bluuebunny/crossref_metadata_2025 huggingface dataset:
Hematological indices reference intervals for a healthy Arab population in Qatar
Authors: Yassin Mohamed A. , Soliman Ashraf T. , Nashwan Abdulqadir J. , Alamami Ans A. , Abdulla Mohammad A. J. , Hmissi Saloua M. , Aldapt Mahmood B. , Chandra Prem , Suliman Aasir M. , Ibrahim Ezzeddin A. , Yassin Khadra S. , Allahverdi Niloofar , Mohamed Shehab F.
Published: June 2022

Hematologic reference intervals vary with gender, age, ethnicity, and geographic area. Therefore, local or national laboratory reference ranges are essential to enhance the accuracy when diagnosing health conditions. Still, no comprehensive list of reference ranges tailored to the Arab population living in Qatar. Accordingly, this study aims at establishing a hematology reference guide for Arabs in Qatar.

This is a retrospective study where 750 healthy volunteers (18–69 years) from 2015 to 2019 were included, analyzed by an automated hematology analyzer. Arab adults were divided into African (Egypt, Libya, Tunisia, Morocco) and Asian (Syria, Lebanon, Jordon, Palestine, Qatar). The Cell-Dyn and Sysmex were used for measuring hematological parameters.

The mean +/- 2SD were established for all the study groups. Arab males had significantly higher Hb, Hct, red cell distribution width, absolute neutrophil count, lymphocytes, and monocyte counts than females. Asian-Arab males had significantly higher Hb concentration and higher WBC, lymphocytes, and eosinophils than African Arabs. Asian-Arab young (>18: < 40 years) males had significantly higher Hb and lymphocytes and lower monocytes than older males (>40 years). African-Arab young males had significantly higher lymphocytes and lower monocytes than older males. Asian-Arab young females had higher WBC and absolute neutrophil count than older Asian Arabs.

The findings of this study will help in establishing specific reference intervals in the Arab world. The differences in hematology reference intervals considering age, gender, and geographical location highlight the importance of establishing blood reference intervals in each country considering the ethnic diversity of each country.
Changes in pain scores and walking distance after epidural steroid injection in patients with lumbar central spinal stenosis
Authors: Kim Minsoo , Cho Soyeon , Noh Yeonji , Goh Daehun , Son Hee-Jeong , Huh Jin , Kang Seong-Sik , Hwang Byeongmun
Published: June 2022

Lumbar spinal stenosis is a common degenerative disorder that is characterized by pain and neurogenic claudication. Previous studies have evaluated the effects of an epidural steroid injection (ESI) on spinal stenosis, based on changes to the spinal canal diameter.

This study aimed to examine the impact of the ESI on pain scores and walking distance in patients with lumbar central spinal stenosis, stratified based on disease severity, which was graded according to the degree of cauda equina separation.

We reviewed the medical records of patients who received the ESI for lumbar spinal central canal stenosis. A total of 128 patients were divided into moderate and severe groups, based on the degree of cauda equina separation.

Relative to baseline values, 2 weeks after the ESI, the moderate group showed a significant decrease in the numeric rating scale (NRS) scores and an increase in walking distance. Meanwhile, the severe group showed a significant decrease in the NRS scores and no significant change in walking distance. The moderate group had lower NRS scores and a longer walking distance than did the severe group 2 weeks after the ESI. The proportion of patients with improved levels of satisfaction was higher in the moderate group than in the severe group.

Lumbar interlaminar ESI may reduce pain scores and increase walking distance in patients with moderate lumbar spinal central canal stenosis. Patients with moderate spinal stenosis achieved better outcomes than did patients with severe stenosis.
Concomitant post-traumatic ocular and cerebral fat embolism syndrome and thrombotic pulmonary embolism
Authors: Li Ying-Sheng , Liu Yi-Hsueh , Chou Hung-Da , Tseng Hsiang-Jui , Fu Yin-Chih , Liu Wen-Chih
Published: June 2022

Rationale:

Fat embolism syndrome (FES) is composed of a triad of symptoms, including respiratory distress, neurologic deficit, and petechiae. Respiratory distress usually presents first before the other symptoms. Thrombotic pulmonary embolism (TPE) is a differential diagnosis of FES. Trauma is a risk factor for both diseases; however, co-occurrence is rare.

Patient concerns:

A 35-year-old male patient presented with altered consciousness, focal neurologic deficit, and respiratory distress after a left femoral subtrochanteric fracture and subsequent open reduction and internal fixation with an intramedullary nail.

Diagnosis:

Computed tomography pulmonary angiography (CTPA) revealed lower pulmonary artery filling defects and ground-glass opacities in bilateral lung, indicating TPE and FES, respectively.

Interventions:

Heparin was initially added and subsequently switched to apixaban. The symptoms improved quickly without major bleeding complications.

Lession Subsections:

Concomitant TPE and FES after trauma are rare and require different treatment approaches. Due to clinical similarities, prompt chest CTPA was advised to detect TPE that was treated with anticoagulant therapy instead of supportive care for FES.
Katanin subunits p60 and p80, potential biomarkers for papillary thyroid carcinoma to distinguish nodular goiter: STROBE
Authors: Wu Zhangming , Guo Miao , Yang Jing , Xiao Yanjie , Liu Wei
Published: June 2022

Katanin subunits p60 and p80 are involved in microtubule-mediated cytoskeletal organization during cell division. Their aberrant expression has been found in prostate, breast, and non-small cell lung (NSCLC) cancers. It has recently been reported that compared with adjacent papillary thyroid carcinoma (PTC) tissues, both are highly expressed in tumor tissues. Here, we investigated whether katanin subunits p60 and p80 can be used as potential biomarkers for PTC to distinguish nodular goiter (NG).

Immunohistochemistry was performed to investigate the expression of katanin subunits p60 and p80 in the tissues of 97 cases of PTC and NG. This cohort included 87 cases with PTC (74 classical or conventional (CPTC) and 13 follicular (FVPTC) variants) and 10 cases with NG.

We found that katanin subunits p60 and p80 were expressed in PTC, but not in NG. The cutoff values of katanin p60 and p80 for PTC were 22.43% and 0.83%, respectively. The katanin subunit p60 was significantly associated with lymph node metastasis. Katanin subunit p80 was more highly expressed in CPTC than in FVPTC. The expression of the katanin subunit p60 was positively correlated with the expression of katanin p80 in PTC. Importantly, we found that overexpression of katanin p60 increased the expression of katanin p80 in a human papillary thyroid carcinoma KTC-1 cell line, which further supports the existence of katanin p60 and p80 feedback loops.

Our results indicate that katanin subunits p60 and p80 may be used as potential PTC biomarkers to distinguish NG and may be novel therapeutic targets for PTC.
Granulocytic sarcoma of cervix
Authors: Ye Zhongxue , Jiang Yafen
Published: June 2022

Rationale:

Granulocytic sarcoma (GS) is an uncommon extramedullary tumor, and involvement of the female reproductive system is very rare.

Patient concerns:

We present a case of cervical GS in a 45-year-old woman who presented with repeated vaginal bleeding after sex for 1 month.

Diagnosis:

The patient was diagnosed with cervical GS mainly based on pathological immunohistochemical examination and further progressed to acute myeloid leukemia (AML) based on bone marrow puncture and cytogenetic analysis.

Interventions and outcomes:

The patient underwent hysterectomy and bilateral adnexectomy, and subsequently received AML-type chemotherapy. She relapsed 3 months after therapy and progressed to AML. The patient was then treated with chemotherapy with cytosine arabinoside and idarubicin again and achieved complete remission after 1 cycle. Currently, she is still receiving therapy combined with cytosine arabinoside and idarubicin, and has been alive for 13 months.

Lessons:

Although GS of the reproductive system is rare, it should be included in the differential diagnosis of gynecological neoplasms and should be treated with AML-type chemotherapy protocols.
Anesthetic management for cesarean section in parturient with an uncorrected single ventricle
Authors: Du Yu , Yang-Liu Yingzi , Chen Bin , Wang Ji
Published: June 2022

Rationale:

Patients with a single ventricle, who have not undergone surgery, reportedly have a lower survival rate. Furthermore, multiple pregnancies are rare among these females. We reported a case of anesthesia management of cesarean section in an uncorrected single-ventricular multi-pregnancy woman and review the anesthesia management of the published similar cases.

Patient concerns:

An uncorrected single ventricular pregnant woman with a cardiac function of New York Heart Association class II, who had experienced one spontaneous abortion and three vaginal deliveries, was scheduled for cesarean section at 37+6 weeks of gestation.

Diagnoses

: Echocardiography revealed a complex congenital heart disease in the mother: a single ventricle (the left ventricle is dominant), atrioventricular valve ectopic, double-inlet left ventricle, abnormal location of the great arteries, probably pulmonary stenosis, atrial septal defect, and left-to-right shunt. The fetus was in breech presentation with umbilical cord around the neck.

Interventions:

Cesarean section was successfully performed under the combined spinal epidural anesthesia with careful monitoring.

Outcomes

: Both mother and newborn recovered good and were discharged from the hospital 5 days after surgery without any adverse reactions.

Lessons:

Single ventricular pregnant woman with a cardiac function of New York Heart Association class I–II could tolerate pregnancy and delivery well. Both general and regional anesthesia are applicable to cesarean section in these patients. The principle of anesthesia management is to maintain the appropriate balance between systemic vascular resistance and pulmonary vascular resistance, as well as to maintain preload and cardiac output.
Pancarpal dissociation, a very rare type of injury
Authors: Park Ho Youn , Sur Yoo Joon , Lim Dohyung , Lee Kwansoo , Park Il-Jung
Published: June 2022

Rationale:

Pan-carpal dissociation is very rare injury and there is little information as to diagnosis, treatment, and prognosis of this injury.

Patient concerns:

A 35-year-man presented to our hospital with severe pain and swelling of the left wrist and forearm after slipping and falling while riding a motorcycle.

Diagnosis:

The wrist simple radiographs demonstrated unrecognizable severe fracture-dislocation of the carpal bones concomitant with fractures of the radioulnar shaft. Three-dimensional computed tomography revealed a capitate fracture-dislocation, as well as hamate dislocation, lunotriquetral (LT), and scapholunate (SL) dissociation. These findings suggested pan-carpal dissociation.

Interventions:

To prevent compartment syndrome, fasciotomy, carpal tunnel release, and open reduction and plate fixation for both bone fracture were performed first. Then, for pan-carpal dissociation, the capitate, carpometacarpal joint (CMCJ), and hamate were reduced and fixed first. Then, the SL, LT, and other intercarpal ligaments were repaired. Finally, additional trans-carpal pins to reinforce the ligament repair and 2.0 mm plate to buttress the third CMCJ were fixed. The patient was instructed to begin gentle range of motion exercises of the wrist with pins from four weeks after surgery and all pins were removed at six weeks postoperatively.

Outcomes:

12 months after the operation, the patient exhibited almost full range of motion with mild pain with VAS (Visual analogue scale) 1–2 at rest and VAS 3–4 with effort. Quick DASH (the disabilities of the arm, shoulder and hand) score was 25 and modified Mayo score was 70. The radiographs demonstrated union of the radioulnar shaft, and the carpal bone alignment was successfully maintained

Lessons:

Pan-carpal dissociation can be diagnosed in patients with capitate fracture-dislocation, hamate dislocation, LT, and SL dissociation. This pattern of injury is very rare and the authors recommend reduction and fixation of the distal carpal row, followed by the proximal row to facilitate an easy approach to the distal carpal row. Although it is very severe injury, rigid anatomical fixation and an early rehabilitation can lead to favorable functional outcomes.
Training School Counselors and Nurses to Enhance Collaboration Through Animal-Assisted Therapy
Authors: Yordy Beverly Morgan , Tuttle Malti , Meyer Jill M.
Published: June 2022

Purpose/Aims

The school nurse and school counselor serve an important role to foster student academic achievement, physical and mental health, and connectiveness. Each is paramount to student success; therefore, efforts should be made to further enhance collaborative efforts. Researchers sought to determine if an online training course centered on integrative methods would enhance collaboration between the school nurse and counselor.

Design

This study used a quasi-experimental design with 3 data points (pretest, posttest, and 6-month follow-up), assessing the impact of educational content and knowledge application based on an online training module incorporating animal-assisted therapy (AAT) concepts and the school counselor and school nurse collaboration model.

Methods

The continuing professional development questionnaire was used to evaluate professionals' behavior, specifically focusing on how knowledge translates into practice. The intervention included a training course designed for school nurses and counselors. Researchers analyzed data to determine how their collaboration and endorsement of AAT changed over time.

Results

School counselors endorsed collaboration and intention of AAT application in schools at a higher rate than school nurses. However, after the intervention, differences between school counselors and nurses diminished over time.

Conclusion

The findings provide recommendations for the clinical nurse specialist to implement evidence-based programs targeting school nurse and school counselor collaboration.
Superficial CD34-Positive Fibroblastic Tumor
Authors: Anderson William J. , Mertens Fredrik , Mariño-Enríquez Adrián , Hornick Jason L. , Fletcher Christopher D.M.
Published: June 2022

Superficial CD34-positive fibroblastic tumor (SCD34FT) is a rare soft tissue neoplasm that shows overlapping features with PRDM10-rearranged soft tissue tumor (PRDM10-STT). This study characterizes the clinicopathologic, immunohistochemical, and molecular features of SCD34FT in a series of 59 cases. Fluorescence in situ hybridization to assess for PRDM10 rearrangement was performed in 12 tumors. Immunohistochemistry for CADM3 and WT1 was performed; CADM3 was also assessed in histologic mimics. Our cohort of 33 male and 26 female had a median age of 42 (range: 14 to 85) years. Tumors were most commonly located in the lower limb (73%), upper limb (8%), back (7%), and supraclavicular region (3%). The median tumor size was 3.0 cm (range: 1.0 to 9.0 cm). Clinical follow-up in 32 patients (median duration: 26 mo) revealed 2 local recurrences (6%). One patient developed regional lymph node metastases which were completely excised. Microscopically, SCD34FT comprised spindled and pleomorphic cells with glassy cytoplasm and occasional granular cell change. Fluorescence in situ hybridization confirmed PRDM10 rearrangement in 3/8 cases (38%). SCD34FT frequently expressed CADM3 (95%) and WT1 (75%). CADM3 was less diffusely positive in pleomorphic hyalinizing angiectatic tumor (40%), pleomorphic liposarcoma (20%), and undifferentiated pleomorphic sarcoma (10%). We corroborate that SCD34FT is indolent but may rarely metastasize to lymph nodes without adverse outcomes. CADM3 and WT1 may be useful in the distinction from histologic mimics. Since cases of SCD34FT with and without demonstrable PRDM10 rearrangement were clinicopathologically indistinguishable, our study further supports that SCD34FT and PRDM10-STT likely constitute a single entity.
68Ga-FAPI-46 and 18F-FDG in Advanced Metastatic Pancreatic Cancer
Authors: Kaghazchi Fatemeh , Divband Ghasemali , Amini Hamidreza , Adinehpour Zohreh , Akbarian Aghdam Ramin
Published: June 2022

Recently imaging with new PET radiotracers that act as fibroblast activation protein inhibitors (FAPIs) showed promising results in oncology and even nononcology imaging. Here we report a case of advanced pancreatic adenocarcinoma, imaged with both 18F-FDG and 68Ga-FAPI-46 PET/CT scans. The result indicated that imaging with 68Ga-FAPI-46 showed significant improvement in detection of metastases as well as local malignancy recurrence. Moreover, the intensity and SUVs of the lesions were higher in 68Ga-FAPI-46 scan compared with 18F-FDG.
Epiglottic Polymorphous Adenocarcinoma With Multiple Bone Metastases Detected by 68Ga-FAPI PET/CT
Authors: Pang Yizhen , Meng Tinghua , Xu Weizhi , Kong Lei , Chen Haojun
Published: June 2022

Polymorphous adenocarcinoma (PAC) is generally an indolent tumor that mostly commonly affects the minor salivary gland. Polymorphous adenocarcinoma with distant metastases is extremely rare. In this case, we reported 18F-FDG and 68Ga-FAPI PET/CT imaging findings in a rare case of epiglottic PAC with multiple bone metastases. 68Ga-FAPI PET/CT showed superiority over 18F-FDG PET/CT for detecting the primary and metastatic PAC. This case highlighted that 68Ga-FAPI may be a promising radiopharmaceutical in the diagnosis of PAC, especially for detecting the PACs arising in uncommon sites.
Infectious Aortic Aneurysm in a Patient With Leriche Syndrome
Authors: Norikane Takashi , Yamamoto Yuka , Takami Yasukage , Tani Ryosuke , Nishiyama Yoshihiro
Published: June 2022

Leriche syndrome is a relatively rare atherosclerotic occlusive disease characterized by total occlusion of the abdominal aorta and/or both iliac arteries. The typical clinical manifestations of Leriche syndrome include intermittent claudication, fatigue, and leg pain. We present the case of a 56-year-old man with Leriche syndrome accompanied by an infectious abdominal aortic aneurysm. 18F-FDG PET angiography/CT and 18F-FDG PET/CT provided important information about the thrombus and infected sites.
Heart Transplantation, Either Alone or Combined With Liver and Kidney, a Viable Treatment Option for Selected Patients With Severe Cardiac Amyloidosis
Authors: Guendouz Soulef , Grimbert Philippe , Radu Costin , Cherqui Daniel , Salloum Chady , Mongardon Nicolas , Maghrebi Sami , Belhadj Karim , Le Bras Fabien , Teiger Emmanuel , Couetil Jean-Paul , Balan Adriana , Kharoubi Mounira , Bézard Mélanie , Oghina Silvia , Bodez Diane , Hittinger Luc , Audard Vincent , Planté-Bordeneuve Violaine , De la Taille Alexandre , Bergoend Eric , Frenkel Valerie , Fanen Pascale , Leroy Vincent , Duvoux Christophe , Carmagnat Maryvonnick , Folliguet Thierry , Damy Thibaud
Published: June 2022

Background.

Heart transplantation in cardiac amyloidosis (CA) patients is possible and generally considered for transplantation if other organs are not affected. In this study, we aimed to describe and assess outcome in patients following heart transplantations at our CA referral center.

Methods.

We assessed all CA patients that had heart transplantations at our center between 2005 and 2018. Patients with New York Heart Association status 3 out of 4, with poor short-term prognosis due to heart failure, despite treatment, and without multiple myeloma, systemic disease, severe neuropathic/digestive comorbidities, cancer, or worsening infections were eligible for transplantation. Hearts were transplanted by bicaval technique. Standard induction and immunosuppressive therapies were used. Survival outcome of CA patients after transplantation was compared with recipients with nonamyloid pathologies in France.

Results.

Between 2005 and 2018, 23 CA patients had heart transplants: 17 (74%) had light chain (light chain amyloidosis [AL]) and 6 (26%) had hereditary transthyretin (hereditary transthyretin amyloidosis [ATTRv]) CA. Also, 13 (57%) were male, and the mean age at diagnosis was 56.5 y (range, 47.7–62.8). Among AL patients, 13 had heart-only and 5 had heart-kidney transplantations. Among ATTRv patients, 1 had heart-only and 5 had heart-liver transplantations. The 1-y survival rate after transplantation was 78%, 70% with AL, and 100% with ATTRv. At 2 y, 74% were alive: 65% with AL and 100% with ATTRv.

Conclusion.

After heart transplantation, French CA and nonamyloid patients have similar survival outcomes. Among CA patients, ATTRv patients have better prognosis than those with AL, possibly due to the combined heart-liver transplantation. Selected CA patients should be considered for heart transplantations.
Prediction of adolescent suicide attempt by integrating clinical, neurocognitive and geocoded neighborhood environment data
Authors: Visoki Elina , Moore Tyler M. , Gur Ruben C. , Ruiz Victor M. , Fein Joel A. , Benton Tami D. , Gur Raquel E. , Tsui Fuchiang R. , Barzilay Ran
Published: June 2022

Objective

The authors used multimodal data collected during pre/early-adolescence in research settings to predict self-report of past suicide attempt (SA) by mid-late adolescence in pediatric care settings. The study further aimed to determine types of data that contribute to the prediction; and to test generalizability of the prediction in an independent sample.

Methods

The authors applied machine learning methods on clinical, neurocognitive and geocoded neighborhood environmental data from the Philadelphia Neurodevelopmental Cohort study (PNC, Mean age 11.1, SD=2.2, 52.3% female and 51.4% Black participants) to predict SA reported ∼5 years later in a community pediatric clinic (n=922, 5.3% SA) or emergency department (n=497, 8.2% SA). The authors compared prediction performance when using all data versus individual data types, then used feature selection algorithms (Lasso, Relief and Random Forest) to identify important predictors and compared performance of models relying on feature subsets.

Results

In the training dataset, SA prediction was good, reaching AUC=0.75, sensitivity/specificity 0.76/0.77 when relying on feature subsets identified using feature selection pipelines. Use of highest-ranking feature subsets from the training dataset yielded similar prediction in the testing dataset with AUC=0.74, sensitivity/specificity 0.66/0.70. Different algorithms showed different high-ranking features, but overall multiple data domains were represented among the highest-ranking predictors selected by each algorithm.

Conclusions

These findings provide evidence for feasibility of predicting youth SA using data collected at a single timepoint early in life in a diverse cohort. Results encourage incorporation of multiple data types including neurocognitive and geocoded environmental measures in machine learning SA prediction pipelines.
TopEnzyme: A framework and database for structural coverage of the functional enzyme space
Authors: van der Weg Karel , Gohlke Holger
Published: June 2022

TopEnzyme is a database of structural enzyme models created with TopModel and is linked to the SWISS-MODEL and AlphaFold Protein Structure Database to provide an overview of structural coverage of the functional enzyme space for over 200,000 enzyme models. It allows the user to quickly obtain representative structural models for 60% of all known enzyme functions. We assessed the models with TopScore and contributed 9039 good-quality and 1297 high-quality structures. Furthermore, we compared these models to AlphaFold2 models with TopScore and found that the TopScore differs only by 0.04 on average in favor of AlphaFold2. We tested TopModel and AlphaFold2 for targets not seen in the respective training databases and found that both methods create qualitatively similar structures. When no experimental structures are available, this database will facilitate quick access to structural models across the currently most extensive structural coverage of the functional enzyme space.
Sex-specific niche signaling contributes to sexual dimorphism following stem cell transplantation
Authors: Smith Julianne N.P. , Cordova Brittany A. , Richardson Brian , Christo Kelsey F. , Campanelli Jordan , Broncano Alyssia V. , Chen Jonathan , Lee Juyeun , Cameron Scott J. , Lathia Justin D. , Goodman Wendy A. , Cameron Mark J. , Desai Amar B.
Published: June 2022

Hematopoietic stem cell (HSC) transplantation (HST) is a curative treatment for many hematopoietic cancers and bone marrow (BM) disorders but is currently limited by numerous complications including a lengthy recovery period, prolonged neutropenia resulting in severe infections and bleeding, and a high incidence of graft vs. host disease (GVHD). While clinical studies have demonstrated that sex mismatch, notably male recipients with female donor cells, results in increased risk of GVHD (likely due to male recipient minor histocompatibility antigens targeted by donor female T-cells 1), increased non-relapse mortality, and decreased overall survival, the mechanisms underlying sex-determinants on hematopoiesis and post-transplant recovery are not clear. In this manuscript we have identified: 1) unique expression of hematopoietic niche factors in the BM and spleens of male and female mice, 2) altered kinetics of hematopoietic reconstitution following transplantation when male vs. female BM is used as the donor cell source, 3) a sex-specific role for the recipient niche in promoting post HST recovery, and 4) a dose-dependent role for exogenous sex hormones in maintaining hematopoietic stem and progenitor cells (HSPCs). Taken together, these data demonstrate that sex-specific cellular and molecular signaling occurs during hematopoietic regeneration. Further identifying novel sex-dependent determinants of regeneration following transplantation will not only enhance understanding of steady state versus regeneration hematopoiesis but may also reveal unique (and potentially sex-specific) therapeutic targets to accelerate hematologic recovery.

Key Points

Male and female mice display altered kinetics of regeneration following HST due to unique niche factors in hematopoietic compartments.

Exogenous steroid sex hormones uniquely regulate the pool of hematopoietic stem and progenitor cells and may impact transplantation outcomes.
Cancer-keeping genes as therapeutic targets
Authors: Zhang Xizhe , Pan Chunyu , Wei Xinru , Yu Meng , Liu Shuangjie , An Jun , Yang Jieping , Wei Baojun , Hao Wenjun , Yao Yang , Zhu Yuyan , Zhang Weixiong
Published: June 2022

Finding cancer-driver genes – the genes whose mutations may transform normal cells into cancerous ones – remains a central theme of cancer research. We took a different perspective; instead of considering normal cells, we focused on cancerous cells and genes that maintained abnormal cell growth which we namedcancer-keeping genes(CKGs). Intervention in CKGs may rectify aberrant cell growth so that they can be adopted as therapeutic targets for cancer treatment. We developed a novel approach to identifying CKGs by extending the well-established theory of network structural controllability, which aims at finding a control scheme (i.e., a minimal set of non-overlapping control paths covering all nodes) and control nodes (driver genes) that can steer the cell from any state to the designated state. Going beyond driver genes defined by one control scheme, we introducedcontrol-hubgenes located in the middle of a control path ofeverycontrol scheme. Control hubs are essential for maintaining cancerous states and thus can be taken as CKGs. We applied our CKG-based approach to bladder cancer (BLCA) as a case study. All the genes on the cell cycle and p53 pathways in BLCA were identified as CKGs, showing the importance of these genes in cancer and demonstrating the power of our new method. Furthermore, sensitive CKGs that could be easily changed by structural perturbation were better suited as therapeutic targets. Six sensitive CKGs (RPS6KA3, FGFR3, N-cadherin (CDH2), EP300, caspase-1, and FN1) were subjected to small-interferencing-RNA knockdown in two BLCA cell lines to validate their cancer-suppressing effects. Knocking down RPS6KA3 in a mouse model of BLCA significantly inhibited the growth of tumor xenografts in mice. Combined, our results demonstrated the value of CKGs as therapeutic targets for cancer therapy.

Key points

Focus on genes that maintain aberrant cell growth, namedcancer-keeping genes(CKGs).

Develop a novel approach for finding CKGs by extending the well-estabilished theory of network structural controllability to total network controllability.

Apply the new method to bladder cancer and experimentally validated the cancer-suppressing function of six CKGs in two bladder cancer cell lines and that of one CKG in bladder cancer mice.
Study and Modeling of Biological Noise-Filtering Properties of Conserved Gene Regulatory Networks Motifs in Animal Development
Authors: Ruiz G. Lina M. , Gloria Machado R , Rodriguez R Boris A.
Published: June 2022

Biological noise results from heterogeneous gene expression levels among a group of cells [1]. This heterogeneity is due to the variation in gene expression that occurs over time at the single-cell level. Some noise-filtering mechanisms like redundancy in genetic circuits have been identified. Likewise, the feed-forward loop network motif has been found to have noise-filtering capacities in animal development. On the other hand, previous studies have contradictory conclusions about the noise-filtering capacities of the feedback loop and none of them have studied this capacity in the activator-inhibitor regulatory system. Here we studied some dynamical properties, such as noise and expression levels, in self-activated and activator-inhibitor regulatory systems, both at the unicellular and multicellular levels. These systems are essential in the self-patterning and community effect processes occurring in development and differentiation. We used the three-stage model to represent the expression of a gene with promoter regulation and Hill functions to represent the regulatory connections between genes. We used Gillespie’s Algorithm and the Chemical Langevin Equation for simulations. The regulatory systems evaluated do not reduce the biological noise. On the contrary, the noise remains at the same level or increases in comparison with an unregulated gene. The noise levels in these systems depend on the gene expression type of both the regulator and the regulated gene. In this way, the particular forms in which genes connect to each other in these regulatory systems do not explain the noise in expression. However, the noise has a propagation pattern different for activation and inactivation types of regulation. Finally, the diffusion and colony size could be mechanisms of noise filtering in gene expression in a colony of cells. The increase in diffusion rate and colony size are necessary to synchronize gene expression and perform the community effect in embryonic development.
The homeodomain transcription factor Ventx2 regulates respiratory progenitor cell number and differentiation timing duringXenopuslung development
Authors: Rankin Scott A. , Zorn Aaron M.
Published: June 2022

Ventx2 is anantennapediasuperfamily / NKL subclass homeodomain transcription factor best known for its role in the regulation of early dorsal-ventral pattern during Xenopus gastrulation and in the maintenance of neural crest multipotency. In this work we characterize an unappreciated spatial-temporal expression domain ofventx2in Xenopus respiratory system epithelial progenitors. We findventx2is directly induced by BMP signaling in the ventral foregut prior tonkx2-1, the earliest epithelial marker of the respiratory lineage. Functional studies demonstrate that Ventx2 regulates the number of Nkx2-1/Sox9+ respiratory progenitors induced during foregut development, the timing and level of surfactant protein gene expression, and proper tracheal-esophageal separation. Our data suggest that Ventx2 regulates the balance of respiratory progenitor expansion and differentiation. While theventxgene family has been lost from the mouse genome during evolution, humans have retained aventx2-like gene(VENTX)and we lastly discuss how our findings might suggest a possible function ofVENTXin human respiratory progenitors.
Mechanical Deformation Behaviors and Structural Properties of Ligated DNA Crystals
Authors: Li Ruixin , Zheng Mengxi , Madhvacharyula Anirudh Sampath , Du Yancheng , Mao Chengde , Choi Jong Hyun
Published: June 2022

DNA self-assembly has emerged as a powerful strategy for constructing complex nanostructures. While the mechanics of individual DNA strands have been studied extensively, the deformation behaviors and structural properties of self-assembled architectures are not well understood. This is partly due to the small dimensions and limited experimental methods available. DNA crystals are macroscopic crystalline structures assembled from nanoscale motifs via sticky-end association. The large DNA constructs may thus be an ideal platform to study structural mechanics. Here we have investigated the fundamental mechanical properties and behaviors of ligated DNA crystals made of tensegrity triangular motifs. We performed coarse-grained molecular dynamics simulations and confirmed the results with nanoindentation experiments using atomic force microscopy. We observed various deformation modes including un-tension, linear elasticity, duplex dissociation, and single-stranded component stretch. We found that the mechanical properties of a DNA architecture are correlated with those of its components, however the structure shows complex behaviors which may not be predicted by components alone.
DNA double helix, a tiny electromotor
Authors: Maffeo Christopher , Quednau Lauren , Wilson James , Aksimentiev Aleksei
Published: June 2022

Flowing fluid past curved objects has been used for centuries to power rotary motion in man-made machines. In contrast, rotary motion in nanoscale biological1, 2or chemical3, 4systems is produced by biasing Brownian motion through cyclic chemical reactions.5, 6Here, we show that a curved biological molecule, a DNA or RNA duplex, rotates, unidirectionally, billions of revolutions per minute when electric field is applied along the duplex, with the rotation direction being determined by the duplex chirality. The rotation is found to be powered by the drag force of the electro-osmotic flow, realizing the operating principle of a macroscopic turbine at the nanoscale. The resulting torques are sufficient to power rotation of nanoscale beads and rods, offering an engineering principle for constructing nanoscale systems powered by electric field.
Human threat learning is associated with gut microbiota composition
Authors: Oyarzun Javiera P. , Kuntz Thomas M. , Stussi Yoann , Karaman Olivia T. , Vranos Sophia , Callaghan Bridget L. , Huttenhower Curtis , LeDoux Joseph E. , Phelps Elizabeth A.
Published: June 2022

Rodent studies have shown that the gut microbiota can influence threat and safety learning, which has been linked to anxiety phenotypes. In humans, it has been demonstrated that microbiota composition varies with anxiety disorders, but evidence showing an association with threat learning is lacking. Here, we tested whether individual variability in threat and safety learning was related to gut microbiota composition in healthy adults. We found that threat, but not safety learning varies with individuals’ microbiome composition. Our results provide evidence that the gut microbiota is associated with excitatory threat learning across species.

Significance Statement

Learning from threats and safety is a core mechanism of anxiety disorders, and studies in rodent models have shown that the gut microbiota can modulate such behaviors. Although previous literature on humans shows a relationship between emotional circuits and gut microbiota, the evidence linking learning and microbiota is lacking. In a Pavlovian threat conditioning paradigm, we show that patterns of gut microbiota composition in healthy humans relate to their patterns of threat learning, but not safety learning. Our findings suggest one mechanism by which the human gut microbiota is associated with anxiety-related behaviors.
A model for generating differences in microtubules between axonal branches depending on the distance from terminals
Authors: Imanaka Chiaki , Simada Satoshi , Ito Shino , Kamada Marina , Iguchi Tokuichi , Konishi Yoshiyuki
Published: June 2022

In the remodeling of axonal arbor, the growth and retraction of branches are differentially regulated within a single axon. Although cell-autonomously generated differences in microtubule (MT) turnover are thought to be involved in selective branch regulation, the cellular system whereby neurons generate differences of MTs between axonal branches has not been clarified. Because MT turnover tends to be slower in longer branches compared with neighboring shorter branches, feedback regulation depending on branch length is thought to be involved. In the present study, we generated a model of MT lifetime in axonal terminal branches by adapting a length-dependent model in which parameters for MT dynamics were constant in the arbor. The model predicted that differences in MT lifetime between neighboring branches could be generated depending on the distance from terminals. In addition, the following points were predicted. Firstly, destabilization of MTs throughout the arbor decreased the differences in MT lifetime between branches. Secondly, differences of MT lifetime existed even before MTs entered the branch point. In axonal MTs in primary neurons, treatment with a low concentration of nocodazole significantly decreased the differences of detyrosination (deTyr) and tyrosination (Tyr) of tubulins, indicators of MT turnover. Expansion microscopy of the axonal shaft before the branch point revealed differences in deTyr/Tyr modification on MTs. Our model recapitulates the differences in MT turnover between branches and provides a feedback mechanism for MT regulation that depends on the axonal arbor geometry.
Early selection of the amino acid alphabet was adaptively shaped by biophysical constraints of foldability
Authors: Makarov Mikhail , Sanchez Rocha Alma C. , Krystufek Robin , Cherepashuk Ivan , Dzmitruk Volha , Charnavets Tatsiana , Faustino Anneliese M. , Lebl Michal , Fujishima Kosuke , Fried Stephen D. , Hlouchova Klara
Published: June 2022

Whereas modern proteins rely on a quasi-universal repertoire of 20 canonical amino acids (AAs), numerous lines of evidence suggest that ancient proteins relied on a limited alphabet of 10 ‘early’ AAs, and that the 10 ‘late’ AAs were products of biosynthetic pathways. However, many non-proteinogenic AAs were also prebiotically available, which begs two fundamental questions: Why do we have the current modern amino acid alphabet, and Would proteins be able to fold into globular structures as well if different amino acids comprised the genetic code? Here, we experimentally evaluated the solubility and secondary structure propensities of several prebiotically relevant amino acids in the context of synthetic combinatorial 25-mer peptide libraries. The most prebiotically abundant linear aliphatic and basic residues were incorporated along with or in place of other early amino acids to explore these alternative sequence spaces. We show that foldability was a critical factor in the selection of the canonical alphabet. Unbranched aliphatic and short-chain basic amino acids were purged from the proteinogenic alphabet despite their high prebiotic abundance because they generate polypeptides that are over-solubilized and have low packing efficiency. Surprisingly, we find that the inclusion of a short-chain basic amino acid also decreases polypeptides’ secondary structure potential. Our results support the view that despite lacking basic residues, the early canonical alphabet was remarkably adaptive at supporting protein folding and explain why basic residues were only incorporated at a later stage of the alphabet evolution.
Condition-Specific Mapping of Operons (COSMO) using dynamic and static genome data
Authors: Calvert-Joshua Tracey , Bendou Hocine , Heusden Peter van , Grobbelaar Melanie , Warren Rob , Christoffels Alan
Published: June 2022

An operon is a set of adjacent genes which are transcribed into a single messenger RNA. Operons allow prokaryotes to efficiently circumvent environmental stresses. It is estimated that about 60% of theMycobacterium tuberculosisgenome is arranged into operons, which makes them interesting drug targets in the face of emerging drug resistance. We therefore developed COSMO - a tool for operon prediction inM. tuberculosisusing RNA-seq data. We analyzed four algorithmic parameters and benchmarked COSMO against two top performing operon predictors. COSMO outperformed both predictors in its accuracy and in its ability to distinguish operons activated under distinct conditions.

Author Summary

Operons may be important drug targets for the development of effective anti-microbials to combat the emerging, global drug resistance challenge. However, there is a shortage of knownMycobacterium tuberculosis (Mtb)operons. This is exacerbated by the fact that current operon predictors are not optimized for the unique genome of Mtb. COSMO removes the limitations imposed by using the constraints of a specific organism’s genome and exploits RNA-seq data instead. This allows COSMO to more accurately predict full-length operons in Mtb, and it also avails COSMO to other microorganisms for the same purpose.
Cell fusion upregulates PD-L1 expression and promotes tumor formation
Authors: Tajima Youichi , Shibasaki Futoshi , Masai Hisao
Published: June 2022

MSCs (mesenchymal stem cells), responsible for tissue repair, rarely undergo cell fusion with somatic cells. Here, we show that approximately 5% of bladder cancer cells (UMUC-3) fuses with bone marrow-derived MSC (BM-MSC) in co-culture and exhibits increased tumorigenicity. Eleven fusion cell clones are established, and 116 genes are identified whose expression is specifically altered in the fusion cells. Many of them are interferon-stimulated genes (ISG), but are activated in a manner independent of interferon. Among them, we show that PD-L1 is induced in fusion cells, and its knockout decreases tumorigenesis in a xenograft model. PD-L1 is induced in a manner independent of STAT1 known to regulate PD-L1 expression, but is regulated by histone modification, and is likely to inhibit phagocytosis by PD1-expressing macrophages, thus protecting cancer cells from immunological attacks. The fusion cells overexpress multiple cytokines including CCL2 that causes tumor progression by converting infiltrating macrophages to tumor-associated-macrophage (TAM). The results present mechanisms of how cell fusion promotes tumorigenesis, revealing a novel link between cell fusion and PD-L1, and underscores the efficacy of cancer immunotherapy.
Single TolC-AcrA complex formation monitored by time dependent single-channel electrophysiology
Authors: Bodrenko Igor V. , Zewdie Tsedenia Alemu , Wang Jiajun , Paul Eshita , Witt Susanne , Winterhalter Mathias
Published: June 2022

Characterizing protein-protein interaction on a single molecular level is a challenge, experimentally as well as the interpretation of the data. For example, Gram-negative bacteria contain protein complexes spanning the outer and inner cell wall being able to efflux effectively cell toxic substances. Within the search for antibiotics with novel modes of action, inhibition of the efflux pump assembly is an interesting possible target. Recent seminal work revealed the high-resolution structure of the tripartic composition TolC-AcrA-AcrB. Here, we reconstitute a single TolC homotrimer into a planar lipid membrane and follow the assembly of AcrA using the modulation of the ion current through TolC during binding. In particular, the presence of AcrA increases the average ionic current through TolC and, moreover, reduces the ion-current fluctuations caused by flickering of TolC. Here, we demonstrate that statistical properties of ion-current fluctuations (the power spectral density) provide a complementary measure of the interaction of the TolC-AcrA complex with potential inhibitors. Both characteristics, the average current and the current noise, taken into consideration together, provide more robust information.
A single-cell atlas of the human brain in Alzheimer’s disease and its implications for personalized drug repositioning
Authors: Pei Guangsheng , Fernandes Brisa S , Wang Yin-Ying , Manuel Astrid M , Jia Peilin , Zhao Zhongming
Published: June 2022

Alzheimer’s disease (AD) is a neurodegenerative disease with complex pathophysiology, and AD-dysregulated pathways are inconsistent across different brain regions and patients. Although single-cell RNA sequencing (scRNA-seq) has been performed in different regions of postmortem AD brains, the common and distinct molecular features among different regions remains largely unclear. This hinders the discovery of repurposable and personalized drugs for AD. We combined four scRNA-seq datasets and systematically investigated the common and distinct cellular responses, cell subpopulations, and transcription factors involved in AD. Moreover, we explored the transcriptional heterogeneity of different AD subtypes at the single-cell level. Finally, we conducted individual-based drug repurposing analysis to explore repurposable and personalized drugs. Six major brain cell types were detected after scRNA-seq batch-effect removal and noise cells filtering. Integration with genome-wide association studies (GWAS) summary statistics demonstrated that AD-susceptible genes were mainly enriched with differentially expressed genes (DEGs) in glial cells rather than neuronal cells. While most of DEGs were regulated in opposite directions among different cell types, cell-cell communication analysis revealed several common cellular interaction events involved in neurogenesis, as well as increased cell-cell adhesion. Our comprehensive drug repositioning analysis identified new candidates for AD treatment, including trichostatin, which was predicted to be broadly applicable to different identified AD subtypes, and vorinostat, which was specific for one subtype of AD. In summary, we delineated a cell-specific atlas of the AD transcriptome. Our work illustrated strong cellular heterogeneity in AD for defining AD subtypes. The cell-specific features are important for understanding AD etiology, progression, and drug discovery.
Single Molecule Imaging Simulations with Advanced Fluorophore Photophysics
Authors: Bourgeois Dominique
Published: June 2022

Advanced fluorescence imaging techniques such as single-molecule localization microscopy (SMLM) fundamentally rely on the photophysical behavior of the employed fluorophores. This behavior is generally complex and impacts data quality in a subtle manner. A simulation software named SMIS (Single-Molecule Imaging Simulator) is introduced that simulates a widefield microscope and incorporates fluorophores with their spectral and photophysical properties. With SMIS, data collection schemes combining 3D, multicolor, single-particle-tracking or quantitative SMLM can be implemented. The influence of advanced fluorophore characteristics, imaging conditions and environmental parameters can be evaluated, facilitating the design of real experiments and their proper interpretation.