet was enriched in pathways related to immune cell-mediated inflammation, with interleukin 6 (IL-6) as a central regulator of differentially expressed proteins. A multiplex assay to measure cytokines confirmed higher IL-6 in the adipose secretome of high fat-fed animals. Exposure of APCs to IL-6 increased adipogenesis, while treatment of APCs with an IL-6 blocking antibodies diminished the adipogenic effect of the adipose secretome. Together, these findings substantiate a role for redox signaling in the regulation of adipogenesis and identify IL-6 as a novel activator of adipogenesis that may mediate APC differentiation via generation of ROS under obesogenic conditions.
A systematic review to identify research gaps in studies modeling vaccination strategies againstNeisseriainfections
Authors: Metelmann S , Thompson A , Donten A , Oke S , Sun S , Borrow R , Feng X , Vivancos R , Decraene V , Pellis L , Hall I
Published: October 2024

The genusNeisseriaincludes two major human pathogens:N. meningitidiscausing bacterial meningitis/septicemia andN. gonorrhoeaecausing gonorrhoea. Mathematical models have been used to simulate their transmission and control strategies, and the recent observation of a meningitis vaccine being partially effective against gonorrhoea has led to an increased modeling interest. Here we conducted a systematic review of the literature, focusing on studies that model vaccination strategies againstNeisseriaincidence and antimicrobial resistance. Using journal, preprint, and grey literature repositories, we identified 52 studies that we reviewed for validity, model approaches and assumptions. Most studies showed a good quality of evidence, and the variety of approaches along with their different modeling angles, was assuring especially for gonorrhoea studies. We identified options for future research, including the combination of both meningococcal and gonococcal infections in studies to have better estimates for vaccine benefits, and the spill over of gonorrhoea infections from the heterosexual to the MSM community and vice versa. Cost-effectiveness studies looking at at-risk and the wider populations can then be used to inform vaccine policies on gonorrhoea, as they have for meningococcal disease.
Distinct prostate cancer neuroendocrine subtypes predict prognosis and guide personalized prostate-specific membrane antigen-targeted therapy
Authors: Hong Yung-Chih , Tsai Cheng-Han , Hu Tze-Yun , Hsu Chih-Sin , Peng Yu-Ching , Chen Weber , Huang William J. , Lin Tzu-Ping , Chang Pei-Ching
Published: October 2024

Background and Objective

Second-generation hormonal therapy inhibits castration-resistant prostate cancer (CRPC), but the tumor eventually recurs as neuroendocrine prostate cancer (NEPC) and turns lethal. Differentiating lineage plasticity that contributed to distinct NEPC subtypes aids in advancing treatments, particularly the recent FDA-approved177Lu-PSMA-617 radiopharmaceutical therapy.

Methods

We integrated single-cell RNA sequencing data from fresh human CRPC cases. This comprehensive approach allowed us to identify distinct NEPC subpopulations and their respective lineage with high confidence.

Key Findings and Limitations

We uncovered N-Myc and REST as key transcription factors driving distinct neuroendocrine subtypes among 5,797 neuroendocrine-like epithelial cells in CRPC: a REST-dependent subtype (NE I), an N-Myc-dependent subtype (NE II), and a combined N-Myc/REST subtype (NE I+II). These subtypes were validated using multiplex immunofluorescence staining. Trajectory analysis of single-cell RNA sequencing data, along with multi-omics time course analysis of publicly available transcriptomic data recapitulated N-Myc and REST lineages. Additionally, we observed PSMA loss in N-Myc lineage NEPC and identified STMN1 as a biomarker for PSMA-negative subtype. We validated the prognostic value of STMN1 using the TCGA dataset and 60 in-house CRPC tissues. Given that surgery is rarely performed in advanced CRPC, leading to limited sample availability, further validation in larger cohorts is needed.

Conclusions and Clinical Implications

Adeno-to-neuroendocrine lineage transition in prostate cancer leads to resistance to new therapies. The lethal NEPC phenotype should be revealed earlier in the disease course of patients with CRPC, providing crucial clues for personalized precision medicine.
Seed specific overexpression of a modified wheatOrgene leads to enhanced β-carotene in rice and wheat grains
Authors: Sirohi Parul , Vishnoi Ritika , Baliyan Suchi , Gupta Bidya Bhushan , Demiwal Pratibha , Germain Hugo , Sircar Debabrata , Chauhan Harsh
Published: October 2024

Vitamin A deficiency is a major public health problem affecting up to 50% of the world’s population, as either wheat or rice, which are poor in many essential micronutrients such as vitamin A, are major staple food crops. Biofortification of cereal crops with β-carotene (provitamin A) through genetic engineering is a potential solution to overcome vitamin A deficiency. The Orange (Or) protein is involved in the regulation of carotenoid accumulation and previous studies demonstrated high carotenoid accumulation due to a single-nucleotide polymorphism (SNP) in the CDS leading to substitution of Arg to His in the OR protein results in carotenoid accumulation. In the present study, we showed that this substitution of a single amino acid at position 110 (Arg to His) of wild-type wheatTaOr(referred to asTaOrHis110) increased β-carotene accumulation in transgenic wheat and rice plants overexpressingTaOrHis110under the control of the seed-specific promoterGlu-1D1. HPLC analysis revealed increase in β-carotene content in rice grain up to 8-fold in case of TP309 (japonica) cultivar, 13-fold in case of IET10364 (indica) cultivar and 7-fold in wheat cv. CPAN1676. Additionally, most of the carotenoid biosynthetic pathway genes were found to be upregulated inTaOrHis110overexpressing seeds of TP309 and IET10364, which positively correlated with maximum increase in β-carotene content.
Chromosome-level genome assembly and annotation of the crested gecko,Correlophus ciliatus, a lizard incapable of tail regeneration
Authors: Gumangan Marc A , Pan Zheyu , Lozito Thomas P
Published: October 2024

The vast majority of gecko species are capable of tail regeneration, but singular geckos ofCorrelophus, Uroplatus, andNephrurusgenera are unable to regrow lost tails. Of these non-regenerative geckos, the crested gecko (Correlophus ciliatus) is distinguished by ready availability, ease of care, high productivity, and hybridization potential. These features makeC. ciliatusparticularly suited as a model for studying the genetic, molecular, and cellular mechanisms underlying loss of tail regeneration capabilities. We report a contiguous genome ofC. ciliatuswith a total size of 1.65 Gb, a total of 152 scaffolds, L50 of 6, and N50 of 109 Mb. Repetitive content consists of 40.41% of the genome, and a total of 30,780 genes were annotated. Assembly of the crested gecko genome provides a valuable resource for future comparative genomic studies between non-regenerative and regenerative geckos and other squamate reptiles.

Findings

We report genome sequencing, assembly, and annotation for the crested gecko,Correlophus ciliatus.
A post-injury immune challenge with lipopolysaccharide following adult traumatic brain injury alters neuroinflammation and the gut microbiome acutely, but has little effect on chronic outcomes
Authors: Rewell Sarah S.J. , Shad Ali , Chen Lingjun , Macowan Matthew , Chu Erskine , Gandasasmita Natasha , Casillas-Espinosa Pablo M. , Li Jian , O’Brien Terence J. , Semple Bridgette D.
Published: October 2024

Patients with a traumatic brain injury (TBI) are susceptible to hospital-acquired infections, presenting a significant challenge to an already-compromised immune system. The consequences and mechanisms by which this dual insult worsens outcomes are poorly understood. This study aimed to explore how a systemic immune stimulus (lipopolysaccharide, LPS) influences outcomes following experimental TBI in young adult mice. Male and female C57Bl/6J mice underwent controlled cortical impact or sham surgery, followed by 1 mg/kg i.p. LPS or saline-vehicle at 4 days post-TBI, before behavioral assessment and tissue collection at 6 h, 24 h, 7 days or 6 months. LPS induced acute sickness behaviors including weight loss, transient hypoactivity, and increased anxiety-like behavior. Early systemic immune activation by LPS was confirmed by increased spleen weight and serum cytokines. In brain tissue, gene expression analysis revealed a time course of inflammatory immune activation in TBI or LPS-treated mice (e.g., IL-1β, IL-6, CCL2, TNFα), which was exacerbated in TBI+LPS mice. This group also presented with fecal microbiome dysbiosis at 24 h post-LPS, with reduced bacterial diversity and changes in the relative abundance of key bacterial genera associated with sub-acute neurobehavioral and immune changes. Chronically, TBI induced hyperactivity and cognitive deficits, brain atrophy, and increased seizure susceptibility, similarly in vehicle and LPS-treated groups. Together, findings suggest that an immune challenge with LPS early after TBI, akin to a hospital-acquired infection, alters the acute neuroinflammatory response to injury, but has no lasting effects. Future studies could consider more clinically-relevant models of infection to build upon these findings.
Neurophysiological Dynamics of Metacontrol States: EEG Insights into Conflict Regulation
Authors: Wang Xi , Talebi Nasibeh , Zhou Xianzhen , Hommel Bernhard , Beste Christian
Published: October 2024

Understanding the neural mechanisms underlying metacontrol and conflict regulation is crucial for insights into cognitive flexibility and persistence. This study employed electroencephalography (EEG), EEG-beamforming and directed connectivity analyses to explore how varying metacontrol states influence conflict regulation at a neurophysiological level. Metacontrol states were manipulated by altering the frequency of congruent and incongruent trials across experimental blocks in a modified flanker task, and both behavioral and electrophysiological measures were analyzed. Behavioral data confirmed the experimental manipulation’s efficacy, showing an increase in persistence bias and a reduction in flexibility bias during increased conflict regulation. Electrophysiologically, theta band activity paralleled the behavioral data, suggesting that theta oscillations reflect the mismatch between expected metacontrol bias and actual task demands. Alpha and beta band dynamics differed across experimental blocks, though these changes did not directly mirror behavioral effects. Post-response alpha and beta activity were more pronounced in persistence-biased states, indicating a neural reset mechanism preparing for future cognitive demands. By using a novel artificial neural networks method, directed connectivity analyses revealed enhanced inter-regional communication during persistence states, suggesting stronger top-down control and sensorimotor integration. Overall, theta band activity was closely tied to metacontrol processes, while alpha and beta bands played a role in resetting the neural system for upcoming tasks. These findings provide a deeper understanding of the neural substrates involved in metacontrol and conflict monitoring, emphasizing the distinct roles of different frequency bands in these cognitive processes.
GeTMoR: Simultaneous genomic, transcriptomic, and morphological profiling of rare single cells
Authors: Prabakar Rishvanth K. , Schmidt Michael J. , Kuhn Peter , Hicks James
Published: October 2024

1

Circulating tumor cells (CTCs), and circulating tumor related cells, are extremely rare cells that intravasate from the tumor into the circulatory system and can be captured via a liquid biopsy. Although CTCs contribute to the metastatic cascade, and diverse phenotypes of CTCs have been observed – including the cytokeratin expressing CTCs, CTC clusters, large polyploid CTCs, and CTCs undergoing epithelial to mesenchymal transition – little is known about their functionality. By virtue of CTCs being rare, a detection method that maximizes the information obtained per cell would be ideal to understand their biology and for use in diagnostic approaches. The challenge is that rare cell detection necessitates extensive processing steps, during which molecular content, such as RNA and DNA, needs to be preserved for downstream single cell analysis. We developed GEnomic, Transcriptomic, and MOrphological profiling of Rare cells (GeTMoR), a method that extends the High Definition Single Cell Assay for detecting rare cancer related cells to simultaneously image and profile the genome and transcriptome from single rare cells. We validated GeTMoR by spiking in cancer cell lines into whole blood to evaluate the quality of recovered gene expression and copy number profile from the same cell. The GeTMoR approach provides the ability to link the phenotype of rare cells, including CTCs, to their genome and transcriptome, thereby enabling insight into rare cell biology.
Multi-Modal Large Language Model Enables All-Purpose Prediction of Drug Mechanisms and Properties
Authors: Liang Youwei , Zhang Ruiyi , Li Yongce , Huo Mingjia , Ma Zinnia , Singh Digvijay , Gao Chengzhan , Rahmani Hamidreza , Bandi Satvik , Zhang Li , Weinreb Robert , Malhotra Atul , Grotjahn Danielle A. , Awdishu Linda , Ideker Trey , Gilson Michael , Xie Pengtao
Published: October 2024

Accurately predicting the mechanisms and properties of potential drug molecules is essential for advancing drug discovery. However, traditional methods often require the development of specialized models for each specific prediction task, resulting in inefficiencies in both model training and integration into work-flows. Moreover, these approaches are typically limited to predicting pharmaceutical attributes represented as discrete categories, and struggle with predicting complex attributes that are best described in free-form texts. To address these challenges, we introduce DrugChat, a multi-modal large language model (LLM) designed to provide comprehensive predictions of molecule mechanisms and properties within a unified framework. DrugChat analyzes the structure of an input molecule along with users’ queries to generate comprehensive, free-form predictions on drug indications, pharmacodynamics, and mechanisms of action. Moreover, DrugChat supports multi-turn dialogues with users, facilitating interactive and in-depth exploration of the same molecule. Our extensive evaluation, including assessments by human experts, demonstrates that DrugChat significantly outperforms GPT-4 and other leading LLMs in generating accurate free-form predictions, and exceeds state-of-the-art specialized prediction models.
Exploring the link between extended red blood cell parameters and platelet indices in voluntary blood donors
Authors: De Ranita , Basavaraju Deepak Marballi , Stephen Leo , Lakshmi Kavitha , Mammen Joy , Edison Eunice Sindhuvi
Published: October 2024

Background

As regular blood donors are prone to iron deficiency, importance of extended red blood cell (eRBC) parameters in identifying donors with depleted iron stores was investigated. Thrombocytosis has been well documented in patients affected with IDA. Thus, significance of eRBC parameters in identifying iron deficiency associated thrombocytosis was also examined in this cohort.

Methods

Blood samples were collected in EDTA tubes from consenting donors for analyses of routine haematological and eRBC parameters. Serum samples were isolated for estimation of iron parameters.

Results

Iron deficient donors had significantly altered eRBC parameters. Among them, Ret-He with a cut-off of ≥32 pg had high AUC (0.822) and showed relatively high sensitivity & specificity in detecting iron deficiency. Combination of Ret-He with CCI increased sensitivity & specificity to 90.6% and 98.2%, in detection of donors affected with iron restricted erythropoiesis. This cohort had increased platelet counts, which showed significant association with Ret-He (β= -0.373), RBC-He (β= -0.384), CCI (β= 0.384), Hypo-He (β=0.494) and Micro-R (β= 0.299). Elevated platelet counts also showed significant correlations with these eRBC parameters, which was absent in iron replete donors.

Conclusions

eRBC parameters are sensitive indicators of non-anaemic iron deficiency, which may be enhanced by combining them. Their significant association with elevated platelet counts in iron deficient donors, highlights their importance in reflecting iron deficiency associated thrombocytosis.

Impact Statement

The present study discusses utility of eRBC parameters in detecting non-anaemic iron deficiency, in regular voluntary blood donors. Previous reports have investigated the importance of these parameters in identifying IDA in blood donors. The present study is the first one which indicates combining different eRBC parameters such as Ret-He and CCI increases their accuracy of detection. They were also significantly associated with elevated platelet counts in iron deficient donors, which was absent in iron replete individuals. This link between eRBC parameters and higher platelet counts in healthy donors affected with non-anaemic iron deficiency has not been reported before.
Estimating the trend of COVID-19 in Norway by combining multiple surveillance indicators
Authors: Rø Gunnar , Lyngstad Trude Marie , Seppälä Elina , Skodvin Siri Nærland , Trogstad Lill , White Richard Aubrey , Paulsen Arve , Paulsen Trine Hessevik , Ofitserova Trine Skogset , Langlete Petter , Madslien Elisabeth Henie , Nygård Karin , Freisleben de Blasio Birgitte
Published: October 2024

Background

Estimating the trend of new infections was crucial for monitoring risk and for evaluating strategies and interventions during the COVID-19 pandemic. The pandemic revealed the utility of new data sources and highlighted challenges in interpreting surveillance indicators when changes in disease severity, testing practices or reporting occur.

Aim

To estimate the trend in new COVID-19 infections by combining estimates of growth rates from all available surveillance indicators in Norway.

Methods

We estimated growth rates from ten different surveillance indicators in Norway by using a negative binomial regression method and aligned the growth rates in time to hospital admissions by maximising correlations. Using a meta-analysis framework, we calculated overall growth rates and reproduction numbers including assessments of the heterogeneity between indicators.

Results

The estimated growth rates reached a maximum of 25% per day in March 2020, but afterwards they were between -10% and 10% per day. The correlations between the growth rates estimated from different indicators were between 0.5 and 1.0. Growth rates from indicators based on wastewater, panel and cohort data can give up to 14 days earlier signals of trends compared to hospital admissions, while indicators based on positive lab tests can give signals up to 7 days earlier.

Conclusions

Combining estimates of growth rates from multiple surveillance indicators provides a good description of the COVID-19 pandemic in Norway. This is a powerful technique for a holistic understanding of the trends of new COVID-19 infections and the technique can easily be adapted to new data sources and situations.