bluuebunny/crossref_metadata_2025 huggingface dataset:
Time-resolved cryogenic electron tomography for the study of transient cellular processes
Authors: Yoniles Joseph , Summers Jacob A. , Zielinski Kara A. , Antolini Cali , Panjalingam Mayura , Lisova Stella , Moss Frank R. , Di Perna Maximus Aldo , Kupitz Christopher , Hunter Mark S. , Pollack Lois , Wakatsuki Soichi , Dahlberg Peter D.
Published: May 2024

Cryogenic electron tomography (cryo-ET) is the highest resolution imaging technique applicable to the life sciences, enabling subnanometer visualization of specimens preserved in their near native states. The rapid plunge freezing process used to prepare samples lends itself to time-resolved studies, which researchers have pursued for in vitro samples for decades. Here, we focus on developing a freezing apparatus for time-resolved studies in situ. The device mixes cellular samples with solution-phase stimulants before spraying them directly onto an electron microscopy grid that is transiting into cryogenic liquid ethane. By varying the flow rates of cell and stimulant solutions within the device, we can control the reaction time from tens of milliseconds to over a second before freezing. In a proof-of-principle demonstration, the freezing method is applied to a model bacterium, Caulobacter crescentus, mixed with an acidic buffer. Through cryo-ET we resolved structural changes throughout the cell, including surface-layer protein dissolution, outer membrane deformation, and cytosolic rearrangement, all within 1.5 s of reaction time. This new approach, Time-Resolved cryo-ET (TR-cryo-ET), enhances the capabilities of cryo-ET by incorporating a subsecond temporal axis and enables the visualization of induced structural changes at the molecular, organelle, or cellular level.
‘Edupreneurship’
Authors: Hebbar N. Nandini
Published: May 2024

Arguing that ‘institutional’ big men (periya aal) have played a significant role in transforming higher education in Tamil Nadu through ‘edupreneurship’, this chapter focuses on their portrayals of power and their characterization of education in familial and gendered terms. This chapter provides further context to the expansion in higher education by mapping how private engineering education has gone hand in hand with models of patronage, philanthropy, and electoral politics in urban and semi-urban milieus in Tamil Nadu. These details serve as necessary background reading to understand the ways in which the college serves as an institution of (im)mobility even as it fuels the aspiration for engineering education.
Neurodevelopmental outcome in preterm infants with intraventricular hemorrhages: the potential of quantitative brainstem MRI
Authors: Kienast Patric , Schmidbauer Victor , Yildirim Mehmet Salih , Seeliger Selina , Stuempflen Marlene , Elis Julia , Giordano Vito , Fuiko Renate , Olischar Monika , Vierlinger Klemens , Noehammer Christa , Berger Angelika , Prayer Daniela , Kasprian Gregor , Goeral Katharina
Published: May 2024

Objectives

This retrospective study aimed to identify quantitative magnetic resonance imaging markers in the brainstem of preterm neonates with intraventricular hemorrhages. It delves into the intricate associations between quantitative brainstem magnetic resonance imaging metrics and neurodevelopmental outcomes in preterm infants with intraventricular hemorrhage, aiming to elucidate potential relationships and their clinical implications.

Materials and methods

Neuroimaging was performed on preterm neonates with intraventricular hemorrhage using a multi-dynamic multi-echo sequence to determine T1 relaxation time, T2 relaxation time, and proton density in specific brainstem regions. Neonatal outcome scores were collected using the Bayley Scales of Infant and Toddler Development. Statistical analysis aimed to explore potential correlations between magnetic resonance imaging metrics and neurodevelopmental outcomes.

Results

Sixty preterm neonates (mean gestational age at birth 26.26 ± 2.69 wk; n = 24 [40%] females) were included. The T2 relaxation time of the midbrain exhibited significant positive correlations with cognitive (r = 0.538, P < 0.0001, Pearson’s correlation), motor (r = 0.530, P < 0.0001), and language (r = 0.449, P = 0.0008) composite scores at 1 yr of age.

Conclusion

Quantitative magnetic resonance imaging can provide valuable insights into neurodevelopmental outcomes after intraventricular hemorrhage, potentially aiding in identifying at-risk neonates. Multi-dynamic multi-echo sequence sequences hold promise as an adjunct to conventional sequences, enhancing the sensitivity of neonatal magnetic resonance neuroimaging and supporting clinical decision-making for these vulnerable patients.
The simple economics of an external shock to a bug bounty platform
Authors: Zrahia Aviram , Gandal Neil , Markovich Sarit , Riordan Michael
Published: May 2024

We first provide background on the “nuts and bolts” of a bug bounty platform: a two-sided marketplace that connects firms and individual security researchers (“ethical” hackers) to facilitate the discovery of software vulnerabilities. Researchers get acknowledged for valid submissions, but only the first submission of a distinct vulnerability is rewarded money in this tournament-like setting. We then empirically examine the effect of an exogenous external shock (COVID-19) on Bugcrowd, one of the leading platforms. The shock presumably reduced the opportunity set for many security researchers who might have lost their jobs or been placed on a leave of absence. We show that the exogenous shock led to a huge rightward shift in the supply curve and increased the number of submissions and new researchers on the platform. During the COVID period, there was a significant growth in duplicate (already known) valid submissions, leading to a lower probability of winning a monetary reward. The supply increase resulted in a significant decline in the equilibrium price of valid submissions, mostly due to this duplicate submission supply-side effect. The results suggest that had there been a larger increase in the number of firms and bug bounty programs on the platform, many more unique software vulnerabilities could have been discovered.
A case report of transthyretin amyloidosis following cardiac transplantation: thick ventricles that look alike
Authors: Lauwers Charlotte , Rosseel Thomas , Droogné Walter , Van Aelst Lucas N L , Van Cleemput Johan
Published: May 2024

Background

Transthyretin (ATTR) amyloidosis is more prevalent than initially thought. As much as 13% of patients hospitalized with heart failure with preserved ejection fraction may have ATTR-cardiomyopathy (CM). Conversely, heart transplant patients may manifest left ventricular hypertrophy or diastolic dysfunction, especially late after transplantation.

Case summary

We present a case of a 82-year-old male heart transplant patient, 31 years following orthotopic heart transplantation. While he was satisfied with his exercise capacity as an octogenarian, several years before, he required pacemaker implantation due to third-degree atrioventricular block, had bilateral carpal tunnel syndrome treated with carpal tunnel release surgery, and experienced idiopathic sudden deafness. Based on increasing left ventricular wall thickness during routine follow-up, a diagnosis of ATTR amyloidosis was suspected. Ultimately, the diagnosis was confirmed non-invasively with a specific scintigraphic exam, while an additional physicochemical stain on an endomyocardial biopsy taken several years before provided pathological proof. We initiated tafamidis, yet stopped this treatment after 1 month because of gastrointestinal intolerance. Ultimately, our patient died 2 years later due to heart failure.

Discussion

Our case shows the long delay between the onset of ATTR deposition, the presence of clinical signs, and the final diagnosis. Echocardiographic findings suggestive for ATTR-CM include left ventricular hypertrophy and diastolic dysfunction, which are both common in heart transplant patients. Yet, ATTR-CM should be considered in the differential diagnosis, especially late after transplantation, in this closely monitored population.
Classical multidimensional scaling on metric measure spaces
Authors: Lim Sunhyuk , Mémoli Facundo
Published: May 2024

We study a generalization of the classical multidimensional scaling procedure (cMDS) which is applicable in the setting of metric measure spaces. Metric measure spaces can be seen as natural ‘continuous limits’ of finite data sets. Given a metric measure space ${\mathcal{X}} = (X,d_{X},\mu _{X})$, the generalized cMDS procedure involves studying an operator which may have infinite rank, a possibility which leads to studying its traceability. We establish that several continuous exemplar metric measure spaces such as spheres and tori (both with their respective geodesic metrics) induce traceable cMDS operators, a fact which allows us to obtain the complete characterization of the metrics induced by their resulting cMDS embeddings. To complement this, we also exhibit a metric measure space whose associated cMDS operator is not traceable. Finally, we establish the stability of the generalized cMDS method with respect to the Gromov–Wasserstein distance.
Paediatric antibiotic prescribing in a nationwide direct-to-consumer telemedicine platform in France, 2018–2021
Authors: Melot Bénédicte , Launay Elise , Drouet Florian , Salomon Julie , Toubiana Julie , Grosjean Julien , Duclos Catherine , Cohen Jérémie F
Published: May 2024

Background

Recent regulatory and reimbursement changes facilitated the development of teleconsultation within primary care. French guidance advises against antibiotic prescribing in children in teleconsultation. We assessed paediatric antibiotic prescribing on a French teleconsultation platform.

Methods

This cross-sectional observational study analysed paediatric (0–14 years) visits on a national direct-to-consumer teleconsultation platform between January 2018 and December 2021. Teleconsultations with complete information regarding diagnosis (ICD-10 coding) and prescriptions were included. We assessed antibiotic prescription rates per 100 visits across diagnoses and used logistic regression to identify factors associated with antibiotic prescribing.

Results

In the 37 587 included paediatric teleconsultations (median age 3 years) performed by 713 general practitioners (GPs) and 89 paediatricians, antibiotics were prescribed for 12.1%. Respiratory tract infections (RTIs) accounted for 49.5% of antibiotic prescriptions. Antibiotic prescription rates per 100 visits were: sinusitis, 69.5%; urinary tract infections, 62.2%; pharyngitis, 59.0%; pneumonia, 45.5%; otitis, 46.6%; bronchitis, 19.6%; rhinitis, 11.6%; bronchiolitis 6.6%. Antibiotic prescription rates were higher in GPs than paediatricians [OR 2.21 (IC95% 2.07–2.35)], among physicians aged 45–54 and over 65 [OR 1.66 (1.48–1.85) and 1.48 (1.32–1.66), respectively], in female practitioners [OR 1.13 (1.05–1.21)], in children 3–6 years old [OR 1.41 (1.28–1.56)] and over 6 [OR 1.50 (1.35–1.66)], during winter [OR 1.28 (1.21–1.37)] and for RTIs [OR 1.99 (1.87–2.10)]. Antibiotic prescription rates were lower in doctors with extensive experience in teleconsultation [OR 0.92 (0.86–0.98)].

Conclusions

Despite current recommendations, paediatric patients were frequently prescribed antibiotics during acute care teleconsultations. Specific antibiotic stewardship campaigns should target paediatric teleconsultations.
Small intestine metastasis from endometrial carcinoma initially presented as enterocutaneous fistula: a case report and literature review
Authors: Nikolovski Andrej , Limani Nimetula , Ristova Tancheva Aleksandra , Manasievska Bogoevska Antonela , Krsteska Blagica
Published: May 2024

Although endometrial cancer is the fourth most common malignancy among women, it rarely metastasizes to the small intestine. Cases of endometrial recurrence to the intestine clinically present with secondary anemia, melena, abdominal cramps, and epigastric pain. Only a dozen cases are reported in the literature, but none presented with an enterocutaneous fistula. In this report, we present a case of an 88-year-old female patient previously treated for endometrial adenocarcinoma with surgery and adjuvant radiotherapy. Fourteen months after the surgery, the patient presented with an enterocutaneous fistula on the anterior abdominal wall, which was confirmed to be a metastasis from the primary tumor. To our knowledge, this is the first case of endometrial cancer metastasizing to the small intestine with involvement of the anterior abdominal wall and the occurrence of an enterocutaneous fistula, which was treated with radical surgery.
Apophis: may a meteor activity happen on Earth after the 2029 closest approach?
Authors: Valvano G , Sfair R , Winter O C , Machado-Oliveira R , Borderes-Motta G
Published: May 2024

The potentially hazardous asteroid 99942 Apophis will have a very close approach to the Earth in 2029. The encounter on its own may provide measurements of Earth’s effects on Apophis’ surface and also contribute to the improvement of some physical characteristics of the asteroid. In a previous work, we assumed the existence of a hypothetical disc of particles around Apophis before the 2029 encounter, and identified the particles that would escape from the gravity domain of Apophis due to the Earth's gravitational perturbation during the close encounter. In the current work, we investigate the possibility of a meteor activity originating from this event. We study the orbital evolution of these particles computing the MOIDs of the particles with respect to the Earth for the following 200 yr. Our results are not favourable for a meteor activity on Earth. However, a meteoroid activity on the Moon might happen during the encircling period after 88 yr of the 2029 encounter.
Transcription factor shapes chromosomal conformation and regulates gene expression in bacterial adaptation
Authors: Chen Mao , Wu Bo , Huang Yuhuan , Wang Weiting , Zheng Yudi , Shabbir Samina , Liu Panting , Dai Yonghua , Xia Mengli , Hu Guoquan , He Mingxiong
Published: May 2024

Genomic mutations allow bacteria to adapt rapidly to adverse stress environments. The three-dimensional conformation of the genome may also play an important role in transcriptional regulation and environmental adaptation. Here, using chromosome conformation capture, we investigate the high-order architecture of the Zymomonas mobilis chromosome in response to genomic mutation and ambient stimuli (acetic acid and furfural, derived from lignocellulosic hydrolysate). We find that genomic mutation only influences the local chromosome contacts, whereas stress of acetic acid and furfural restrict the long-range contacts and significantly change the chromosome organization at domain scales. Further deciphering the domain feature unveils the important transcription factors, Ferric uptake regulator (Fur) proteins, which act as nucleoid-associated proteins to promote long-range (>200 kb) chromosomal communications and regulate the expression of genes involved in stress response. Our work suggests that ubiquitous transcription factors in prokaryotes mediate chromosome organization and regulate stress-resistance genes in bacterial adaptation.
Fluoropyrimidines trigger decay of hypomodified tRNA in yeast
Authors: Görlitz Katharina , Bessler Larissa , Helm Mark , Schaffrath Raffael , Klassen Roland
Published: May 2024

Therapeutic fluoropyrimidines 5-fluorouracil (5-FU) and 5-fluorocytosine (5-FC) are in long use for treatment of human cancers and severe invasive fungal infections, respectively. 5-Fluorouridine triphosphate represents a bioactive metabolite of both drugs and is incorporated into target cells’ RNA. Here we use the model fungus Saccharomyces cerevisiae to define fluorinated tRNA as a key mediator of 5-FU and 5-FC cytotoxicity when specific tRNA methylations are absent. tRNA methylation deficiency caused by loss of Trm4 and Trm8 was previously shown to trigger an RNA quality control mechanism resulting in partial destabilization of hypomodified tRNAValAAC. We demonstrate that, following incorporation into tRNA, fluoropyrimidines strongly enhance degradation of yeast tRNAValAAC lacking Trm4 and Trm8 dependent methylations. At elevated temperature, such effect occurs already in absence of Trm8 alone. Genetic approaches and quantification of tRNA modification levels reveal that enhanced fluoropyrimidine cytotoxicity results from additional, drug induced uridine modification loss and activation of tRNAValAAC decay involving the exonuclease Xrn1. These results suggest that inhibition of tRNA methylation may be exploited to boost therapeutic efficiency of 5-FU and 5-FC.
Prokaryotic Argonaute nuclease cooperates with co-encoded RNase to acquire guide RNAs and target invader DNA
Authors: Agapov Aleksei , Panteleev Vladimir , Kropocheva Ekaterina , Kanevskaya Anna , Esyunina Daria , Kulbachinskiy Andrey
Published: May 2024

Argonautes are an evolutionary conserved family of programmable nucleases that identify target nucleic acids using small guide oligonucleotides. In contrast to eukaryotic Argonautes (eAgos) that act on RNA, most studied prokaryotic Argonautes (pAgos) recognize DNA targets. Similarly to eAgos, pAgos can protect prokaryotic cells from invaders, but the biogenesis of guide oligonucleotides that confer them specificity to their targets remains poorly understood. Here, we have identified a new group of RNA-guided pAgo nucleases and demonstrated that a representative pAgo from this group, AmAgo from the mesophilic bacterium Alteromonas macleodii, binds guide RNAs of varying lengths for specific DNA targeting. Unlike most pAgos and eAgos, AmAgo is strictly specific to hydroxylated RNA guides containing a 5′-adenosine. AmAgo and related pAgos are co-encoded with a conserved RNA endonuclease from the HEPN superfamily (Ago-associated protein, Agap-HEPN). In vitro, Agap cleaves RNA between guanine and adenine nucleotides producing hydroxylated 5′-A guide oligonucleotides bound by AmAgo. In vivo, Agap cooperates with AmAgo in acquiring guide RNAs and counteracting bacteriophage infection. The AmAgo-Agap pair represents the first example of a pAgo system that autonomously produces RNA guides for DNA targeting and antiviral defense, which holds promise for programmable DNA targeting in biotechnology.
Hemizygous deletion of cyclin-dependent kinase inhibitor 2A/B with p16 immuno-negative and methylthioadenosine phosphorylase retention predicts poor prognosis in IDH-mutant adult glioma
Authors: Otsuji Ryosuke , Hata Nobuhiro , Yamamoto Hidetaka , Kuga Daisuke , Hatae Ryusuke , Sangatsuda Yuhei , Fujioka Yutaka , Noguchi Naoki , Sako Aki , Togao Osamu , Yoshitake Tadamasa , Nakamizo Akira , Mizoguchi Masahiro , Yoshimoto Koji
Published: May 2024

Background

Homozygous deletion of the tumor suppression genes cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) is a strong adverse prognostic factor in IDH-mutant gliomas, particularly astrocytoma. However, the impact of hemizygous deletion of CDKN2A/B is unknown. Furthermore, the influence of CDKN2A/B status in IDH-mutant and 1p/19q-codeleted oligodendroglioma remains controversial. We examined the impact of CDKN2A/B status classification, including hemizygous deletions, on the prognosis of IDH-mutant gliomas.

Methods

We enrolled 101 adults with IDH-mutant glioma between December 2002 and November 2021. CDKN2A/B deletion was evaluated with multiplex ligation-dependent probe amplification (MLPA). Immunohistochemical analysis of p16/MTAP and promoter methylation analysis with methylation-specific MLPA was performed for cases with CDKN2A/B deletion. Kaplan − Meier plots and Cox proportion hazards model analyses were performed to evaluate the impact on overall (OS) and progression-free survival.

Results

Of 101 cases, 12 and 4 were classified as hemizygous and homozygous deletion, respectively. Immunohistochemistry revealed p16-negative and MTAP retention in cases with hemizygous deletion, whereas homozygous deletions had p16-negative and MTAP loss. In astrocytoma, OS was shorter in the order of homozygous deletion, hemizygous deletion, and copy-neutral groups (median OS: 38.5, 59.5, and 93.1 months, respectively). Multivariate analysis revealed hazard ratios of 9.30 (P = .0191) and 2.44 (P = .0943) for homozygous and hemizygous deletions, respectively.

Conclusions

CDKN2A/B hemizygous deletions exerted a negative impact on OS in astrocytoma. Immunohistochemistry of p16/MTAP can be utilized to validate hemizygous or homozygous deletions in combination with conventional molecular diagnosis.
Irritable bowel syndrome and erectile dysfunction in medical students at a Peruvian university: an analytical cross-sectional analysis
Authors: Valladares-Garrido Mario J , Zapata-Castro Luis E , Quiroga-Castañeda Pedro P , Berrios-Villegas Iván , Vera-Ponce Víctor J , León-Figueroa Darwin A , Pereira-Victorio César J , Valladares-Garrido Danai
Published: May 2024

Background

There is inconclusive evidence regarding the role of irritable bowel syndrome (IBS) in the development of erectile dysfunction (ED), especially among medical students due to high academic stress.

Aim

To determine the association between IBS and ED in medical students from a Peruvian university in 2022.

Methods

An analytical cross-sectional study was conducted with secondary data analysis on 133 medical students from a university in northern Peru during the 2021-II academic semester. The dependent variable was ED as measured with the 5-item International Index of Erectile Function, and the exposure variable was IBS as assessed with the Rome IV–Bristol questionnaire.

Outcomes

The results were the prevalence rates of IBS and ED and the association of these variables.

Results

Of the 133 medical students surveyed, the median age was 22 years (IQR, 19-24). The median score on the 5-item International Index of Erectile Function was 21 (IQR, 10-24). The prevalence of ED was 38.4% (95% CI, 30.05%-47.17%). Among the medical students 3% and 9% displayed moderate and severe ED, respectively, and 24.8%, 13.5%, and 24.1% showed moderate depressive, anxious, and severe symptoms. An overall 10.5% had IBS. Medical students with IBS had a 108% higher prevalence of ED than those without the syndrome (prevalence ratio, 2.08; 95% CI, 1.06-4.06). Other confounding variables were not significantly associated (P > .05).

Clinical Implications

The results underline the importance of comprehensive sexual and mental health assessment, with an emphasis on the relationship between IBS and ED in medical students.

Strengths and Limitations

Strengths include the use of validated and reliable instruments and rigorous biostatistical methods, and this is the first Peruvian investigation to explain the association between IBS and ED in medical students. Limitations include the cross-sectional design and nonprobability sampling, and there may be bias in applying the instruments.

Conclusion

This study reveals a significant association between IBS and a higher prevalence of ED in these students.
Application of the Delphi method to the development of common data elements for social drivers of health: A systematic scoping review
Authors: Levites Strekalova Yulia A , Nelson July D , Weber Haley M , Wang Xiangren , Midence Sara M
Published: May 2024

Collaborative data science requires standardized, harmonized, interoperable, and ethically sourced data. Developing an agreed-upon set of elements requires capturing different perspectives on the importance and feasibility of the data elements through a consensus development approach. This study reports on the systematic scoping review of literature that examined the inclusion of diverse stakeholder groups and sources of social drivers of health variables in consensus-based common data element (CDE) sets. This systematic scoping review included sources from PubMed, Embase, CINAHL, WoS MEDLINE, and PsycINFO databases. Extracted data included the stakeholder groups engaged in the Delphi process, sources of CDE sets, and inclusion of social drivers data across 11 individual and 6 social domains. Of the 384 studies matching the search string, 22 were included in the final review. All studies involved experts with healthcare expertise directly relevant to the developed CDE set, and only six (27%) studies engaged health consumers. Literature reviews and expert input were the most frequent sources of CDE sets. Seven studies (32%) did not report the inclusion of any demographic variables in the CDE sets, and each demographic SDoH domain was included in at least one study with age and sex assigned at birth included in all studies, and social driver domains included only in four studies (18%). The Delphi technique engages diverse expert groups around the development of SDoH data elements. Future studies can benefit by involving health consumers as experts.
Biographies of uncertainty regulation in the labor market and extension of working life in Chile
Authors: Cabib Ignacio , Yopo Díaz Martina , Biehl Andrés , Cereceda Trinidad , Ormeño Juan Pablo , Ortiz Francisca
Published: May 2024

Despite lacking policies targeting the extension of working life, Chile is the Latin American country that has exhibited the largest increase in the labor force participation rate of people aged 65+ in the last two decades. In this research, following an analytical framework on regulation of endogenous uncertainty and relying on rich qualitative data (life story interviews of 90 older workers aged 60–86, across 21 cities and 6 regions), we approached the complexity of extended working lives in Chile by addressing an unexplored dimension. Specifically, we explore individuals’ agency over their employment trajectories (i.e., both in adulthood and old age) among those who remained active in the labor market after the legal retirement age. Our findings provide strong evidence that extended working lives not only result from precarious social conditions, but are also shaped by complex processes involving both expansive and adaptive individual agency in which people engaged throughout their life course. Therefore, the high exogenous uncertainty in the labor market should not merely be interpreted from the perspective of “precarity,” but also as a scenario that encouraged individuals to behave in a way that led them to engage in the labor force across their lives in accordance with their preferred level of endogenous uncertainty.
The immunometabolic function of VGLL3 and female-biased autoimmunity
Authors: Kennicott Kameron , Liang Yun
Published: May 2024

Autoimmune diseases exhibit a pronounced yet unexplained prevalence among women. Vestigial-like family member 3 (VGLL3), a female-biased factor that promotes autoimmunity, has recently been discovered to assist cells in sensing and adapting to nutritional stress. This role of VGLL3 may confer a selective advantage during the evolution of placental mammals. However, the excessive activation of the VGLL3-mediated energy-sensing pathway can trigger inflammatory cell death and the exposure of self-antigens, leading to the onset of autoimmunity. These observations have raised the intriguing perspective that nutrient sensing serves as a double-edged sword in immune regulation. Mechanistically, VGLL3 intersects with Hippo signaling and activates multiple downstream, immune-associated genes that play roles in metabolic regulation. Understanding the multifaceted roles of VGLL3 in nutrient sensing and immune modulation provides insight into the fundamental question of sexual dimorphism in immunometabolism and sheds light on potential therapeutic targets for autoimmune diseases.
False-Negative 68Ga-FAPI PET/CT in Pediatric Thyroid Medullary Carcinoma Seen With 68Ga-DOTATOC PET/CT and 18F-FDG PET/CT
Authors: Haidar Mohamad B. , Abou Zeid Farah A. , Meguerian Zarouhie Z. , Al-Ibraheem Akram N. , Noun Peter E.
Published: May 2024

In adults, 68Ga-FAP inhibitor (68Ga-FAPI) PET/CT outperforms 68Ga-radiolabeled somatostatin analog peptides (68Ga PET/CT) and 18F-FDG PET/CT in detecting thyroid lesions. This is the case of a 13-year-old boy newly diagnosed with medullary thyroid cancer with high calcitonin level. 68Ga PET/CT revealed the presence of only a primary thyroid lesion. Proven to be superior in detecting metastasis, 68Ga-FAPI PET/CT was performed. The results came out negative for primary and potential metastatic lesions. This case sheds shed light on false-negatives reported in 68Ga-FAPI PET/CT scans in pediatric patients, emphasizing the need for alternate radiotracers when a negative study is met.
Prognostic Risks for Tracheostomy in Pierre Robin Sequence
Authors: Chaisrisawadisuk Sarut , Lauvalert Aekachai , Vathanophas Vannipa , Kongchu Nachasa , Vongviriyangkoon Tara
Published: May 2024

Background

Pierre Robin sequence (PRS), characterized by micrognathia, glossoptosis, cleft palate, and obstructed airways, is one of the craniofacial conditions challenging various approaches to managing compromised airways, ranging from conservative measures to invasive airway surgery. This study was conducted to identify predictive risk factors for tracheostomy in the PRS.

Methods

A retrospective chart review was conducted at a tertiary referral hospital in Thailand. Children diagnosed with PRS from January 2010 to December 2021 were enrolled. Univariate and multivariate analysis methods were used to identify the risk factors.

Results

Sixty-five patients with PRS were identified in electronic medical records, but 6 were excluded. Thirteen of the remaining 59 patients underwent tracheostomy. There were no significant differences in sex, preterm gestational age, cleft palate, associated syndromes, chromosome abnormalities, or cardiac or neurological involvement between patients who received tracheostomy and those who did not. However, patients with oropharyngeal dysfunction who received tracheostomy tended to use a nasogastric tube or percutaneous gastrostomy 92.3% of the time (P = 0.043). In addition, patients with abnormal airways from endoscopy were more likely to undergo tracheostomy (odds ratio, 2.17; 95% confidence interval [CI], 1.20–3.90). Interestingly, patients with a sum of Apgar scores at 1 and 5 minutes <15 were more likely to undergo tracheostomy (adjusted odds ratio, 9.91; 95% CI, 1.32–74.52). Furthermore, patients with at least 3 identified comorbidities were more likely to undergo tracheostomy (adjusted odds ratio, 11.34; 95% CI, 1.16–111.15).

Conclusions

The need for tracheostomy depends on comorbidities, Apgar scores, and abnormal airway anatomy. Feeding methods can become more complex with tracheostomy. Prognostic risk factors can help guide treatment and counseling for health care workers and caregivers.
Defining the phylogenetics and resistome of the major Clostridioides difficile ribotypes circulating in Australia
Authors: O’Grady Keeley , Hong Stacey , Putsathit Papanin , George Narelle , Hemphill Christine , Huntington Peter G. , Korman Tony M. , Kotsanas Despina , Lahra Monica , McDougall Rodney , McGlinchey Andrew , Levy Avram , Moore Casey V. , Nimmo Graeme , Prendergast Louise , Robson Jennifer , Speers David J. , Waring Lynette , Wehrhahn Michael C. , Weldhagen Gerhard F. , Wilson Richard M. , Riley Thomas V. , Knight Daniel R.
Published: May 2024

Clostridioides difficile infection (CDI) remains a significant public health threat globally. New interventions to treat CDI rely on an understanding of the evolution and epidemiology of circulating strains. Here we provide longitudinal genomic data on strain diversity, transmission dynamics and antimicrobial resistance (AMR) of C. difficile ribotypes (RTs) 014/020 (n=169), 002 (n=77) and 056 (n=36), the three most prominent C. difficile strains causing CDI in Australia. Genome scrutiny showed that AMR was uncommon in these lineages, with resistance-conferring alleles present in only 15/169 RT014/020 strains (8.9 %), 1/36 RT056 strains (2.78 %) and none of 77 RT002 strains. Notably, ~90 % of strains were resistant to MLSB agents in vitro, but only ~5.9 % harboured known resistance alleles, highlighting an incongruence between AMR genotype and phenotype. Core genome analyses revealed all three RTs contained genetically heterogeneous strain populations with limited evidence of clonal transmission between CDI cases. The average number of pairwise core genome SNP (cgSNP) differences within each RT group ranged from 23.3 (RT056, ST34, n=36) to 115.6 (RT002, ST8, n=77) and 315.9 (RT014/020, STs 2, 13, 14, 49, n=169). Just 19 clonal groups (encompassing 40 isolates), defined as isolates differing by ≤2 cgSNPs, were identified across all three RTs (RT014/020, n=14; RT002, n=3; RT056, n=2). Of these clonal groups, 63 % (12/19) comprised isolates from the same Australian State and 37 % (7/19) comprised isolates from different States. The low number of plausible transmission events found for these major RTs (and previously documented populations in animal and environmental sources/reservoirs) points to widespread and persistent community sources of diverse C. difficile strains as opposed to ongoing nationwide healthcare outbreaks dominated by a single clone. Together, these data provide new insights into the evolution of major lineages causing CDI in Australia and highlight the urgent need for enhanced surveillance, and for public health interventions to move beyond the healthcare setting and into a One Health paradigm to effectively combat this complex pathogen.
The Effects of vibrotactile stimulation of the upper extremity on sensation and perception
Authors: Abdel Khaleq Abeer , More Yash , Skaufel Brody , Al Borno Mazen
Published: May 2024

Vibrotactile stimulation has applications in a variety of fields, including medicine, virtual reality, and human-computer interaction. Eccentric Rotating Mass (ERM) vibrating motors are widely used in wearable haptic devices for their small size, low cost, and low energy features. The effect of ERM motor vibrations on upper extremity sensation and perception have not been thoroughly studied previously, which is important to design better wearable haptic devices. We conducted experiments with vibrotactile stimulation on 15 healthy participants. Eight motors were placed on a consistent set of muscles on the upper extremity and one motor was placed on the index finger. We found a significant correlation between voltage and sensation intensity (r=0.39). However, we did not find a significant aggregate-level correlation on the perceived pleasantness of the simulation. The sensation intensity varied based on the location of the vibration on the upper extremity (with the lowest intensity on the triceps brachii and brachialis) and slightly decreased (5.9 ± 2.9 %) when participants performed reaching movements. When a single motor was vibrating, the participants’ accuracy at identifying the motor without visual feedback increased as voltage increased, reaching up to 81.4 ± 14.2 %. When we stimulated three muscles simultaneously, we found that most participants were able to identify only two out of three vibrating motors (41.7 ± 32.3 %). Our findings can help tune stimulation parameters in human- machine interaction applications.
A Decade in a Systematic Review: The Evolution and Impact of Cell Painting
Authors: Seal Srijit , Trapotsi Maria-Anna , Spjuth Ola , Singh Shantanu , Carreras-Puigvert Jordi , Greene Nigel , Bender Andreas , Carpenter Anne E.
Published: May 2024

High-content image-based assays have fueled significant discoveries in the life sciences in the past decade (2013-2023), including novel insights into disease etiology, mechanism of action, new therapeutics, and toxicology predictions. Here, we systematically review the substantial methodological advancements and applications of Cell Painting. Advancements include improvements in the Cell Painting protocol, assay adaptations for different types of perturbations and applications, and improved methodologies for feature extraction, quality control, and batch effect correction. Moreover, machine learning methods recently surpassed classical approaches in their ability to extract biologically useful information from Cell Painting images. Cell Painting data have been used alone or in combination with other - omics data to decipher the mechanism of action of a compound, its toxicity profile, and many other biological effects. Overall, key methodological advances have expanded Cell Painting’s ability to capture cellular responses to various perturbations. Future advances will likely lie in advancing computational and experimental techniques, developing new publicly available datasets, and integrating them with other high-content data types.
Bilirubin is a new ligand for nuclear receptor Liver Receptor Homolog-1
Authors: Chapagain Pratima , Haratipour Zeinab , Malabanan M. Merced , Choi Woong Jae , Blind Raymond D.
Published: May 2024

The nuclear receptor Liver Receptor Homolog-1 (LRH-1,NR5A2) binds to phospholipids that regulate important LRH-1 functions in the liver. A recent compound screen unexpectedly identified bilirubin, the product of liver heme metabolism, as a possible ligand for LRH-1. Here, we show unconjugated bilirubin directly binds LRH-1 with apparentKd=9.3uM, altering LRH-1 interaction with all transcriptional coregulator peptides tested. Bilirubin decreased LRH-1 protease sensitivity, consistent with MD simulations predicting bilirubin stably binds LRH-1 within the canonical ligand binding site. Bilirubin activated a luciferase reporter specific for LRH-1, dependent on co-expression with the bilirubin membrane transporterSLCO1B1, but bilirubin failed to activate ligand-binding genetic mutants of LRH-1. Gene profiling in HepG2 cells shows bilirubin selectively regulated transcripts from endogenous LRH-1 ChIP-seq target genes, which was significantly attenuated by either genetic knockdown of LRH-1, or by a specific chemical competitor of LRH-1. Gene set enrichment suggests bilirubin and LRH-1 share roles in cholesterol metabolism and lipid efflux, thus we propose a new role for LRH-1 in directly sensing intracellular levels of bilirubin.
Type-I interferons drive the gastrointestinal inflammatory response in a mouse model of Parkinson’s disease
Authors: Waters Harrison , Chen Shuyan , Vincan Elizabeth , Flanagan Dustin J. , Schwab Renate H.M. , Crack Peter J. , Taylor Juliet M.
Published: May 2024

Background and Aims

Parkinson’s disease (PD) is an age-related neurodegenerative disorder characterised by classical motor symptoms due to a loss of dopaminergic neurons in the substantia nigra pars compacta. The type-I interferons (IFNs) are elevated in the aging brain and we have implicated them in the neuroinflammatory response in PD. With increasing evidence of gastrointestinal (GI) dysfunction in PD patients, this study explored the contribution of the type-I IFNs to the transmission of pathology from the brain to the gut in PD.

Methods

Young (10-12 weeks) and aged (40-50 weeks) wildtype and IFNAR1−/−mice received an intrastriatal injection of human alpha-synuclein (α-Syn) pre-formed fibrils (PFF) (8ug) with gut tissue analysed 6-months post-injection (p.i). A mouse intestinal organoid culture model was established to further characterise the α-Syn induced inflammatory response in the gut.

Results

An intrastriatal injection of human α-Syn PFFs was shown to initiate a type-I IFN-dependent neuroinflammatory response in the GI tract of wildtype mice at 6-months p.i. This response was attributed to an elevation in type-I IFN signalling in aged mice that was absent in the IFNAR1−/−mice. Mouse intestinal organoid cultures confirmed α-Syn was taken up by the enteroendocrine cells (EECs) to induce a type-I IFN mediated pro-inflammatory response that was attenuated in IFNAR1−/−cultures.

Conclusion

This study has confirmed the type-I IFNs modulate the α-Syn PFF induced inflammatory response within the gut potentiating pathology progression along the gut-brain axis. Early intervention of this type-I IFN response may be a potential therapeutic target to limit the progression of PD.
Chromatin protein complexes involved in gene repression in lamina-associated domains
Authors: Manzo Stefano G , Mazouzi Abdelghani , Leemans Christ , van Schaik Tom , Neyazi Nadia , van Ruiten Marjon S , Rowland Benjamin D , Brummelkamp Thijn , van Steensel Bas
Published: May 2024

Lamina-associated domains (LADs) are large chromatin regions that are associated with the nuclear lamina (NL) and form a repressive environment for transcription. The molecular players that mediate gene repression in LADs are currently unknown. Here we performed FACS-based whole-genome genetic screens in human cells using LAD-integrated fluorescent reporters to identify such regulators. Surprisingly, the screen identified very few NL proteins, but revealed roles for dozens of known chromatin regulators. Among these are the negative elongation factor (NELF) complex and interacting factors involved in RNA polymerase pausing, suggesting that regulation of transcription elongation is a mechanism to repress transcription in LADs. Furthermore, the chromatin remodeler complex BAF and the activation complex Mediator can work both as activators and repressors in LADs, depending on the local context and possibly rewiring of heterochromatin. Our data clearly emphasize that the fundamental regulatory steps of the transcription process and chromatin remodeling factors, rather than interaction with NL proteins, play a major role in the regulation of transcription within LADs.

HIGHLIGHTS

Haploid genetic screens identify proteins that control gene activity in LADs

Chromatin proteins rather than NL proteins control repression in LADs

Regulators of elongation contribute to repression of transcription in LADs

BAF and Mediator can both repress and activate transcription in LADs
Association of mid-age Life’s Essential 8 score with digital cognitive performance and incident Alzheimer’s disease: the Framingham Heart Study
Authors: Yang Jian , Ding Huitong , Li Yi , Ang Ting Fang Alvin , Devine Sherral , Liu Yulin , Qiu Wendy , Au Rhoda , Ma Jiantao , Liu Chunyu
Published: May 2024

Background

Emerging studies indicate that cardiovascular health (CVH) is a modifiable risk factor for AD. However, studies on how mid-life Life’s Essential 8 (LE8) scores affect the AD risk and digital cognitive performance are limited.

Objective

To examine the associations between CVH in middle age, as defined by LE8 scores, and subsequent digital cognitive performance and incident AD.

Methods

Linear regression and Cox proportional-hazard models were used to examine the associations of mid-age CVH with dCDT performance and incident AD, respectively. Prediction performance of mid-age LE8 scores for incident AD were assessed using ROC curve analysis.

Results

Every one-SD increase in mid-age LE8 total score was associated with a 0.16-SD increase in dCDT total score (p < 0.001). Ideal CVH in middle age was associated with higher dCDT scores compared to intermediate CVH. Furthermore, higher mid-age LE8 scores were associated to a decreased risk of AD, with ideal CVH significantly lowering AD risk compared to intermediate CVH. The combination of dCDT performance, mid-age LE8 scores, APOE ε4 status, and other covariates provided the best prediction performance for incident AD, with an AUC of 0.84. Notably, mid-life LE8 scores improved its predictive accuracy by 5.7%.

Conclusion

Our findings emphasize the critical role of CVH in middle age as a predictor of both digital cognitive performance and the risk of developing AD, highlighting the importance of early intervention on CVH to delay the progression of cognitive decline.
Mitral Annular Disjunction in Heritable Thoracic Aortic Disease: Insights From the Montalcino Aortic Consortium
Authors: Asokan Kishan L. , Landes Jennifer R. , Renders Wannes , Muiño Mosquera Laura , De Backer Julie , Jantzen David W , Yetman Anji T. , Teixido-Tura Gisela , Evangelista Arturo , Jeremy Richmond , Jones Edward G. , Morris Shaine , Doan Tam , Ouzonian Maral , Braverman Alan , Jondeau Guillaume , Milleron Olivier , Prakash Siddharth K. , Milewicz Dianna M.
Published: May 2024

Background

Mitral annular disjunction (MAD), posterior displacement of the mitral valve leaflet hinge point, predisposes to arrhythmias or sudden cardiac death. We evaluated the burden of MAD, mitral valve prolapse (MVP), and mitral regurgitation (MR) by heritable thoracic aortic disease (HTAD) gene in a cross-sectional analysis of 2014-2023 data in the Montalcino Aortic Consortium (MAC) registry.

Methods

MAD was determined by direct measurement of echocardiographic images. MR and MVP were defined according to current clinical guidelines. Associations were evaluated using chi-squared or Fisher exact tests.

Results

MR and MVP were enriched in MAC participants (672) with pathogenic variants (PV) in TGF-β pathway genes. The combination of MR and MVP was associated with mitral surgery and arrhythmias. In the subgroup with available images, MAD was enriched inSMAD3PV compared to other TGF-β PV (PR 1.8 [1.1-2.8],P< 0.02). Severe disjunction (>10 mm) was only observed in the TGF-β subgroup and was further enriched in participants withSMAD3PV (PR 3.1 [1.1-8.6]). MVP (PR 5.2 [3.0-9.0]) and MR (PR 2.7 [1.8-3.9) were increased in participants with MAD, but MAD was not independently associated with adverse cardiac or aortic events.

Conclusions

Mitral phenotypes are more prevalent in individuals with PV in TGF-β pathway genes, particularlySMAD3, and are associated with adverse aortic and cardiac events. Because congenital mitral disease may be the primary presenting feature of SMAD3 PV, genetic testing for HTAD should be considered for such individuals, especially if they also have a family history of HTAD.

Clinical/Research Perspective

What Is New?

1)

Mitral regurgitation, mitral valve prolapse, and mitral annular disjunction (MAD) are common in heritable thoracic aortic disease (HTAD) caused by pathogenic variants (PV) in TGF-β pathway genes (SMAD3,TGFBR1,TGFBR2,TGFB2, orTGFB3) and are associated with adverse cardiac events.

2)

Pathological mitral phenotypes are particularly prominent in people withSMAD3PV and may be the presenting feature of HTAD in some cases.

What Are the Clinical Implications?

3)

Pathological mitral valve phenotypes may identify a high-risk subgroup of HTAD cases with more frequent adverse cardiovascular events. Because congenital mitral disease may be the primary presenting feature ofSMAD3PV, genetic testing for HTAD should be considered for such individuals, especially if they also have a family history of HTAD.