bluuebunny/crossref_metadata_2025 huggingface dataset:
Transient states during the annealing of mismatched and bulged oligonucleotides
Authors: Todisco Marco , Ding Dian , Szostak Jack W
Published: February 2024

Oligonucleotide hybridization is crucial in various biological, prebiotic and nanotechnological processes, including gene regulation, non-enzymatic primer extension and DNA nanodevice assembly. Although extensive research has focused on the thermodynamics and kinetics of nucleic acid hybridization, the behavior of complex mixtures and the outcome of competition for target binding remain less well understood. In this study, we investigate the impact of mismatches and bulges in a 12 bp DNA or RNA duplex on its association (kon) and dissociation (koff) kinetics. We find that such defects have relatively small effects on the association kinetics, while the dissociation kinetics vary in a position-dependent manner by up to 6 orders of magnitude. Building upon this observation, we explored a competition scenario involving multiple oligonucleotides, and observed a transient low specificity of probe hybridization to fully versus partially complementary targets in solution. We characterize these long-lived metastable states and their evolution toward equilibrium, and show that sufficiently long-lived mis-paired duplexes can serve as substrates for prebiotically relevant chemical copying reactions. Our results suggest that transient low accuracy states may spontaneously emerge within all complex nucleic acid systems comprising a large enough number of competing strands, with potential repercussions for gene regulation in the realm of modern biology and the prebiotic preservation of genetic information.
A combinatorial approach for achieving CNS-selective RNAi
Authors: Ferguson Chantal M , Godinho Bruno M D C , Echeverria Dimas , Hassler Matthew , Vangjeli Lorenc , Sousa Jacquelyn , McHugh Nicholas , Alterman Julia , Hariharan Vignesh , Krishnamurthy Pranathi Meda , Watts Jonathan , Rogaev Eveny , Khvorova Anastasia
Published: February 2024

RNA interference (RNAi) is an endogenous process that can be harnessed using chemically modified small interfering RNAs (siRNAs) to potently modulate gene expression in many tissues. The route of administration and chemical architecture are the primary drivers of oligonucleotide tissue distribution, including siRNAs. Independently of the nature and type, oligonucleotides are eliminated from the body through clearance tissues, where their unintended accumulation may result in undesired gene modulation. Divalent siRNAs (di-siRNAs) administered into the CSF induce robust gene silencing throughout the central nervous system (CNS). Upon clearance from the CSF, they are mainly filtered by the kidneys and liver, with the most functionally significant accumulation occurring in the liver. siRNA- and miRNA-induced silencing can be blocked through substrate inhibition using single-stranded, stabilized oligonucleotides called antagomirs or anti-siRNAs. Using APOE as a model target, we show that undesired di-siRNA-induced silencing in the liver can be mitigated through administration of liver targeting GalNAc-conjugated anti-siRNAs, without impacting CNS activity. Blocking unwanted hepatic APOE silencing achieves fully CNS-selective silencing, essential for potential clinical translation. While we focus on CNS/liver selectivity, coadministration of differentially targeting siRNA and anti-siRNAs can be adapted as a strategy to achieve tissue selectivity in different organ combinations.
The Impact of Three Alternate Nicotine-Delivery Products on Combusted Cigarette Use: A Randomized Controlled Trial
Authors: Piper Megan E , Schlam Tanya R , Donny Eric C , Kobinsky Kate , Matthews Julia , Piasecki Thomas M , Jorenby Douglas E
Published: February 2024

Introduction

Smoking cessation is a critical public health goal. This study examined the ability of e-cigarettes and very low nicotine cigarettes (VLNCs) to serve as cigarette substitutes and whether a substitution was supported by steady-state nicotine from a nicotine patch.

Aims and Methods

This mixed design experiment with study product (between-subjects) and patch (within-subjects) factors recruited adults smoking cigarettes daily and not motivated to quit (N = 160). Participants were randomized to 4 weeks of: (1) VLNCs; (2) e-cigarettes; or (3) no product. During two switch weeks, one with an active nicotine patch and one with a placebo patch (in a double-blind and counterbalanced fashion), participants were told to not smoke their usual cigarettes.

Results

During the switch weeks, participants in the VLNC (M = 2.88, SD = .65) and e-cigarette (M = 3.20, SD = .63) groups smoked fewer of their own cigarettes per day than did no product group participants who continued to smoke their own cigarettes (M = 5.48, SD = .63); the VLNC and e-cigarette groups did not differ. There was no main effect of patch on mean usual brand cigarettes smoked per day (P = .09), nor was there a product × patch interaction (P = .51). There was a product × age interaction (P = .03); smokers aged 60–74 smoked more of their own cigarettes if they were randomized to no product group.

Conclusions

VLNCs and e-cigarettes appear to reduce usual brand cigarettes smoked per day to a similar degree, regardless of patch condition. Behavioral factors, in addition to nicotine dependence, play an important role in sustaining smoking behavior and need to be addressed in smoking cessation treatment.

Implications

This study found that behavioral substitutes for cigarettes, whether or not they delivered nicotine, reduced the number of usual brand cigarettes smoked. Specifically, both e-cigarettes delivering nicotine and VLNCs equally reduce usual brand cigarettes smoked among adults who smoke daily and do not want to quit.
Biological Control of Avocado Branch Blight Caused by Lasiodiplodia theobromae Using Bacillus velezensis
Authors: Li Xiaoyu , Tan Chenxing , Li Ping , Lin Lizhen , Zhou Jianuan , Tao Huan , Cai Yanfei
Published: February 2024

In recent years, avocado branch blight has gradually become one of the major diseases causing mortality of avocado trees, which seriously affects the economic development of avocado planting regions. In order to investigate the cause of the disease, the pathogens were isolated from the interroot of avocado trees with the onset of the disease and identified as Lasiodiplodia theobromae. At the same time, three Bacillus velezensis strains, YK194, YK201, and YK268, with better antagonistic effects and high stability against L. theobromae, were isolated from the rhizospheric soil of healthy avocado plants. The results of branch experiments and field trials showed that the avocado leaves as well as branches treated with the strains YK194, YK201, and YK268 did not develop disease, and the incidence of avocado trees was significantly reduced. In the branch experiments, the biological control effect of the strains YK194, YK201, and YK268 reached 62.07, 52.70, and 72.45%, respectively. In the field experiments, it reached 63.85, 63.43, and 73.86%, respectively, which indicated that all these three strains possessed good biological control effects on avocado branch blight. Further investigation on the mechanism of action of antagonistic strains revealed that B. velezensis YK268 could produce lipopeptides, namely, surfactin, fengycin, and iturin, which could significantly inhibit the spore germination of L. theobromae. Consequently, these three isolates have potential as biocontrol agents against L. theobromae.
Endophytic Streptomyces sp. NEAU-DD186 from Moss with Broad-Spectrum Antimicrobial Activity: Biocontrol Potential Against Soilborne Diseases and Bioactive Components
Authors: Gao Congting , Wang Zhiyan , Wang Chengqin , Yang Jingquan , Du Rui , Bing Hui , Xiang Wensheng , Wang Xiangjing , Liu Chongxi
Published: February 2024

Soilborne diseases cause significant economic losses in agricultural production around the world. They are difficult to control because a host plant is invaded by multiple pathogens, and chemical control often does not work well. In this study, we isolated and identified an endophytic Streptomyces sp. NEAU-DD186 from moss, which showed broad-spectrum antifungal activity against 17 soilborne phytopathogenic fungi, with Bipolaris sorokiniana being the most prominent. The strain also exhibited strong antibacterial activity against soilborne phytopathogenic bacteria Ralstonia solanacearum. To evaluate its biocontrol potential, the strain was prepared into biofertilizer by solid-state fermentation. Response surface methodology was employed to optimize the fermentation conditions for maximizing spore production and revealed that the 1:1 ratio of vermicompost to wheat bran, a temperature of 28°C, and 50% water content with an inoculation amount of 15% represented the optimal parameters. Pot experiments showed that the application of biofertilizer with a spore concentration of 108 CFU/g soil could effectively suppress the occurrence of tomato bacterial wilt caused by R. solanacearum and wheat root rot caused by B. sorokiniana, and the biocontrol efficacy was 81.2 and 72.2%, respectively. Chemical analysis of strain NEAU-DD186 extracts using nuclear magnetic resonance spectrometry and mass analysis indicated that 25-O-malonylguanidylfungin A and 23-O-malonylguanidylfungin A were the main active constituents, which showed high activity against R. solanacearum (EC50 of 2.46 and 2.58 µg ml−1) and B. sorokiniana (EC50 of 3.92 and 3.95 µg ml−1). In conclusion, this study demonstrates that Streptomyces sp. NEAU-DD186 can be developed as biofertilizer to control soilborne diseases.
The Story of ECMO
Authors: Bartlett Robert H.
Published: February 2024

Extracorporeal Circulation in Neonatal Respiratory Failure: A Prospective Randomized Study. By RH Bartlett, DW Roloff, RG Cornell, AF Andrews, PW Dillon, JB Zwischenberger. Pediatrics 1985; 76:479–87.

Extracorporeal membrane oxygenation (ECMO) is the use of mechanical devices to replace cardiac and pulmonary function in critical care. In the 1960s, laboratory research showed that extracorporeal circulation could be maintained for days using a membrane oxygenator. In the 1970s, the first clinical trials showed that ECMO could sustain life in severe cardiac and pulmonary failure for days or weeks, leading to organ recovery. From 1980 to 2000, ECMO became standard practice for neonatal and pediatric respiratory and cardiac failure. The critical clinical trial was a prospective randomized trial of ECMO in newborn respiratory failure, published in 1985. This is the classic article reviewed in this publication. This was the first use of a randomized, adaptive design trial to minimize the potential ethical dilemma inherent to clinical trials in which the endpoint is death. Other randomized trials followed, and ECMO is now standard practice for severe respiratory and cardiac failure in all age groups.
Incidence and Prevalence of Pain Medication Prescriptions in Pathologies with a Potential for Chronic Pain
Authors: Goudman Lisa , Moens Maarten , Pilitsis Julie G.
Published: February 2024

Background

Heightened risks of dependence, addiction, anxiolytic effects, or prescription overdose death due to long-term use of pain medication have increased awareness about extended pain medication use in chronic pain populations. The goal of this study was to evaluate the incidence and prevalence of pain medication prescriptions from 2012 to 2022 in common pathologies with a potential for chronic pain.

Methods

A retrospective cohort study was conducted using electronic health records from TriNetX (Cambridge, Massachusetts) Global Collaborative Network. For 10 distinct cohorts (total n = 9,357,584 patients), pain medication prescriptions were extracted for five classes, namely nonsteroidal anti-inflammatory drug (NSAIDs) and acetaminophen, opioids, gabapentinoids, neuropathic mood agents, and muscle relaxants. Annual incidence and prevalence of each class of medication were evaluated for the past 11 yr.

Results

From 2012 to 2022, there was a significant increase in prescriptions of NSAIDs, except for patients with fibromyalgia, and persistent spinal pain syndrome (PSPS) type 2. Interestingly, over time, prescriptions of opioids in patients with complex regional pain syndrome, endometriosis, osteoarthritis, and PSPS type 2 increased, as did prescriptions of muscle relaxants for all cohorts except those with fibromyalgia. Incidence of prescriptions of neuropathic mood agents is high for patients with complex regional pain syndrome (both types) and PSPS type 2. Only for benzodiazepines did there seem to be a decline over the years, with a significantly decreased time trend in patients with complex regional pain syndrome type 1, fibromyalgia, and PSPS type 2.

Conclusions

During the last 11 yr, an increase in incidence of NSAIDs and acetaminophen, opioids, neuropathic agents, and muscle relaxants was observed. Only prescriptions of benzodiazepines significantly decreased over time in specific cohorts. Overall, patients with PSPS type 2 and complex regional pain syndrome (both types) consume a broad variety of pain medication classes.

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Migraines, vasomotor symptoms, and cardiovascular disease in the Coronary Artery Risk Development in Young Adults study
Authors: Kim Catherine , Schreiner Pamela J. , Yin Zhe , Whitney Rachael , Sidney Stephen , Ebong Imo , Levine Deborah A.
Published: February 2024

Objective

To examine whether vasomotor symptoms (VMS) and migraine headaches, hypothesized to be vasoactive conditions, are associated with greater risk for cardiovascular disease (CVD) events including strokes.

Methods

We performed a secondary data analysis of a subset of women (n = 1,954) in the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based cohort, which began data collection at 18 to 30 y of age. We examined whether migraine headaches and VMS trajectories (characterized as minimal, increasing, and persistent) at CARDIA year 15 examination were associated with higher risk of CVD events and stroke (both ischemic and hemorrhagic) using Cox proportional hazards regression models and adjustment for traditional CVD risk factors (age, cigarette use, and levels of systolic and diastolic blood pressure, fasting glucose, high- and low-density cholesterol, and triglycerides) and reproductive factors.

Results

Among women with minimal VMS (n = 835), increasing VMS (n = 521), and persistent VMS (n = 598), there were 81 incident CVD events including 42 strokes. Women with histories of migraine and persistent VMS had greater risk of CVD (hazard ratio [HR], 2.25; 95% CI, 1.15-4.38) after adjustment for age, race, estrogen use, oophorectomy, and hysterectomy compared with women without migraine histories and with minimal/increasing VMS. After adjustment for CVD risk factors, these associations were attenuated (HR, 1.51; 95% CI, 0.73-3.10). Similarly, women with histories of migraine and persistent VMS had greater risk of stroke (HR, 3.15; 95% CI, 1.35-7.34), but these associations were attenuated after adjustment for CVD risk factors (HR, 1.70; 95% CI, 0.66-4.38).

Conclusions

Migraines and persistent VMS jointly associate with greater risk for CVD and stroke, although risk is attenuated with adjustment for traditional CVD risk factors.
Regional Variations in Corneal Epithelial Cell Density and Morphology Assessed Using In Vivo Confocal Microscopy
Authors: Bhattacharya Pradipta , Edwards Katie , Schmid Katrina L.
Published: February 2024

Aim:

To characterize the regional variations in corneal epithelial cell density and morphology using in vivo confocal microscopy (IVCM).

Methods:

Corneal imaging (IVCM) at 10 locations was performed; corneal apex (i.e., the center), immediately anterior to the corneal nerve whorl (i.e., slightly inferior to the apex), and four quadrants (superior, nasal, inferior, and temporal) both at 1.5 mm and 4.5 mm from the corneal apex (corresponding to 3 mm central and 9 mm peripheral diameter rings). The data of 21 young adults, aged 18 to 35 years, were analyzed. Cell morphometric parameters, including cell density, area, perimeter, Feret diameter, and circularity, were measured for basal and wing cells using Image J software.

Results:

There was a significant difference in basal cell density (BCD) (P<0.001) and wing cell density (WCD) (P<0.001) for different corneal locations. The BCD (mean±SD: 8,839±416 cells/mm2) and WCD (mean±SD: 5,932±310 cells/mm2) were highest at the corneal nerve whorl compared with all other corneal locations. There were significant differences in wing cell area (P<0.001), perimeter (P<0.001), Feret diameter (P<0.001), and circularity (P<0.001) at varying corneal locations.

Conclusion:

There are significant regional variations in corneal epithelial cell density and morphology. The BCD and WCD was highest anterior to the corneal nerve whorl.
Innovative utilization of ultra-wide field fundus images and deep learning algorithms for screening high-risk posterior polar cataract
Authors: Mai Elsa L.C. , Chen Bing-Hong , Su Tai-Yuan
Published: February 2024

Purpose:

To test a cataract shadow projection theory and validate it by developing a deep learning algorithm that enables automatic and stable posterior polar cataract (PPC) screening using fundus images.

Setting:

Department of Ophthalmology, Far Eastern Memorial Hospital, New Taipei, Taiwan.

Design:

Retrospective chart review.

Methods:

A deep learning algorithm to automatically detect PPC was developed based on the cataract shadow projection theory. Retrospective data (n = 546) with ultra-wide field fundus images were collected, and various model architectures and fields of view were tested for optimization.

Results:

The final model achieved 80% overall accuracy, with 88.2% sensitivity and 93.4% specificity in PPC screening on a clinical validation dataset (n = 103).

Conclusions:

This study established a significant relationship between PPC and the projected shadow, which may help surgeons to identify potential PPC risks preoperatively and reduce the incidence of posterior capsular rupture during cataract surgery.
Quality of vision and tear film osmolarity
Authors: Gallagher David , Hurley Daire J. , O'Tuama Brian , Hughes Emily , Fulcher Tim
Published: February 2024

SIGNIFICANCE

We evaluate the relationship between tear film osmolarity measurements and quality of vision in patients presenting for routine eye clinic appointments. We found that the hyperosmolar group (>316 mOsm/L) had a worse quality-of-vision score than the normal osmolarity group, with glare being the most problematic symptom.

PURPOSE

Quality of vision is a perception and measure of real-world vision, which is not measured routinely in a clinical setting. This study aimed to evaluate the relationship between tear film osmolarity measurements and quality of vision in patients presenting for routine eye clinic appointments.

METHODS

This was an observational nonrandomized study. The participants were placed in groups based on tear film osmolarity (normal, ≤316 mOsm/L; hyperosmolar, >316 mOsm/L; or a difference of >8 mOsm/L between each eye). Thirty-three participants were enrolled in the study, of whom 22 were deemed to have a hyperosmolar tear film. A 30-item questionnaire including 10 symptoms rated on scales of frequency, severity, and bothersomeness was administered to participants in both groups. The quality-of-vision score ranged from 25 to 100 points, with lower scores indicating better quality of vision.

RESULTS

The hyperosmolar group had a significantly worse quality-of-vision score than the normal osmolarity group across all three scales; mean differences for frequency, severity, and bothersomeness were 12.66 ± 9.75 (p=0.003), 9.44 ± 7.45 (p=0.003), and 11.90 ± 11.14 (p=0.008), respectively. Of the 10 symptoms that were included in the questionnaire, glare was the most problematic in the hyperosmolar group.

CONCLUSIONS

In this study, we demonstrated a significant relationship between tear film hyperosmolarity and quality of vision, as patients with hyperosmolar tear films had worse quality of vision
Journey to 1 Million Steps: A Retrospective Case Series Analyzing the Implementation of Robotic-Assisted Gait Training Into an Outpatient Pediatric Clinic
Authors: Dierwechter Brittany , Kolakowsky-Hayner Stephanie A.
Published: February 2024

Purpose:

To describe the implementation of an exoskeleton program in a rehabilitation setting using a Design Thinking framework.

Methods:

This is a retrospective case series of 3 randomly selected children who participated in skilled physical therapy using a pediatric exoskeleton that occurred on our journey to walking 1 000 000 steps in the exoskeleton devices. Participants ranged in age from 3 to 5 years, and all had neurologic disorders.

Results:

All participants improved toward achieving their therapy goals, tolerated the exoskeleton well, and had an increased number of steps taken over time.

Conclusion:

The implementation of new technology into pediatric care and an established outpatient therapy clinic is described. The Design Thinking process applies to health care professionals and improves clinical care. Exoskeletons are effective tools for use in pediatric physical therapy.
Differences in internalized HIV stigma across subpopulations of people with HIV in care across the United States
Authors: Drumright Lydia N. , Johnson Mallory O. , Mayer Kenneth H. , Christopoulos Katerina , Cachay Edward , Crawford Timothy N. , Whitney Bridget M. , Dai Mindy , Ruderman Stephanie A. , Mixson L. Sarah , Keruly Jeanne C. , Chander Geetanjali , Saag Michael S. , Kitahata Mari M. , Moore Richard D. , Willig Amanda L. , Eron Joseph J. , Napravnik Sonia , Nance Robin M. , Hahn Andrew , Ma Jimmy , Bamford Laura , Fredericksen Rob J. , Delaney Joseph A.C. , Crane Heidi M.
Published: February 2024

Background:

Few studies have examined which subgroups of people with HIV (PWH) carry the greatest burden of internalized HIV stigma (IHS), which may be important to care provision and interventions.

Methods:

PWH in the CFAR Network of Integrated Clinical Systems (CNICS) longitudinal, US-based, multisite, clinical care cohort completed tablet-based assessments during clinic visits including a four-item, Likert scale (low 1–5 high), IHS instrument. Associations between sociodemographic characteristics and IHS scores were assessed in adjusted linear regression models.

Results:

Twelve thousand six hundred and fifty-six PWH completed the IHS assessment at least once from February 2016 to November 2022, providing 28 559 IHS assessments. At baseline IHS assessment, the mean age was 49 years, 41% reported White, 38% Black/African American, and 16% Latine race/ethnicity, and 80% were cisgender men. The mean IHS score was 2.04, with all subgroups represented among those endorsing IHS. In regression analyses, younger PWH and those in care fewer years had higher IHS scores. In addition, cisgender women vs. cisgender men, PWH residing in the West vs. the Southeast, and those with sexual identities other than gay/lesbian had higher IHS scores. Compared with White-identifying PWH, those who identified with Black/African American or Latine race/ethnicity had lower IHS scores. Age stratification revealed patterns related to age category, including specific age-related differences by gender, geographic region and race/ethnicity.

Discussion:

IHS is prevalent among PWH, with differential burden by subgroups of PWH. These findings highlight the benefits of routine screening for IHS and suggest the need for targeting/tailoring interventions to reduce IHS among PWH.
Coexistence of Langerhans Cell Histiocytosis and Ganglioneuroblastoma Revealed by 18F-FDG PET/CT in a Pediatric Patient
Authors: Xu Yanfeng , Lu Xia , Wang Wei , Yang Jigang
Published: February 2024

Coexistence of Langerhans cell histiocytosis and ganglioneuroblastoma is rare and seldom reported in the literature. A 3-year-old girl with Langerhans cell histiocytosis underwent 18F-FDG PET/CT imaging for staging, which demonstrated significant 18F-FDG accumulation in the mandibles. Unexpectedly, a mild hypermetabolic soft mass was detected in the upper retroperitoneum. Results of surgical pathology of the abdominal mass were consistent with ganglioneuroblastoma.
Gastroesophageal Reflux Revealed by 18F-MFBG PET/CT
Authors: He Jian , Yang Liqing , He Limeng , Zhang Wei , Guo Lu
Published: February 2024

A 56-year-old woman who had a lung transplant 4 months ago presented frequent vomiting for 1 month. Barium meal and 99mTc gastroesophageal scintigraphy showed no gastroesophageal reflux. The patient was enrolled in a clinical trial and underwent 18F-MFBG PET/CT dynamic imaging. At the seventh minute of dynamic imaging, the images revealed reflux from the cardia into the esophagus and reached the oral cavity.
Uncommon Detection of Leiomyoma in the Penile Corpus Spongiosum Using FDG PET/CT
Authors: Hod Nir , Levin Daniel , Ben-Arie Gal , Pinsk Ilia , Osyntsov Lidia , Mekayten Matan
Published: February 2024

Primary tumors of the penile corpus spongiosum are rare. Hereby we describe the scintigraphic findings of a case of penile leiomyoma within the corpus spongiosum tissue, which was incidentally detected on FDG PET/CT. The benign neoplasm was growing in close proximity to the urethra showing increased focal FDG uptake on sequential PET/CT studies. Subsequently, the patient experienced obstructive urinary symptoms, and the tumor was resected. We concluded that the possibility of neoplasm should be kept in mind while evaluating a patient with persistent focal penile FDG uptake, which may be the first and only manifestation of the disease.
Mitral Annular Calcification as a Potential False-Positive for Cardiac Amyloidosis in 99mTc-DPD Scintigraphy Accurately Identified by SPECT/CT
Authors: Nunes Ana Rita Pereira , Alves Victor Manuel
Published: February 2024

99mTc-PYP/DPD/HDMP cardiac scintigraphy has a pivotal role in the diagnosis of ATTR cardiac amyloidosis. The combined findings of a Perugini visual score of 2 or 3 in the scan and the absence of monoclonal proteins in blood and urine are highly specific for the diagnosis of ATTR cardiac amyloidosis without a tissue biopsy. We report a case of mitral annular and valve calcification accurately identified in the SPECT/CT, but which could be misinterpreted as ATTR cardiac amyloidosis if only acquiring planar and SPECT images.
Unveiling Neurobrucellosis: A Case Report Emphasizing Early Diagnosis for Better Outcomes
Authors: Haripriya Sivakumar , Malhotra Shikhir , Gadepalli Ravisekhar , Tak Vibhor , Kumar Bharat
Published: February 2024

Introduction. Brucellosis is a pervasive zoonotic disease causing considerable human morbidity worldwide. This report focuses on a case of neurobrucellosis in a rural Indian patient, emphasizing the need for timely microbiological confirmation given its nonspecific clinical presentation.

Case Presentation. A 55-year-old rural Indian farmer presented with a 3 week history of insidious, low-grade fever, myalgia, and arthralgia. He developed acute right-sided weakness and neurological symptoms, including disorientation and neck rigidity. Laboratory tests indicated abnormal blood counts, elevated inflammatory markers, and liver dysfunction. Cerebrospinal fluid analysis showed pleocytosis with lymphomononuclear cells and elevated protein levels. Blood cultures eventually grew Gram-negative coccobacilli. Serological tests confirmed neurobrucellosis. Prompt antibiotic therapy led to clinical and laboratory improvement.

Conclusion. This case underscores the importance of recognizing neurobrucellosis, particularly in endemic areas, given its nonspecific clinical presentation. Early microbiological diagnosis, supported by positive blood cultures and serological tests, was crucial. The patient’s rapid response to appropriate antibiotics emphasizes the significance of timely recognition and management.
Neurobiological slowdown in later life manifests in tempo of popular music
Authors: Luck Geoff
Published: February 2024

Degradation of motor control across the adult lifespan due to neurobiological decay is well-established. Correspondences between the dynamics of motor behaviour and the timing of musical performance are also well-documented. In light of the former, the conspicuous absence of age as a mediating factor in investigation of the latter reveals a remarkable gap in our understanding of creative performance across the life course. To examine effects of ageing on musical timing, physical tempo of almost 2000 songs released by top-tier recording artists over their decades-long careers were annotated via a listening and tapping task. A series of regression analyses revealed i) an age-driven downward trend in performance tempo for all artists, ii) significant between-artist variation across time, and iii) within-artist variation that was independent of broader musical trends. Overall, tempo decreased by almost one and a half standard deviations from artists’ early twenties to their late fifties, a rate of decline comparable to that observed in studies of spontaneous motor tempo. Results are consistent with the slowing-with-age hypothesis, and reveal that, not only is such tempo decline discernible in commercial recordings, the impact of age on tempo is overwhelming for artists most physically connected with their music.
Assessing the effects of an 8-week mindfulness training program on neural oscillations and self-reports during meditation practice
Authors: Rodriguez-Larios Julio , Wong Kian Foong , Lim Julian
Published: February 2024

Previous literature suggests that mindfulness meditation can have positive effects on mental health, however, its mechanisms of action are still unclear. In this pre-registered study, we investigate the effects of mindfulness training on lapses of attention (and their associated neural correlates) during meditation practice. For this purpose, we recorded Electroencephalogram (EEG) during meditation practice before and after 8 weeks of mindfulness training (or waitlist) in 41 participants (21 treatment and 20 controls). In order to detect lapses of attention and characterize their EEG correlates, we interrupted participants during meditation to report their level of focus and drowsiness. First, we show that self-reported lapses of attention during meditation practice were associated to an increased occurrence of theta oscillations (3-6 Hz), which were slower in frequency and more spatially widespread than theta oscillations occurring during focused attention states. Then, we show that mindfulness training did not reduce the occurrence of lapses of attention nor their associated EEG correlate (i.e. theta oscillations) during meditation. Instead, we find that mindfulness training was associated with a significant slowing of alpha oscillations in frontal electrodes during meditation. Crucially, frontal alpha slowing during meditation practice has been reported in highly experienced meditators and is thought to reflect relative decreases in arousal levels. Together, our findings provide insights into the EEG correlates of mindfulness meditation, which could have important implications for the identification of its mechanisms of action and/or the development of neuromodulation protocols aimed at facilitating meditation practice.
Genetic newborn screening stakeholder perspectives
Authors: Kariyawasam Didu , Scarfe Joanne , Meagher Christian , Farrar Michelle A. , Bhattacharya Kaustav , Carter Stacy M. , Newson Ainsley J. , Otlowski Margaret , Watson Jo , Millis Nicole , Norris Sarah
Published: February 2024

Background

Newborn bloodspot screening is a well-established population health initiative that detects serious, childhood-onset, treatable conditions to improve health outcomes. With genomic technologies advancing rapidly, many countries are actively discussing the introduction of genomic assays into newborn screening programs. While adding genomic testing to Australia’s newborn screening program could improve outcomes for infants and families, it must be considered against potential harms, ethical, legal, equity and social implications, and economic and health system impacts. We must ask not only ‘can’we use genomics to screen newborns?’ but‘should we’?’ and ‘how much should health systems invest in genomic newborn screening?’.

Methods

This study will use qualitative methods to explore understanding, priorities, concerns and expectations of genomic newborn screening among parents/carers, health professionals/scientists, and health policy makers across Australia. In-depth, semi-structured interviews will be held with 30-40 parents/carers recruited via hospital and community settings, 15-20 health professionals/scientists, and 10-15 health policy makers. Data will be analysed using inductive content analysis. The Sydney Children’s Hospital Network Human Research Ethics Committee approved this study protocol [2023/ETH02371]. The Standards for Reporting Qualitative Research will guide study planning, conduct and reporting.

Discussion

Few studies have engaged a diverse range of stakeholders to explore the implications of genomics in newborn screening in a culturally and genetically diverse population, nor in a health system underpinned by universal health care. As the first study within a multi-part research program, findings will be used to generate new knowledge on the risks and benefits and importance of ethical, legal, social and equity implications of genomic newborn screening from the perspective of key stakeholders. As such it will be the foundation on which child and family centered criteria can be developed to inform health technology assessments and drive efficient and effective policy decision-making on the implementation of genomics in newborn screening.
Glyoxalase 1: emerging biomarker and therapeutic target in cervical cancer progression
Authors: Kim Ji-Young , Jung Ji-Hye , Jung Soryung , Lee Sanghyuk , Lee Hyang Ah , Ouh Yung-Taek , Hong Seok-Ho
Published: February 2024

Introduction

Cervical cancer presents a significant global health challenge, disproportionately impacting underserved populations with limited access to healthcare. Early detection and effective management are vital in addressing this public health concern. This study focuses on Glyoxalase-1 (GLO1), an enzyme crucial for methylglyoxal detoxification, in the context of cervical cancer.

Methods

We assessed GLO1 expression in cervical cancer patient samples using immunohistochemistry.In vitroexperiments using HeLa cell lines were conducted to evaluate the impact of GLO1 inhibition on cell viability and migration. Single-cell RNA sequencing (scRNA-seq) and gene set variation analysis were utilized to investigateGLO1’s role in the metabolism of cervical cancer. Additionally, public microarray data were analyzed to determineGLO1expression across various stages of cervical cancer.

Results

Our analysis included 58 cervical cancer patients, and showed that GLO1 is significantly upregulated in cervical cancer tissues compared to normal cervical tissues, independent of pathological findings and disease stage.In vitroexperiments indicated thatGLO1downregulation decreased cell viability and migration in cervical cancer cell lines. Analyses of scRNA-seq data and public gene expression datasets corroborated the overexpression ofGLO1and its involvement in cancer metabolism, particularly glycolysis. An examination of expression data from precancerous lesions revealed a progressive increase inGLO1expression from normal tissue to invasive cervical cancer.

Conclusions

This study highlights the critical role of GLO1 in the progression of cervical cancer, presenting it as a potential biomarker and therapeutic target. These findings contribute valuable insights towards personalized treatment approaches and augment the ongoing efforts to combat cervical cancer. Further research is necessary to comprehensively explore GLO1’s potential in clinical applications.

Synopsis

This study examines Glyoxalase-1 (GLO1) in cervical cancer and reveals its significant upregulation in cancerous tissues compared to normal counterparts.In vitroexperiments show that downregulating GLO1 decreases cell viability and migration. Single-cell RNA sequencing and gene expression analysis substantiate GLO1’s involvement in cancer metabolism, notably in glycolysis. These findings identify GLO1 as a potential biomarker and therapeutic target, offering insights for personalized treatment approaches in cervical cancer management.
Quantification of [11C]ABP688 binding in human brain using cerebellum as reference region: biological interpretation and limitations
Authors: Milella Michele S , Minuzzi Luciano , Benkelfat Chawki , Soucy Jean-Paul , Kirlow Alexandre , Schirrmacher Esther , Angle Mark , Verhaeghe Jeroen AJ , Massarweh Gassan , Reader Andrew J , Aliaga Antonio , Peixoto-Santos Jose Eduardo , Guiot Marie-Christine , Kobayashi Eliane , Rosa-Neto Pedro , Leyton Marco
Published: February 2024

In vitrodata from primates provide conflicting evidence about the cerebellum’s suitability as a reference region for quantifying type 5 metabotropic glutamate receptor (mGluR5) binding parameters with positron emission tomography (PET). To address this, we first measured mGluR5 density in postmortem human cerebellum using [3H]ABP688 autoradiography (n=5) and immunohistochemistry (n=6). Next,in vivoexperiments were conducted in healthy volunteers (n=6) using a high-resolution PET scanner (HRRT) to compare [11C]ABP688 binding potential (BPND) values obtained with reference tissue methods and the two-tissue compartment model vs. metabolite-corrected arterial input function. The postmortem data showed that, relative to the hippocampus, the cerebellum had 26% less mGluR5 immunoreactivity and 94% fewer [3H]ABP688 binding sites.In vivobrain regional [11C]ABP688 BPNDvalues using the cerebellum as a reference region were highly correlated with BPNDvalues and distribution volumes derived by arterial input methods (R2> 0.9). The absence of cerebellar allosteric binding sites might reflect the presence of distinct mGluR5 isoforms or conformational state. Together with our PET data, these results support the proposition that [11C]ABP688 BPNDusing cerebellum as a reference region provides accurate quantification of mGluR5 allosteric bindingin vivo.
A proteogenomic analysis of the adiposity colorectal cancer relationship identifies GREM1 as a probable mediator
Authors: Lee Matthew A , Hatcher Charlie A , Hazelwood Emma , Goudswaard Lucy J , Tsilidis Konstantinos K , Vincent Emma E , Martin Richard M , Smith-Byrne Karl , Brenner Hermann , Cheng Iona , Kweon Sun-Seog , Le Marchand Loic , Newcomb Polly A , Schoen Robert E , Peters Ulrike , Gunter Marc J , Van Guelpen Bethany , Murphy Neil
Published: February 2024

Adiposity is an established risk factor for colorectal cancer (CRC). However, the pathways underlying this relationship, and specifically the role of the circulating proteome, is unclear.

Utilizing two-sample Mendelian randomization and colocalization, based on summary data from large sex-combined and sex-specific genetic studies, we estimated the univariable (UV) associations between: (I) adiposity measures (body mass index, BMI; waist hip ratio, WHR) and overall and site-specific (colon, proximal colon, distal colon, and rectal) CRC risk, (II) adiposity measures and plasma proteins, and (III) adiposity-associated plasma proteins and CRC risk. We used multivariable MR (MVMR) to investigate the potential mediating role of adiposity- and CRC-related proteins in the adiposity-CRC association.

BMI and WHR were positively associated with CRC risk, with similar associations by anatomical tumour site. 6,591 adiposity-protein (2,628 unique proteins) and 33 protein-CRC (8 unique proteins) associations were identified using UVMR and colocalization. 1 protein, GREM1 was associated with BMI only and CRC outcomes in a manner that was consistent with a potential mediating role in sex-combined and female-specific analyses. In MVMR, adjusting the BMI-CRC association for GREM1, effect estimates were attenuated - suggestive of a potential mediating role - most strongly for the BMI-overall CRC association in women.

These results highlight the impact of adiposity on the plasma proteome and of adiposity-associated circulating proteins on the risk of CRC. Supported by evidence fromcis-SNP UVMR and colocalization analyses, GREM1 was identified as a potential mediator of the BMI-CRC association, particularly in women, and warrants further experimental investigation.
The ChAHP chromatin remodelling complex regulates neurodevelopmental disorder risk genes to scale the production of neocortical layers
Authors: Clémot-Dupont Samuel , Lourenço Fernandes José Alex , Larrigan Sarah , Sun Xiaoqi , Medisetti Suma , Stanley Rory , Hankouri Ziyad El , Joshi Shrilaxmi V. , Picketts David J. , Shekhar Karthik , Mattar Pierre
Published: February 2024

Although chromatin remodellers are among the most important risk genes associated with neurodevelopmental disorders (NDDs), the roles of these complexes during brain development are in many cases unclear. Here, we focused on the recently discovered ChAHP chromatin remodelling complex. The zinc finger and homeodomain transcription factor ADNP is a core subunit of this complex, andde novo ADNPmutations lead to intellectual disability and autism spectrum disorder. However, germlineAdnpknockout mice were previously shown to exhibit early embryonic lethality, obscuring subsequent roles for the ChAHP complex in neurogenesis. Here, we employed single cell transcriptomics, cut&run-seq, and histological approaches to characterize mice conditionally ablated for the ChAHP subunitsAdnpandChd4. We show that during neocortical development, Adnp and Chd4 orchestrate the production of late-born, upper-layer neurons through a two-step process. First, Adnp is required to sustain progenitor proliferation specifically during the developmental window for upper-layer cortical neurogenesis. Accordingly, we found that Adnp recruits Chd4 to genes associated with progenitor proliferation. Second, in postmitotic differentiated neurons, we define a network of risk genes linked to NDDs that are regulated by Adnp and Chd4. Taken together, these data demonstrate that ChAHP is critical for driving the expansion upper-layer cortical neurons, and for regulating neuronal gene expression programs, suggesting that these processes may potentially contribute to NDD etiology.

Highlights

AdnpandChd4cKOs exhibit similar deficits in cortical growth

Adnp sustains the proliferation of apical progenitors to scale the production of upper-layer neurons

Adnp recruits Chd4 to genes involved in corticogenesis

Adnp is a master regulator of risk genes associated with neurodevelopmental disorders
One to rule them all? Assessing the performance of sustainable forest management indicators against multitaxonomic data for biodiversity conservation
Authors: Paillet Yoan , Zapponi Livia , Schall Peter , Monnet Jean-Matthieu , Ammer Christian , Balducci Lorenzo , Boch Steffen , Brazaitis Gediminas , Campanaro Alessandro , Chianucci Francesco , Doerfler Inken , Fischer Markus , Gosselin Marion , Gossner Martin M. , Heilmann-Clausen Jacob , Hofmeister Jenyk , Hosek Jan , Jung Kisten , Kepfer-Rojas Sebastian , Odor Peter , Tinya Flora , Trentanovi Giovanni , Vacchiano Giorgio , Vandekerkhove Kris , Weisser Wolfgang W. , Wohlwend Michael , Burrascano Sabina
Published: February 2024

Several regional initiatives and reporting efforts assess the state of forest biodiversity through broad-scale indicators based on data from national forest inventories. Although valuable, these indicators are essentially indirect and evaluate habitat quantity and quality rather than biodiversity per se. Therefore, their link to biodiversity may be weak, which decreases their usefulness for decision-making. For several decades, Forest Europe indicators assessed the state of European forests, in particular their biodiversity. However, no extensive study has been conducted to date to assess their performance - i.e. the capacity of the indicators to reflect variations in biodiversity - against multitaxonomic data. We hypothesized that no single biodiversity indicator from Forest Europe can represent overall forest biodiversity, but that several indicators would reflect habitat quality for at least some taxa in a comprehensive way. We tested the set of Forest Europe's indicators against the species richness of six taxonomic and functional groups across several hundreds of sampling units over Europe. We showed that, while some indicators perform relatively well across groups (e.g. deadwood volume), no single indicator represented all biodiversity at once, and that a combination of several indicators performed better. Forest Europe indicators were chosen for their availability and ease of understanding for most people. However, we showed that gaps in the monitoring framework persist, and that surveying certain taxa along with stand structure is necessary to support policymaking and tackle forest biodiversity loss at the large scale. Adding context (e.g. forest type) may also contribute to increase the performance of biodiversity indicators.
De novoORFs are more likely to shrink than to elongate during neutral evolution
Authors: Lebherz Marie Kristin , Iyengar Bharat Ravi , Bornberg-Bauer Erich
Published: February 2024

For protein coding genes to emergede novofrom a non-genic DNA, the DNA sequence must gain an open reading frame (ORF) and the ability to be transcribed. The newbornde novogene can further evolve to accumulate changes in its sequence. Consequently, it can also elongate or shrink with time. Existing literature shows that olderde novogenes have longer ORF, but it is not clear if they elongated with time or remained of the same length since their inception. To address this question we developed mathematical model of ORF elongation as a Markov-jump process, and show that ORFs tend to keep their length in short evolutionary timescales. We also show that if change occurs it is likely to be a truncation. Our genomics and transcriptomics data analyses of sevenDrosophila melanogasterpopulations is also in agreement with the model’s prediction. We conclude that selection could facilitate ORF length extension that may explain why longer ORFs were observed in oldde novogenes in studies analysing longer evolutionary time scales.

Significance

New protein coding genes can emerge from non-genic DNA through a process calledde novogene emergence. Genes thus emerged usually have a small open reading frame (ORF). However, studies show thatde novogenes with an older evolutionary origin have longer ORF than younger genes. To understand how ORF length evolves, we use a combination of mathematical modeling and population level genome data analysis. We find that in the absence of evolutionary selection, ORFs tend to become shorter than becoming longer. Therefore, long ORFs are probably selected by evolution to be retained in the genome.
Sensing the bactericidal and bacteriostatic antimicrobial mode of action using Raman-Deuterium stable isotope probing (DSIP)
Authors: Karlo Jiro , Vijay Arun Sree , Phaneeswar Mahamkali Sri , Pratap Singh Surya
Published: February 2024

The mode of actions of antibiotics can be broadly classified as bacteriostatic and bactericidal. The bacteriostatic mode leads to the arrested growth of the cells while the bactericidal mode causes cell death. In this work, we report the applicability of Deuterium stable isotope probing (DSIP) in combination with Raman spectroscopy (Raman DSIP) for discrimination among antibiotics on the basis of their mode of action at community level. We optimized the concentration of deuterium oxide required for metabolic activity monitoring without compromising the microbial growth. We also identified a novel carbon-deuterium Raman metabolic qualitative spectral marker in the biofingerprint region. This can be used for early identification of the antibiotic’s mode of action. Our results explores the new perspective which supports the utility of Deuterium based vibrational tags in the field of clinical spectroscopy. Understanding the antibiotic’s mode of action on bacterial cells in a short and objective manner can significantly enhance the clinical management abilities of infectious diseases and may also help in personalised antimicrobial therapy.

Abstract Figure