bluuebunny/crossref_metadata_2025 huggingface dataset:
Signaling dynamics distinguish high- and low-priority neutrophil chemoattractant receptors
Authors: Lundgren Stefan M. , Rocha-Gregg Briana L. , Akdoğan Emel , Mysore Maya N. , Hayes Samantha , Collins Sean R.
Published: October 2023

Human neutrophils respond to multiple chemoattractants to guide their migration from the vasculature to sites of infection and injury, where they clear pathogens and amplify inflammation. To properly focus their responses during this complex navigation, neutrophils prioritize pathogen- and injury-derived signals over long-range inflammatory signals, such as the leukotriene LTB4, secreted by host cells. Different chemoattractants can also drive qualitatively different modes of migration even though their receptors couple to the same Gα
i
family of G proteins. Here, we used live-cell imaging to demonstrate that the responses differed in their signaling dynamics. Low-priority chemoattractants caused transient responses, whereas responses to high-priority chemoattractants were sustained. We observed this difference in both primary neutrophils and differentiated HL-60 cells, for downstream signaling mediated by Ca
2+
, a major regulator of secretion, and Cdc42, a primary regulator of polarity and cell steering. The rapid attenuation of Cdc42 activation in response to LTB4 depended on the phosphorylation sites Thr
308
and Ser
310
in the carboxyl-terminal tail of its receptor LTB4R in a manner independent of endocytosis. Mutation of these residues to alanine impaired chemoattractant prioritization, although it did not affect chemoattractant-dependent differences in migration persistence. Our results indicate that distinct temporal regulation of shared signaling pathways distinguishes between receptors and contributes to chemoattractant prioritization.
Gene recoding by synonymous mutations creates promiscuous intragenic transcription initiation in mycobacteria
Authors: Hegelmeyer Nuri K. , Parkin Lia A. , Previti Mary L. , Andrade Joshua , Utama Raditya , Sejour Richard J. , Gardin Justin , Muller Stephanie , Ketchum Steven , Yurovsky Alisa , Futcher Bruce , Goodwin Sara , Ueberheide Beatrix , Seeliger Jessica C.
Published: October 2023

Each genome encodes some codons more frequently than their synonyms (codon usage bias), but codons are also arranged more frequently into specific pairs (codon pair bias). Recoding viral genomes and yeast or bacterial genes with non-optimal codon pairs has been shown to decrease gene expression. Gene expression is thus importantly regulated not only by the use of particular codons but also by their proper juxtaposition. We therefore hypothesized that non-optimal codon pairing could likewise attenuate
Mycobacterium tuberculosis
(
Mtb
) genes. We explored the role of codon pair bias by recoding
Mtb
genes (
rpoB, mmpL3
, and
ndh
) and assessing their expression in the closely related and tractable model organism
M. smegmatis
. To our surprise, recoding caused the expression of multiple smaller protein isoforms from all three genes. We confirmed that these smaller proteins were not due to protein degradation but instead issued from new transcription initiation sites positioned within the open reading frame. New transcripts gave rise to intragenic translation initiation sites, which, in turn, led to the expression of smaller proteins. We next identified the nucleotide changes associated with these new sites of transcription and translation. Our results demonstrated that apparently benign, synonymous changes can drastically alter gene expression in mycobacteria. More generally, our work expands our understanding of the codon-level parameters that control translation and transcription initiation.

IMPORTANCE

Mycobacterium tuberculosis
(
Mtb
) is the causative agent of tuberculosis, one of the deadliest infectious diseases worldwide. Previous studies have established that synonymous recoding to introduce rare codon pairings can attenuate viral pathogens. We hypothesized that non-optimal codon pairing could be an effective strategy for attenuating gene expression to create a live vaccine for
Mtb
. We instead discovered that these synonymous changes enabled the transcription of functional mRNA that initiated in the middle of the open reading frame and from which many smaller protein products were expressed. To our knowledge, this is one of the first reports that synonymous recoding of a gene in any organism can create or induce intragenic transcription start sites.
Ex-chitin-g news on drug-induced fungal epitope unmasking
Authors: Wheeler Robert T.
Published: October 2023

The microbial cell wall is an essential cellular organelle commonly targeted by antimicrobials. It is also a battleground of innate immune recognition where microbes can evade immune recognition by masking essential cell wall components. A recent study (A. S. Wagner, S. W. Lumsdaine, M. M. Mangrum, and T. B. Reynolds, mBio
https://doi.org/10.1128/mbio.00074-23
, 2023) provides insight into how echinocandin antifungals cause exposure of proinflammatory β(1,3)-glucan by driving excess chitin production in the weakened cell wall. Although many environmental and biological activities perturb cell wall integrity and regulate β(1,3)-glucan exposure, we still know little about which intracellular signaling components regulate the cell wall changes that result in disrupted cell wall architecture. Wagner et al. showed that calcineurin and the Mkc1p kinase regulate chitin deposition and β(1,3)-glucan unmasking. They further identified chitin synthesis as a key driving force in cell wall structure disruption leading to epitope exposure. Their findings highlight how fungal cell wall dynamics have important implications for antifungal immunity and future drug development.
Complete genome sequence of multi-drug-resistant
Salmonella enterica
subsp.
enterica
serovar Typhimurium strain Bnaya isolated from a dairy calf in Israel
Authors: Davidovich Chagai , Awwad Aya , Fleker Marcelo , Weisblit Limor , Cytryn Eddie , Blum Shlomo E.
Published: October 2023

This manuscript reports the complete genome sequence of a
Salmonella enterica
subsp.
enterica
serovar Typhimurium strain (designated “Bnaya”), isolated from a dead dairy calf with severe diarrhea in Israel. The isolate exhibited multi-drug resistance, which is highly unusual in bovine
Salmonella
spp. in Israel, prompting further investigation.
Leveraging existing 16S rRNA microbial data to identify diagnostic biomarker in Chinese patients with gastric cancer: a systematic meta-analysis
Authors: Chen Jijun , Nie Siru , Qiu Xunan , Zheng Shuwen , Ni Chuxuan , Yuan Yuan , Gong Yuehua
Published: October 2023

Gastric cancer is the second most prevalent and deadly cancer in China. Microbiota play an important role in gastric tumorigenesis. However, the available microbial marker studies for gastric cancer do not have consistent results. We searched PubMed for 16S rRNA sequencing in relevant literature on Chinese patients from 1 January 2005 to 18 July 2022, and 16 original articles were finally obtained. Alpha diversity, beta diversity, and bacterial taxa were used to explore the differences in gastric microbiota. Linear discriminant analysis of effect size and a random forest model were used to find the combination of genera with the best diagnostic efficacy.
Streptococcus
,
Pseudomonas
,
Fusobacterium
,
Selenomonas
,
Peptostreptococcus
, and
Prevotella
showed significant differences between gastric cancer and non-gastric cancer, but a single genus performed poorly in identifying patients with gastric cancer. However, a combination of genera
Streptococcus
,
Peptostreptococcus
,
Selenomonas
,
Pseudomonas
, and
Prevotella
had excellent performance in screening gastric cancer with the median area under the curve values of 0.7525 (range: 0.5859–0.9350), 0.8818 (range: 0.7397–0.9533), and 0.7435 (range: 0.7131–0.8483) in the Matched, Unmatched, and Other groups, respectively. Therefore, the results indicated that this combination of genera has good diagnostic efficacy and wide applicability for patients with gastric cancer, which may provide new clues for the non-invasive diagnosis of gastric cancer.

Importance

Gastric cancer is a significant and growing health problem in China. Studies have revealed significant differences in gastric microbiota between patients with gastric cancer and non-cancerous patients, suggesting that microbiota may play a role in tumorigenesis. In this meta-analysis, existing 16S rRNA microbial data were analyzed to find combinations consisting of five genera, which had good efficacy in distinguishing gastric cancer from non-cancerous patients in multiple types of samples. These results lend support to the use of microbial markers in detecting gastric cancer. Moreover, these biomarkers are plausible candidates for further mechanistic research into the role of the microbiota in tumorigenesis.
Abuse, neglect and neurodevelopment across the life course: what can paediatricians and child psychiatrists do about this together? The Illingworth-Rees keynote lecture 2023
Authors: Minnis Helen
Published: October 2023

Paediatricians and child psychiatrists share complex cases, often associated with abuse, neglect and other ‘Adverse Childhood Experiences (ACEs)’. ACEs are associated in a dose-response relationship with both mental and physical health problems across the life span. We found that 9-year-old children who had been abused and neglected were much more likely to also have symptoms of heritable neurodevelopmental conditions (NDCs) such as ADHD, autism and intellectual disabilities. To our surprise, these were not caused by the abuse and neglect. Instead, both the NDCs and the abuse and neglect were being caused by additional genetic factors. We also found that children who have experienced abuse and neglect, and who also have NDCs, are at twice the risk of developing symptoms of severe mental illness in adolescence. This has caused us to develop our ‘Double Jeopardy’ hypothesis—that experiencing both abuse and neglect and NDCs in childhood might double the risk of a range of physical and mental health problems across the life span.

Both paediatricians and child psychiatrists will be faced with children who have complex problems, and they will sometimes need to work together to solve these—whether or not abuse or neglect is in the mix.

Dr Corinne Rees’s words were prescient: ‘The truth that psychological issues and behaviour are integral to all illness indicates the necessity for every doctor to feel competent in considering their relevance’. As paediatricians and child psychiatrists, let’s move forward together to overcome the mind-body dichotomy for the benefit of our patients.
Anaesthetic management for caesarean section in a patient with hereditary haemorrhagic telangiectasia and severe epistaxis during pregnancy
Authors: Fogang D Claudie , Martin Gallice , Boehlen Françoise , Savoldelli Georges L
Published: October 2023

A primigravida patient, with a history of hereditary haemorrhagic telangiectasia (HHT) manifesting as nasal angiodysplasia and hepatic arteriovenous malformations (AVM), presented for delivery planning and anaesthetic evaluation at 29 weeks of gestation. She was hospitalised several times during the second and third trimester for serious recurrent epistaxis, leading to severe anaemia. In total, she required the transfusion of 20 units of packed red blood cells during her pregnancy as well as surgical nasal haemostasis under general anaesthesia (GA). The patient was referred to our tertiary centre for delivery. In the context of recurrent severe epistaxis and high cardiac output (due to hepatic AVM) in the third trimester, a multidisciplinary decision was made to plan an elective caesarean section at 35 4/7 weeks combined with nasal packing under GA. This report discusses the implications of HHT, the multidisciplinary planning of the caesarean section, intraoperative anaesthetic management and patient follow-up.
Orthopaedic Out of Bed Project (OOBP): improving early mobilisation following femoral fracture using a therapy-led education programme
Authors: Gray Rene , Taylor Melissa , Bullock Ryan
Published: October 2023

Delayed mobilisation following hip fracture surgery is detrimental to patients and health systems. Prolonged hospital stay additionally results in decreased function and increased mortality. Our hospital was underperforming against the national metric for mobilisation by the day after surgery and physiotherapists were the primary healthcare professionals expected to do this. The therapy team therefore undertook a service improvement to increase the number of patients mobilised by the day after their femoral fracture surgery. This was through a ward-based education programme aimed at increasing confidence and competence of the trauma ward healthcare assistants (HCAs) to complete this task when appropriate instead of physiotherapists.

The model for improvement was used, with two Plan-Do-See-Act cycles completed between 2020 and 2022. On completion of the therapy-led intervention, the percentage of patients mobilised by the day after surgery was shown to have increased from a mean average of 60% in 2019 to 79% in 2022. The number of patients mobilised by HCAs prior to physiotherapy assessment increased from 2% prior to and 30% following the intervention.

The programme improved HCA confidence and competence using a rehabilitation ethos to mobilise patients following hip fracture surgery. It also showed a clinically significant improvement in the percentage of patients with hip fracture mobilising by the day after surgery and a large increase in the number of patients mobilised by our trauma ward HCAs prior to an initial physiotherapy assessment. This work has demonstrated implications for orthopaedic trauma services and the patients who receive them. It reduces the single point of failure of relying on a physiotherapist to mobilise a patient through increasing multidisciplinary confidence and capability on the ward to perform the task. In turn, this increases physiotherapy capacity to provide acute rehabilitation, which is another important part of femoral fracture recovery.
Quality improvement initiative: implementing routine vertebral fracture assessments into an Australian Fracture Liaison Service
Authors: Greene Leanne , Shah Deval , Laver Kate , Holton Kirrily , Manuel Kisani , Bajger Bogda
Published: October 2023

Osteoporosis is a global health concern and a major contributor to worldwide mortality rates. Vertebral fractures due to osteoporosis are common and often undetected. Since vertebral fractures are often missed, evidence and guidelines suggest that vertebral fracture assessment (VFA) may optimise current approaches to bone density tests. We aimed to integrate VFA into an Australian Fracture Liaison Service (FLS) and measure the impact it had on osteoporosis treatment initiation.

A retrospective case note review was undertaken to determine the number of clinic patients receiving VFA before the change in practice. Proctor’s seven domains of implementation strategy were used to facilitate quality improvement outcomes.

The percentage of eligible patients receiving a routine VFA at the FLS imaging centre increased from 0% to 90%. The remaining 10% of patients did not receive a scan due to the patient not being able to assume the correct position, skilled staff being unavailable to perform the scan, or the patient declining. Post implementation, almost half (41%) of patients who underwent a VFA displayed abnormalities and 16 (4%) of these recorded a normal bone measure density score but abnormal VFA. Despite the successful adoption of the new screening protocol, there was no statistically significant increase in treatment initiation rates for patients with normal bone mass density scores.

The FLS successfully integrated routine VFA into the osteoporosis care pathway. However, the introduction of VFA did not significantly increase treatment initiation. It may be more effective to offer VFAs to a proportion of patients based on a tailored approach rather than offering them routinely to all patients who access the FLS.
Advanced rehabilitation in ischaemic stroke research
Authors: Wang Jixian , Li Yongfang , Qi Lin , Mamtilahun Muyassar , Liu Chang , Liu Ze , Shi Rubing , Wu Shengju , Yang Guo-Yuan
Published: October 2023

At present, due to the rapid progress of treatment technology in the acute phase of ischaemic stroke, the mortality of patients has been greatly reduced but the number of disabled survivors is increasing, and most of them are elderly patients. Physicians and rehabilitation therapists pay attention to develop all kinds of therapist techniques including physical therapy techniques, robot-assisted technology and artificial intelligence technology, and study the molecular, cellular or synergistic mechanisms of rehabilitation therapies to promote the effect of rehabilitation therapy. Here, we discussed different animal and in vitro models of ischaemic stroke for rehabilitation studies; the compound concept and technology of neurological rehabilitation; all kinds of biological mechanisms of physical therapy; the significance, assessment and efficacy of neurological rehabilitation; the application of brain–computer interface, rehabilitation robotic and non-invasive brain stimulation technology in stroke rehabilitation.
Gluon radiation from a classical point particle: recoil effects
Authors: Kolbé Isobel , Lushozi Mawande
Published: October 2023

The gluon radiation spectrum of a classical particle struck by a sheet of colored glass, is a key ingredient in understanding the distribution of energy and baryon density in the fragmentation region, particularly in the initial stages of heavy ion collisions. However, the currently known classical spectrum has a troublesome high-momentum tail (Kajantie et al. in Phys. Rev. D 100(5):054011, 2019; Phys Rev D 101(5):054012, 2020). By comparing tree-level bremsstrahlung of a spin-less quark to the above-mentioned known result, we propose an interpolating formula that takes into account the recoil of the struck particle, and therefore produces the correct perturbative behaviour at high momentum of the radiated gluon.
Cross-scale study of pore fractal characteristics and the pore structure of weathered granite
Authors: Zhao Kang , Chen Jiale , Wu Jun , Yan Yajing , Huang Qizheng , Nie Qiang , Xiao Weiling
Published: October 2023

Weathering of granite leads to weakening of its crushing and mechanical properties, as well as changes in mineral composition. In order to investigate the correlation between the effects of weathering on granite and the characterization of the pore structure at the micro- and fine-scale, in this paper the pore structure of weathered granite is tested by the NMR technique. The pore distribution characteristics of weathered granite were explored in conjunction with
T
2
spectral relaxation time and fractal theory. The microstructure of weathering-prone granite was monitored using scanning electron microscopy equipment. The results show that the pores can be classified into the three categories of small, medium and large pores based on their pore size distribution characteristics. Weathered granite has fractal features in the mesopores and macropores. Compared with unweathered granite, weathered granite has significantly more small pore throats and fewer medium and large pore throats, which expand into microfissures and micropores under conditions of weathering. The microstructure of weathered granite is mainly flaky and shell-like, with good connectivity, resulting in the poor overall structure of weathered granite.
Understanding Persistent-memory-related Issues in the Linux Kernel
Authors: Gatla Om Rameshwar , Zhang Duo , Xu Wei , Zheng Mai
Published: October 2023

Persistent memory (PM) technologies have inspired a wide range of PM-based system optimizations. However, building correct PM-based systems is difficult due to the unique characteristics of PM hardware. To better understand the challenges as well as the opportunities to address them, this article presents a comprehensive study of PM-related issues in the Linux kernel. By analyzing 1,553 PM-related kernel patches in depth and conducting experiments on reproducibility and tool extension, we derive multiple insights in terms of PM patch categories, PM bug patterns, consequences, fix strategies, triggering conditions, and remedy solutions. We hope our results could contribute to the development of robust PM-based storage systems.
Adaptation and Survival of Marine-Associated Spiders (Araneae)
Authors: Leggett Marlene A. , Vink Cor J. , Nelson Ximena J.
Published: October 2023

Aquatic environments are an unusual habitat for most arthropods. Nevertheless, many arthropod species that were once terrestrial dwelling have transitioned back to marine and freshwater environments, either as semiaquatic or, more rarely, as fully aquatic inhabitants. Transition to water from land is exceptional, and without respiratory modifications to allow for extended submergence and the associated hypoxic conditions, survival is limited. In this article, we review marine-associated species that have made this rare transition in a generally terrestrial group, spiders. We include several freshwater spider species for comparative purposes. Marine-associated spiders comprise less than 0.3% of spider species worldwide but are found in over 14% of all spider families. As we discuss, these spiders live in environments that, with tidal action, hydraulic forces, and saltwater, are more extreme than freshwater habitats, often requiring physiological and behavioral adaptations to survive. Spiders employ many methods to survive inundation from encroaching tides, such as air bubble respiration, airtight nests, hypoxic comas, and fleeing incoming tides. While airway protection is the primary survival strategy, further survival adaptations include saltwater-induced osmotic regulation, dietary composition, predator avoidance, reproduction, locomotory responses, and adaptation to extreme temperatures and hydrostatic pressures that challenge existence in marine environments.
Bubble Plumes in Nature
Authors: Cardoso Silvana S.S. , Cartwright Julyan H.E.
Published: October 2023

Bubble plumes are ubiquitous in nature. Instances in the natural world include the release of methane and carbon dioxide from the seabed or the bottom of a lake and from a subsea oil well blowout. This review describes the dynamics of bubble plumes and their various spreading patterns in the surrounding environment. We explore how the motion of the plume is affected by the density stratification in the external environment, as well as by internal processes of dissolution of the bubbles and chemical reaction. We discuss several examples, such as natural disasters, global warming, and fishing techniques used by some whales and dolphins.
Philippine Psycholinguistics
Authors: Pizarro-Guevara Jed Sam , Garcia Rowena
Published: October 2023

Over the last decade, there has been a slow but steady accumulation of psycholinguistic research focusing on typologically diverse languages. In this review, we provide an overview of the psycholinguistic research on Philippine languages at the sentence level. We first discuss the grammatical features of these languages that figure prominently in existing research. We identify four linguistic domains that have received attention from language researchers and summarize the empirical terrain. We advance two claims that emerge across these different domains: ( a) The agent-first pressure plays a central role in many of the findings, and ( b) the generalization that the patient argument is the syntactically privileged argument cannot be reduced to frequency, but instead is an emergent phenomenon caused by the alignment of competing pressures toward an optimal candidate. We connect these language-specific claims to language-general theories of sentence processing.
The Mineralocorticoid Receptor in the Vasculature: Friend or Foe?
Authors: Ibarrola Jaime , Jaffe Iris Z.
Published: October 2023

Originally described as the renal aldosterone receptor that regulates sodium homeostasis, it is now clear that mineralocorticoid receptors (MRs) are widely expressed, including in vascular endothelial and smooth muscle cells. Ample data demonstrate that endothelial and smooth muscle cell MRs contribute to cardiovascular disease in response to risk factors (aging, obesity, hypertension, atherosclerosis) by inducing vasoconstriction, vascular remodeling, inflammation, and oxidative stress. Extrapolating from its role in disease, evidence supports beneficial roles of vascular MRs in the context of hypotension by promoting inflammation, wound healing, and vasoconstriction to enhance survival from bleeding or sepsis. Advances in understanding how vascular MRs become activated are also reviewed, describing transcriptional, ligand-dependent, and ligand-independent mechanisms. By synthesizing evidence describing how vascular MRs convert cardiovascular risk factors into disease (the vascular MR as a foe), we postulate that the teleological role of the MR is to coordinate responses to hypotension (the MR as a friend).
What Does the Human Olfactory System Do, and How Does It Do It?
Authors: Dikeçligil Gülce Nazlı , Gottfried Jay A.
Published: October 2023

Historically, the human sense of smell has been regarded as the odd stepchild of the senses, especially compared to the sensory bravado of seeing, touching, and hearing. The idea that the human olfaction has little to contribute to our experience of the world is commonplace, though with the emergence of COVID-19 there has rather been a sea change in this understanding. An ever increasing body of work has convincingly highlighted the keen capabilities of the human nose and the sophistication of the human olfactory system. Here, we provide a concise overview of the neuroscience of human olfaction spanning the last 10–15 years, with focus on the peripheral and central mechanisms that underlie how odor information is processed, packaged, parceled, predicted, and perturbed to serve odor-guided behaviors. We conclude by offering some guideposts for harnessing the next decade of olfactory research in all its shapes and forms.
Intestinal-specific Hdac3 deletion increases susceptibility to colitis and small intestinal tumor development in mice fed a high-fat diet
Authors: Ng Irvin , Luk Ian Y. , Nightingale Rebecca , Reehorst Camilla M. , Dávalos-Salas Mercedes , Jenkins Laura J. , Fong Chun , Williams David S. , Watt Matthew J. , Dhillon Amardeep S. , Mariadason John M.
Published: October 2023

We reveal a novel role for the transcriptional corepressor Hdac3 in suppressing colitis and intestinal tumorigenesis, particularly in the context of consumption of an HFD, and reveal a potential mechanism by which HFDs may increase intestinal tumorigenesis by increasing fatty acid oxidation, DNA damage, and intestinal epithelial cell turnover. We also identify a unique mouse model for investigating the complex interplay between diet, metabolic reprogramming, and tumor predisposition in the intestinal epithelium.
Fine-Grained Point Cloud Semantic Segmentation of Complex Railway Bridge Scenes from UAVs Using Improved DGCNN
Authors: Qiu Shi , Liu Xianhua , Peng Jun , Wang Weidong , Wang Jin , Wang Sicheng , Xiong Jianping , Hu Wenbo
Published: October 2023

Automatic semantic segmentation of point clouds in railway bridge scenes is a crucial step in the digitization process and is required for a variety of subapplications including digital twin reconstruction and component geometric quality verification. This paper details a method for reliably and effectively segmenting point clouds acquired from complex railway bridge scenes by unmanned aerial vehicles (UAVs). The method involves segmenting seven common infrastructure elements in railway bridge point clouds using an improved DGCNN after processing low-quality point clouds from UAVs with a score-based denoising algorithm. The segmentation performance of the network is measured by averaging the intersection to union ratio between the segmentation results and the true labels of different elements, i.e., the mean intersection over union (mIoU). The proposed method is evaluated on three different scenes of railway bridges and achieved mIoU values of 99.18%, 90.76%, and 85.84%, respectively, at three levels of complexity ranging from easy to difficult. The results demonstrate that the proposed method captures the most discriminative features from low-quality point clouds, allowing for the accurate and efficient digital representation of railway bridge scenes.
Analysis of Postural Control in Patients Diagnosed with Unilateral Knee Osteoarthrosis and Its Relationship with the Risk of Falls
Authors: de Freitas Robson Emiliano José , de Freitas Jaqueline Gleice Aparecida , Vieira Carolina Pereira , Endres Daniela Cristina , Inacio Fábio Martins , da Silva Azevedo Nora Fernanda Grazielle
Published: October 2023

Introduction. Knee osteoarthrosis, whether subtle or marked, appears to alter the stability and performance of the knee joint in activities of daily living that prevent the maintenance of bipedal posture. However, there is still a gap in the literature as to how knee osteoarthritis can affect static balance. Objective. To analyze the performance of postural control in elderly diagnosed with unilateral knee osteoarthrosis. Materials and Methods. 40 elderly people of both sexes participated in this study, divided into two groups containing 20 elderly each. Group 1 (G1) consists of elderly patients who have received a diagnosis of unilateral knee osteoarthritis. Despite undergoing conservative treatment, their condition has shown insufficient improvement, leading to a clinical recommendation for total knee arthroplasty (TKA). The G2 group was made up of 20 elderly with an average age of 71.09 years, considered active, who do not have a diagnosis of osteoarthritis in the knee joint and practice physical activity. With the aid of a Baroscan pressure platform, the center of pressure (COP) displacement in the anteroposterior (COPAP) direction and mediolateral direction (COPML) and the area of center of pressure displacement were evaluated during bipedal postural control with eyes open and eyes closed. Results. During postural control with eyes open and eyes closed, the G1 group showed greater displacement of the COP in the anteroposterior direction—COPAP (

p
=
0.007

)—and mediolateral direction—COPML (

p
=
0.033

)—when compared to the G2 group. As for the area of displacement of the COP, group G1 presented a larger area of displacement (

p
=
0.002

) than group G2 during bipedal postural control with open eyes. For the condition with eyes closed, both groups showed similar behaviors, which resulted in no present statistically significant differences. Conclusion. The results suggest that unilateral knee osteoarthritis influences bipedal postural control and activities of daily living that require this static balance, since information from the somatosensory system is reduced, resulting in stability of tasks that require body control and promoting the risk of falls. From a clinical perspective, the results suggest that the assessment of bipedal postural control can assist orthopedic physicians in assessing joint stability in patients with unilateral knee osteoarthrosis.
Prevalence and Morphology of C-Shaped Canals in Mandibular First and Second Molars of an Iranian Population: A Cone-Beam Computed Tomography Assessment
Authors: Nouroloyouni Ahmad , Moradi Neda , Salem Milani Amin , Noorolouny Sara , Ghoreishi Amin Nazila
Published: October 2023

Objectives. The complex anatomy of C-shaped canals poses challenges for clinicians compared to teeth with normal root canal anatomy. This study is aimed at evaluating the frequency and morphology of C-shaped canals in the mandibular first and second molars among an Iranian population using cone-beam computed tomography (CBCT). Materials and Methods. This cross-sectional study evaluated 369 CBCT scans from the archives of a radiology clinic in Ardabil, Iran. The sample included 248 mandibular first molars and 478 mandibular second molars. The presence of C-shaped canals and their classification, according to Fan et al., were evaluated at four levels: orifice, coronal, middle, and apical. Prevalence based on gender and tooth type was also assessed. Results. A total of 199 (53.9%) males and 170 (46.1%) females were evaluated. C-shaped canals were found in 11 (8 males/3 females) out of 248 (4.4%) first molars and in 20 (11 males/9 females) out of 478 (3.7%) second molars. The C2 configuration was most prevalent in the orifice, coronal, and middle levels of both molar types, while C3 and C4 morphologies were most commonly found apically in the second and first molars, respectively. A significant difference in configuration was found only at the coronal level between molar types. A significant association between gender and configuration was observed only at the orifice level of the second molars. No other significant differences were found (

P
>
0.05

). Conclusion. C-shaped canal configurations should be expected in 4.4% of mandibular first molars and 3.7% of the second molars in this Iranian population, with a predominance of the C2 configuration in the orifice, coronal, and middle levels.
The Efficacy, Safety, and Recurrence Rate of Diphenylcyclopropenone Topical Immunotherapy for Alopecia Areata: A Systemic Review and Meta‐Analysis
Authors: Zhu Jiaping , Qiao Rui , Li Yufen , Lan Xuemei , Gong Xiangdong , Jiang Yiqun
Published: October 2023

Background and Objective. Diphenylcyclopropenone topical immunotherapy is widely used in the treatment of alopecia areata. However, previous studies have shown significant differences in its efficacy. We conducted this systemic review and meta‐analysis to investigate the efficacy, safety, and recurrence rate of diphenylcyclopropenone topical immunotherapy for alopecia areata. Methods. Literatures related to diphenylcyclopropenone topical immunotherapy for alopecia areata between January 1st, 2002, and July 2nd, 2022, were searched in the following databases: PubMed, Embase, Cochrane Library, Sinomed, WanFang Data, and Chinese Medical Journal Network. Results. This meta‐analysis included a total of 40 moderate to high quality studies involving 3,002 patients. The overall rate of any hair regrowth was 69%, and the overall rate of complete hair regrowth was 23%. The rate of any hair regrowth in patients with alopecia totalis or alopecia universalis was 42%, and the rate of any hair regrowth in patients with other types of alopecia areata was 75%. Common side effects were mild contact dermatitis (36%), severe contact dermatitis (31%), regional lymphadenopathy (22%), hyperpigmentation (22%), and hypopigmentation (7%). The recurrence rate was 37%. Conclusion. Diphenylcyclopropenone topical immunotherapy is an effective treatment for various types of alopecia areata, and most of its common side effects are acceptable.
Melatonin Supplementation to the Freezing Extender Improves the Quality of Canine Epididymal Spermatozoa
Authors: Fayez Eman , Samir Haney , El Sayed Mohamed A. I. , Rawash Zaher M. , Salama Ali
Published: October 2023

The present study aimed to determine the cryoprotective effect of melatonin supplements on the extender on the quality of canine epididymal spermatozoa. Epididymis from 20 castrated dogs were minced and incubated in Tris buffer. Spermatozoa were diluted in tris-citric acid-fructose (TCF) extender with two doses of melatonin (0.002 and 0.0035 mol) as well as a control (0.0 mol). The samples were packed in 0.25 ml straws after 2 hr of equilibration at 5°C and kept in liquid nitrogen (−196°C). Sperm parameters such as viability, motility, integrity of acrosome, sperm membrane functioning, and DNA integrity were assessed after thawing (37°C for 30 s). In addition, lipid peroxidation was assessed using the determination of malondialdehyde (MDA) levels. Results revealed that adding 0.0035 mol melatonin to the cryopreservation medium enhanced (P<0.05) the measured parameters of spermatozoa compared to the control and 0.002 mol melatonin. Levels of MDA were obviously (P<0.05) lower when 0.0035 mol melatonin was added in comparison to 0.002 mol melatonin and the control. Eventually, adding 0.0035 mol melatonin to the TCF extender significantly improved the percentage of motility, viability, and integrity of both plasma membrane and acrosome integrity of dog epididymal spermatozoa. In addition, melatonin supplementation improved DNA integrity and reduced membrane lipid peroxidation.
Psychometric Properties of the Posttraumatic Stress Disorder Checklist among the Lebanese Population Exposed to the Beirut Explosion: A Cross-Sectional Study during the COVID-19 Pandemic
Authors: Alhalaiqa Fadwa , Alfuqaha Othman A. , Masa’Deh Rami , Khalifeh Anas H. , Alsaraireh Mahmoud , Manaa Natija S. , Alkouri Osama , Al Omari Omar
Published: October 2023

Objective. This study was aimed at testing the psychometric properties of the posttraumatic stress disorder (PTSD) checklist for the Diagnostic Statistical Manual version 5 (DSM-5) (PCL-5) among the Lebanese population and at identifying the prevalence of PTSD. Design. A cross-sectional survey of PCL-5 among 950 Lebanese, using the online survey platform by Google Form, was conducted. Snowball recruitment was used to identify participants for the survey. Results. Face, content, construct, discriminant, and convergent validity had been accomplished through the survey. The reliability using Cronbach’s alpha, composite, and average variance extracted was identified as superior. We also found that more than half of the participants (55.6%) scored 33 or above which is the cut-off score for a likely diagnosis of PTSD. Conclusion. The current study provides further support for the validity and reliability of the Arabic version of PCL-5 among non-Western populations. This supports using the checklist in the screening of probable PTSD.
Intratumoral Delivery of Chimeric Antigen Receptor T Cells Targeting CD133 Effectively Treats Brain Metastases
Authors: Kieliszek Agata M. , Mobilio Daniel , Upreti Deepak , Bloemberg Darin , Escudero Laura , Kwiecien Jacek M. , Alizada Zahra , Zhai Kui , Ang Patrick , Chafe Shawn C. , Vora Parvez , Venugopal Chitra , Singh Sheila K.
Published: October 2023

Purpose:

Brain metastases (BM) are mainly treated palliatively with an expected survival of less than 12 months after diagnosis. In many solid tumors, the human neural stem cell marker glycoprotein CD133 is a marker of a tumor-initiating cell population that contributes to therapy resistance, relapse, and metastasis.

Experimental Design:

Here, we use a variant of our previously described CD133 binder to generate second-generation CD133-specific chimeric antigen receptor T cells (CAR-T) to demonstrate its specificity and efficacy against multiple patient-derived BM cell lines with variable CD133 antigen expression.

Results:

Using both lung- and colon-BM patient-derived xenograft models, we show that a CD133-targeting CAR-T cell therapy can evoke significant tumor reduction and survival advantage after a single dose, with complete remission observed in the colon-BM model.

Conclusions:

In summary, these data suggest that CD133 plays a critical role in fueling the growth of BM, and immunotherapeutic targeting of this cell population is a feasible strategy to control the outgrowth of BM tumors that are otherwise limited to palliative care.

See related commentary by Sloan et al., p. 477
Potential of Fecal Microbiota Transplantation to Prevent Acute GVHD: Analysis from a Phase II Trial
Authors: Rashidi Armin , Ebadi Maryam , Rehman Tauseef Ur , Elhusseini Heba , Kazadi David , Halaweish Hossam , Khan Mohammad H. , Hoeschen Andrea , Cao Qing , Luo Xianghua , Kabage Amanda J. , Lopez Sharon , Holtan Shernan G. , Weisdorf Daniel J. , Khoruts Alexander , Staley Christopher
Published: October 2023

Purpose:

Intestinal microbiota disruptions early after allogeneic hematopoietic cell transplantation have been associated with increased risk for acute GVHD (aGVHD). In our recent randomized phase II trial of oral, encapsulated, third-party fecal microbiota transplantation (FMT) versus placebo, FMT at the time of neutrophil recovery was safe and ameliorated dysbiosis. Here, we evaluated in post hoc analysis whether donor microbiota engraftment after FMT may protect against aGVHD.

Experimental Design:

We analyzed pre- and post-FMT stool samples and estimated donor microbiota engraftment (a preplanned secondary endpoint) by determining the fraction of post-FMT microbiota formed by unique donor taxa (donor microbiota fraction; dMf).

Results:

dMf was higher in patients who later developed grade I or no aGVHD (median 33.9%; range, 1.6%–74.3%) than those who developed grade II–IV aGVHD (median 25.3%; range, 2.2%–34.8%; P = 0.006). The cumulative incidence of grade II–IV aGVHD by day 180 was lower in the group with greater-than-median dMf than the group with less-than-median dMf [14.3% (95% confidence interval, CI, 2.1–37.5) vs. 76.9% (95% CI, 39.7–92.8), P = 0.008]. The only determinant of dMf in cross-validated least absolute shrinkage and selection operator (LASSO)-regularized regression was the patient's pre-FMT microbiota diversity (Pearson correlation coefficient −0.82, P = 1.6 × 10−9), indicating more potent microbiota modulation by FMT in patients with more severe dysbiosis. Microbiota network analysis revealed major rewiring including changes in the most central nodes, without emergence of keystone species, as a potential mechanism of FMT effect.

Conclusions:

FMT may have protective effects against aGVHD, especially in patients with more severe microbiota disruptions.
Development of a Novel CLDN18.2-directed Monoclonal Antibody and Antibody–Drug Conjugate for Treatment of CLDN18.2-Positive Cancers
Authors: O'Brien Neil A. , McDermott Martina S.J. , Zhang Jun , Gong Ke Wei , Lu Ming , Hoffstrom Benjamin , Luo Tong , Ayala Raul , Chau Kevin , Liang Min , Madrid Athena M. , Donahue Timothy R. , Glaspy John A. , Presta Leonard , Slamon Dennis J.
Published: October 2023

Gastric and pancreatic cancers are malignancies of high unmet clinical need. Expression of CLDN18.2 in these cancers, coupled with it's absence from most normal tissues, provides a potential therapeutic window against this target. We present preclinical development and characterization of a novel therapeutic mAb and antibody–drug conjugate (ADC) targeting CLDN18.2. A humanized CLDN18.2 specific mAb, CLDN18.2-307-mAb, was generated through immunization in mice followed by full humanization of the mouse mAb sequences. Antibody clones were screened by flow cytometry for selective binding to membrane bound CLDN18.2. A CLDN18.2-directed ADC (CLDN18.2–307-ADC) was also generated by conjugating MMAE to CLDN18.2 mAb using a cleavable linker. Tissue expression of CLDN18.2 was determined by IHC assay using a CLDN18.2-specific mAb. CLDN18.2-307-mAb binds with high affinity to CLDN18.2-positive (CLDN18.2+) cells and induces antibody-dependent cell-mediated cytotoxicity (ADCC). Treatment with this CLDN18.2-mAb blocked the growth of CLDN18.2+ gastric and pancreas cancer cell line xenograft (CDX) models. Upon binding to the extracellular domain of this target, the CLDN18.2-ADC/CLDN18.2 protein was internalized and subsequently localized to the lysosomal compartment inducing complete and sustained tumor regressions in CLDN18.2+ CDXs and patient-derived pancreatic cancer xenografts (PDX). A screen of human cancer tissues, by IHC, found 58% of gastric, 60% of gastroesophageal junction, and 20% of pancreatic adenocarcinomas to be positive for membrane expression of CLDN18.2. These data support clinical development of the CLDN18.2-307-mAb and CLDN18.2-307-ADC for treatment of CLDN18.2+ cancers. Both are now being investigated in phase I clinical studies.
Clinical Performance of hrHPV Primary Screening Using Vaginal versus Cervical Samples to Detect High-grade Intraepithelial Lesions
Authors: King Jonathan , Flores Yvonne N. , Meneses-León Joacim , Hernández-Salazar Sonia , Robles-Rivera Karina , Rivera-Paredez Berenice , León-Maldonado Leith , Hernández-López Rubí , Torres-Ibarra Leticia , Lazcano-Ponce Eduardo , Salmerón Jorge
Published: October 2023

High-risk human papillomavirus (hrHPV) testing is now the most recommended primary method for cervical cancer screening worldwide. Clinician-collected cervical sampling continues to be the main sampling method, but hrHPV vaginal self-sampling is an appealing alternative because of its greater acceptability and potentially higher cost-effectiveness. This study aimed to determine whether hrHPV vaginal self-sampling is comparable with clinician-collected cervical sampling for detecting histologically confirmed high-grade cervical intraepithelial neoplasia (CIN2/3) as part of a cervical cancer screening program in Mexico. We analyzed data from 5,856 women screened during a hrHPV-based screening study. Clinical performance and diagnostic efficiency metrics were estimated for the two sampling methods for the CIN3 and CIN2+ endpoints, using three triage strategies: HPV16/18 genotyping, HPV16/18/33/58 extended genotyping, and HPV16/18/31/33/58 extended genotyping. hrHPV-positivity was found in 801 (13.7%) cervical and 897 (15.3%) vaginal samples. All women with hrHPV-positive samples were referred to colposcopy, which detected 17 total CIN3 cases before considering retrospective triage strategies. Using the HPV16/18/31/33/58 extended genotyping strategy, 245 women had hrHPV-positive cervical samples and 269 had hrHPV-positive vaginal samples. Ten CIN3 cases were detected each among women with hrHPV-positive cervical samples and among those with hrHPV-positive vaginal samples when using this strategy, with no significant differences in sensitivity and specificity observed. We observe that self- and clinician-collected sampling methods are comparable for detecting CIN3 and CIN2+ regardless of the triage strategy used. These findings can help public health officials to develop more cost-effective cervical cancer screening programs that maximize participation.

Prevention Relevance:

We found that hrHPV vaginal self-sampling is comparable with hrHPV clinician cervical sampling when using any triage strategy to refer women to colposcopy, so self-sampling is a viable cervical screening method. Therefore, policymakers should consider incorporating self-sampling into cervical screening programs to increase screening coverage and reduce cervical cancer burden.

See related Spotlight, p. 649
Supplementary Data Figure 1 from Metastatic Competency and Tumor Spheroid Formation Are Independent Cell States Governed by RB in Lung Adenocarcinoma
Authors: Freeburg Nelson F. , Peterson Nia , Ruiz Dain A. , Gladstein Amy C. , Feldser David M.
Published: October 2023

Frt-flanked and lineage-marking tdTomato allele
FIGURE 5 from Metastatic Competency and Tumor Spheroid Formation Are Independent Cell States Governed by RB in Lung Adenocarcinoma
Authors: Freeburg Nelson F. , Peterson Nia , Ruiz Dain A. , Gladstein Amy C. , Feldser David M.
Published: October 2023

RB restoration reverses metastatic competency. A, Contingency analysis of the number of mice injected with single-cell suspensions produced from Group 1 tumor spheroids and treated with tamoxifen (RbR/R) or vehicle (RbTR/TR). Outcome of interest is tumor formation 5 weeks after injection. Statistical significance was assessed by χ2 test. For KP;RbTR/TR mice, n = 9, and for KP;RbR/R mice, n = 8. B, Number of tumors forming in mice five weeks after injection with single-cell suspensions produced from Group 1 tumor spheroids. Statistical significance assessed by Student t test. For KP;RbTR/TR mice, n = 9, and for KP;RbR/R mice, n = 8. Error bars represent mean ± SD. C, Lung mass in mice 5 weeks after injection with single-cell suspensions produced from Group 1 tumor spheroids. Statistical significance assessed by Student t test. For KP;RbTR/TR mice, n = 9, and for KP;RbR/R mice, n = 8. Error bars represent mean ± SD. D, Representative lung sections stained with hematoxylin and eosin from mice injected with single-cell suspensions produced from Group 1 tumor spheroids. Lung section images were taken with a Leica DMI6000 using a 5X objective.