bluuebunny/crossref_metadata_2025 huggingface dataset:
Biomarkers for the diagnosis and monitoring of celiac disease: can you count on me?
Authors: Topa Matilde , Sanders David Surendran , Elli Luca
Published: February 2022

Purpose of review

Different markers are available to diagnose and monitor celiac disease (CeD); however, the concordance among them and their efficacy are still controversial. We aim at defining the efficacy of CeD biomarkers, their advantages and limits.

Recent findings

CeD diagnostic criteria are widely accepted, being a positive serology and duodenal atrophy (according to the Marsh-Oberhuber score) the main hallmarks. Flow cytometry and other molecular biomarkers support the diagnosis of refractory CeD. On the other side, CeD monitoring is less defined, as the biomarkers are not always reliable. To date, the reference standard to detect mucosal healing is represented by duodenal histology, but its timing and significance are debated. Novel scores may better define the trend of mucosal damage and MicroRNAs are among the innovative noninvasive biomarkers. The assessment of a correct gluten-free diet (GFD) is another aspect of CeD monitoring, based upon questionnaires and recently developed tools such as dosage of urinary or faecal gluten immunogenic peptides.

Clinicians lack of a widely acknowledged tools to monitor CeD and GFD. Here, we present the efficacy of the most used markers.
Severe Hepatitis in Pediatric Coronavirus Disease 2019
Authors: Antala Swati , Diamond Tamir , Kociolek Larry K. , Shah Amit A. , Chapin Catherine A.
Published: February 2022

Hepatic involvement in coronavirus disease 2019 (COVID‐19) is typically characterized as mild hepatitis with preserved synthetic function in children. Severe hepatitis is a rare complication of COVID‐19 infection that has not been extensively described in the pediatric population. We report a case series of four previously healthy children who presented with significant hepatitis as the primary manifestation of COVID‐19 infection. Two of these patients met criteria for acute liver failure. None of the patients had respiratory symptoms. One patient was found to have complement dysfunction resulting in microangiopathic features and was treated successfully with eculizumab. This case is in line with adult post‐mortem data showing that more severe cases of hepatic dysfunction secondary to COVID‐19 infection may be associated with complement activation and microangiopathic features. Liver function should be evaluated in cases of severe COVID‐19, and severe acute respiratory syndrome coronavirus 2 infection should be considered as a cause of acute severe hepatitis even in patients without significant respiratory or other systemic symptoms.
Esophageal Microbiome in Healthy Children and Esophageal Eosinophilia
Authors: Parashette Kalyan Ray , Sarsani Vishal Kumar , Toh Evelyn , Janga Sarath Chandra , Nelson David E. , Gupta Sandeep K.
Published: February 2022

Objectives:

There is limited knowledge about the role of esophageal microbiome in pediatric esophageal eosinophilia (EE). We aimed to characterize the esophageal microbiome in pediatric patients with and without EE.

Methods:

In the present prospective study, esophageal mucosal biopsies were obtained from 41 children. Of these, 22 had normal esophageal mucosal biopsies (“healthy”), 6 children had reflux esophagitis (RE), 4 had proton pump inhibitor (PPi)‐responsive esophageal eosinophilia (PPi‐REE), and 9 had eosinophilic esophagitis (EoE). The microbiome composition was analyzed using 16S rRNA gene sequencing. The age median (range) in years for the healthy, RE, PPi‐REE, and EoE group were 10 (1.5–18), 6 (2–15), 6.5 (5–15), and 9 (1.5–17), respectively.

Results:

The bacterial phylum Actinobacteria, Bacteroidetes, Firmicutes, Fusobacteria, and Proteobacteria were the most predominant. The Epsilonproteobacteria, Betaproteobacteria, Flavobacteria, Fusobacteria, and Sphingobacteria class were underrepresented across groups. The Vibrionales was predominant in healthy and EoE group but lower in RE and PPi‐REE groups. The genus Streptococcus, Rahnella, and Leptotrichia explained 29.65% of the variation in the data with an additional 10.86% variation in the data was explained by Microbacterium, Prevotella, and Vibrio genus. The healthy group had a higher diversity and richness index compared to other groups, but this was not statistically different.

Conclusions:

The pediatric esophagus has an abundant and diverse microbiome, both in the healthy and diseased states. The healthy group had a higher, but not significantly different, diversity and richness index compared to other groups.
Case Report: Bilateral Corneal Ectasia Developed during Pregnancy after Small-incision Lenticule Extraction
Authors: Huang Tian-Ze , Jin Hong-Ying
Published: February 2022

SIGNIFICANCE

This case highlights that hormonal changes during pregnancy could affect the biomechanical stability of the cornea and lead to corneal ectasia during pregnancy after corneal refractive surgery.

PURPOSE

We report an unusual case of bilateral corneal ectasia after small-incision lenticule extraction that developed during pregnancy.

CASE REPORT

A 27-year-old woman experienced post–small-incision lenticule extraction corneal ectasia. Her pre-operative corneal topography was normal, with a minimum central corneal thickness of 538 μm in the right eye and 530 μm in the left eye. The manifest refraction was −7.75 −0.25 × 180 and −7.50 −0.75 × 10, and the lenticule thickness was 140 and 139 μm in the right and left eyes, respectively. After 11 months, in her first trimester, the patient began to experience gradually deteriorating blurred vision. Two years post-operatively, corneal ectasia was diagnosed based on topographic data. The automatic optometer examination was −7.25 −2.50 × 42 in the right eye and −11.00 −5.00 × 140 in the left eye. Later, the patient underwent corneal collagen cross-linking to control further progression and was recommended to wear rigid gas-permeable contact lenses.

CONCLUSIONS

Surgeons should be alert for cornea ectasia after refractive surgery in pregnant patients, as hormonal changes during pregnancy may affect corneal biomechanical stability.
Building a Community-Centered Public Health Advocacy Training Program for Medical Students
Authors: Shankar Sruthi , Phinney Robin , Krapek Annie , Surapaneni Vishnu Laalitha
Published: February 2022

Context:

Public health advocacy is increasingly acknowledged as an essential component of practice in medicine. Medical schools, residency programs, and professional organizations have begun developing curricula in an effort to teach advocacy. This article describes the structuring and evolution of the Dr Pete Dehnel Public Health Advocacy Fellowship, an innovative program prioritizing a community-centered approach to teaching physician advocacy to medical students.

Program:

Created by the Twin Cities Medical Society (TCMS), the fellowship's curriculum adopts a cohort-based learning model organized around skills training, personalized physician-mentor pairing in a shared field of interest, and hands-on advocacy activities. The curriculum also centers insights and practical knowledge from community members who are outside of the health care sphere alongside those of experienced physician-advocates.

Implementation:

TCMS partnered with an independent research organization to conduct an ongoing developmental evaluation (DE) of the fellowship. DE focuses on rapid-cycle feedback and utilization of findings to inform the development of program components. This enables TCMS to customize the fellowship's curricular components to the local context and in response to student and mentor feedback.

Evaluation:

Early findings have allowed TCMS to refine curricular components while providing evidence of significant gains in 3 areas of growth among fellows: perceived knowledge and advocacy skills proficiency; perceived self-efficacy; and motivation for lifelong advocacy practice.

Discussion:

Key fellowship components, including a flexible curricular structure with built-in adaptability and emphasis on long-term health advocacy engagement, are associated with student growth. These core elements along with a focus on community-centeredness can be integrated into curricula of other programs seeking to train medical learners and physicians to embrace a lifelong commitment to public health advocacy.
Extracorporeal Shock Wave Therapy on Spasticity After Upper Motor Neuron Injury
Authors: Zhang Hui-Ling , Jin Rong-Jiang , Guan Li , Zhong Dong-Ling , Li Yu-Xi , Liu Xiao-Bo , Xiao Qi-Wei , Xiao Xi-Li , Li Juan
Published: February 2022

Objective

The aim of the study was to evaluate the effectiveness and safety of extracorporeal shock wave therapy on spasticity after upper motor neuron injury.

Design

Eight electronic databases were searched systematically from their inception to August 3, 2021, to provide robust evidence for the efficacy of extracorporeal shock wave therapy for spasticity and range of motion after upper motor neuron injury. Study screening, data extraction, risk of bias assessment, and evaluation of the certainty of evidence were performed independently by two independent reviewers. Data analysis was conducted using RevMan 5.3.5 and R 3.6.1 software.

Results

Forty-two studies with 1973 patients who met the eligibility criteria were selected from articles published from 2010 to 2021, of which 34 were included in the meta-analysis. A comparison intervention revealed that extracorporeal shock wave therapy significantly decreased the Modified Ashworth Scale score and increased the passive range of motion of a joint. Regarding the safety of extracorporeal shock wave therapy, slightly adverse effects, such as skin injury, bone distortion, muscle numbness, pain, petechiae, and weakness, were reported in five studies.

Conclusions

Extracorporeal shock wave therapy may be an effective and safe treatment for spasticity after upper motor neuron injury. However, because of poor methodological qualities of the included studies and high heterogeneity, this conclusion warrants further investigation.

To Claim CME Credits

Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME

CME Objectives

Upon completion of this article, the reader should be able to: (1) Determine the impact of extracorporeal shock wave therapy on spasticity after upper motor neuron injury; (2) Describe the factors that affect the efficacy of extracorporeal shock wave therapy on spasticity; and (3) Discuss the mechanism of action of extracorporeal shock wave therapy on spasticity.

Level

Advanced

Accreditation

The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
The Hippocampal–Ventral Medial Prefrontal Cortex Neurocircuitry Involvement in the Association of Daily Life Stress With Acute Perceived Stress and Cortisol Responses
Authors: Ren Xi , Zhao Xiaolin , Li Jiwen , Liu Yadong , Ren Yipeng , Pruessner Jens C. , Yang Juan
Published: February 2022

Objective

Daily life stressors include everyday irritants, hassles, and inconveniences, such as problems in traffic and unexpected work deadlines. A growing body of research has suggested higher daily stress is associated with blunted cortisol response to acute psychosocial stressors. However, so far, the neural mechanism underlying this association has not been elucidated. The current study aimed to examine the role of stress neurocircuitry between the hippocampus and the ventral medial prefrontal cortex in this relationship.

Methods

To this end, as an index of daily stress in 44 young healthy individuals (23 females; mean [standard deviation] age = 19.07 [1.11] years), the total stressful rating score of daily life stress events that occurred in a 24-hour period was quantified. Individuals were then administered a modified version of the Montreal Imaging Stress Task while undergoing functional magnetic resonance imaging scans, and their saliva samples were collected for assessment of the stress hormone cortisol.

Results

Results revealed that a higher level of daily stress was associated with lower salivary cortisol secretion (r = −0.39, p = .008) and lower activation of the left hippocampus (t
peak = −5.51) in response to the Montreal Imaging Stress Task. Furthermore, a higher level of daily stress was associated with stronger functional connectivity between the left hippocampus and the ventral medial prefrontal cortex/subgenual anterior cingulate cortex (t
peak = 4.91, R
2
= 0.365).

Conclusions

Taken together, the current study suggested a possible neurocircuitry of the hippocampus and ventral medial prefrontal cortex in the relationship between daily life stress and acute psychosocial stress.
A Pragmatic Method for Measuring Inpatient Complications and Complication-Specific Mortality
Authors: Blike George T. , Perreard Irina M. , McGovern Krystal M. , McGrath Susan P.
Published: February 2022

Objectives

The primary objective of this study was to develop hospital-level metrics of major complications associated with mortality that allows for the identification of opportunities for improvement. The secondary objective is to improve upon current metrics for failure to rescue (i.e., death from serious but treatable complications.)

Methods

Agency for Healthcare Research and Quality metrics served as the basis for identifying specific complications related to major organ system morbidity associated with death. Complication-specific occurrence rates, observed mortality, and risk-adjusted mortality indices were calculated for the study institution and 182 peer organizations using component International Classification of Disease, Tenth Revision codes. Data were included for adults over a 4-year period, with exclusion of hospice patients and complications present on admission. Temporal visualizations of each metric were used to compare past and recent performance at the study hospital and in comparison to peers.

Results

The complication-specific method showed statistically significant differences in the study hospital occurrence rates and associated mortality rates compared with peer institutions. The monthly control-chart presentation of these metrics provides assessment of hospital-level interventions to prevent complications and/or reduce failure to rescue deaths.

Conclusions

The method described supplements existing metrics of serious complications that occur during the course of acute hospitalization allowing for enhanced visualization of opportunities to improve care delivery systems. This method leverages existing measure components to minimize reporting burden. Monthly time-series data allow interventions to prevent and/or rescue patients to be rapidly assessed for impact.
Use of Online Information in Musculoskeletal Conditions
Authors: Fritsch Carolina G. , Duong Vicky , Chen Lingxiao , Hunter David J. , McLachlan Andrew J. , Ferreira Paulo H. , Ferreira Manuela L.
Published: February 2022

Background/Objective

We aimed to investigate the yearly online public interest for gout, low back pain, neck pain, osteoarthritis, and rheumatoid arthritis, the most popular topics searched for these conditions, and the association between the change in their interest over time and the sociodemographic index of the search location.

Methods

We conducted online searches in Google Trends for the aforementioned conditions between 2004 and 2020. The search volumes for each condition (relative to all searches conducted in the period) and the top and rising related queries and topics were downloaded and summarized.

Results

There was a rise in the online interest for musculoskeletal conditions between 2008 and 2020, with low back pain (annual percent change, 7.4; 95% confidence interval [CI], 7.1–7.7) and neck pain (annual percent change, 7.2; 95% CI, 6.9–7.5) presenting the highest increases. There was a negative, statistically significant, but small association between change in online interest and the country's sociodemographic index for low back pain (−0.007; 95% CI, −0.011 to−0.003), neck pain (−0.005; 95% CI, 0.009 to −0.001), and rheumatoid arthritis (−0.009; 95% CI, −0.017 to −0.001) between 2013 and 2020. The interest for the cause and symptoms of the selected conditions increased over time, except for gout. The proportion of queries and topics related to treatment of all conditions decreased over time.

Conclusions

The worldwide interest in musculoskeletal conditions increased between 2008 and 2020. The public seems more interested in understanding what musculoskeletal conditions are and less interested in which treatment options are available. The results can guide the development of educational campaigns for musculoskeletal conditions.
Hybrid Preservation Rhinoplasty: Combining Mix-Down and Semi Let-Push Down Techniques
Authors: Öztürk Güncel
Published: February 2022

Rhinoplasty is 1 of the most applied procedures among aesthetic and plastic surgery areas. Dorsal hump deformity is a common deformity among Caucasians based on the natural anatomy of the nose. Dorsal preservation techniques arose as a necessity for overcoming the negative outcomes of traditional hump reduction surgery in patients with hump deformity. Beside the strong advantages of dorsal preservation techniques such as push-down and let-down techniques in the fixation of dorsal hump deformity, innovations on these procedures would bring better outcomes in terms of aesthetic and functional manners. In present research, the author defines a new technique, which combines new procedures as mix-down and semi let-down and semi push-down techniques. This study was designed as a retrospective. According to the inclusion and exclusion criteria, 36 patients (26 females and 10 males) were included in the study. The author applied to patients hybrid preservation rhinoplasty approach, which is a combination of mix-down and semi let-down and semi push-down techniques. All patients completed the Rhinoplasty Outcome Evaluation (ROE) questionnaire before surgery and at their 1-year follow-up appointment. The follow-up period ranged between 13 and 28 months (median of 19.8months). The initial median ROE score was 55.5, and it increased to 91.00 points at 12 months after surgery (P < 0.001). According to the ROE scale, patients’ satisfaction was found as excellent in 91.6% of patients. Present study showed satisfactory outcomes of hybrid dorsal preservation technique, which is a combination of mix-down and semi-let down and semi-push down approaches. This new approach will be suitable for selected patients and easy to perform by the surgeons. Moreover, patients who have concomitant hump and deviation deformities will benefit from hybrid dorsal preservation technique.

Level of Evidence: 3
Nocardioides humilatus sp. nov., isolated from farmland soil in the Republic of Korea
Authors: Lee Jong Min , Jin Chun-Zhi , Kang Min-Kyoung , Park So Hee , Park Dong-Jin , Kim Dong-Gyun , Kim Chang-Jin
Published: February 2022

A Gram-stain positive, aerobic, irregularly rod-shaped, non-spore-forming bacterium, designated as BN130099T, was isolated from farmland soil sampled in Goesan-gun, Chungbuk, Republic of Korea. Phylogenetic analysis of its 16S rRNA gene sequence showed that the strain is closely related to

Nocardioides pelophilus

KACC 19192T with 98.11 % similarity. The DNA G+C content of strain BN130099T was 68.84 mol% (draft genome sequence). The genome sequence of BN130099T displayed key enzymes involved in bioremediation of organic pollutants and biosynthetic clusters of saquayamycin. The strain contained ll-2,6-diaminopimelic acid in the cell-wall peptidoglycan and MK-8(H4) as the major respiratory quinone. The predominant fatty acid was iso-C16 : 0. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine and phosphatidylinositol. The results of physiological and biochemical characterization allowed the phenotypic differentiation of strain BN130099T from

N. pelophilus

KACC 19192T. The strain represents a novel species of the genus

Nocardioides

, for which we propose the name Nocardioides humilatus sp. nov. The type strain is BN130099T (=KCTC 49079T=CCTCC AB 2018135T).
Faecalicatena absiana sp. nov., an obligately anaerobic bacterium from a pig farm faeces dump
Authors: Shin Yeseul , Paek Jayoung , Kim Hongik , Kook Joong-Ki , Chang Young-Hyo
Published: February 2022

An obligately anaerobic, Gram-stain-positive, spore-forming, short-rod-shaped bacterium, designated strain YH-C36aT, was isolated from a pig farm faeces dump. Phylogenetic analysis based on 16S rRNA gene sequences indicated that the isolate belongs to the genus

Faecalicatena

and is most closely related to

Faecalicatena contorta

KCTC 5831T,

Faecalicatena fissicatena

KCTC 15010T and

Faecalicatena orotica

KCTC 15331T, with 96.3, 96.2, and 96.0 % sequence similarity, respectively. The average nucleotide identity values for strain YH-C36aT and the closest related strains were lower than 72 %. The G+C content of the isolate was 43.0 mol%. The cell-wall peptidoglycan was A1γ type and contained meso-diaminopimelic acid. The predominant fatty acids were C16 : 0, C18 : 1
cis 9, C16 : 0 DMA, C18 : 0 DMA and C18:0. The major end products of glucose fermentation were lactate, formate and acetate. Based on its phenotypic, phylogenetic and chemotaxonomic properties, a novel species, named Faecalicatena absiana sp. nov., is proposed for strain YH-C36aT (=KCTC 25106T=NBRC 114768T).
Outbreak of KPC-producing Klebsiella pneumoniae ST15 strains in a Chinese tertiary hospital: resistance and virulence analyses
Authors: Huang Jiansheng , Chen Xiuying , Yang Jie , Zhao Yunan , Shi Yang , Ding Hui , Zhao Xinmi , Xu Jianfen , Wu Rongzhen , Zhao Zhigang
Published: February 2022

Introduction. Carbapenem-resistant

Klebsiella pneumoniae

(CRKP) is a major cause of clinical infection. However,

K. pneumoniae

carbapenemase (KPC)-producing

K. pneumoniae

ST15 strains are occasionally identified and have seldom been reported to cause hospital outbreaks in PR China.

Hypothesis/Gap Statement. In this study, we describe nosocomial outbreaks caused by KPC-producing

K. pneumoniae

ST15 strains in a Chinese tertiary hospital.

Aim. To characterize the molecular relationship, resistance and virulence factors of the 32 KPC-producing

K. pneumoniae

ST15 strains isolated in a Chinese hospital.

Methodology. A total of 102 non-repetitive carbapenem-resistant

Enterobacteriaceae

(CRE) strains were collected from a Chinese tertiary hospital in 2018. Multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE) were performed to characterize the clonal relationship of the

K. pneumoniae

isolates, and the ST15 strains were selected for further study. Minimum inhibitory concentrations (MICs) were determined using the broth microdilution method and interpreted according to the Clinical and Laboratory Standards Institute (CLSI) guidelines. Fifteen carbapenem resistance genes, bla
KPC genetic structures and 12 virulence factors were detected by PCR. Whole-genome sequencing (WGS) was performed using next-generation sequencing combined with single-molecule real-time sequencing.

Results. Thirty-two

K. pneumoniae

ST15 strains were characterized, and 31 of them presented a PFGE similarity of >92 %, indicating clonal spread. In 81.3 % (26/32) of strains, the imipenem (IPM) and meropenem (MEM) MICs were ≤8 and≤16 µg ml−1, while only 1 isolate (KP18069) exhibited ≥64 µg ml−1 for both agents. The bla
KPC-2 gene embedded in the Tn3-Tn4401 chimaera and synonymous mutations of the ompK35 gene were detected in all the strains. However, a nonsense mutation at amino acid position 248 (K248X) of OmpK36 was found in the highly carbapenem-resistant strain KP18069. No virulence gene was detected in any of the ST15 strains. WGS analyses further confirmed the genetic characteristics of the

K. pneumoniae

KP18069 strain.

Conclusion. Nosocomial outbreaks caused by the clonal spread of

K. pneumoniae

ST15 strains were characterized in a Chinese tertiary hospital, and strict monitoring of highly resistant CRKP is required.
Phototherapy with physically and molecularly produced light for Alzheimer’s disease
Authors: Kuang Shi , Zhu Biyue , Zhang Jing , Yang Fan , Wu Bo , Ding Weihua , Shen Shiqian , Zhang Can , Ran Chongzhao
Published: February 2022

Over the past decades, classical drug development approaches for Alzheimer’s disease have yielded limited success, and this futileness has prompted scientists to seek non-classical approaches. In this report, we demonstrated that, with irradiation of LED light or with molecularly generated light (dubbed as “molecular light”) from chemiluminescence probe ADLumin-4, photolabile curcumin analogue CRANAD-147 could change properties, structures (sequences) and neurotoxicity of amyloid beta (Aβ) species in vitro. We further demonstrated that, with the assistance from molecular chemiluminescence imaging, the combination of CRANAD-147/LED or CRANAD-147/ADLumin-4 (molecular light) could slow down the accumulation of Aβs in transgenic 5xFAD mice in vivo. Due to the unlimited capacity of tissue penetration of molecular light in vivo, phototherapy with the combination of photolabile Aβ ligand and molecular light has great potential as an alternative approach for AD drug discovery.
Predicting Math Ability using Working Memory, Number Sense, and Neurophysiology in Children and Adults
Authors: van Bueren Nienke E. R. , van der Ven Sanne H. G. , Roelofs Karin , Kadosh Roi Cohen , Kroesbergen Evelyn H.
Published: February 2022

Previous work has shown relations between domain-general processes, domain-specific processes, and mathematical ability. However, the underlying neurophysiological effects of mathematical ability are less clear. Recent evidence highlighted the potential role of beta oscillations in mathematical ability. Here we investigate whether domain-general (working memory) and domain-specific (number sense) mediate the relation between resting-state beta oscillations and mathematical ability, and how this may differ as a function of development (children vs. adults). We compared a traditional analysis method normally used in EEG studies with a more recently developed parameterization method that separates periodic from aperiodic activity. Regardless of methods chosen, we found no support for mediation of working memory and number sense, neither for children nor for adults. However, we found subtle differences between the methods. Additionally, we showed that the traditional EEG analysis method conflates periodic activity with aperiodic activity, and the latter is strongly related to mathematical ability and this relation differs between children and adults. At the cognitive level, our findings do not support previous suggestions of a mediation of working memory and number sense. At the neurophysiological level our findings suggest that aperiodic, rather than periodic, activity is linked to mathematical ability as a function of development.
MIAMI: Mutual Information-based Analysis of Multiplex Imaging data
Authors: Seal Souvik , Ghosh Debashis
Published: February 2022

Motivation

Studying the interaction or co-expression of the proteins or markers in the tumor microenvironment (TME) of cancer subjects can be crucial in the assessment of risks, such as death or recurrence. In the conventional approach, the cells need to be declared positive or negative for a marker based on its intensity. For multiple markers, manual thresholds are required for each marker, which can become cumbersome. The performance of the subsequent analysis relies heavily on this step and thus suffers from subjectivity and lacks robustness.

Results

We present a new method where different marker intensities are viewed as dependent random variables, and the mutual information (MI) between them is considered to be a metric of co-expression. Estimation of the joint density, as required in the traditional form of MI, becomes increasingly challenging as the number of markers increases. We consider an alternative formulation of MI which is conceptually similar but has an efficient estimation technique for which we develop a new generalization. With the proposed method, we analyzed a lung cancer dataset finding the co-expression of the markers, HLA-DR and CK to be associated with survival. We also analyzed a triple negative breast cancer dataset finding the co-expression of the immuno-regulatory proteins, PD1, PD-L1, Lag3 and IDO, to be associated with disease recurrence. We demonstrated the robustness of our method through different simulation studies.

Availability

The associatedRpackage can be found here,https://github.com/sealx017/MIAMI.

Contact

souvik.seal@cuanschutz.edu

Supplementary information

The Supplementary Material is attached.
HIV, Pathology and epigenetic age acceleration in different human tissues
Authors: Horvath Steve , Lin David T.S. , Kobor Michael S. , Said Jonathan W. , Morgello Susan , Singer Elyse , Yong William H. , Jamieson Beth D. , Levine Andrew J.
Published: February 2022

Background

Epigenetic clocks based on patterns of DNA methylation have great importance in understanding aging and disease; however, there are basic questions to be resolved in their application. It remains unknown whether epigenetic age acceleration (EAA) within an individual shows strong correlation between different primary tissue sites, the extent to which tissue pathology and clinical illness correlates with EAA in the target organ, and if EAA variability across tissues differs according to sex. Considering the outsized role of age-related illness in Human Immunodeficiency Virus-1 (HIV), these questions were pursued in a sample enriched for tissue from HIV-infected individuals.

Methods

We used a custom methylation array to generate DNA methylation data from 661 samples representing 11 human tissues (adipose, blood, bone marrow, heart, kidney, liver, lung, lymph node, muscle, spleen, and pituitary gland) from 133 clinically-characterized, deceased individuals, including 75 infected with HIV. We developed a multimorbidity index based on the clinical disease history.

Results

Epigenetic age was moderately correlated across tissues. Blood had the greatest number and degree of correlation, most notably with spleen and bone marrow. However, blood did not correlate with epigenetic age of liver. EAA in liver was weakly correlated with EAA in kidney, adipose, lung, and bone marrow. Clinically, hypertension was associated with EAA in several tissues, consistent with the multi-organ impacts of this illness. HIV infection was associated with positive age acceleration in kidney and spleen. Male sex was associated with increased epigenetic acceleration in several tissues. Preliminary evidence indicates that Amyotrophic Lateral Sclerosis is associated with positive EAA in muscle tissue. Finally, greater multimorbidity was associated with greater EAA across all tissues.

Conclusion

Blood alone will often fail to detect EAA in other tissues. While hypertension is associated with increased EAA in several tissues, many pathologies are associated with organ-specific age acceleration.
The First Inhibitor of Meso-Diaminopimelate Biosynthesis with Antibacterial Activity Against Multi-Drug Resistant Bacteria
Authors: Soares da Costa Tatiana P. , Wyllie Jessica A. , Ghardi Chamodi K. , Hulett Mark D. , Abbott Belinda M. , Sutton J. Mark , Perugini Matthew A.
Published: February 2022

Antibiotic resistance represents one of the biggest threats to global health. While several of our current antibiotics target the peptidoglycan within the bacterial cell wall, only a fraction of its components has been explored for antibiotic development. A component that remains under-exploited is meso-diaminopimelate (meso-DAP), a constituent of the cross-linking peptide in Gram-negative bacteria. In this study, we employed a high throughput chemical screen to identify the first inhibitor of meso-DAP biosynthesis with antibacterial activity. Indeed, the compound was shown to have minimum inhibitory concentration values of 8–16 μg/mL against a panel of multi-drug resistant Acinetobacter baumannii strains, including those resistant to the last resort antibiotic carbapenem. Importantly, the compound targets the meso-DAP biosynthesis pathway specifically, with no off-target effects observed in human cell lines, and no resistance exhibited upon continuous treatment, under the conditions tested. Furthermore, we revealed for the first time that meso-DAP biosynthesis inhibition prevents biofilm formation and disrupts established biofilms in A. baumannii. Using a Galleria mellonella model, we showed that this compound improves survival rates against A. baumannii infection by up to 40% relative to the no treatment controls. Lastly, we determined that the inhibitor potentiates the activity of several antibiotic classes, including carbapenems. Thus, this study provides proof-of-concept that meso-DAP biosynthesis represents a promising target for the development of standalone antibacterial agents with a new mode of action as well as adjuvants to be used in combinatorial regimens to rejuvenate our current antibiotic arsenal to combat resistance.

Importance

Resistance levels to available antibiotics continues to rise, with a growing number of Gram-negative bacterial infections, in particular A. baumannii infections, becoming life-threatening. Despite this, there have been no new classes of antibiotics against Gram-negative bacteria introduced to the market over the last 40 years. Hence, new targets and therapeutics are urgently required to combat these clinically important pathogens. One such target is meso-DAP, a critical component of the cross-linking peptides in the cell walls of Gram-negative bacteria. Here, we describe the first inhibitor of bacterial meso-DAP biosynthesis, with antibacterial activity against multi-drug resistant Gram-negative bacterial strains, including carbapenem-resistant A. baumannii. We also reveal that meso-DAP biosynthesis inhibition affects biofilm stability and potentiates the activity of several antibiotic classes. This study highlights the need to further explore meso-DAP biosynthesis and other unexploited targets in the search for antibiotics with new modes of action.
A single-cell resolution gene expression atlas of the larval zebrafish brain
Authors: Shainer Inbal , Kuehn Enrico , Laurell Eva , Kassar Mariam Al , Mokayes Nouwar , Sherman Shachar , Larsch Johannes , Kunst Michael , Baier Herwig
Published: February 2022

The advent of multimodal brain atlases promises to accelerate discoveries in neuroscience by offering in silico queries of cell types, connectivity and gene expression in regions of interest. We employed multiplexed fluorescent in situ RNA hybridization chain reaction (HCR) to generate expression maps for an initial set of 200 marker genes across the larval zebrafish brain. The data were registered to the Max Planck Zebrafish Brain (mapzebrain) atlas, thus allowing co-visualization of gene expression patterns, single-neuron tracings, transgenic lines and anatomical segmentations. Additionally, brain activity maps of freely swimming larvae were generated at single-cell resolution using HCR labeling of the immediate-early gene cfos and integrated into the atlas. As a proof of concept, we identified a novel class of cerebellar eurydendroid cells that express calb2a, project to the hypothalamus and are activated in animals that have recently ingested food. Thus, a cellular-resolution gene expression atlas will not only help with rapid identification of marker genes for neuronal populations of interest, but also bridge the molecular and circuit levels by anchoring genetic information to functional activity maps and synaptic connectivity.
BORIS/CTCFL-mediated chromatin accessibility alterations promote a pro-invasive transcriptional signature in melanoma cells
Authors: Moscona Roy , Janssen Sanne Marlijn , Elchebly Mounib , Papadakis Andreas Ioannis , Rubin Eitan , Spatz Alan
Published: February 2022

Melanoma is the deadliest form of skin cancer, due to its tendency to metastasize early. Brother of Regulator of Imprinted Sites (BORIS), also known as CCCTC binding factor-Like (CTCFL), is a transcription regulator that becomes ectopically expressed in melanoma. We recently showed that BORIS contributes to melanoma phenotype switching by altering the gene expression program of proliferative melanoma cells in favor of a more invasive phenotype. However, how BORIS alters the transcriptome remains unclear. Here, ATAC-seq was used to study BORIS-mediated chromatin accessibility alterations in proliferative melanoma cells. Genes that gained promoter accessibility following ectopic BORIS expression, were enriched for melanoma-specific invasive genes as well as invasion-associated biological processes, while promoters of genes associated with proliferation show reduce accessibility. Integration of ATAC-Seq and RNA-Seq data demonstrates that increased chromatin accessibility is associated with transcriptional upregulation of genes involved in tumor progression processes, and the aberrant activation of oncogenic transcription factors, while reduced chromatin accessibility and downregulated genes, were associated with repressed activity of tumor suppressors. Together, these findings indicate that BORIS mediates transcriptional reprogramming in melanoma cells by altering chromatin accessibility and gene expression, shifting the cellular transcription landscape of proliferative melanoma cells towards a pro-invasive genetic signature.

Significance

We recently reported that BORIS contributes to melanoma phenotype switching by altering the transcriptional landscape of melanoma cells from a proliferative to an invasive state. In this study, using ATAC-Seq, we demonstrate that ectopic BORIS expression in proliferative melanoma cells leads to increased chromatin accessibility at promoters of upregulated invasion-associated genes. Importantly, by integrating the ATAC-Seq data with RNA-Seq data, we were able to identify key cancer-associated transcription factors that become aberrantly activated or repressed following ectopic BORIS expression. Taken together, this study sheds light on the mechanisms by which BORIS mediates phenotype switching in melanoma cells.
Whole-Genome Sequencing and Comparative Genomic Analysis of Potential Biotechnological Strains of Trichoderma harzianum, Trichoderma atroviride, andTrichoderma reesei
Authors: Rosolen Rafaela Rossi , Horta Maria Augusta Crivelente , de Azevedo Paulo Henrique Campiteli , da Silva Carla Cristina , Sforca Danilo Augusto , Goldman Gustavo Henrique , de Souza Anete Pereira
Published: February 2022

Trichoderma atrovirideandTrichoderma harzianumare widely used as commercial biocontrol agents against plant diseases. Recently,T. harzianumIOC-3844 (Th3844) andT. harzianumCBMAI-0179 (Th0179) demonstrated great potential in the enzymatic conversion of lignocellulose into fermentable sugars. Herein, we performed whole-genome sequencing and assembly of the Th3844 and Th0179 strains. To assess the genetic diversity within the genusTrichoderma, the results of both strains were compared with strains ofT. atrovirideCBMAI-00020 (Ta0020) andT. reeseiCBMAI-0711 (Tr0711). The sequencing coverage value of all genomes evaluated in this study was higher than that of previously reported genomes for the same species ofTrichoderma. The resulting assembly revealed total lengths of 40 Mb (Th3844), 39 Mb (Th0179), 36 Mb (Ta0020), and 32 Mb (Tr0711). A genome-wide phylogenetic analysis provided details on the relationships of the newly sequenced species with otherTrichodermaspecies. Structural variants revealed genomic rearrangements among Th3844, Th0179, Ta0020, and Tr0711 relative to theT. reeseiQM6a reference genome and showed the functional effects of such variants. In conclusion, the findings presented herein allow the visualization of genetic diversity in the evaluated strains and offer opportunities to explore such fungal genomes in future biotechnological and industrial applications.
Local structural dynamics of alpha-synuclein correlate with aggregation in different physiological conditions
Authors: Seetaloo Neeleema , Zacharopoulou Maria , Stephens Amberley D. , Kaminski Schierle Gabriele S. , Phillips Jonathan J.
Published: February 2022

In Parkinson’s disease and other synucleinopathies, the intrinsically disordered, presynaptic protein alpha-synuclein misfolds and aggregates. We hypothesise that the exposure of alpha-synuclein to different cellular environments, with different chemical compositions, pH and binding partners, alters its biological and pathological function by inducing changes in molecular conformation. Our custom instrumentation and software enable measurement of the amide hydrogen exchange rates of wild-type alpha-synuclein at amino acid resolution under physiological conditions, mimicking those in the extracellular, intracellular, and lysosomal compartments of cells. We characterised the aggregation kinetics and morphology of the resulting fibrils and correlate these with structural changes in the monomer. Our findings reveal that the C-terminal residues of alpha-synuclein are driving its nucleation and thus its aggregation. Furthermore, the entire NAC region and specific other residues strongly promoted elongation of fibrils. This provides new detail on our current understanding of the relationship between the local chemical environment and monomeric conformations of alpha-synuclein.
The nature and chromosomal landscape of endogenous retroviruses (ERVs) integrated in the sheep nuclear genome
Authors: Mustafa Sarbast Ihsan , Schwarzacher Trude , Heslop-Harrison JS
Published: February 2022

Endogenous retroviruses (ERVs) represent genomic components of retroviral origin that are found integrated in the genomes of various species of vertebrates. These genomic elements have been widely characterized in model organisms and humans. However, composition and abundances of ERVs have not been categorized fully in all domestic animals. The advent of next generation sequencing technologies, development of bioinformatics tools, availability of genomic databases and molecular cytogenetic techniques have revolutionized the exploration of the genome structure. Here, we investigated the nature, abundance, organization and assembly of ERVs and complete genomes of Jaagsiekte sheep retrovirus (JSRV) from high-throughput sequencing (HTS) data from two Iraqi domestic sheep breeds. We used graph-based read clustering (RepeatExplorer), frequency analysis of short motifs (k-mers), alignment to reference genome assemblies and fluorescent in situ hybridization (FISH). Three classes of ERVs were identified with the total genomic proportions of 0.55% from all analyzed whole genome sequencing raw reads, while FISH to ovine metaphase chromosomes exhibited abundant centromeric to dispersed distribution of these ERVs. Furthermore, the complete genomes of JSRV of two Iraqi sheep breeds were assembled and phylogenetically clustered with the known enJSRV proviruses in sheep worldwide. Characterization of partial and complete sequences of mammalian ERVs is valuable to provide insights into the genome landscape, to help with future genome assemblies and to identify potential sources of disease when ERVs become active.
The Genetics of Participation: Method and Analysis
Authors: Benonisdottir Stefania , Kong Augustine
Published: February 2022

Participation in a genetic study likely has a genetic component. Identifying such component is difficult as we cannot compare genetic information of participants with non-participants directly, the latter being unavailable. Here, we show that alleles that are more common in participants than non-participants would be further enriched in genetic segments shared by two related participants. Genome-wide analysis was performed by comparing allele frequencies in shared and not-shared genetic segments of first-degree relative pairs of the UK Biobank. A polygenic score constructed from that analysis, in non-overlapping samples, is associated with educational attainment (P = 2.1 × 10−52), body mass index (P = 1.5 × 10−19), and participation in a dietary study (P = 6.9 × 10−21). Further analysis shows that inclination to participate is a behavioural trait in its own right, and not simply a consequence of other established phenotypes. Understanding the basis of this trait is important for data analyses and the design of future surveys, genetic or otherwise.
Predictive link between systemic metabolism and cytokine signatures in the brain of apolipoprotein E ε4 mice
Authors: Fleeman Rebecca M , Snyder Amanda M , Kuhn Madison K , Chan Dennis C , Smith Grace C , Crowley Nicole A , Arnold Amy C , Proctor Elizabeth A
Published: February 2022

The ε4 variant of apolipoprotein E (APOE) is the strongest and most common genetic risk factor for Alzheimer’s disease (AD). While the mechanism of conveyed risk is incompletely understood, promotion of inflammation, dysregulated metabolism, and protein misfolding and aggregation are contributors to accelerating disease. Here we determined the concurrent effects of systemic metabolic changes and brain inflammation in young (3-month-old) and aged (18-month-old) male and female mice carrying theAPOE4gene. Using functional metabolic assays alongside multivariate modeling of hippocampal cytokine levels, we found that brain cytokine signatures are predictive of systemic metabolic outcomes, independent of AD proteinopathies. Male and female mice each produce different cytokine signatures as they age and as their systemic metabolic phenotype declines, and these signatures areAPOEgenotype dependent. Ours is the first study to identify a quantitative and predictive link between systemic metabolism and specific pathological cytokine signatures in the brain. Our results highlight the effects of APOE4 beyond the brain and suggest the potential for bi-directional influence of risk factors in the brain and periphery.

Abstract Figure
ClonoCluster: a method for using clonal origin to inform transcriptome clustering
Authors: Richman LP , Goyal Y , Jiang CL , Raj A
Published: February 2022

Clustering cells based on their high dimensional profiles is an important data reduction process by which researchers infer distinct categories of cellular state. The advent of cellular barcoding, however, provides an alternative means by which to group cells: by their clonal origin. We developed ClonoCluster, a computational method that combines both clone and transcriptome information to create hybrid clusters that weight both kinds of data with a tunable parameter. We generated hybrid clusters across six independent datasets and found that ClonoCluster generated qualitatively different clusters in all cases. The markers of these hybrid clusters were different but had equivalent fidelity to transcriptome-only clusters. The genes most strongly associated with the rearrangements in hybrid clusters were ribosomal function and extracellular matrix genes. We also developed the complementary tool Warp Factor that incorporates clone information in popular 2D visualization techniques like UMAP. Integrating ClonoCluster and Warp Factor revealed biologically relevant markers of cell identity.