bluuebunny/crossref_metadata_2025 huggingface dataset:
Vowel Harmony in the Munda Languages
Authors: Anderson Gregory D. S. , Horo Luke , Harrison K. David
Published: October 2024

This chapter presents data on vowel harmony systems from Ho and Santali, languages belonging to the Munda family of the Austroasiatic language phylum. The Munda family provides a wide range of scenarios for restricted vowel harmony systems of height, tense/lax, or tongue-root harmony operating within the domain of a single foot. These may be seen to emerge, change, and decay over time. Ho is unusual in that, despite being a language with only five phonemic vowels, it shows harmony. The study is preliminary; more research is needed on the origins, extent, and nature of vowel harmony processes in Munda languages.
Umlaut in Germanic Languages
Authors: Hansson Gunnar Ólafur , Wiese Richard
Published: October 2024

This chapter focuses on i-umlaut in German (involving vowel fronting) and Icelandic (involving fronting and unrounding), and on u-umlaut in Icelandic (involving rounding and fronting of the vowel /a/). ‘Umlaut’ refers to a variety of word-internal vowel alternations found in Germanic languages, which are the present-day reflexes of regressive assimilation induced by suffix vowels of certain kinds. I-umlaut in present-day Standard German is discussed as a partially productive, partially unproductive historical remnant of a word-final high front vowel. In contrast, u-umlaut in Icelandic is a far more productive phenomenon, although the common view that it still involves a synchronically active phonological assimilation process is shown to be problematic. In both languages, umlaut is triggered by derivational and inflectional morphology alike. Various approaches to the interpretation of umlaut in recent theoretical literature are discussed as well.
Religion: Rites vs Rights
Authors: Hernández-Truyol Berta Esperanza
Published: October 2024

Tensions in civil society based on religion are nothing new. The world is home to many religions and religious traditions that differ in culture and rituals, beliefs, and commands but that promote peace, harmony, and coexistence, yet religion often becomes a deep and delicate source of conflict. Religious liberty also is a location of tension with the rights to non-discrimination and equality. For example, religion was used to justify (and to oppose) the inhuman and inhumane institution of slavery and to justify sex discrimination. In the twenty-first century, the tension between religious freedom and LGBT equality has become a major battleground. This chapter addresses whether tensions between LGBT equality and religious liberty are intractable or whether there can be reconciliation that allows all sides to live their lives without being subjected to discrimination in the public, employment, and commercial services spheres. To explore this question this chapter provides the legal context in which these conflicts develop, including international, regional, and national law. The chapter concludes that the appropriate way to resolve the conflict is by adopting an awakened balancing approach that recognizes that both religious freedom and non-discrimination are high-value fundamental rights in the international, regional, and national spheres. Such a model allows for a reasoned solution to the legal and emotional tensions that arise from this clash of rights.
Equality and Non-Discrimination
Authors: Wintemute Robert
Published: October 2024

Many human rights claims by lesbian, gay, and bisexual (LGB) persons have been framed as ones of ‘equality’ or ‘non-discrimination’ based on their sexual orientation. LGB persons can litigate under an international human rights treaty or a national constitution (‘constitutional antidiscrimination law’) and ask a court to read ‘sexual orientation’ into an open-ended prohibition of discrimination. If the treaty or constitution is being drafted for the first time, or is being amended, they can engage in lobbying and ask for express inclusion of sexual orientation, but full protection against discrimination requires ‘statutory antidiscrimination law’, applying both to the public and private sectors. Once again, LGB persons can turn to litigation and argue that an existing ground such as ‘sex’ applies, or they can lobby for the express inclusion of sexual orientation in the relevant legislation.
Improving rice grain shape through upstream ORF editing-mediated translation regulation
Authors: Yang Qingqing , Zhu Wenjie , Tang Xu , Wu Yuechao , Liu Guanqing , Zhao Dongsheng , Liu Qiaoquan , Zhang Yong , Zhang Tao
Published: October 2024

Upregulating gene expression by disturbing or destroying the upstream ORF of target genes is an efficient strategy for improving rice grain traits.
The Effects of Macroeconomic Shocks: Household Financial Distress Matters
Authors: Mustre-del-Río José , Sánchez Juan M , Mather Ryan , Athreya Kartik
Published: October 2024

When a macroeconomic shock arrives, variation in household balance sheet health (captured by the presence of financial distress, or “FD”) leads to differential access to credit and hence a distribution in consumption responses. As we document, though, over the past two recessions, households in prior FD also experienced macroeconomic shocks more intensely than others, leading to a distribution of shock severity. Quantifying the importance of each dimension of heterogeneity (FD or shock severity) for consumption requires a structural model. We find that heterogeneity in FD matters more for shaping the responses of individual and aggregate consumption to shocks.
School start times and their association with rurality in British Columbia, Canada: An environmental scan
Authors: Keys Elizabeth , Michon Tai-Lin , Boogaart Kayleigh , Beck Amy
Published: October 2024

Study Objectives

Since later school start times are associated with increased sleep duration, our objectives were to identify mean school start times, the proportion of schools that start at 08:30 am or later, and determine if rurality was associated with school start times.

Methods

We conducted web searches for start times of 1759 standard schools in British Columbia (BC), Canada. Schools were categorized as elementary, elementary-middle, middle, middle-high, or high school and linked to an Index of Remoteness. We calculated descriptive statistics and used Analysis of Variance to assess for start time differences by grade category. We used Spearman’s rank-order correlation to assess if there was a relationship between start time and rurality.

Results

We found start times for 1553 (88.2%) of the included schools. The mean start time was 08:40 am (SD = 0:15) and ranged from 07:10 am to 09:45 am. There was a significant effect of grade category on start time, F (5, 1600) = 6.03, p < .001, η2 =.02, 95% CI [.006, .031] such that elementary-middle schools started significantly earlier (M = 08:34 am, SD = 0:17) than other grade categories. Overall, 1388 (86.4%) schools started at 08:30 am or later. Rurality was significantly correlated with school start time (r = −.198), such that more rural schools started earlier.

Conclusions

For the most part, school start times in BC meet recommendations that support childhood and adolescent sleep. Future research is needed to understand factors that promote the successful implementation of delayed school start times.
Sex-specific dementia risk in known or suspected obstructive sleep apnea: a 10-year longitudinal population-based study
Authors: Braley Tiffany J , Lyu Xiru , Dunietz Galit Levi , Schulz Paul C , Bove Riley , Chervin Ronald D , Paulson Henry L , Shedden Kerby
Published: October 2024

Study Objectives

To evaluate sex-specific associations between known or suspected obstructive sleep apnea (OSA) and dementia risk over 10 years among older women and men.

Methods

This study included 18 815 women and men age 50+ years (dementia-free at baseline) who participated in the Health and Retirement Study (HRS), a nationally representative cohort of US adults. Presence of OSA was defined by self-reported diagnosis or key HRS items that correspond to elements of a validated OSA screening tool (STOP-Bang). Incident dementia cases were identified using a validated, HRS-based algorithm derived from objective cognitive assessments. Survey-weighted regression models based on pseudo-values were utilized to estimate sex- and age-specific differences in cumulative incidence of dementia by OSA status.

Results

Data from 18 815 adults were analyzed, of which 9% of women and 8% of men (weighted proportions) met criteria for incident dementia. Known/suspected OSA was more prevalent in men than in women (weighted proportions 68% vs. 31%). Unadjusted sex-stratified analyses showed that known/suspected OSA was associated with higher cumulative incidence of dementia across ages 60–84 years for women and men. By age 80, relative to adults without known/suspected OSA, the cumulative incidence of dementia was 4.7% higher (CI 2.8%, 6.7%) for women with known/suspected OSA, and 2.5% (CI 0.5%, 4.5%) for men with known/suspected OSA, respectively. Adjusted associations between age-specific OSA and cumulative incidence of dementia attenuated for both women and men but remained statistically significant.

Conclusions

OSA contributes to dementia risk in older adults, particularly women. This study illuminates the impact of a potentially modifiable yet frequently overlooked risk factor for dementia onset.
The effects of deep brain stimulation on sleep: a systematic review and meta-analysis
Authors: Wadhwa Aryan , Pacheco-Barrios Niels , Tripathy Shreya , Jha Rohan , Wadhwa Millen , Warren Aaron E L , Luo Lan , Rolston John D
Published: October 2024

Background

Deep brain stimulation (DBS) is a standard treatment for movement disorders, epilepsy, and others, yet its influence on postprocedural sleep quality remains an under-researched topic.

Study Objectives

We performed a systematic review and meta-analysis of all DBS effects on sleep.

Methods

The use of preferred reporting items for systematic reviews and meta-analyses guidelines (PRISMA) was utilized. We extracted demographic data, disease type/duration, DBS target, stimulation laterality (unilateral vs bilateral), follow-up lengths, and sleep pre/post-op measurements with polysomnography or across four standard sleep scales. The Cochrane methodology for evaluating RCTs was employed using the risk of bias assessments, data synthesis, and statistical methods, including forest plots (risk ratio; M-H random effects; 95% CI).

Results

Sixty-three studies were included in the overall analysis, representing 3022 patients. In a subgroup meta-analysis of subthalamic nucleus (STN) DBS for Parkinson’s disease (PD), patients showed significant sleep improvement at three but not 12 months postoperatively with PDSS, at 12 but not 3 months with Epworth sleep scale, and at 6 months with nonmotor symptom scale. Pittsburgh sleep quality index (PSQI) showed no significant improvement in sleep at any time. Bilateral DBS showed significantly more improvement than unilateral DBS in the PSQI at 6 but not 3 months. Polysomnography showed significant sleep improvement at 1 week but not at 3 or 6 months. Most studies showed no significant sleep improvement for globus pallidus internus, centromedian thalamus, and ventral intermediate nucleus DBS.

Conclusions

STN-DBS for PD likely improves sleep; however, significant standardization in sleep scale outcome reporting and follow-up time is needed to effectively determine the target-dependent effects of DBS surgery on sleep.
The Microbial Metabolite Wuyiencin Potentially Targets Threonine Dehydratase in Didymella segeticola to Achieve Control of Tea Leaf Spot
Authors: Ma Youli , Li Peiying , Xie Wenjing , Liu Fenghua , Li Dongxue , Rehman Atta Ur , Wang Delu , Zhou Jing-Jiang , Ma Yue , Chen Zhuo
Published: October 2024

Tea leaf spot caused by Didymella segeticola is a disease that has recently been discovered in the tea plantations of Southwest China and that has a significant negative impact on the yield and quality of tea leaves. Wuyiencin is a nucleotide antimicrobial that is effective against a range of fungal diseases. However, its mode of action is still unclear. The current study found that wuyiencin inhibited the mycelial growth of D. segeticola in vitro. Meanwhile, in vivo experiments confirmed that wuyiencin had a significant curative effect on tea leaf spot. Microscopic observation indicated that it damaged the organelles and nucleus in fungal cells. Reverse transcription quantitative PCR assays revealed that mycelium treated with wuyiencin at the half-maximal effective concentration (EC50) dosage for 1 h exhibited 3.23 times lower expression of threonine dehydratase ( td) gene, which is responsible for producing pyruvate. The wild-type (WT) strain had a 1.77-fold higher pyruvate concentration than that in the td mutant ( P < 0.05). The td mutant was more sensitive than the WT to wuyiencin treatment, with the EC50 value in the td mutant being 30.01 μg/ml compared with 82.34 μg/ml in the WT. Molecular docking demonstrated that wuyiencin bound to td, with a binding energy of −10.47 kcal/mol. Compared with the WT strain, wuyiencin significantly reduced ATP concentration of the td mutant strain at dosages of 80.0 and 160.0 µg/ml. In total, wuyiencin reduced td activity, inhibited pyruvate production, and decreased ATP content in the phytopathogenic fungus, ultimately disturbing the growth of the mycelium.
Breast Milk Application as a Natural Method for Umbilical Cord Care: A Community-Label 3-Arm Pilot Clinical Trial
Authors: Alemu Bekalu Kassie , Wondimagegn Leltework Yismaw , Bazezew Yibelu , Liyeh Tewachew Muche , Muluneh Abebaw Abeje , Mihretie Gedefaye Nibret , Sema Alekaw , Endalifer Melese Linger , Azeze Getnet Gedefaw , Woldeamanuel Gashaw Garedew , Tlaye Kenean Getaneh , Lee Wing Fong , Wang Yao , Wang Chi Chiu
Published: October 2024

Objective

To compare the effects of human breast milk with those of chlorhexidine and the dry method on umbilical cord separation in Ethiopia.

Methods

This open-label 3-arm nonrandomized pilot clinical trial was conducted among 45 neonates (15 in each arm) with more than 630 home visits. After a standard cord cut, human breast milk, chlorhexidine, or nothing was applied once per day for 7 days. The primary outcome was the duration of cord separation, while the secondary outcomes were umbilical cord infection, neonatal fever, jaundice, feeding and breathing difficulty, and persistent crying.

Results

There were statistically significant differences in the time-to-cord separation between the human breast milk group and the chlorhexidine (P < 0.001) and dry alone (P = 0.038) groups. Compared to those of chlorhexidine, the rates of cord separation among human breast milk and the dry-alone group were 16.02, with 95% confidence intervals (3.81, 37.43; P < 0.001) and 3.15 (0.99, 10.00; P = 0.052), respectively. One (6.7%) cord site infection was observed in the dry-alone groups only.

Conclusion

This community-label study indicated that human breast milk application significantly shortened the length of umbilical cord separation time compared to chlorhexidine and dry methods. A large-scale randomized controlled trial is needed to confirm these results.

Registration

PACTR202310902873290; https://pactr.samrc.ac.za
Mechanism-Based Pharmacokinetic/Pharmacodynamic Model of Voriconazole for Predicting the Clinical Outcomes of Adult Patients with Invasive Aspergillosis
Authors: Duangpraphat Monchai , Wilson Richard C. , Rawson Timothy M. , Santimaleeworagun Wichai , Nasomsong Worapong , Holmes Alison H. , Vasikasin Vasin
Published: October 2024

Background:

Voriconazole is the first-line therapy for invasive aspergillosis (IA). To determine the minimum inhibitory concentration of Aspergillus, a voriconazole pharmacokinetic–pharmacodynamic (PK–PD) model linked to galactomannan response was developed and evaluated, and its clinical correlation for IA treatment was elucidated.

Methods:

Adult patients with probable or definite IA and at least one serum voriconazole measurement were included. A two-compartment voriconazole PK model was linked to a previously described PD model of galactomannan response. PK and PD parameters were estimated using a nonparametric adaptive grid technique. The relationship between the ratio of voriconazole exposure that induced half-maximum galactomannan response (EC50) and the observed terminal galactomannan concentration was evaluated. The factors associated with the PK–PD parameters and mortality were also determined.

Results:

Between January 2013 and December 2022, 41 patients were prescribed voriconazole for IA. The 30-day mortality rate was 17%. A high correlation was found for the observed–predicted Bayesian posterior estimates of voriconazole and galactomannan levels. Moreover, a nonlinear relationship was identified between AUC:EC50 and terminal galactomannan. The factors associated with higher AUC:EC50 were intravenous administration and intubation. In the survival analysis, higher EC50 tended to be associated with mortality, higher AUC was significantly associated with increased mortality, and higher AUC:EC50 tended to be associated with higher mortality. After adjusting for the intravenous route, higher AUC and AUC:EC50 were not associated with mortality.

Conclusions:

Individual EC50 estimation can provide insights into in vivo host and organism responses. Elevated EC50 showed comparable and unfavorable trends to higher minimum inhibitory concentration. Thus, determining EC50 might help guide individualized target serum voriconazole levels.
Never Assume Successful Treatment of Septic Arthritis: Bacteria Isolated at Revision ACL Reconstruction 3 Years After Primary ACL Reconstruction “Successfully” Treated for Infection
Authors: Nicholas Patrick Richard Michael , Jones Mary , Williams Andy
Published: October 2024

Infection after anterior cruciate ligament (ACL) reconstruction is uncommon with an incidence of between 0.1% and 2.25%. Delayed or ineffective treatment may lead to destruction of articular cartilage. Furthermore, joint stiffness may complicate recovery. As in all cases of septic arthritis, antibiotic therapy alone is inadequate, and surgical lavage and debridement of abnormal tissue are required. In approximately 85% of cases, retention of the ACL graft is possible. It is known that bacteria can lie “dormant” without causing clinically noticeable infection, especially when adhering to orthopedic implants only to reactivate later and cause clinically obvious infection. There are no reports in the literature relating to bacteria causing septic arthritis of a primary ACL reconstruction that was apparently successfully treated being isolated in subsequent revision ACL reconstruction after a new injury. Such a case is presented.

Level of Evidence:

Level IV.
The accuracy of fine-needle aspiration cytology and ultrasonography in assessing thyroid nodules in correlation with histopathology: a retrospective study
Authors: Alhajlan Mana , Al-Masabi Mohammed , Al Mansour Mohammed , Saihb Abdullah , AlAyed Salem , Alwadai Rakan , Alhamami Abdullah , Alzarra Abdullah , Almarzooq Mohammed , Ahmed Faisal
Published: October 2024

Background:

Accurately diagnosing thyroid nodules is vital for preventing unnecessary surgeries and providing prompt therapy. Although fine-needle aspiration cytology (FNAC) and ultrasonography (US) are widely used diagnostic methods, their reliability is questioned. This study investigates the effectiveness of US and FNAC in thyroid nodule diagnosis and differentiates benign from malignant nodules in relation to final histopathological diagnosis.

Method:

A retrospective study including 307 adult patients with thyroid diseases who underwent neck US and FNAC before surgery was conducted between April 2019 and May 2023. The diagnostic efficacy of US, FNAC, and their combination usage was compared to histopathological results.

Result:

Histopathological findings revealed that 187 (61%) cases were benign, while 120 (39%) were malignant. The US features of ‘taller-than-wider’ forms and hypoechoic appearance had the highest diagnostic accuracy in characterizing malignant thyroid nodules, with 83 and 73% accuracy, respectively. The combination of US parameters demonstrated high sensitivity, specificity, positive predictive value, and negative predictive value (NPV) of 88.33, 63.10, 60.6, and 89.4%, with a statistically significant area under the ROC curve (AUC: 0.828, P<0.001) than individual parameters. FNAC’s sensitivity, specificity, PPV NPV, and accuracy in detecting malignant lesions were 50, 95, 86, 75, and 77%, respectively, with acceptable discrimination and statistical significance (AUC: 0.723, P<0.0001). The combination of US parameters and FNAC significantly improved the AUC value (AUC: 0.878, P<0.0001), sensitivity (83.33%), and specificity (79.14%). Univariate analysis showed that hypoechoic appearance, heterogenicity, large mass size (>4 cm), ‘taller-than-wider’, infiltrative margins, and microcalcifications were risk factors for malignancy in thyroid nodules and were statistically significant (all P-values <0.05).

Conclusion:

Combining US characteristics with FNAC results can afford the maximum analytical accuracy in distinguishing benign from malignant thyroid nodules. This strategy is practical due to its simplicity, minimal invasiveness, and cost-effectiveness, enabling robust management regimens and avoiding additional surgical procedures.
Misuse of External Urine Management Devices in Hospitalized Patients
Authors: Crosby Lauren , Booher Lydia
Published: October 2024

External urine management devices were introduced into healthcare as a novel solution to avoid indwelling urinary catheter placement and the associated urinary tract infection risk for adult patients. These devices are favored among healthcare workers and patients. However, the downstream impacts of this device can be detrimental to patient outcomes when immobility is promoted through their use. Clinical nurse specialists are the ideal team member to evaluate the introduction of new technology to promote patient-focused care over task-focused care.
A Quantitative Comparison Between Human and Artificial Intelligence in the Detection of Focal Cortical Dysplasia
Authors: Walger Lennart , Bauer Tobias , Kügler David , Schmitz Matthias H. , Schuch Fabiane , Arendt Christophe , Baumgartner Tobias , Birkenheier Johannes , Borger Valeri , Endler Christoph , Grau Franziska , Immanuel Christian , Kölle Markus , Kupczyk Patrick , Lakghomi Asadeh , Mackert Sarah , Neuhaus Elisabeth , Nordsiek Julia , Odenthal Anna-Maria , Dague Karmele Olaciregui , Ostermann Laura , Pukropski Jan , Racz Attila , von der Ropp Klaus , Schmeel Frederic Carsten , Schrader Felix , Sitter Aileen , Unruh-Pinheiro Alexander , Voigt Marilia , Vychopen Martin , von Wedel Philip , von Wrede Randi , Attenberger Ulrike , Vatter Hartmut , Philipsen Alexandra , Becker Albert , Reuter Martin , Hattingen Elke , Sander Josemir W. , Radbruch Alexander , Surges Rainer , Rüber Theodor
Published: October 2024

Objectives

Artificial intelligence (AI) is thought to improve lesion detection. However, a lack of knowledge about human performance prevents a comparative evaluation of AI and an accurate assessment of its impact on clinical decision-making. The objective of this work is to quantitatively evaluate the ability of humans to detect focal cortical dysplasia (FCD), compare it to state-of-the-art AI, and determine how it may aid diagnostics.

Materials and Methods

We prospectively recorded the performance of readers in detecting FCDs using single points and 3-dimensional bounding boxes. We acquired predictions of 3 AI models for the same dataset and compared these to readers. Finally, we analyzed pairwise combinations of readers and models.

Results

Twenty-eight readers, including 20 nonexpert and 5 expert physicians, reviewed 180 cases: 146 subjects with FCD (median age: 25, interquartile range: 18) and 34 healthy control subjects (median age: 43, interquartile range: 19). Nonexpert readers detected 47% (95% confidence interval [CI]: 46, 49) of FCDs, whereas experts detected 68% (95% CI: 65, 71). The 3 AI models detected 32%, 51%, and 72% of FCDs, respectively. The latter, however, also predicted more than 13 false-positive clusters per subject on average. Human performance was improved in the presence of a transmantle sign (P < 0.001) and cortical thickening (P < 0.001). In contrast, AI models were sensitive to abnormal gyration (P < 0.01) or gray-white matter blurring (P < 0.01). Compared with single experts, expert-expert pairs detected 13% (95% CI: 9, 18) more FCDs (P < 0.001). All AI models increased expert detection rates by up to 19% (95% CI: 15, 24) (P < 0.001). Nonexpert+AI pairs could still outperform single experts by up to 13% (95% CI: 10, 17).

Conclusions

This study pioneers the comparative evaluation of humans and AI for FCD lesion detection. It shows that AI and human predictions differ, especially for certain MRI features of FCD, and, thus, how AI may complement the diagnostic workup.
Development of acute kidney injury following repair of Stanford type A aortic dissection is associated with increased mortality and complications: a systematic review, meta-analysis, and meta-regression analysis
Authors: Goyal Aman , Maheshwari Surabhi , Abbasi Haleema Qayyum , Mashkoor Yusra , Shamim Urooj , Chambari Mahla , Kelaiya Arjun , Safi Darsh , Saeed Humza , Jain Hritvik , Pokhrel Prakriti , Ullah Irfan
Published: October 2024

Acute kidney injury (AKI) frequently complicates the repair of Stanford type A aortic dissection (TAAD). This systematic review, meta-analysis, and meta-regression analysis aimed to elucidate the prognostic impact of AKI in these patients. A literature search in PubMed, EMBASE, and Google Scholar identified relevant studies on the predictors and outcomes of AKI following TAAD repair. The primary endpoint was 30-day mortality; secondary endpoints included stroke, dialysis/continuous renal replacement therapy (CRRT), and other complications. Random-effects meta-analyses were used, with significance set at P < 0.05. Twenty-one studies (10 396 patients) were analyzed. AKI was associated with higher risks of 30-day mortality (risk ratio = 3.98), stroke (risk ratio = 2.05), dialysis/CRRT (risk ratio = 32.91), cardiovascular (risk ratio = 2.85) and respiratory complications (risk ratio = 2.13), sepsis (risk ratio = 4.92), and re-exploration for bleeding (risk ratio = 2.46). No significant differences were noted in sternal wound infection, tracheostomy, paraplegia, or hepatic failure. AKI significantly increases mortality, morbidity, hospital, and ICU stay duration in TAAD repair patients.
Overcoming challenges to access ecological function: a marine soft-bottom perspective
Authors: Martins A. , Di Domenico M. , Costa Y. , Barros F.
Published: October 2024

Ecosystem functioning studies have gained prominence due to concerns about the decline of species. In marine sediments, benthic invertebrates perform important ecological functions. However, the challenges within the field of functional ecology are sparsely discussed. Our aim was to systematize the problems and suggest pathways forward. To achieve this, we review recent articles on functional ecology on marine sediments and identified two main issues. First, the absence of a clear definition of terms. Second, in terms of applicability, we observed a mismatch between the scales of functioning and traits, incomplete information on trait databases, inappropriate selection of traits, subjective measures of traits, overlooked trait variability and data analyses without the link between the taxonomy and the traits associated with functions. We propose some pathways to overcome the challenges, such as (i) reasoning of the concept of function, process and trait, (ii) increasing experiments to measure functions, (iii) clarification of the relationship between traits and functions, (iv) clear procedure for assigning trait scores, (v) experiments for understanding trait variability and function performance, and (vi) analyses that consider the sets of traits of each taxon. Overcoming these challenges will allow us to advance research and fill gaps in knowledge of ecosystem functioning.
Characterization of hydromagnetic waves propagating over a steady, non-axisymmetric background magnetic field
Authors: Barrois O. , Aubert J.
Published: October 2024

Motivated by recent observations of rapid (interannual) signals in the geomagnetic data, and by advances in numerical simulations approaching the Earth’s outer core conditions, we present a study on the dynamics of hydromagnetic waves evolving over a static base state. Under the assumption of timescales separation between the rapid waves and the slow convection, we linearize the classical magneto-hydrodynamics equations over a steady non-axisymmetric background magnetic field and a zero velocity field. The initial perturbation is a super-rotating pulse of the inner core, which sets the amplitude and length scales of the waves in the system. The initial pulse triggers axisymmetric, outward propagating torsional Alfvén waves, with characteristic thickness scaling with the magnetic Ekman number as

E

k
M

1
/
4

. Because the background state is non-axisymmetric, the pulse also triggers non-axisymmetric, quasi-geostrophic (QG) Alfvén waves. As these latter waves propagate outwards, they turn into QG, magneto-Coriolis (QG-MC) waves as the Coriolis force supersedes inertia in the force balance. The period of the initial wave packet is preserved across the shell but the QG-MC wavefront disperses and a westward drift is observed after this transformation. Upon reaching the core surface, the westward drift of the QG-MC waves presents an estimated phase speed of about

1100

k
m

y

−
1

. This analysis confirms the QG-MC nature of the rapid magnetic signals observed in geomagnetic field models near the Equator.
Performance analysis and accuracy of numerical methods for solving simultaneous nonlinear particulate processes with multi-dimensional extension
Authors: Kushwah Prakrati , Saha Jitraj
Published: October 2024

The simultaneous population balance equation (PBE) incorporating diverse particulate process aggregation, breakage, growth, nucleation and source is a long-standing and significant problem in the field of particulate sciences such as pharmaceutical industry, chemical engineering, astrophysics and biology. Owing to the complex and nonlinear nature of the governing equations, finding an analytical solution is quite challenging for empirical kernels. In this work, simultaneous PBEs are solved using sectional and semi-analytical techniques. The performance, adaptability and accuracy of both methods for solving simultaneous PBEs are discussed in detail. The iterative semi-analytical scheme for solving simultaneous PBE is introduced, and a detailed convergence analysis using Banach fixed point theory is also presented. Both the schemes are further extended to solve simultaneous PBE in multi-dimensions. Performance analysis is also executed for multi-dimensional models. This article is a comprehensive study on various solution techniques for solving simultaneous PBEs. Therefore, it will be beneficial for the researchers working in industry and computational fluid dynamics modelling to identify the best method according to their requirements.
Hydrogenimonas leucolamina sp. nov., a hydrogen- and sulphur-oxidizing mesophilic chemolithoautotroph isolated from a deep-sea hydrothermal vent chimney at the Suiyo Seamount in the Western Pacific Ocean
Authors: Hatakeyama Shuya , Mino Sayaka , Mizobata Mana , Takada Mako , Tsuchiya Jiro , Yamaki Shogo , Ando Yasuhiro , Sawabe Tomoo , Takai Ken
Published: October 2024

A novel mesophilic bacterium, strain SS33T, was isolated from a deep-sea hydrothermal vent chimney at Suiyo Seamount, Izu-Bonin Arc, Western Pacific Ocean. The cells of strain SS33T were motile short rods with a single polar flagellum. The growth of strain SS33T was observed at the temperature range between 33 and 55 °C (optimum growth at 45 °C), at the pH range between 5.0 and 7.1 (optimum growth at pH 6.0) and in the presence of between 2.0 and 4.5% (w/v) NaCl [optimum growth at 3.5% (w/v)]. Strain SS33T was a facultative anaerobic chemolithoautotroph using molecular hydrogen and elemental sulphur as the sole electron donor. Nitrate, nitrous oxide, sulphate, elemental sulphur and molecular oxygen were capable of serving as the sole electron acceptor. Phylogenetic analysis based on 16S rRNA gene sequences placed strain SS33T in the genus Hydrogenimonas belonging to the class Epsilonproteobacteria. The closely related species of strain SS33T were Hydrogenimonas urashimensis SSM-Sur55T (95.96%), Hydrogenimonas thermophila EP1-55-1%T (95.75%) and Hydrogenimonas cancrithermarum ISO32T (95.24%). According to the taxonomic and physiological characteristics, it is proposed that strain SS33T was classified into a novel species of genus Hydrogenimonas, Hydrogenimonas leucolamina sp. nov., with SS33T (=JCM 39184T =KCTC 25253T) as the type strain. Furthermore, the genome comparison of Epsilonproteobacteria revealed that their [NiFe] hydrogenase genes belonging to Group 1b could be divided into two phylogenetic lineages and suggested that the reverse gyrase gene has been lost after division to the genus Hydrogenimonas.
Morphine-induced hyperalgesia impacts small extracellular vesicle miRNA composition and function
Authors: Reddy Deepa , Lin Zhucheng , Ramanathan Sujay , Luo Xuan , Pande Richa , Tian Yuzhen , Side Christine , Barker Jacqueline M. , Sacan Ahmet , Blendy Julie A. , Ajit Seena K.
Published: October 2024

Morphine and other synthetic opioids are widely prescribed to treat pain. Prolonged morphine exposure can paradoxically enhance pain sensitivity in humans and nociceptive behavior in rodents. To better understand the molecular mechanisms underlying opioid-induced hyperalgesia, we investigated changes in miRNA composition of small extracellular vesicles (sEVs) from the serum of mice after a morphine treatment paradigm that induces hyperalgesia. We observed significant differential expression of 18 miRNAs in sEVs from morphine-treated mice of both sexes compared to controls. Several of these miRNAs were bioinformatically predicted to regulate cyclic AMP response element binding protein (CREB), a well-characterized transcription factor implicated in pain and drug addiction. We confirmed the binding and repression ofCrebmRNA by miR-155 and miR-10a. We tested if serum-derived sEVs from morphine-treated mice could elicit nociceptive behavior in naïve recipient mice. Intrathecal injection of 1 μg sEVs did not significantly impact basal mechanical and thermal threshold in naïve recipient mice. However, prophylactic 1 μg sEV administration in recipient mice resulted in faster resolution of complete Freund’s adjuvant-induced mechanical and thermal inflammatory hypersensitivity. Other behaviors assayed following administration of these sEVs were not impacted including sEV conditioned place preference and locomotor sensitization. These results indicate that morphine regulation of serum sEV composition can contribute to analgesia and suggest a potential for sEVs to be a non-opioid therapeutic intervention strategy to treat pain.
Physics-inspired accuracy estimator for model-docked ligand complexes
Authors: Bae Byunghyun , Choi Jungyoon , Seok Chaok , Park Hahnbeom
Published: October 2024

Model docking, which refers to ligand docking into the protein model structures, is becoming a promising avenue in drug discovery with the advances in artificial intelligence (AI)-based protein structure prediction. However, a significant challenge remains; even when sampling was successful in model docking, typical docking score functions fail to identify correct solutions for two-thirds of them. This discrepancy between scoring and sampling majorly arises because these scoring functions poorly tolerate minor structural inaccuracies. In this work, we propose a deep neural network named DENOISer to address the scoring challenge in model-docking scenario. In the network, ligand poses are ranked by the consensus score of two independent sub-networks: the Native-likeness prediction and the Binding energy prediction networks. Both networks incorporate physical knowledge as inductive bias in order to enhance pose discrimination power while ensuring tolerance to small interfacial structural noises. Combined with Rosetta GALigandDock sampling, DENOISer outperformed existing docking tools on the PoseBusters model-docking benchmark set as well as on a broad cross-docking benchmark set. Further analyses reveal the physics-based components and the consensus ranking approach are the two most crucial factors contributing to its ranking success. We expect DENOISer may assist future drug discovery endeavors by providing more accurate structural models for protein-ligand complexes. The network is freely available at https://github.com/HParklab/DENOISer.
Expression-Driven Genetic Dependency Reveals Targets for Precision Medicine
Authors: Elmas Abdulkadir , Layden Hillary M. , Ellis Jacob D. , Bartlett Luke N. , Zhao Xian , Kawabata-Iwakawa Reika , Obinata Hideru , Hiebert Scott W. , Huang Kuan-lin
Published: October 2024

Cancer cells are heterogeneous, each harboring distinct molecular aberrations and are dependent on different genes for their survival and proliferation. While successful targeted therapies have been developed based on driver DNA mutations, many patient tumors lack druggable mutations and have limited treatment options. Here, we hypothesize that new precision oncology targets may be identified through “expression-driven dependency”, whereby cancer cells with high expression of a targeted gene are more vulnerable to the knockout of that gene. We introduce a Bayesian approach, BEACON, to identify such targets by jointly analyzing global transcriptomic and proteomic profiles with genetic dependency data of cancer cell lines across 17 tissue lineages. BEACON identifies known druggable genes, e.g.,BCL2, ERBB2, EGFR, ESR1, MYC, while revealing new targets confirmed by both mRNA- and protein-expression driven dependency. Notably, the identified genes show an overall 3.8-fold enrichment for approved drug targets and enrich for druggable oncology targets by 7 to 10-fold. We experimentally validate that the depletion ofGRHL2,TP63, andPAX5effectively reduce tumor cell growth and survival in their dependent cells. Overall, we present the catalog of express-driven dependency targets as a resource for identifying novel therapeutic targets in precision oncology.
Investigating the role of CpG island DNA methylation at 3’UTRs in cancer
Authors: Wilson Claire , Kanhere Aditi
Published: October 2024

DNA methylation is one of the most important epigenetic processes that regulates gene expression. While the human genome is predominately methylated, CpG-rich regions known as CpG islands (CGIs) are unmethylated and are sites of transcriptional control. While the importance of CGI and DNA methylation at gene promoters is well understood, the significance of CGIs at 3’ untranslated regions (3’UTRs) remains largely unexplored. In this study, we characterised CGIs located within 3’UTRs and investigated their role in gene regulation. Here, we show that around 3% of CGIs (909 CGIs) are exclusively located at 3’UTR and are not associated with any nearby promoters. Importantly, 3’UTR CGIs are highly conserved, with a conservation score even higher than promoter CGI implying their importance. In contrast to promoter CGIs which are predominantly unmethylated, 3’UTR CGIs are often methylated. Genes with 3’UTR CGIs are associated with several different cancers and cancer-related signalling pathways. Moreover, 3’UTR CGIs are differentially methylated in cancers, with changes in methylation associated with changes in gene expression. Together this data suggests the importance of 3’UTR CGIs and their methylation in gene expression regulation in cancer.
Prioritization of Lung Cancer Candidate Genes using Moment of Inertia Tensor Analysis
Authors: Dwivedi Ayushi , Thippana Mallikarjuna , Manimaran P. , Vindal Vaibhav
Published: October 2024

A variety of factors contribute to the complexity of lung cancer progression. To comprehend the disease, candidate genes must be investigated. Present study aimed to employ an alignment-free method to prioritize candidate genes based on the physicochemical properties of the amino acids. It uses the moment of inertia tensor that measures the mass distribution around an axis of rotation, to compute the rotational energy and angular momentum of amino acids in protein sequences. The computed features were compared to those of established lung cancer genes, leading to the identification of 26 candidate genes with a high degree of similarity. These genes participate in critical biological processes that regulate the mitotic cell cycle and cell development. The prognostic significance of these genes was also assessed and four genes (IL1A, CDC25C, IL4R, and TGFBR1) were found to be associated with poor survival. Additionally, the role of prioritized genes and potential drugs that target these genes in other cancer types was also examined. Our method will help to discover new biomarkers and intervention strategies for lung cancer.
Proteasome inhibition enhances latency reversal and boosts NK cell-mediated elimination of HIV-1 infected cells through HLA-E downregulation
Authors: Laeremans Thessa , den Roover Sabine , Nezic Stefan Johan , Allard Sabine D. , Aerts Joeri L.
Published: October 2024

The shock and kill strategy primarily depends on using latency reversal agents (LRAs) to reactivate the dormant viral reservoir, rendering it visible for recognition and subsequent elimination by the host’s immune system. While this approach has shown high efficacyin vitroandex vivo, itsin vivoapplication has yet to show significant delays in time to viral rebound. This lack ofin vivoefficacy is most likely due to the insufficient elimination of reactivated reservoir cells by the host’s immune effector cells, including natural killer (NK) cells. Given the pivotal role of NK cells in antiviral immune responses, we hypothesized that they are crucial players in pursuing a functional cure against HIV-1. However, the inhibitory interaction between NKG2A and HLA-E diminishes their effectiveness. Notably, proteasome inhibition has been effective in reducing HLA-E expression on various tumor cell types, thereby enhancing NK-cell mediated killing. However, its impact on HIV-1 latency remains unexplored. We found that the proteasome inhibition could reverse the latent state of J-Lat cells while substantially reducing HLA-E expression. Additionally, a reduced expression of NKGA on primary NK cells was observed which led to an increase in NK-cell cytotoxicity. These results suggest that disrupting the NKG2A/HLA-E interaction could potentially augment the effectiveness of the shock and kill strategy by improving NK cell-mediated clearance of reactivated cells.

Importance

Despite promisingin vitroresults, purging the viral reservoir using LRAs has yet to demonstrate clinical benefits. A significant challenge lies in the inadequate activation of immune effector cells, such as CD8+T cells and NK cells. Therefore, developing therapeutic strategies to address these challenges could enhance the effectiveness of the shock and kill strategy. This study highlights the need for therapeutic interventions to overcome these hurdles. Our findings show that proteasome inhibition not only triggers latency reversal but also enhances NK-cell mediated elimination of latently infected cellsin vitroby downregulating HLA-E. This suggests that targeting the proteasome could be a novel therapeutic approach in the shock and kill strategy, potentially improving clinical outcomes.
Lifting the degeneracy of optical fiber neural interfaces for optogenetics and electrophysiology by using axialtrodes
Authors: Sui Kunyang , Codadu Neela K. , Rathore Daman , Li Guanghui , Meneghetti Marcello , Berg Rune W , Wykes Rob C. , Markos Christos
Published: October 2024

Optogenetics and electrophysiology are powerful methods in neuroscience for precise spatiotemporal control and recording of neural activity. Conventional flat optical fibers, commonly used in deep brain regions, can only interface with limited tissue volume at their distal end. However, depth-resolved neuromodulation and recordings are crucial for decoding neuronal connections across various brain domains. In this work, we address this limitation by introducing an axialtrode developed using soft polymers integrated with multiple metal electrodes via a scalable thermal drawing process. We employ the developed fiber-based neural interface, controllably angled-cleaved, for multisite optogenetics and electrophysiology at different brain regions. Its suppressed inflammatory responses indicate improved biocompatibility compared to conventional fibers. This concept can be adapted to any fiber material and application where depth-resolved stimulation and electrical recordings are important, bringing the community a step closer to understanding complex neuronal dynamics.
Analytical and clinical validation of a genome sequencing-based comprehensive rare disease genomic profiling test
Authors: Sriram Shruthi , Lee Sang Yeon , Ferguson Stephanie , Koh June-Young , Wallace Jonathan Kyle , Lee Jeonghoon , Kim Jung-Ah , Lee Yoonsuh , Oh Brian Baek-Lok , Lee Won Chul , Lee Sangmoon , Connolly-Strong Erin
Published: October 2024

This study evaluates the performance of the RareVision Whole Genome Sequencing (WGS) assay for comprehensive genomic profiling in rare genetic diseases. The analytical validation assessed the assay’s sensitivity and positive predictive values (PPV) for single nucleotide variants (SNVs), insertions/deletions (indels), and structural variants (SVs), revealing a sensitivity of 99.4% for SNVs and 98.7% for indels, with PPVs of 99.3% for SNVs and 98.7% for indels. Clinical validation involved benchmarking against established orthogonal methods, demonstrating high concordance in variant detection with reference laboratories. The assay’s reproducibility was confirmed with 100% inter-precision and intra-precision concordance. The RareVision WGS assay provides detailed genomic insights, enhancing the diagnosis and management of rare genetic disorders by offering a comprehensive and accurate genomic profiling tool.
Bridging the Gap between Database Search andDe NovoPeptide Sequencing with SearchNovo
Authors: Xia Jun , Liu Sizhe , Zhou Jingbo , Chen Shaorong , Xiang Hongxin , Liu Zicheng , Liu Yue , Li Stan Z.
Published: October 2024

Abstract

Accurate protein identification from mass spectrometry (MS) data is fundamental to unraveling the complex roles of proteins in biological systems, with peptide sequencing being a pivotal step in this process. The two main paradigms for peptide sequencing are database search, which matches experimental spectra with peptide sequences from databases, andde novosequencing, which infers peptide sequences directly from MS without relying on pre-constructed database. Although database search methods are highly accurate, they are limited by their inability to identify novel, modified, or mutated peptides absent from the database. In contrast,de novosequencing is adept at discovering novel peptides but often struggles with missing peaks issue, further leading to lower precision. We introduce SearchNovo, a novel framework that synergistically integrates the strengths of database search andde novosequencing to enhance peptide sequencing. SearchNovo employs an efficient search mechanism to retrieve the most similar peptide spectrum match (PSM) from a database for each query spectrum, followed by a fusion module that utilizes the reference peptide sequence to guide the generation of the target sequence. Furthermore, we observed that dissimilar (noisy) reference peptides negatively affect model performance. To mitigate this, we constructed pseudo reference PSMs to minimize their impact. Comprehensive evaluations on multiple datasets reveal that SearchNovo significantly outperforms state-of-the-art models. Also, analysis indicates that many retrieved spectra contain missing peaks absent in the query spectra, and the retrieved reference peptides often share common fragments with the target peptides. These are key elements in the recipe for SearchNovo’s success. The code for reproducing the results are available in the supplementary materials.