bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of Nirmatrelvir-Ritonavir for the Prevention of COVID-19–Related Hospitalization and Mortality: A Systematic Literature Review
Authors: Cha-Silva Ashley S. , Gavaghan Meghan B. , Bergroth Tobias , Alexander-Parrish Ronika , Yang Jingyan , Draica Florin , Patel Jaymin , Garner Denise A. , Stanford Richard H. , Meier Genevieve , McLaughlin John M. , Nguyen Jennifer L.
Published: May 2024

Background:

Nirmatrelvir/ritonavir (NMV/r) is an oral antiviral drug used to treat mild-to-moderate coronavirus disease 2019 (COVID-19) in patients aged 12 years or older at high risk of progression to severe disease (eg, hospitalization and death). Despite being the preferred option for outpatient treatment in the majority of countries worldwide, NMV/r is currently underutilized in real-world clinical practice.

Areas of Uncertainty:

As numerous real-world studies have described patient outcomes following treatment with NMV/r, this systematic literature review provides a comprehensive summary of evidence on NMV/r effectiveness against hospitalization and mortality further organized by clinically meaningful categories, such as acute versus longer-term follow-up, age, underlying health conditions, and vaccination status, to help inform health care decision making.

Data Sources:

We searched Embase and PubMed (December 22, 2021–March 31, 2023) and congress abstracts (December 1, 2021–December 31, 2022) for reports describing NMV/r effectiveness.

Therapeutic Advances:

In total, 18 real-world studies met final selection criteria. The evidence showed that NMV/r significantly reduced postinfection risk of all-cause and COVID-19-related hospitalization and mortality in both acute (≤30 days) (21%–92%) and longer-term (>30 days) (1%–61%) follow-up. The reduction in postinfection risk was higher when treatment was received within 5 days of symptom onset. Real-world effectiveness of NMV/r treatment was observed regardless of age, underlying high-risk conditions, and vaccination status.

Conclusion:

The systematic literature review findings demonstrated the effectiveness of NMV/r against hospitalization and mortality during the Omicron period among individuals at high risk of progression to severe COVID-19 disease.
Sex Differences in Cardiovascular Management: A Call for Better Acknowledgment—Part 1 Pharmacological Differences in Women and Men; How Relevant Are They?
Authors: Ivanescu Andreea-Cristina , Dan Gheorghe-Andrei
Published: May 2024

Background:

Sex differences (SDs) in pharmacology of cardiovascular (CV) drugs have been described previously; however, paradoxically, there are scarce recommendations in therapy based on these differences. It is of utmost importance to identify whether these SDs determine a modified clinical response and the potential practical implications for this, to provide a base for personalized medicine.

Area of uncertainty:

The aim of this article was to outline the most important pharmacological drivers of cardiovascular drugs that differ between women and men, along with their implications and challenges in clinical practice.

Data sources:

A detailed assessment of English-written resources reflecting SDs impact in CV drug pharmacology was performed using PubMed and Embase databases.

Results:

Despite large variations in CV drug pharmacokinetics and pharmacodynamics in individuals, correcting for height, weight, surface area, and body composition compensate for most “sex-dependent” differences. In addition, individual, cultural, and social factors significantly impact disease management in women versus men. Gender-biased prescribing patterns and gender-dependent adherence to therapy also influence outcomes. The development of sex-specific guidelines requires that they should reflect the SDs implications for the management of a disease and that the evidence should be carefully evaluated as to whether there is an adequate representation of both sexes and whether sex-disaggregated data are reported.

Conclusions:

Pharmacological drivers are under the influence of an impressive number of differences between women and men. However, to establish their significance in clinical practice, an adequate representation of women in studies and the reporting of distinct results is mandatory.
Updated Recommendations on the Prevention and Treatment of Infections in Children With Asplenia/Hyposplenism
Authors: Guri Alex , Ben-Ami Tal
Published: May 2024

Children with congenital or acquired asplenia or hyposplenism have an increased risk for severe and even life-threatening infections mainly due to encapsulated bacteria. Current practice focuses on preventing severe infections with timely administration of vaccinations, antibacterial prophylaxis when indicated, and urgent evaluation and treatment of febrile events. As new vaccines are now available for both children and adults with asplenia/hyposplenism, we present an up-to-date recommendation on the prevention and management of acute infections in children with asplenia/hyposplenism.
Contribution of Syphilis to Adverse Pregnancy Outcomes in People Living With and Without HIV in South Brazil: 2008 to 2018
Authors: Yang Lanbo Z. , Sundar Kavya G. , Cambou Mary Catherine , Swayze Emma J. , Segura Eddy R. , de Melo Marineide Gonçalves , Santos Breno Riegel , dos Santos Varella Ivana Rosângela , Nielsen-Saines Karin
Published: May 2024

Background

Syphilis coinfection among pregnant people living with HIV (PLH) may worsen pregnancy outcomes. We evaluated the impact of syphilis coinfection on pregnancies in south Brazil.

Methods

Data were extracted from hospital records between January 1, 2008, and December 31, 2018. Preterm birth (PTB), low birth weight (LBW <2500 g), and a composite adverse infant outcome (AIO: HIV vertical transmission, loss to follow-up before HIV diagnosis, stillbirth, congenital syphilis) were evaluated among pregnancies without HIV and syphilis (PWOH + S), PLH monoinfection, syphilis monoinfection (PLS), and PLH with syphilis (PLH + S).

Results

Among 48,685 deliveries where patients were tested for HIV and syphilis, 1353 (2.8%) occurred in PLH; of these, 181 (13.4%) were HIV/syphilis coinfected (PLH + S). Among PLH, 2.4% of infants acquired HIV and 13.1% were lost to follow-up before HIV diagnosis. Among all PLS, 70.5% of infants acquired congenital syphilis. Across the cohort, 1.2% stillbirths/neonatal deaths occurred. Thirty-seven percent of PLH + S did not initiate antiretroviral therapy versus 15.4% of PLH monoinfection (P < 0.001). Less than half (37.6%) of PLH + S had VDRL titers ≥1:16 compared with 21.7% of PLS only (P < 0.001). Among PLH, syphilis coinfection and unknown/high VDRL titers (≥1:16) increased AIO risk more (adjusted relative risk [aRR], 3.96; 95% confidence interval [CI], 3.33–4.70) compared with low VDRL titers (≤1:8; aRR, 3.51; 95% CI, 2.90–4.25). Unsuppressed viremia (≥50 copies/mL) was associated with risk of PTB (aRR, 1.43; 95% CI, 1.07–1.92) and AIO (aRR, 1.38; 95% CI, 1.11–1.70) but not LBW. Lack of prenatal care was significant in predicting PTB and LBW in all PLH and PLS monoinfection.

Conclusions

Syphilis coinfection worsens AIOs in all women and compounds negative effects of HIV infection during pregnancy. Effective syphilis treatment and HIV viral load suppression are paramount for optimal obstetric care.
Undermining the Translational Potential of Clinical Research With Adolescents and Young Adults: Differential Enrollment in Randomized Clinical Trials During COVID-19
Authors: Perin Jamie , Anders Jennifer , Barfield Ashle , Gaydos Charlotte , Rothman Richard , Matson Pamela A. , Huettner Steven , Toppins Jacquelyn , Trent Maria
Published: May 2024

Background

COVID-19 stay-at-home orders and research restrictions halted recruitment and follow-up of clinical research patients. Although clinical research has resumed, it is an open question whether research participation has returned to levels similar to those before COVID-19.

Methods

We used data from the TECH-PN (NCT No. NCT03828994) study, a single-center randomized controlled trial enrolling 13- to 25-year-olds with mild-moderate pelvic inflammatory disease (PID) receiving ambulatory care. We examined enrollment patterns before COVID-19 and during/after COVID-19 among those assessed for eligibility by estimating the average rate of recruitment visits for each period. We focused on this monthly rate by pandemic status, the length of stay (LOS) by pandemic status, as well as the relationship between the LOS and patient demographics. Descriptive analyses were conducted, including Student t test to compare rates between time periods and a χ
2 test to compare the proportion refusing enrollment.

Results

The monthly enrollment rate during/after the pandemic was significantly lower than before COVID-19 (4.8 per month compared with 7.4 per month, P < 0.001). However, eligible participants' age, race, and insurance type were similar before and during/after the pandemic. Among eligible patients, LOS for receiving PID care was slightly increased, from a median of 5.4 to 6.4 hours (P = 0.650), and the rate of refusal to participate among those eligible was similar (23% vs. 27%, P = 0.362). There were a similar number of ineligible patients because of inpatient admissions during both periods.

Conclusion

COVID-19 pandemic restrictions negatively impacted recruitment into this randomized controlled trial. Enrollment differences may reflect ongoing perceptions of restrictions in care access or a hesitancy to use health services. More research is needed to stabilize access to ambulatory sexually transmitted infection/PID care and access to clinical trials.
Proteomics discovery in children and young adults with HIV identifies fibrosis, inflammatory, and immune biomarkers associated with myocardial impairment
Authors: Harrington Josephine , McCrary Andrew W. , Nguyen Maggie , Nyandiko Winstone , Barker Piers C.A. , Koech Myra , Thielman Nathan M. , Muehlbauer Michael J. , Shah Svati H. , Bloomfield Gerald S.
Published: May 2024

People with HIV are at increased risk of cardiac dysfunction; however, limited tools are available to identify patients at highest risk for future cardiac disease. We performed proteomic profiling using plasma samples from children and young adults with perinatally acquired HIV without clinical cardiac disease, comparing samples from participants with and without an abnormal myocardial performance index (MPI). We identified four proteins independently associated with subclinical cardiac dysfunction: ST2, CA1, EN-RAGE, and VSIG2.
Having More Tender Than Swollen Joints Is Associated With Worse Patient-Reported Outcomes in Patients With Early RA
Authors: Meng Charis F. , Lee Yvonne C. , Schieir Orit , Valois Marie-France , Butler Margaret A. , Boire Gilles , Hazlewood Glen , Hitchon Carol , Keystone Edward , Tin Diane , Thorne Carter , Bessette Louis , Pope Janet , Bartlett Susan J. , Bykerk Vivian P. ,   on behalf of the Canadian Early Arthritis Cohort Investigators
Published: May 2024

Background/Objective

In patients with rheumatoid arthritis (RA), high tender-swollen joint differences (TSJDs) have been associated with worse outcomes. A better understanding of the phenotype and impact of high TSJD on patient-reported outcomes (PROs) in early RA may lead to earlier personalized treatment targeting domains that are important to patients today. Our objectives were to evaluate the impact of TSJD on updated PROs in patients with early RA over 1 year and to determine differences in associations by joint size.

Methods

This longitudinal cohort study followed patients with active, early RA enrolled in the Canadian Early Arthritis Cohort between 2016 and 2022, who completed clinical assessments and PROMIS-29 measures over 1 year. Twenty-eight joint counts were performed and TSJDs calculated. Adjusted associations between TSJD and PROMIS-29 scores were estimated using separate linear-mixed models. Separate analyses of large versus small-joint TJSDs were performed.

Results

Patients with early RA (n = 547; 70% female; mean [SD] age, 56 [15] years; mean [SD] symptom duration, 5.3 [2.9] months) were evaluated. A 1-point increase in TSJD was significantly associated with worse PROMIS T-scores in all domains: physical function (adjusted regression coefficient, −0.27; 95% confidence interval [CI], −0.39, −0.15), social participation (adjusted regression coefficient, −0.34; 95% CI, −0.50, −0.19), pain interference (adjusted regression coefficient, 0.49; 95% CI, 0.35, 0.64), sleep problems (adjusted regression coefficient, 0.29; 95% CI, 0.16, 0.43), fatigue (adjusted regression coefficient, 0.34; 95% CI, 0.18, 0.50), anxiety (adjusted regression coefficient, 0.23; 95% CI, 0.08, 0.38), and depression (adjusted regression coefficient, 0.20; 95% CI, 0.06, 0.35). Large-joint TSJD was associated with markedly worse PROs compared with small-joint TSJD.

Conclusions

Elevated TSJD is associated with worse PROs particularly pain interference, social participation, and fatigue. Patients with more tender than swollen joints, especially large joints, may benefit from earlier, targeted therapeutic interventions.
Bilateral Adrenal Metastasis of Prostatic Adenocarcinoma on 68Ga-PSMA PET/CT Imaging
Authors: Beyhan Ediz , Turan Bektaş Ceyda , Baloğlu Mehmet Can , Tosunoğlu Zehranur , Çermik Tevfik Fikret
Published: May 2024

An 84-year-old man with prostate adenocarcinoma underwent 68Ga-PSMA PET/CT due to PSA recurrence. Foci of 68Ga-PSMA uptake were observed in bilateral adrenal glands. Adrenal MRI showed metastasis only in the left adrenal gland. Metastatic 68Ga-PSMA uptake was also observed in the mediastinum and bone. Enzalutamide treatment was started. Follow-up 68Ga-PSMA PET/CT scan showed regression in both adrenal gland metastases and other metastases.
Two Cases of Synchronous Hodgkin Lymphoma and Papillary Thyroid Carcinoma in 18F-FDG PET/CT
Authors: Wang Ru , Cai Haidong , Liu Changcun , LV Zhongwei , Ma Chao
Published: May 2024

The concurrence of Hodgkin lymphoma and papillary thyroid carcinoma is a rare clinical event. Two women presented with a painless mass in the neck that was suspected malignancy by ultrasonography. Both cases shown in the18F-FDG PET/CT images demonstrated multiple foci of increased FDG uptake in the neck, mimicking thyroid carcinoma with contralateral cervical lymph node metastases. Unexpectedly, the postoperative pathologies confirmed the thyroid lesion of papillary carcinoma and contralateral cervical lymph nodes of classical Hodgkin lymphoma.
Transcriptome Sequencing of the Oral Mucosa Reveals Gene Expression Differences in Patients With Parry-Romberg Syndrome
Authors: Ma Lun-kun , Zhang Zhi-yong , Tang Xiao-jun , Liu Wei , Xu Xi , Feng Shi , Zhao Shan-baga , Liu Bing-yang , Zang Tian-ying , Li Chuan
Published: May 2024

Objective:

Parry-Romberg syndrome (PRS) is an acquired disease characterized by progressive unilateral atrophy of the facial skin, subcutaneous tissue, muscle, and bone. There are various hypotheses to try to explain the occurrence of the disease, but the specific etiology and pathogenesis remain unclear. This study aimed to explore the potential molecular pathogenesis of the disease by using next-generation RNA-sequencing technology.

Methods:

The authors collected oral mucosal tissue from the affected side and the healthy side from 3 patients with PRS. Tissue samples were subjected to RNA extraction, whole transcriptome sequencing, and bioinformatics analysis. Differentially expressed genes were obtained from both groups of samples and then analyzed for functional enrichment.

Results:

A total of 186 differentially expressed genes were screened from the 2 groups of samples. Compared with the healthy side, several immune-related genes, including immunoglobulin kappa variable (IGKV)2D-28, IGKV1D-33, IGKV1-33, and NLRP10, were significantly upregulated in the affected tissue. In addition, the differential genes were significantly enriched in metabolic pathways including pancreatic secretion, protein and fat digestion, and absorption.

Conclusions:

The authors described the gene expression differences between the affected and healthy tissues of patients with PRS for the first time. Immune responses may play a role in the pathogenesis of PRS.
Renal protective effect and clinical analysis of vitamin B6 in patients with sepsis
Authors: Wang Yao , Lu Wen-Long , Feng Wen-Ming , Xu Wei , Liu Li-hua , He Li-Min
Published: May 2024

Objective

To investigate the protective effect and possible mechanisms of vitamin B6 against renal injury in patients with sepsis.

Methods

A total of 128 patients with sepsis who met the entry criteria in multiple centres were randomly divided into experimental (intravenous vitamin B6 therapy) and control (intravenous 0.9% sodium chloride therapy) groups based on usual care. Clinical data, the inflammatory response indicators interleukin 6 (IL-6), interleukin 8 (IL-8), tumour necrosis factor (TNF-α) and endothelin-1 (ET-1), the oxidative stress response indicators superoxide dismutase, glutathione and malondialdehyde, and renal function (assessed by blood urea nitrogen [BUN], serum creatinine [SCr] and renal resistance index [RRI] monitored by ultrasound) were compared between the two groups.

Results

After 7 d of treatment, the IL-6, IL-8, TNF-α and ET-1 levels in the experimental group were significantly lower than those in the control group, the oxidative stress response indicators were significantly improved in the experimental group and the BUN, SCr and RRI values in the experimental group were significantly lower than those in the control group (p< 0.05). There was no statistical difference between the two groups in the rate of renal replacement therapy and 28 d mortality (p> 0.05). However, the ICU length of stay and the total hospitalisation expenses in the experimental group were significantly lower than those in the control group (p< 0.05).

Conclusion

The administration of vitamin B6 in the treatment of patients with sepsis attenuates renal injury, and the mechanism may be related to pyridoxine decreasing the levels of inflammatory mediators and their regulation by redox stress.

Clinical trial registration: ClinicalTrials.gov Identifier: NCT06008223
Gun violence revictimization in New York State: What increases the risk of being shot again?
Authors: L’Huillier Joseph C. , Boccardo Joseph D. , Stewart Morgan , Wang Suiyuan , Myneni Ajay A. , Bari ASM Abdul , Nitsche Lindsay J. , Taylor Henry L. , Lukan James , Noyes Katia
Published: May 2024

BACKGROUND

While gun injuries are more likely to occur in urban settings and affect people of color, factors associated with gun violence revictimization—suffering multiple incidents of gun violence—are unknown. We examined victim demographics and environmental factors associated with gun violence revictimization in New York State (NYS).

METHODS

The 2005 to 2020 NYS hospital discharge database was queried for patients aged 12 years to 65 years with firearm-related hospital encounters. Patient and environmental variables were extracted. Patient home zip code was used to determine the Social Deprivation Index (SDI) for each patient’s area of residence. We conducted bivariate and multivariate analyses among patients who suffered a single incident of gun violence or gun violence revictimization.

RESULTS

We identified 38,974 gun violence victims among whom 2,243 (5.8%) suffered revictimization. The proportion of revictimization rose from 4% in 2008 to 8% in 2020 (p< 0.01). The median [interquartile range] time from first to second incident among those who suffered revictimization was 359 days [81–1,167 days]. Revictimization was more common among Blacks (75.0% vs. 65.1%,p< 0.01), patients with Medicaid (54.9% vs. 43.2%,p< 0.01), and in areas of higher deprivation (84.8 percentile vs. 82.1 percentile,p< 0.01).

CONCLUSION

Gun violence revictimization is on the rise. People of color and those residing in areas with high social deprivation are more likely to be re-injured. Our findings emphasize the importance of community-level over individual-level interventions for prevention of gun violence revictimization.

LEVEL OF EVIDENCE

Prognostic and Epidemiological; Level IV.
What Do We Owe Our Patients? Surgeon Obligations When Patients Are Too Sick for Surgery
Authors: Lazenby Kevin A , Angelos Peter
Published: May 2024

As the principle of respect for patient autonomy has gained salience over the past 75 years, surgeons now struggle to resolve conflicts between autonomy and beneficence in certain clinical scenarios. One such conflict occurs when a patient desires a surgical intervention, but the surgeon concludes that the patient is “too sick for surgery” and hence would not benefit from the operation. We provide historical context for the principle of respect for patient autonomy and review recent qualitative data that demonstrate surgeons experience significant moral distress when asked to perform nonbeneficial surgery. Therefore, we sought to empower surgeons with the appropriate ethical justifications to decline to perform surgery when they believe it would be nonbeneficial or harmful to patients. We outline 4 concepts that can help surgeons engage with patients, families, and colleagues in these scenarios. First, we describe the term “futility” and explain the difficulty in precisely defining and using the term in practice. Second, we contrast patients’ positive and negative rights, drawing on historical context to argue that patients have robust negative rights but limited positive rights to request nonbeneficial interventions. Third, we use the centuries-old notion of medicine as a profession to show that surgeons have a fiduciary responsibility to act in the best interests of their patients, including and especially when patients request interventions that are not beneficial. Finally, we draw on virtue ethics to give surgeons character-based resources for fulfilling their professional obligations to patients. We contend that surgeons owe their patients the ability to trust that they will always use their knowledge and skills for patients’ benefit, even if surgeons must limit patients’ autonomy in certain ways to do so.
Female-biased birth sex ratio in a female dispersal primate suggests local resource competition
Authors: Borries Carola , Koenig Andreas
Published: May 2024

Group living may entail local resource competition (LRC) which can be reduced if the birth sex ratio (BSR) is biased towards members of the dispersing sex who leave the group and no longer compete locally with kin. In primates, the predicted relationship between dispersal and BSR is generally supported although data for female dispersal species are rare and primarily available from captivity. Here, we present BSR data for Phayre’s leaf monkeys (
Trachypithecus phayrei crepusculus
) at the Phu Khieo Wildlife Sanctuary, Thailand (
N
= 104). In this population, nearly all natal females dispersed, while natal males stayed or formed new groups nearby. The slower reproductive rate in larger groups suggests that food can be a limiting resource. In accordance with LRC, significantly more females than males were born (BSR 0.404 males/all births) thus reducing future competition with kin. This bias was similar in 2-year-olds (no sex-differential mortality). It became stronger in adults, supporting our impression of particularly fierce competition among males. To better evaluate the importance of BSR, more studies should report sex ratios throughout the life span, and more data for female dispersal primates need to be collected, ideally for multiple groups of different sizes and for several years.
Uncertainty principles for coupled fractional Wigner–Ville distribution
Authors: Nur Andi Tenri Ajeng , Bahri Mawardi , Bachtiar Nasrullah , Rahim Amran
Published: May 2024

The coupled fractional Wigner–Ville distribution is a more general version of the fractional Wigner–Ville distribution. Main properties including boundedness, Moyal’s formula and inversion formula are studied in detail for the transformation. Additionally, the relation of the coupled fractional Wigner–Ville distribution with the two-dimensional Fourier transform is studied. We also present the relationship between the coupled fractional Wigner–Ville distribution with the two-dimensional Wigner–Ville distribution. We show how the properties and relations allow us to derive several versions of the uncertainty inequalities related to the coupled fractional Wigner–Ville distribution.
Horizontal running inside circular walls of Moon settlements: a comprehensive countermeasure for low-gravity deconditioning?
Authors: Minetti Alberto E. , Luciano Francesco , Natalucci Valentina , Pavei Gaspare
Published: May 2024

Long-lasting exposure to low gravity, such as in lunar settlements planned by the ongoing Artemis Program, elicits muscle hypotrophy, bone demineralization, cardio-respiratory and neuro-control deconditioning, against which optimal countermeasures are still to be designed. Rather than training selected muscle groups only, ‘whole-body’ activities such as locomotion seem better candidates, but at Moon gravity both ‘pendular’ walking and bouncing gaits like running exhibit abnormal dynamics at faster speeds. We theoretically and experimentally show that much greater self-generated artificial gravities can be experienced on the Moon by running horizontally inside a static 4.7 m radius cylinder (motorcyclists’ ‘Wall of Death’ of amusement parks) at speeds preventing downward skidding. To emulate lunar gravity, 83% of body weight was unloaded by pre-tensed (36 m) bungee jumping bands. Participants unprecedentedly maintained horizontal fast running (5.4–6.5 m s
−1
) for a few circular laps, with intense metabolism (estimated as 54–74 mlO
2
 kg
−1
 min
−1
) and peak forces during foot contact, inferred by motion analysis, of 2–3 Earth body weight (corresponding to terrestrial running at 3–4 m s
−1
), high enough to prevent bone calcium resorption. A training regime of a few laps a day promises to be a viable countermeasure for astronauts to quickly combat whole-body deconditioning, for further missions and home return.
The robustness of some Carboniferous fossil leaf venation networks to simulated damage
Authors: Mander Luke , Williams Hywel T. P.
Published: May 2024

Biological networks vary widely in their architecture and functional properties. Branching networks are good for transportation efficiency, while networks including loops offer good resistance to damage, and examples of these two topologies are found in leaf venation networks. The first plants with reticulate (loopy) leaf venation evolved in the Pennsylvanian of the Carboniferous, but the responses of different venation network architectures from this time period to damage are currently largely unknown. Here we address this issue with a computational analysis of venation network robustness that is focused on fossil leaves from the Pennsylvanian. We attacked fossil venation networks with simulated damage to individual vein segments and leaf blades. For both types of attack, branched venation networks are the least robust to damage, with greater robustness shown by the net-like reticulate networks found in the Pennsylvanian. A living angiosperm
Betula alba
was the most robust in our analysis. This may highlight a role for resistance to damage in the evolution of reticulate leaf venation in the Carboniferous, but further work is needed to answer the broader question of why reticulate leaf venation first evolved in the Pennsylvanian.
Sacrificing Adaptability for Functionality: The Ivory Tower of Macular Müller Cells
Authors: Zhang Ting , Jin Kaiyu , Zeng Shaoxue , Yang Penghui , Zhu Meidong , Zhang Jialing , Chen Yingying , Lee Sora , Yam Michelle , Zeng Yue , Lu Xiaoyan , Loo Lipin , Neely G. Gregory , Chang Andrew , Zhou Fanfan , Du Jianhai , Fan Xiaohui , Zhu Ling , Gillies Mark C.
Published: May 2024

The predilection of many retinal diseases for the macula suggests it may be less resistant to stress than the peripheral retina. Profiling of single-cell level transcriptional changes found that the peripheral retina exhibited more transcriptional changes than the macula in response to stress. One pronounced change was in a subgroup of Müller cells (MCs) that were dominant in the peripheral retina. Genes more abundantly expressed in peripheral MCs were mainly associated with stress responses and were more influenced by light stress. In contrast, genes highly expressed in MCs that predominated in the macula had roles in cellular function and were less influenced by light stress. Metallothionein 1, A Kinase Anchor Protein 12 and MAF BZIP Transcription Factor F were more abundantly expressed in peripheral MCs than in macular MCs. Knockdown of these genes in primary MCs reduced their viability under stress. Our findings indicate that macular MCs are more directed toward maintaining retinal function rather than mounting a stress response when exposed to stress, which may contribute to the macula’s vulnerability to degenerative diseases.
Impacts of the feedback loop between sense-antisense RNAs in regulating circadian rhythms
Authors: Uriu Koichiro , Hernandez-Sanchez Juan P. , Kojima Shihoko
Published: May 2024

Antisense transcripts are a unique group of non-coding RNAs that are transcribed from the opposite strand of a sense coding gene in an antisense orientation. Even though they do not encode a protein, these transcripts play a regulatory role in a variety of biological processes, including circadian rhythms. We and others found an antisense transcript,Per2AS, that is transcribed from the strand opposite the sense transcriptPeriod2(Per2) and exhibits a rhythmic and antiphasic expression pattern compared toPer2in mouse. By assuming thatPer2ASandPer2mutually repress each other, our previous mathematical model predicted thatPer2ASregulates the robustness and the amplitude of circadian rhythms. In this study, we revised our previous model and developed a new mathematical model that mechanistically described the mutually repressive relationship betweenPer2andPer2ASvia transcriptional interference. We found that the simulation results are largely consistent with experimental observations including the counterintuitive ones that could not be fully explained by our previous model. These results indicate that our revised model serves as a foundation to build more detailed models in the future to better understand the impact ofPer2AS-Per2interaction in the mammalian circadian clock. Our mechanistic description ofPer2AS-Per2interaction can also be extended to other mathematical models that involve sense-antisense RNA pairs that mutually repress each other.
Roodmus: A toolkit for benchmarking heterogeneous electron cryo-microscopy reconstructions
Authors: Joosten Maarten , Greer Joel , Parkhurst James , Burnley Tom , Jakobi Arjen J.
Published: May 2024

Conformational heterogeneity of biological macromolecules is a challenge in single particle averaging (SPA). Current standard practice is to employ classification and filtering methods which may allow a discrete number of conformational states to be reconstructed. However, the conformation space accessible to these molecules is continuous and therefore explored incompletely by a small number of discrete classes. Recently developed heterogeneous reconstruction algorithms (HRAs) to analyse continuous heterogeneity rely on machine learning methods employing low-dimensional latent space representations. The non-linear nature of many of these methods pose challenges to their validation and interpretation, and to identifying functionally relevant conformational trajectories. We believe these methods would benefit from in-depth benchmarking using high quality synthetic data and concomitant ground truth information. Here we present a framework for the simulation and subsequent analysis with respect to ground-truth of cryo-EM micrographs containing particles whose conformational heterogeneity is sourced from molecular dynamics simulations. This synthetic data can then be processed as if it were experimental data allowing aspects of standard SPA workflows, as well as heterogeneous reconstruction methods, to be compared with known ground-truth using available utilities. We will demonstrate the simulation and analysis of several such datasets and present an initial investigation into HRAs.
Investigating intestinal epithelium metabolic dysfunction in Celiac Disease using personalized genome-scale models
Authors: McCreery Chloe V. , Alessi Drew , Mollo Katarina , Fasano Alessio , Zomorrodi Ali R.
Published: May 2024

Celiac Disease (CeD) is an autoimmune condition characterized by an aberrant immune response triggered by the ingestion of gluten, which damages epithelial cells lining the small intestine. Small intestinal epithelial cells (sIECs) play a key role in various metabolic processes, including the enzymatic digestion and absorption of nutrients. Although nutritional malabsorption is widely recognized in CeD, the underlying disrupted metabolic processes remain largely undefined. To address this knowledge gap, we constructed personalized gender-specific genome-scale models of sIEC metabolism using transcriptional data from 42 subjects with active CeD, remission CeD, and healthy controls. We computationally simulated these models under a relevant diet for each group of subjects to assess the activity of 59 metabolic tasks essential for sIEC function and to profile metabolite secretion into the bloodstream and intestinal lumen. These investigations revealed significant variations in the activity of 25 metabolic tasks in active and remission CeD models. These tasks impact critical processes integral to sIEC function such as amino acid metabolism, nucleotide synthesis and DNA repair, ATP generation, and oxidative stress regulation. Additionally, we identified 54 metabolites with altered secretion profiles in CeD, encompassing amino acids, vitamins, antioxidants, and fatty acids. Furthermore, we pinpointed 22 FDA-approved drugs that target the genes associated with differentially active metabolic functions whose altered activities adversely affect sIECs in CeD, potentially helping to restore their normal activity. Our study unveils new insights into the metabolic reprogramming of sIECs in CeD, paving the way for therapeutic interventions targeting dysregulated metabolic processes.
Altered DNA methylation pattern contributes to differential epigenetic immune signaling in the upper respiratory airway of COVID-19 patients
Authors: Govender Melissa , Das Jyotirmoy , Hopkins Francis R. , Svanberg Cecilia , Nordgren Johan , Hagbom Marie , Klingström Jonas , Nilsdotter-Augustinsson Åsa , Yong Yean K. , Velu Vijayakumar , Raju Sivadoss , Sjöwall Johanna , Shankar Esaki M. , Nyström Sofia , Larsson Marie
Published: May 2024

The emergence of SARS-CoV-2 has had a profound adverse impact on global health and continues to remain a threat worldwide. The disease spectrum of COVID-19 ranges from asymptomatic to fatal clinical outcomes especially in the elderly population and in individuals with underlying medical conditions. The impact of COVID-19 on host immune responses and immune cells at the protein and DNA levels remains largely ambiguous. In a case-control study, here we explored the impact of COVID-19 on DNA methylation patterns in the upper respiratory airway to determine how SARS-CoV-2 infection altered the immune status of individuals requiring hospitalization for COVID-19. We performed DNA methylation arrays on nasopharyngeal swabs at inclusion/hospitalization as well as 6 weeks post-inclusion. Our study reveals a distinct DNA methylation pattern in COVID-19 patients compared to healthy controls, characterized by 317 779 differentially methylated CpGs. Notably, within the transcription start sites and gene body, COVID-19 patients exhibited a higher number of genes/CpGs with elevated methylation levels. Enrichment analysis of methylated genes at transcription start sites highlighted the impact on genes associated with inflammatory responses and immune functions. Some SARS-CoV-2 -induced CpG methylations were transient, returning to normal levels by 6 weeks post-inclusion. Enriched genes of interest included IL-17A, a pivotal cytokine implicated with inflammation and healing, and NUP93, associated with antiviral innate immunity. Further, six genes in our data set, OAS1, CXCR5, APP, CCL20, CNR2, and C3AR1, were found in enrichment analysis with previous COVID-19 studies. Additionally, RNAse1 and RNAse2 emerged as key regulators, while IL-18 played a role in various biological processes in COVID-19 patients. Overall, our results demonstrates that COVID-19 has a major impact on the upper airway by modifying the methylation pattern of many genes and this could have implications for the conditioning of the airways and how the individual response to future airway infections.
Language Models Outperform Cloze Predictability in a Cognitive Model of Reading
Authors: Rego Adrielli Lopes , Snell Joshua , Meeter Martijn
Published: May 2024

Although word predictability is commonly considered an important factor in reading, sophisticated accounts of predictability in theories of reading are yet lacking. Computational models of reading traditionally use cloze norming as a proxy of word predictability, but what cloze norms precisely capture remains unclear. This study investigates whether large language models (LLMs) can fill this gap. Contextual predictions are implemented via a novel parallel-graded mechanism, where all predicted words at a given position are pre-activated as a function of contextual certainty, which varies dynamically as text processing unfolds. Through reading simulations with OB1-reader, a cognitive model of word recognition and eye-movement control in reading, we compare the model’s fit to eye-movement data when using predictability values derived from a cloze task against those derived from LLMs (GPT2 and LLaMA). Root Mean Square Error between simulated and human eye movements indicates that LLM predictability provides a better fit than Cloze. This is the first study to use LLMs to augment a cognitive model of reading with higher-order language processing while proposing a mechanism on the interplay between word predictability and eye movements.

Author Summary

Reading comprehension is a crucial skill that is highly predictive of later success in education. One aspect of efficient reading is our ability to predict what is coming next in the text based on the current context. Although we know predictions take place during reading, the mechanism through which contextual facilitation affects ocolarmotor behaviour in reading is not yet well-understood. Here, we model this mechanism and test different measures of predictability (computational vs. empirical) by simulating eye movements with a cognitive model of reading. Our results suggest that, when implemented with our novel mechanism, a computational measure of predictability provide better fits to eye movements in reading than a traditional empirical measure. With this model, we scrutinize how predictions about upcoming input affects eye movements in reading, and how computational approches to measuring predictability may support theory testing. In the short term, modelling aspects of reading comprehension helps reconnect theory building and experimentation in reading research. In the longer term, more understanding of reading comprehension may help improve reading pedagogies, diagnoses and treatments.
MBL-1/Muscleblind regulates neuronal differentiation and controls the splicing of a terminal selector inCaenorhabditis elegans
Authors: Lee Ho Ming Terence , Lim Hui Yuan , He Haoming , Lau Chun Yin , Zheng Chaogu
Published: May 2024

The muscleblind family of mRNA splicing regulators is conserved across species and regulate the development of muscles and the nervous system. However, how Muscleblind proteins regulate neuronal fate specification and neurite morphogenesis at the single-neuron level is not well understood. In this study, we found that theC. elegansMuscleblind/MBL-1 promotes axonal growth in the touch receptor neurons (TRNs) by regulating microtubule stability and polarity. Transcriptomic analysis identified dozens of MBL-1-controlled splicing events in genes related to neuronal differentiation or microtubule functions. Among the MBL-1 targets, the LIM-domain transcription factormec-3is the terminal selector for the TRN fate and induces the expression of many TRN terminal differentiation genes. MBL-1 promotes the splicing of themec-3long isoform, which are essential for TRN fate specification, and inhibits the short isoforms that have much weaker activities in activating downstream genes. MBL-1 promotesmec-3splicing through three “YGCU(U/G)Y” motifs located downstream of the included exon, which is similar to the mechanisms used by mammalian Muscleblind and suggests a deeply conserved context-dependency of the splicing regulation. Interestingly, the expression ofmbl-1in the TRNs is dependent on themec-3long isoform, indicating a positive feedback loop between the splicing regulator and the terminal selector. Finally, through a forward genetic screen, we found that MBL-1 promotes neurite growth partly by inhibiting the DLK-1/p38 MAPK pathway. In summary, our study provides mechanistic understanding of the role of Muscleblind in regulating cell fate specification and neuronal morphogenesis.
Multimodal analyses of immune cells during bone repair identify macrophages as a therapeutic target in musculoskeletal trauma
Authors: Hachemi Yasmine , Perrin Simon , Ethel Maria , Julien Anais , Vettese Julia , Geisler Blandine , Göritz Christian , Colnot Céline
Published: May 2024

Musculoskeletal traumatic injuries (MTI) involve soft tissue lesions adjacent to a bone fracture leading to fibrous nonunion. The impact of MTI on the inflammatory response to fracture and on the immunomodulation of skeletal stem/progenitor cells (SSPCs) remains unknown. Here, we used single cell transcriptomic analyses to describe the immune cell dynamics after bone fracture and identified distinct macrophage subsets with successive pro-inflammatory, pro-repair and anti-inflammatory profiles. Concurrently, SSPCs transition via a pro- and anti-inflammatory fibrogenic phase of differentiation prior to osteochondrogenic differentiation. In a preclinical MTI mouse model, the injury response of immune cells and SSPCs is disrupted leading to a prolonged pro-inflammatory phase and delayed resolution of inflammation. Macrophage depletion improves bone regeneration in MTI demonstrating macrophage involvement in fibrous nonunion. Finally, pharmacological inhibition of macrophages using the CSF1R inhibitor Pexidartinib ameliorates healing. These findings reveal the coordinated immune response of macrophages and skeletal stem/progenitor cells as driver of bone healing and as a primary target for the treatment of trauma-associated fibrosis.

Hachemi et al. report the immune cell atlas of bone repair revealing macrophages as pro-fibrotic regulators and a therapeutic target for musculoskeletal regeneration. Genetic depletion or pharmacological inhibition of macrophages improves bone healing in musculoskeletal trauma.
An integrative taxonomy approach reveals Saccharomyces chiloensis sp. nov. as a newly discovered species from Coastal Patagonia
Authors: Peña Tomas A. , Villarreal Pablo , Agier Nicolas , Chiara Matteo De , Barría Tomas , Urbina Kamila , Villarroel Carlos A. , Santos Ana R. O. , Rosa Carlos A. , Nespolo Roberto F. , Liti Gianni , Fischer Gilles , Cubillos Francisco A.
Published: May 2024

Species delineation in microorganisms is challenging due to the limited markers available for accurate species assignment. Here, we applied an integrative taxonomy approach, combining extensive sampling, whole-genome sequence-based classification, phenotypic profiling, and assessment of interspecific reproductive isolation. Our work reveals the presence of a distinctSaccharomyceslineage inNothofagusforests of coastal Patagonia. This lineage, designatedSaccharomyces chiloensissp. nov., exhibits 7% genetic divergence from its sister speciesS. uvarum, as revealed by whole-genome sequencing and population analyses. The South America-C (SA-C) coastal Patagonia population forms a unique clade closely related to a previously described divergentS. uvarumpopulation from Oceania (AUS, found in Australia and New Zealand). Our species reclassification is supported by a low Ortho Average Nucleotide Identity (OANI) of 93% in SA-C and AUS relative toS. uvarum, which falls below the suggested species delineation threshold of 95%, indicating an independent evolutionary lineage. Hybrid spore viability assessment provided compelling evidence that SA-C and AUS are reproductively isolated fromS. uvarum. In addition, we found unique structural variants betweenS. chiloensissp. nov. lineages, including large-scale chromosomal translocations and inversions, together with a distinct phenotypic profile, emphasizing their intraspecies genetic distinctiveness. We suggest thatS. chiloensissp. nov diverged fromS. uvarumin allopatry due to glaciation, followed by post-glacial dispersal, resulting in distinct lineages on opposite sides of the Pacific Ocean. The discovery ofS. chiloensissp. nov. illustrates the uniqueness of Patagonia’s coastal biodiversity and underscores the importance of adopting an integrative taxonomic approach in species delineation to unveil cryptic microbial species. The holotype ofS. chiloensissp. nov. is CBS 18620T.
Feathers of Grace: The “After You” Gesture in Japanese Tits
Authors: Da Silva Sergio , Matsushita Raul
Published: May 2024

A recent study found evidence of symbolic gesture use in Japanese tits (Parus minor). The study reveals how these birds use wing-fluttering movements to transmit an “after you” to their partners, implying a degree of cognitive skill previously thought to be unique to humans and great apes. If confirmed, this research contradicts long-held notions about animal communication by proving that Japanese tits not only participate in intricate vocal communications, which can comprise phrases with specific grammatical rules, but also use body language as a form of engagement. Here, we evaluate this claim by inspecting the data and utilizing bootstrapping to expand the sample size. We find a large variation in how frequently the “after you” gesture is employed in different bootstrap samples, suggesting that while the gesture is a consistent behavior, its frequency can vary significantly. Moreover, the timing of the male’s response to the female’s gesture can fluctuate, though the response itself appears to be a stable phenomenon. Because the frequency of the “after you” gesture varied greatly, especially in light of potential cognitive and other biases influencing the study, this bold claim should be taken with caution.