bluuebunny/crossref_metadata_2025 huggingface dataset:
Hypoglycemic Events May Trigger Acute Ischemic Stroke Within 30 Days in Those With Diabetes: A Case-Crossover Study
Authors: Makam Supriya , Stein Laura K. , Dhamoon Mandip S.
Published: November 2024

BACKGROUND:

Stroke triggers are factors that may precipitate a stroke within a given time interval and can predict the timing of a stroke. While hypoglycemia has been established as a risk factor for cardiovascular events such as acute ischemic stroke (AIS), there is limited research demonstrating hypoglycemic events as stroke triggers. We hypothesize an association between hypoglycemic events and the occurrence of stroke among patients with diabetes.

METHODS:

We used Medicare inpatient, outpatient, emergency department, and subacute nursing facility data sets from January 1, 2016, to December 31, 2019, and validated using
International Classification of Diseases
,
Tenth Revision
, Clinical Modification codes to identify conditions. We used a case-crossover study design, testing whether exposure to a hypoglycemia encounter within progressively longer case periods (up to 30 days before index AIS) was associated with the subsequent occurrence of AIS, compared with control periods of equal length exactly 1 year before the case period. We used conditional logistical regression models to estimate odds ratios and 95% CIs.

RESULTS:

There were 237 667 index admissions with AIS and diabetes during the study period. There were increased odds of AIS following an encounter with hypoglycemia. The risk was the highest immediately on the first day following the hypoglycemia encounter (odds ratio, 3.694 [95% CI, 2.694–5.065];
P
<0.0001) and gradually became lower as the case-control period lengthened. At a 30-day case-control interval, the risk was lowest but still significant (odds ratio, 2.345 [95% CI, 2.179–2.523];
P
<0.0001).

CONCLUSIONS:

We found that hypoglycemic events in patients with diabetes are associated with a more than 3-fold greater risk of AIS in the first day but can trigger AIS in the 30 days following the event. More research is needed to assess the link between the severity of hypoglycemia and stroke occurrence, as well as the severity of the stroke. These results, if confirmed in other studies, emphasize the importance of avoiding hypoglycemic events in patients with diabetes.
Complexity, Artificial Life, and Artificial Intelligence
Authors: Gershenson Carlos
Published: November 2024

The scientific fields of complexity, Artificial Life (ALife), and artificial intelligence (AI) share commonalities: historic, conceptual, methodological, and philosophical. Although their origins trace back to the 1940s birth of cybernetics, they were able to develop properly only as modern information technology became available. In this perspective, I offer a personal (and thus biased) account of the expectations and limitations of these fields, some of which have their roots in the limits of formal systems. I use interactions, self-organization, emergence, and balance to compare different aspects of complexity, ALife, and AI. Even when the trajectory of the article is influenced by my personal experience, the general questions posed (which outweigh the answers) will, I hope, be useful in aligning efforts in these fields toward overcoming—or accepting—their limits.
The Protocols of the Elders of Zion in the Jewish Press
Authors: Katz Maya Balakirsky
Published: November 2024

This article explores the overlooked response from the Jewish press to the first 1903 edition of what became known as the Protocols of the Elders of Zion during the period when a second edition became public in 1905. The study recovers and analyzes a public apology that its second publisher wrote to the Jewish people, caricatures, and carnivalesque ditties. The results indicate that the first edition is not what we think it is – a rabid antisemitic text – but rather a revolutionary anti-liberalism text that the state and the secret police tried to ban, retract, and override with new editions.
The Use of the Moods in the Root *wekw- in Homer
Authors: De Decker Filip
Published: November 2024

In this article, I investigate the use of the subjunctive and optative moods of the root *wekw- (ἔειπον) in Homer. First, I explain the choice of this root; give a brief overview of the scholarship on the moods in Homeric Greek, focusing on two theories, the one arguing that both moods belong to an irrealis-continuum, and the other that they were in origin future forms (some explanations combine both theories); and describe the problems in determining the moods. Then I proceed to the actual analysis and divide the corpus into broad categories, as I cannot discuss all the instances. Special attention is devoted to the optatives (as they are much less common than the subjunctive), to the instances where optative and subjunctive have both been transmitted, and to the instances of the verba timendi (verbs of fearing). I start with the subjunctive, proceed to the optative afterwards, and discuss the passages with -ωμι and -οιμι and the ones where both forms are transmitted. Thereafter, I turn to Iliad 6.479 and compare it to Iliad 6.459. I devote an entire section to the verba timendi with past reference, as this is an element in which Homeric syntax differs from later (Attic) Greek. Finally, in three passages, I contrast the use of the moods of the root *wekw- with those of the other verbs in the same passage. A separate analysis of the use and absence of the modal particle (MP) is beyond the scope of this paper.
Imparting Textuality
Authors: Minchin Elizabeth
Published: November 2024

Forward planning and rehearsal were essential to a successful oral performance of the Homeric kind. Drawing on the work of linguistic anthropologist Karin Barber, on research in cognitive psychology, and ethnographical studies, I propose that we may find in the epics good evidence for poetic preparation. I present a number of passages from the Homeric epics that, I argue, were the product of composition and rehearsal in tandem; to use Barber’s phrase, they “pre-existed the moment of utterance.”
In a Different Voice: Pandita Ramabai’s Gendered Critique as Intellectual Biography
Authors: Malhotra Meenakshi
Published: November 2024

This paper explores the life and work of Pandita Ramabai (1858–1922), a reformer who strongly resisted Brahmanical epistemology and patriarchal ideologies in late nineteenth–early twentieth-century India, using the theoretical perspective of intellectual biography and focusing on the ideational aspects of Ramabai’s life and work in late nineteenth-century colonial India. The paper utilises her auto/biographical accounts and social critiques and analyses them in the context of burgeoning contemporary nineteenth-century discourses on the condition of women and their emancipation, with particular reference to high-caste Hindu women. I argue that Ramabai’s narrativizing of her life approximates to “autobiography as manifesto” (Smith). Her scathing social critique of Brahmanical patriarchies articulated in The High-Caste Hindu Woman (1887) and her slim autobiography My Testimony (1907) present a rational justification for her conversion and for her work to rehabilitate widows, both of which elicited criticism and censure.
Sexual dimorphism in prokinetic effects of a ghrelin agonist acting through the lumbosacral defecation center in rats
Authors: Tsukamoto Shumpei , Sawamura Tomoya , Yuki Natsufu , Horii Kazuhiro , Horii Yuuki , Homma Takeshi , Saito Shouichiro , Shiina Takahiko , Shimizu Yasutake
Published: November 2024

We investigated the effects of a centrally penetrant ghrelin agonist, RQ-00538053, on colorectal motility in female rats in comparison with that in male rats. Intravenous administration of RQ-00538053 enhanced colorectal motility in female rats. However, approximately tenfold higher doses were required to induce responses in female rats similar to those in male rats. Higher doses were required even when the agonist was intrathecally administered to the lumbosacral spinal cord in female rats. The results of RT-qPCR showed that the level of ghrelin receptor expression in the lumbosacral spinal cord was lower in female rats than in male rats, suggesting that the lower expression level of the receptor may contribute, at least in part, to the sex differences in the action of RQ-00538053. The sexually dimorphic action of a ghrelin agonist will be important for future works aiming to utilize ghrelin agonists as novel drugs to improve constipation.
A comparison of patients receiving vertebral body tethering for adolescent idiopathic scoliosis in the public and private hospital setting
Authors: Ng Samuel , Changmeng Zhang , Cheung Jason , Shea Graham Ka Hon
Published: November 2024

Purpose

Vertebral body tethering (VBT) is a new growth-modulating surgery for adolescent idiopathic scoliosis (AIS) requiring a distinct skillset and intraoperative setup. We compared perioperative details and outcomes of VBTs performed in a public pediatric orthopedic hospital and a general private hospital setting.

Methods

We identified all patients receiving VBT for AIS from 1/2020 to 12/2023 with ≥ 6 months post-operative follow-up, with surgeries performed by the same senior surgeons. Clinical, radiological, and surgical details were retrieved.

Results

24 VBTs were performed in the private setting and 16 in the public setting. Average age at operation was 11.9 ± 1.1 at a Sanders staging of 3.8 ± 1.2 when the major curve Cobb angle was 50.5 ± 8.0°. Tethered curves were most often thoracic in location (23/40) followed by thoracolumbar/lumbar curves (10/40) and double curve tethers (7/40). Overall correction ratio of 68.0 ± 19.0% was achieved. Time from booking to operation (82.2 ± 39.2 vs 63.1 ± 34.4 days, p = 0.112) and operation time (310 ± 86.4 min vs. 289 ± 87.4 min, p = 0.054) were longer in the public and private setting respectively but failed to reach statistical significance. Time to chest drain removal (1.5 ± 0.8 vs. 3.5 ± 1.7 days, p < 0.001) and length of stay (4.3 ± 0.9 vs. 6.6 ± 1.8 days, p < 0.001) were significantly shorter in the private setting, whilst complication rates remained similar (7/24 vs. 3/16, p = 0.456).

Conclusion

Expertise, resource availability, and costs differ in the public and private healthcare setting. With regards to VBT, the conditions for referral and surgical outcomes remained similar. Earlier drain removal and discharge for patients managed in the private setting was not associated with an increase in complication rate.
Pedunculoside alleviates cognitive deficits and neuronal cell apoptosis by activating the AMPK signaling cascade
Authors: Li Liwei , Sun Jinfeng , Chen Fan , Xiong Li , She Lingyu , Hao Tang , Zeng Yuqing , Li Luyao , Wang Wei , Zhao Xia , Liang Guang
Published: November 2024

Background

Mitochondrial dysfunction emerges as an early pathological hallmark of Alzheimer's disease (AD). The reduction in mitochondrial membrane potential and the elevation of reactive oxygen species (ROS) production are pivotal in the initiation of neuronal cell apoptosis. Pedunculoside(Ped), a novel triterpene saponin derived from the dried barks of Ilex rotunda Thunb, exhibits a potent anti-inflammatory effect. In the course of drug screening, we discovered that Ped offers significant protection against apoptosis induced by Aβ1-42. Nevertheless, the role and mechanism of Ped in AD are yet to be elucidated.

Methods

Oxidative stress was evaluated by measuring mitochondrial membrane potential and intracellular ROS production. The expression of proteins associated with apoptosis was determined using western blot analysis and flow cytometry. In vivo, the pathological characteristics of AD were investigated through Western blot and tissue immunofluorescence techniques. Cognitive function was assessed using the Morris Water Maze and Novel Object Recognition tests.

Results

We demonstrated that Ped decreased apoptosis in PC12 cells, reduced the generation of intracellular ROS, and restored mitochondrial membrane potential. Mechanistically, we found that the protective effect of Ped against Aβ-induced neurotoxicity was associated with activation of the AMPK/GSK-3β/Nrf2 signaling pathway. In vivo, Ped alleviated memory deficits and inhibited neuronal apoptosis, inflammation, and oxidative stress in the hippocampus of 3 × Tg AD mice, along with the activation of the AMPK signaling pathway.

Conclusion

The findings indicate that Ped exerts its neuroprotective effects against oxidative stress and apoptosis through the AMPK signaling cascade. The results demonstrate that Ped is a potential candidate for the treatment of AD.

Graphical Abstract
Engineering Saccharomyces cerevisiae for the production of natural osmolyte glucosyl glycerol from sucrose and glycerol through Ccw12-based surface display of sucrose phosphorylase
Authors: Martinić Cezar Tea , Marđetko Nenad , Trontel Antonija , Paić Antonia , Slavica Anita , Teparić Renata , Žunar Bojan
Published: November 2024

Background

Yeast Saccharomyces cerevisiae is widely recognised as a versatile chassis for constructing microbial cell factories. However, producing chemicals from toxic, highly concentrated, or cell-impermeable substrates, or chemicals dependent on enzymatic reactions incompatible with the yeast’s intracellular environment, remains challenging. One such chemical is 2-O-(α-D-glucopyranosyl)-sn-glycerol (glucosyl glycerol, αGG), a natural osmolyte used in the cosmetics and healthcare industries. This compound can be synthesised in a one-enzyme reaction from sucrose and glycerol by Leuconostoc mesenteroides sucrose phosphorylase (SucP), an enzyme which, in a low-water, glycerol-rich, phosphate-free environment, transfers the glucosyl moiety from sucrose to glycerol.

Results

In this study, we engineered a yeast microbial cell factory for αGG production. For this purpose, we first focused on the abundant yeast GPI-anchored cell wall protein Ccw12 and used our insights to develop a miniature Ccw12-tag, which adds only 1.1 kDa to the enzyme of interest while enabling its covalent attachment to the cell wall. Next, we Ccw12-tagged SucP and expressed it in an invertase-negative strain of yeast S. cerevisiae from the PHO5 promoter, i.e., promoter strongly induced under phosphate-free conditions. Such SucP isoform, covalently C-terminally anchored to the outer cell surface, produced extracellularly 37.3 g l− 1 (146 mM) of αGG in five days, while the underlying chassis metabolised reaction by-products, thereby simplifying downstream processing.

Conclusions

The here-described S. cerevisiae strain, displaying C-terminally anchored sucrose phosphorylase on its cell surface, is the first eukaryotic microbial cell factory capable of a one-step αGG production from the readily available substrates sucrose and glycerol.
Mapping in silico genetic networks of the KMT2D tumour suppressor gene to uncover novel functional associations and cancer cell vulnerabilities
Authors: Takemon Yuka , Pleasance Erin D. , Gagliardi Alessia , Hughes Christopher S. , Csizmok Veronika , Wee Kathleen , Trinh Diane L. , Huff Ryan D. , Mungall Andrew J. , Moore Richard A. , Chuah Eric , Mungall Karen L. , Lewis Eleanor , Nelson Jessica , Lim Howard J. , Renouf Daniel J. , Jones Steven JM. , Laskin Janessa , Marra Marco A.
Published: November 2024

Background

Loss-of-function (LOF) alterations in tumour suppressor genes cannot be directly targeted. Approaches characterising gene function and vulnerabilities conferred by such mutations are required.

Methods

Here, we computationally map genetic networks of KMT2D, a tumour suppressor gene frequently mutated in several cancer types. Using KMT2D loss-of-function (KMT2DLOF) mutations as a model, we illustrate the utility of in silico genetic networks in uncovering novel functional associations and vulnerabilities in cancer cells with LOF alterations affecting tumour suppressor genes.

Results

We revealed genetic interactors with functions in histone modification, metabolism, and immune response and synthetic lethal (SL) candidates, including some encoding existing therapeutic targets. Notably, we predicted WRN as a novel SL interactor and, using recently available WRN inhibitor (HRO761 and VVD-133214) treatment response data, we observed that KMT2D mutational status significantly distinguishes treatment-sensitive MSI cell lines from treatment-insensitive MSI cell lines.

Conclusions

Our study thus illustrates how tumour suppressor gene LOF alterations can be exploited to reveal potentially targetable cancer cell vulnerabilities.
Food, nutrition and sustainability education in Australian primary schools: a cross-sectional analysis of teacher perspectives and practices
Authors: Kempler Jessica V , Margerison Claire , Nanayakkara Janandani , Booth Alison
Published: November 2024

Background

Healthy eating patterns from sustainable food systems are crucial for population and planetary health. Primary schools are opportune settings for teaching children about food, nutrition and sustainability (FNS) though little is known about the delivery of FNS education in this sector. This study aimed to analyse current approaches to FNS education in Australian primary schools.

Methods

A cross-sectional online survey with closed- and open-ended questions collected data about (i) teacher perceptions and attributes regarding FNS education; (ii) FNS teaching practices; and (iii) factors influencing FNS education. Statistical analyses were conducted using STATA including descriptive statistics and chi-square analyses to test for associations between categorical variables. Qualitative content and thematic analyses of open-ended questions were conducted using NVivo 14.

Results

Participants were 413 Australian primary school teachers. Teachers considered FNS education as equally important to most curriculum subjects, though frequency of FNS education was low. Less than a third of teachers were trained in FNS education, had access to funding for FNS-related activities or were from schools with policies about including FNS education in the curriculum. There was a significant association between frequency of FNS education and teacher training, access to funding and presence of FNS curriculum policies (all p < 0.001). Teachers who were trained to teach nutrition, food skills or food sustainability (all p < 0.05) were more likely to teach this as both stand-alone and cross-curricular subjects. Teachers described personal factors (workload, stress, scope of practice) that influenced their FNS teaching practices, as well as factors related to students’ families (family responsibility for FNS education, family food practices, family engagement in FNS activities), the curriculum (overcrowding, prioritisation, access to resources) and the broader school environment (time, facilities, funding, training).

Conclusions

Strengthening the position of FNS education in the primary school sector is an important next step for public health research, policy and practice. Researchers and policy makers should explore future opportunities for training, funding and policy approaches that prioritise FNS within the primary school curriculum and in everyday teaching practice.
Dietary inclusion of fibrous corn silages reduces gastric mucosa damage in fattening heavy pigs
Authors: Spanghero M. , Braidot M. , Orioles M. , Sarnataro C. , Pividori I. , Romanzin A.
Published: November 2024

Background

Several surveys conducted at slaughter sites have highlighted that gastric lesions are a widespread issue in fattening pigs, mainly due to feeding regimes. Diets with small particle sizes and low fibre contents guarantee high digestibility and performance but generate more rapid stomach emptying with a negative effect on gastric mucosa integrity. Providing fattening pigs with fibrous materials (e.g., straw provided in racks) or coarse fibrous ingredients (e.g., coarse silages) reduced the presence of gastric ulcers. The present research compares a traditional corn-soy-based diet with an experimental diet where bran and a portion of corn meal was substituted with whole ear and whole plant corn silages at the maximum dosages permitted by new Protected Designation of Origin for Italian dry-cured ham (20 and 10% of DM, respectively). This study aimed to examine the impact of the inclusion of corn silages in the diet on the productive performance of heavy Italian pigs and their ability to mitigate gastric mucosa damage.

Results

The growth performances were satisfactory (750–800 g/d) given the advanced interval of growth of animals (from 120 to 180 kg). However, the inclusion of corn silages tended to reduce the growth rate by 5–6% due to the reduction of organic matter digestibility, without compromising the slaughter traits or the back-fat fatty acid profile. The experimental diet substantially affected both stomach development and mucosal integrity. The first consequence was an increase in stomach weight of approximately 6% (P < 0.01) but the most notable advantage of coarse feeding was a reduction in stomach damage severity, with a low number of cases with higher scores in animals fed coarse materials (P < 0.01).

Conclusions

The dietary inclusion of corn silages (30% of diet DM) decrease effectivelly the severity of stomach damage in finishing heavy pigs. Based on the feeding trial performances, the perspective of feeding heavy pigs corn silage should consider specific agronomic and harvesting techniques to improve digestibility and not reduce the growth rate.
Clinical and pathological characteristics in 214 Danish weaners euthanized because of umbilical outpouchings
Authors: Hansen Marie-Louise , Larsen Inge , Jensen Tina Birk , Kristensen Charlotte Sonne , Pedersen Ken Steen
Published: November 2024

Background

Umbilical outpouchings (UO) are common in Danish weaners. In slaughter pigs UOs consist of various pathological diagnoses; however, no studies have assessed the pathology in weaners from randomly selected herds, nor the agreement between clinical examination findings and post-mortem results. The primary objective was to estimate the prevalence of UO-related clinical findings in weaners before euthanasia and the pathologic macroscopic findings after euthanasia. A secondary objective was to assess the agreement between the size of the UO, the presence of ulcers, and the diagnosis before and after euthanasia. Pigs were selected for euthanasia and included in the study because the individual farmer believed the pigs were already unfit for transport, would not make it to slaughter, or would become unsellable.

Results

In total 214 weaners euthanized due to UOs were examined both clinically and post-mortem. Clinically 65.4% of the UOs were large (≥ 11 cm) and 52.3% were unreducible. In the autopsy 78.5% of the UOs were large, and 54.2% had ulcers on their UO. The most prevalent pathological diagnoses were hernia (36.4%), hernia combined with cysts/abscesses (30.8%), cysts (11.7%), and abscesses (11.2%). Adhesions were found in 32.7%, haemorrhage in 22.7%, incarcerated intestines in 8.9%, and connective tissue related to the UO in 51.9% of the pigs post-mortem. The agreement between the size of the UO in the clinical examination and post-mortem was good, as was the sensitivity and specificity for detecting ulcers in the clinical examination compared to post-mortem.

Conclusion

Hernias were the most common pathological diagnosis in weaners euthanized due to UOs, and many pigs had complications related to their UO such as ulcers, adhesions, haemorrhage, or incarcerated intestines—all conditions that could impact the pig’s welfare. The presence of connective tissue in the UO in more than half of the pigs indicated that many of the UOs had been present for an extended period. Clinical identification of the umbilical ring is difficult, but the clinical examination is useful for determining the size of the UO and the presence or absence of an ulcer, both critical factors when assessing a pig’s welfare and fitness for transport. Clinical examination, however, has limited value in determining the aetiology of UOs.
Contemporary diagnosis and treatment of valvular heart disease in Korea: a nationwide hospital-based registry study
Authors: Kim Hyung Yoon , Lee Hee Jeong , Kim In-Cheol , Son Jung-Woo , Park Jun-Bean , Lee Sahmin , Kim Eun Kyoung , Park Seong-Mi , Chung Woo-Baek , Cho Jung Sun , Park Jin-Sun , Seo Jeong-Sook , Lee Sun Hwa , Sun Byung Joo , Shim Chi Young , Kim Hyungseop , Kim Kye Hun , Kang Duk-Hyun , Ha Jong-Won ,   on behalf of the Korean Valve Survey Registry Investigators, Chung Wook-Jin , Park Chan Seok , Ahn Hyo-Suk , Cho Eun Joo , Ryu Dong Ryeol , Yang Dong Heon , Park Jeong Rang , Kim Woo-Shik , Sohn Il Suk , Na Jin Oh , Ho Hwang Sun , Ji-Yong Choi , Park Tae-Ho , Park Yong Hyun , Choi Jung Hyun , Kim Hack-Lyoung , Seo Hye Sun , Choi Eui-Young , Son Jang-Won , Kim Shin-Jae , Rhee Sang Jae , Cho In-Jeong , Byun Young Sup , Shin Sung-Hee , Yoon Se-Jung , Beom Jong Wook , Lee Ju-Hee , Bae Dae-Hwan , Kim Sung-Ai , Park Dae Gyun , Kang Min-Kyung , Hong Kyung-Soon , Heo Ran
Published: November 2024

Background

This study was designed to determine the current status of diagnosis and treatment of valvular heart disease (VHD) in Korea.

Methods

A nationwide registry study was conducted in 45 hospitals in Korea involving adult patients with at least moderate VHD as determined by echocardiography carried out between September and October of 2019. Of a total of 4,094 patients with at least moderate VHD, 1,482 had severe VHD (age, 71.3 ± 13.5 years; 49.1% male). Echocardiographic data used for the diagnosis of each case of VHD were analyzed. Experts from each center determined the diagnosis and treatment strategy for VHD based on current guidelines and institutional policy. The clinical outcome was in-hospital mortality.

Results

Each valve underwent surgical or transcatheter intervention in 19.3% cases of severe mitral stenosis, 31.4% cases of severe primary mitral regurgitation (MR), 7.5% cases of severe secondary MR, 43.7% cases of severe aortic stenosis, 27.5% cases of severe aortic regurgitation, and 7.2% cases of severe tricuspid regurgitation. The overall in-hospital mortality rate for patients with severe VHD was 5.4%, and for secondary severe MR and severe tricuspid regurgitation, the rates were 9.0% and 7.5%, respectively, indicating a poor prognosis. In-hospital mortality occurred in 73 of the 1,244 patients (5.9%) who received conservative treatment and in 18 of the 455 patients (4.0%) who received a surgical or transcatheter intervention, which was significantly lower in the intervention group (P = 0.037).

Conclusions

This study provides important information about the current status of VHD diagnosis and treatment through a nationwide registry in Korea and helps to define future changes.
Genomic Alterations in DNA Mismatch Repair Genes Across Different Cancer Types
Authors: Holla Vijaykumar R. , Kahle Michael P. , Kim Sun-Hee , Ronaghy Arash , Yang Richard K. , Patel Keyur P. , Routbort Mark J. , Overman Michael J. , Dumbrava Ecaterina E. , Mills Shaw Kenna R. , Karp Daniel D. , Meric-Bernstam Funda
Published: November 2024

PURPOSE

PD-1 inhibition is effective in patients with mismatch repair deficient (dMMR) solid tumors in a tumor-agnostic fashion. However, dMMR testing by immunohistochemistry (IHC) is not routinely performed across tumor types. By contrast, next-generation sequencing (NGS) for somatic genomic alterations is frequently performed across tumor types. We hypothesized that NGS would identify patients with alterations in mismatch repair (MMR) genes and that these patients would have higher rates of MMR protein loss by IHC. This would support the utility of IHC reflex testing after NGS and potential matching to approved therapeutic options.

METHODS

From January 2016 to December 2021, 15,701 patients with solid tumors received NGS covering the MMR genes, and 4,994 patients had both IHC and NGS. Sequencing results were analyzed for mutations in MMR genes, tumor type distribution, and concordance with IHC results when available.

RESULTS

Six hundred and ninety-eight (4.4%) of 15,701 patients had mutations in one of the MMR genes. Mutations were found across tumor types. Three hundred and seventeen (6.3%) of 4,994 patients displayed IHC loss for at least one MMR protein. 33.8% patients (110/325) patients with MMR mutations had dMMR, compared with just 4.4% (207/4,669) patients without mutations (
P
< .001); dMMR rate varied by mutation type.

CONCLUSION

Mutations in MMR genes are found in multiple tumor types where IHC testing is not routine. Reflex IHC testing of patients carrying MMR gene mutations, especially those known or inferred to be inactivating, may identify more patients with dMMR and matched treatment options. However, dedicated IHC screening is needed to capture majority of the patients.
Safety and Efficacy of Osimertinib in Patients With Non–Small-Cell Lung Cancer and Uncommon Tumoral Epidermal Growth Factor Receptor Mutations: A Systematic Review and Single-Arm Meta-Analysis
Authors: Priantti Jonathan N. , Fujiwara Yu , Aquino de Moraes Francisco Cezar , Michelon Isabella , Castro Caio , Leighl Natasha B. , Cavalcante Ludimila , Addeo Alfredo , Bar Jair , Horita Nobuyuki , Cortellini Alessio , Nassar Amin H. , Vilbert Maysa , Naqash Abdul Rafeh
Published: November 2024

PURPOSE

The activity of osimertinib is not fully characterized in non–small-cell lung cancer (NSCLC) with uncommon epidermal growth factor receptor (
EGFR
) mutations. Therefore, we conducted a systematic review and meta-analysis to assess the safety and efficacy of osimertinib in patients with NSCLC harboring uncommon somatic
EGFR
mutations.

METHODS

PubMed, Embase, and the Cochrane Library were searched for eligible studies reporting the efficacy and safety of osimertinib in NSCLC with uncommon
EGFR
mutations defined as any mutations other than exon 19 deletion, L858R and T790M mutations, and exon 20 insertion, except when in compound. Then, we performed a meta-analysis to pool survival outcomes and antitumoral activity, including intracranial (ic) response and adverse events.

RESULTS

Fifteen studies comprising 594 patients were included. The most frequently observed uncommon solitary mutations were G719X in 25% (81/327) of patients and L861Q in 21% (69/327). The most common compound mutations were G719X with T790M in 12% (23/192) of patients and G719X with S768I in 11% (22/192). Pooled analysis showed an objective response rate (ORR) of 51.30% (95% CI, 45.80 to 56.81), a disease control rate (DCR) of 90.11% (95% CI, 86.27 to 92.96), a median progression-free survival of 9.71 months (95% CI, 7.96 to 11.86), and a median overall survival of 16.79 months (95% CI, 9.93 to 28.39). icORR was 45.96% (95% CI, 30.18 to 62.17), and icDCR was 95.76% (95% CI, 69.84 to 100). Osimertinib was well tolerated with a frequency of grade 3 or more adverse events of 21.77% (95% CI, 6.24 to 43.33).

CONCLUSION

Osimertinib demonstrated robust response in NSCLC harboring uncommon
EGFR
mutations, without unanticipated safety concerns.
Postnatal Ovarian Transdifferentiation in the Absence of Estrogen Receptor Signaling Is Dependent on Genetic Background
Authors: Binder April K , Burns Katherine A , Rodriguez Karina F , Hamilton Katherine , Pardo-Manuel de Villena Fernando , Korach Kenneth S
Published: November 2024

Normal ovarian function requires the expression of estrogen receptors α (ESR1) and β (ESR2) in distinct cell types within the ovary. The double estrogen receptor knockout (αβERKO) ovary had the appearance of seminiferous tubule–like structures that expressed SOX9; this phenotype was lost when the animals were repeatedly backcrossed to the C57BL/6J genetic background. A new line of ERKO mice, Ex3αβERKO, was developed for targeted disruption on a mixed genetic background. Histological examination of the ovaries in the Ex3αβERKO showed the appearance of seminiferous tubule–like structures in mice aged 6 to 12 months. These dismorphogenic regions have cells that no longer express granulosa cell–specific FOXL2, while other cells express Sertoli cell–specific SOX9 as examined by immunohistochemistry. Whole ovarian gene expression analysis in Ex3αERKO, Ex3βRKO, and Ex3αβERKO found many genes differentially expressed compared to controls with one Esr1 and Esr2 allele. The genes specific to the Ex3αβERKO ovary were compared to other models of postnatal ovarian transdifferentiation, identifying 21 candidate genes. To examine the genetic background contributions, DNA was isolated from αβERKO mice that did not show ovarian transdifferentiation and compared to DNA from Ex3αβERKO using Mouse Diversity Array. A genomic region putatively associated with transdifferentiation was identified on Chr18 (5-15 M) and genes in this region were compared to the genes differentially expressed in models of ovarian transdifferentiation. This work demonstrates the importance of ESRs in maintaining granulosa cell differentiation within the ovary, identifies several potential gene candidates, and suggests that genetic background can be a confounding factor.
The Memories of Shipmates: Claims to Freedom in Mauritius, 1833–1835
Authors: Hooper Jane
Published: November 2024

In the years immediately prior to legal emancipation, dozens of enslaved people approached the Protectors of Slaves in Mauritius to demand their freedom. They argued that they had been illegally introduced to the island after the slave trade was abolished by the British. Their testimonies offer insights into the development of Afro-Creole communities in the Mascarenes and how people successfully advocated for increased autonomy. Historians of the transatlantic slave trade have argued for the significance of shipmate bonds for people who endured the Middle Passage and labored in the Americas. Such communities were also important in the Indian Ocean world for those who sought manumission. Those who were illegally enslaved shared memories of capture, transportation, and forced acculturation. Their memories and bonds highlight the complex diasporic communities that coexisted on Mauritius during the first half of the nineteenth century.
Africans, Muwallad, and the Myth of Mild Slavery: Testimonies of the Enslaved in the Persian Gulf, 1887–1949
Authors: Suzuki Hideaki
Published: November 2024

This article examines the testimonies prepared for manumission certificates issued by British authorities in the early twentieth-century Persian Gulf. Based on the dataset on which the author is currently working, it examines the category of “African” recorded by the colonial record keepers to distinguish between “Africans” who were born in Africa and those born in the Gulf who were also categorized as “African” by the British officers who interviewed them. Those who were born locally from enslaved parents were called muwallad and it is widely regarded that the masters treated them better than those newly enslaved. Such discourse about muwallad is called “the myth of mild slavery.” This article analyzes the dataset both quantitatively and qualitatively to clarify the experience of “African” muwallad in order to shed light on the diverse experiences of the enslaved “African” population in the early twentieth-century Persian Gulf.
Creating a Public Database of Slaving Voyages across the Indian Ocean and Asia
Authors: Allen Richard B. , Domingues da Silva Daniel B. , Hooper Jane , Hopper Matthew S.
Published: November 2024

This article describes a major new initiative funded by a grant from the United States National Endowment for the Humanities to identify slaving voyages by Arab, Chinese, European, Indian, Southeast Asian, Swahili, and other vessels in the Indian Ocean and Asia and add them to the existing SlaveVoyages website. The article argues that the new database is needed to expand our historical knowledge about slave trading as a global phenomenon by reconstructing the maritime commerce in slave and other forms of coerced labor in the Indian Ocean and maritime Asia in ways that will help historians and the public trace the movement and life histories of enslaved peoples within and beyond the Indian Ocean world. The article concludes with a call for collaboration from researchers who can identify and contribute new voyages to this important project.
“Unique, Divine, Unrepeatable”
Authors: Pérez Elizabeth
Published: November 2024

The late Bishop S. F. Makalani-MaHee (1972–2017) was a minister, activist, actor/singer, composer, and spoken word artist. His essays, songs, poetry, plays, and sermons reflect his “Blackpentecostal” and Southern Baptist upbringing as well as his embrace of liberation theology, womanism, and Black feminist thought. This article analyzes his only published collection of poems, Don’t!, as a profound repertoire and theological manifesto with the aid of his autobiographical writings, performances, and eponymous archive housed at the Stonewall National Museum and Archives. Don’t! contests patriarchal, cisgender-sexist constructions of masculinity by paying homage to Black grandmothers, mothers, femmes, and cisgender (or “nontrans”) “sister friends.” This article argues that Don’t! is a declaration of his woman-centered theorization of transmasculinity and his queer/trans Christology, which should be brought into conversation with texts in the womanist canon. The article further contends that Don’t! enriches the Black trans Christian archive and disrupts the “whitewashed” master narratives of LGBTQ experience.
Cellular retinoic acid-binding proteins regulate germ cell proliferation and sex determination in zebrafish
Authors: Fung Lianna , Dranow Daniel B. , Subramanian Arul , Libby Natalia , Schilling Thomas F.
Published: November 2024

Cellular retinoic acid (RA)-binding proteins (Crabps) solubilize intracellular RA and transport it to its nuclear receptors or cytoplasmic degradation enzymes. Despite their extreme conservation across chordates, genetic studies of Crabp function have revealed few essential functions. We have generated loss-of-function mutations in all four zebrafish Crabps and find essential roles for Crabp2 proteins in gonad development and sex determination. Transgenic RA reporters show strong RA responses in germ cells at the bipotential stage of gonad development. Double mutants lacking the functions of both Crabp2a and Crabp2b predominantly become male, which correlates with their smaller gonad size and reduced germ cell proliferation during gonad development at late larval and early juvenile stages. In contrast, mutants lacking the functions of both Crabp1a and Crabp1b have normal sex ratios. Exogenous RA treatments at bipotential gonad stages increase germ cell number, consistent with a direct role for RA in promoting germ cell proliferation. Our results suggest essential functions for Crabps in gonad development and sex determination.
ARPP19 phosphorylation site evolution and the switch in cAMP control of oocyte maturation in vertebrates
Authors: Meneau Ferdinand , Lapébie Pascal , Daldello Enrico Maria , Le Tran , Chevalier Sandra , Assaf Sarah , Houliston Evelyn , Jessus Catherine , Miot Marika
Published: November 2024

cAMP-PKA signaling initiates the crucial process of oocyte meiotic maturation in many animals, but inhibits it in vertebrates. To address this ‘cAMP paradox’, we exchanged the key PKA substrate ARPP19 between representative species, the vertebrate Xenopus and the cnidarian Clytia, comparing its phosphorylation and function. We found that, as in Xenopus, Clytia maturing oocytes undergo ARPP19 phosphorylation on a highly conserved Gwl site, which inhibits PP2A and promotes M-phase entry. In contrast, despite a PKA phosphorylation signature motif recognizable across most animals, Clytia ARPP19 was only poorly phosphorylated by PKA in vitro and in vivo. Furthermore, unlike Xenopus ARPP19, exogenous Clytia ARPP19 did not delay Xenopus oocyte maturation. We conclude that, in Clytia, ARPP19 does not intervene in oocyte maturation initiation because of both poor recognition by PKA and the absence of effectors that mediate vertebrate oocyte prophase arrest. We propose that ancestral ARPP19 phosphorylated by Gwl has retained a key role in M-phase across eukaryotes and has acquired new functions during animal evolution mediated by enhanced PKA phosphorylation, allowing co-option into oocyte maturation regulation in the vertebrate lineage.
Barcoding Notch signaling in the developing brain
Authors: Siniscalco Abigail M. , Perera Roshan Priyarangana , Greenslade Jessie E. , Veeravenkatasubramanian Hemagowri , Masters Aiden , Doll Hannah M. , Raj Bushra
Published: November 2024

Developmental signaling inputs are fundamental for shaping cell fates and behavior. However, traditional fluorescent-based signaling reporters have limitations in scalability and molecular resolution of cell types. We present SABER-seq, a CRISPR-Cas molecular recorder that stores transient developmental signaling cues as permanent mutations in cellular genomes for deconstruction at later stages via single-cell transcriptomics. We applied SABER-seq to record Notch signaling in developing zebrafish brains. SABER-seq has two components: a signaling sensor and a barcode recorder. The sensor activates Cas9 in a Notch-dependent manner with inducible control, while the recorder obtains mutations in ancestral cells where Notch is active. We combine SABER-seq with an expanded juvenile brain atlas to identify cell types derived from Notch-active founders. Our data reveal rare examples where differential Notch activities in ancestral progenitors are detected in terminally differentiated neuronal subtypes. SABER-seq is a novel platform for rapid, scalable and high-resolution mapping of signaling activity during development.
A new cell culture resource for investigations of reptilian gene function
Authors: Samudra Sukhada P. , Park Sungdae , Esser Elizabeth A. , McDonald Tryggvi P. , Borges Arianna M. , Eggenschwiler Jonathan , Menke Douglas B.
Published: November 2024

The establishment of CRISPR/Cas9 gene editing in Anolis sagrei has positioned this species as a powerful model for studies of reptilian gene function. To enhance this model, we developed an immortalized lizard fibroblast cell line (ASEC-1) for the exploration of reptilian gene function in cellular processes. We demonstrate the use of this cell line by scrutinizing the role of primary cilia in lizard Hedgehog (Hh) signaling. Using CRISPR/Cas9 mutagenesis, we disrupted the ift88 gene, which is required for ciliogenesis in diverse organisms. We determined that loss of itf88 from lizard cells leads to an absence of primary cilia, a partial derepression of gli1 transcription, and an inability of the cells to respond to the Smoothened agonist, SAG. Through a cross-species analysis of SAG-induced transcriptional responses in cultured limb bud cells, we further determined that ∼46% of genes induced as a response to Hh pathway activation in A. sagrei are also SAG responsive in Mus musculus limb bud cells. Our results highlight conserved and diverged aspects of Hh signaling in anoles and establish a new resource for investigations of reptilian gene function.
Detecting subtle subterranean movement via laser speckle imaging
Authors: Bagheri Hosain , Goodisman Michael A. D. , Goldman Daniel I.
Published: November 2024

A diversity of organisms live within underground environments. However, visualizing subterranean behavior is challenging because of the opacity of most substrates. We demonstrate that laser speckle imaging, a non-invasive technique resolving nanometer-scale movements, facilitates quantifying biological activity in a granular medium. We monitored fire ants (Solenopsis invicta) at different developmental stages, burial depths (1–5 cm) and moisture fractions (0 and 0.1 by volume) in a container of 0.7 mm glass particles. Although the speckle pattern from the backscattered light precludes direct imaging of animal kinematics, analysis of integrated image differences revealed that spiking during ant movement increased with the developmental phase. Greater burial depth and saturation resulted in fewer and lower magnitude spikes. We verified that spiking correlated with movement via quasi-2D experiments. This straightforward method, involving a laser and digital camera, can be applied to laboratory and potentially field situations to gain insight into subterranean organism activities.
Intratumoral Bacteria are Uncommon in Gastrointestinal Stromal Tumor
Authors: Tardy Katherine J. , Kwak Hyunjee V. , Tieniber Andrew D. , Mangold Alina K. , Perez Juan E. , Do Kevin , Zeng Shan , Rossi Ferdinando , DeMatteo Ronald P.
Published: November 2024

Background

Gastrointestinal stromal tumor (GIST) is the most common human sarcoma with over 5000 new patients diagnosed in the USA each year. The tumor originates from the interstitial cells of Cajal and forms an intramural lesion most commonly in the stomach or small intestine. The gut microbiome has been linked to other gastrointestinal cancers and a recent paper purported that GISTs contain substantial intratumoral bacteria. The purpose of this study is to further evaluate the presence of bacteria in GISTs.

Patients and Methods

We collected 25 tumor samples of varying size and location from 24 patients under sterile conditions in the operating room immediately following surgical resection. 16S quantitative polymerase chain reaction (qPCR) and 16S ribosomal RNA (rRNA) gene amplicon sequencing were performed to evaluate the bacterial species present in each tumor. Retrospective chart review was performed to determine tumor characteristics, including tumor size, location, imatinib exposure, and mucosal involvement.

Results

In 23 of the 25 tumor samples, there were fewer than 100 copy numbers of 16S rRNA per uL, indicating an absence of a significant bacterial load. 16S rRNA gene amplicon sequencing of the remaining two samples, one gastric tumor and one duodenal tumor, revealed the presence of normal intestinal bacteria. These two tumors, along with three others, had disruption of the mucosal lining.

Conclusions

GISTs generally lack substantial bacteria, except in some cases when the tumor disrupts the mucosa.
High prevalence of ankle, knee and low back problems in highly trained adolescent basketball players at the beginning of their competitive season
Authors: Arend Mati , Toomsalu Liis , Kaasik Priit
Published: November 2024

Background: Adolescent team sport athletes with high training volume and overscheduling have increased incidences of injuries (Osgood-Schlatter disease, low-back pain etc.) compared to their less active counterparts. These overuse injuries may begin to negatively affect young athletes’ attitudes towards physical activity. The aim of this study was to investigate the prevalence of low back, knee and ankle problems in young male basketball players.
Methods: The Oslo Sports Trauma Research Centre Overuse Injury Questionnaire (OSTRC) was distributed weekly to 16 adolescent athletes who regularly participated in basketball training and who volunteered to participate in the study (age 15 ± 1.2 years; body weight 72.1 ± 11.8 kg; height 183.5 ± 8.2 cm; BMI 21.1 ± 2.5; training experience 7.4 ± 1.2 years; training hours per week 6.6 ± 3.8) for 12 weeks at the start of their season.
Results: The response rate to the weekly OSTRC questionnaire was 96.4%. A total of 94 overuse conditions were identified, affecting 15 athletes (94% of the cohort). 93.8% of the athletes in this group reported having had knee problems, while low back and ankle problems were reported by 43.8% and 31.3% respectively.
Conclusions: Knee and low back problems seem to be very common in adolescent basketball players and should be the focus of regular injury prevention programmes. Problems in these areas were more prevalent at the start of the study indicating the need for better pre-season physical preparation. Also, the weekly questionnaire helps to better regulate training loads and, therefore, is a good monitoring system for coaches and physiotherapists to prevent overuse problems.