bluuebunny/crossref_metadata_2025 huggingface dataset:
Microbiology and Antibiotic Resistance in Peripartum Bacteremia
Authors: Wilkie Gianna L. , Prabhu Malavika , Ona Samsiya , Easter Sarah Rae , Tuomala Ruth E. , Riley Laura E. , Diouf Khady
Published: January 2019

OBJECTIVE:

To examine the microbiology and associated antibiotic resistance patterns among febrile peripartum women with positive blood cultures.

METHODS:

We conducted a retrospective cohort study in which we reviewed all bacteremia cases between 2009 and 2016 that occurred between 7 days before and 30 days after delivery. Institutional guidelines include obtaining blood cultures and promptly initiating intravenous antibiotics for all obstetric patients with fever of 100.4°F or higher. We describe antibiotic resistance patterns for the most frequently isolated organisms and perform univariate analyses regarding maternal and neonatal outcomes based on type of bacteremia.

RESULTS:

Among 56,835 deliveries, 3,797 (6.7%) obstetric patients had blood cultures drawn and 120 (3.2%) had documented bacteremia. The most commonly cultured organisms were Escherichia coli (17.5%, n=21), Bacteroides species (10.8%, n=13), Enterococcus species (10.8%, n=13), group B streptococci (10.8%, n=13), and group A streptococci (5.0%, n=6). E coli had high rates of resistance to ampicillin (n=17, 81.0%) and extended spectrum beta lactams (n=10, 47.6%). Gram-positive bacteremia was noted in 65/120 patients (54.2%), gram-negative bacteremia in 39/120 (32.5%), and anaerobic bacteremia in 16/120 (13.3%) (P=.02). Neonatal bacteremia was identified in 8/120 cases (6.7%), of which 7/8 (87.5%) were attributable to gram-negative bacteria and 1/8 (12.5%) were attributable to gram-positive bacteremia (P=.004). There were no differences in neonatal death or maternal intensive care unit admission.

CONCLUSION:

Peripartum bacteremia is uncommon, with the most frequently isolated organism being E coli. The evolution of antibiotic resistance patterns in E coli at our institution may be of clinical significance in determining antibiotic choice for peripartum fever.
Concordance of Fingerstick and Venipuncture Sampling for Fertility Hormones
Authors: Burke Erin E. , Beqaj Safedin , Douglas Nataki C. , Luo Robert
Published: January 2019

BACKGROUND:

Minimally invasive fingerstick sampling allows testing of reproductive hormone levels at home, providing women with increased access to tests that can screen for conditions such as polycystic ovarian syndrome, primary ovarian insufficiency, and pituitary and thyroid dysfunction.

METHOD:

We present a measurement procedure comparison study of matched venipuncture and fingerstick samples from 130 women aged 18–40 years, tested on menstrual cycle day 3. Samples were measured for anti-müllerian hormone, estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), prolactin (PRL), testosterone, thyroid-stimulating hormone (TSH), and free thyroxine (T4) levels. Samples were tested using U.S. Food and Drug Administration–cleared immunoassays, with a modified reconstitution step for fingerstick samples.

EXPERIENCE:

Venipuncture and fingerstick hormone values were concordant and linear across all assay ranges. There was no evidence of systematic bias across the assay ranges, and bias measures were below recommended guidelines. The correlation between venipuncture and fingerstick was between 0.99 and 1.0 for each hormone. Each assay displayed a high degree of precision (less than 13% coefficient of variation) and a high level of accuracy (average recovery equaled 95.5–102.3%).

CONCLUSION:

Venipuncture and fingerstick samples can be used interchangeably to measure anti-müllerian hormone, E2, FSH, LH, PRL, testosterone, TSH, and free T4 levels. Fingerstick sampling provides doctors and women more convenient testing options.

FUNDING SOURCE:

The study was sponsored by Modern Fertility.
Effects of Delivery Volume and High-Risk Condition Volume on Maternal Morbidity Among High-Risk Obstetric Patients
Authors: Bozzuto Laura , Passarella Molly , Lorch Scott , Srinivas Sindhu
Published: January 2019

OBJECTIVE:

To evaluate the effect of obstetric delivery volume, high-risk condition volume, and their combined effect on maternal outcomes.

METHODS:

This retrospective cohort study examined more than 10 million deliveries in three states from 1995 to 2009 using linked birth-hospital discharge records. Surgical high-risk patients had one of three prenatally identifiable conditions; the high-risk medical cohort had 1 or more of 14 complicating diagnoses. Hospitals were divided into quartiles of total obstetric delivery volume and tertiles of high-risk patient volume. The primary outcome was a composite outcome of severe maternal morbidity identified by International Classification of Diseases, 9th Revision, Clinical Modification, codes. Data were controlled for nonindependence using clustering by hospital and results were adjusted for patient and hospital level factors.

RESULTS:

We identified 142,194 high-risk surgical deliveries and 1,322,276 high-risk medical deliveries for evaluation. Among surgical high-risk patients, higher hospital total obstetric delivery volume was associated with 22% decreased risk for maternal morbidity (4th quartile adjusted odds ratio [AOR] 0.78; 95% CI 0.64–0.94); likewise for medical high-risk patients, higher total delivery volume was associated with a 28% decreased risk (4th quartile AOR 0.72; 95% CI 0.59–0.86). Conversely, as the volume of medical high-risk patients at hospitals increased, the AOR for severe morbidity increased (AOR=1.27, 95% CI 1.10–1.48). There was a significant interaction effect of both types of volume on maternal complications for both surgical (likelihood ratio [LR] χ2=18.2, P=.006) and medical high-risk patients (LR χ2=99.4, P<.001).

CONCLUSION:

Patients with high-risk medical and surgical conditions had decreasing adverse maternal outcomes as total obstetric delivery volume increased. There were increased odds of adverse maternal outcomes in centers with high volumes of high-risk patients. These two types of volume had significant combined effect on maternal risk. Both types of volume should be considered in assessing hospital obstetric performance.
What Is New in Ovulation Induction?
Authors: Hansen Keith A.
Published: January 2019

This month we focus on current research in ovulation induction. Dr. Hansen discusses five recent publications, which are concluded with a “bottom-line” that is the take-home message. A complete reference for each can be found on Box 1 on this page along with direct links to abstracts.
Nivolumab to pembrolizumab switch induced a durable melanoma response
Authors: Lepir Tanja , Zaghouani Mehdi , Roche Stéphane P. , Li Ying-Ying , Suarez Miguel , Irias Maria Jose , Savaraj Niramol
Published: January 2019

Rationale:

While checkpoint inhibitors have revolutionized the treatment of melanoma, it is not known whether switching from one monoclonal antibody drug to another one would be justified in the case of a treatment failure. Herein, we report a case illustrating a durable response to pembrolizumab after a failure with nivolumab.

Patient concerns:

A 76-year-old white male noticed an enlarging papular lesion on his neck.

Diagnosis:

Malignant melanoma.

Interventions:

The patient underwent surgery in December 2013 and was found to have a B-Rapidly Accelerated Fibrosarcoma (BRAF) V600E mutated melanoma. Treatment with BRAF and MAPK/Erk kinase (MEK) inhibitors along with radiation was initiated. After 1 year, the disease progressed, and the treatment was switched to the cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocking antibody, ipilimumab. As the tumor did not respond, the treatment was changed to programmed cell death receptor-1 (PD-1) blockers: nivolumab followed by pembrolizumab. Since the initial diagnosis, the tumor response was monitored by computed tomography (CT) scans. Immunohistochemistry (IHC) was also used for the assessment of programmed death ligand 1 PD-L1) expression in the neck, lung, and spleen lesions.

Outcomes:

The patient had an initial mixed response to nivolumab, but the disease ultimately progressed as evidenced by new metastases to the spleen, thus the treatment was switched to pembrolizumab. After 46 cycles of treatment, all sites of metastases disappeared, including a substantial shrinkage of the splenic metastasis. To gain understanding about the pharmacological differences between nivolumab and pembrolizumab, the PD-1–ligands interactions and conformational dynamics responsible for the PD-1/PD-L1 checkpoint blockade were investigated. The higher affinity of pembrolizumab might likely arise from a unique and large patch of interactions engaging the C’D loop of PD-1, thus forcing an important motion across the PD-1 immunoreceptor.

Lessons:

In this case report, we described the tolerance and response of a melanoma patient to a sequence of various agents, including ipilimumab, nivolumab, and pembrolizumab. To the best of our knowledge, this is the first clinical report highlighting differences between PD-1 blockers, as shown by the unexpected and durable response of the tumor to pembrolizumab, after a treatment failure with nivolumab.
Isolated hypothalamic-pituitary langerhans’ cell histiocytosis in female adult
Authors: Tan Huiwen , Yu Kai , Yu Yerong , An Zhengmei , Li Jianwei
Published: January 2019

Rationale:

Langerhans cell histiocytosis (LCH) is characterized by clonal proliferation of immature dendritic cells, mainly affects children. LCH in adult sellar region is extremely rare. In literature, optimal treatments remain unclear and only a few cases of LCH were treated using surgery. Here, we present a rare case of isolated hypothalamic-pituitary LHC in female adult. We focused on elucidating the clinical manifestations and immunohistochemical features of LCH, and exploring the proper treatment in adults.

Patient concerns:

A 50-year-old woman was admitted to our hospital, presenting with polydipsia and polyuria for over 3 months.

Diagnoses:

Radiological studies revealed lesions (0.5 × 0.9 × 0.4 cm) on posterior pituitary and enlarged pituitary stalk, which was moderately enhanced on contrast magnetic resonance imaging (MRI) of sellar region. In biopsy, pathological examination of Langerhans cells were observed with positive S-100 protein and Ki-67 antigen markers, findings were sufficient to establish a diagnosis of central nervous system (CNS) LCH.

Interventions:

The patient with LCH restricted in the sellar region received both surgery and chemotherapy. Gamma knife radiosurgery was performed after diagnosed as central diabetes insipidus (CDI) induced by pituitary lesion. And tumorectomy was performed 5 years later. However, in the latest MRI in 2017, the nodular shadow became larger (about 1.4 cm), chemotherapy and further systemic therapy were given.

Outcomes:

At 12-month follow-up, no local reoccurrence was noticed.

Lessons:

For LCH, though difficult to be diagnosed and none defined standard therapeutic approach to adults, surgery should be considered if there are neurological symptoms or histological diagnosis. The present study showed that some manifestations can be meaningful when central nervous system (CNS) is involved. For complex diseases in the sellar region, multi-disciplinary team (MDT) model of diagnosis and treatment should be helpful for better clinical efficacy.
Foot reconstruction with the superficial circumflex iliac artery perforator flap under local anesthesia
Authors: Hayashida Kenji , Yamakawa Sho , Saijo Hiroto , Fujioka Masaki
Published: January 2019

Rationale:

The superficial circumflex iliac artery perforator (SCIP) free flap is a popular method used in foot reconstruction. Although the SCIP flap has a relatively short pedicle and does not require intramuscular dissection, general anesthesia is largely preferred for SCIP flap reconstruction. We report 2 cases with the free SCIP flap for skin and soft tissue reconstruction of the foot under local anesthesia.

Patient concerns:

Case 1 was a 34-year-old man sustained a crush injury to the dorsal foot, resulting in a soft tissue defect with bone and tendon exposure. Case 2 was a 41-year-old man with type 2 diabetes was referred to our division for an intractable ankle wound after surgery for a calcaneal bone fracture.

Diagnosis:

The diagnosis was intractable wounds on feet caused by trauma and surgery. Patients were unable to receive general anesthesia because of asthma or elevated liver enzymes.

Interventions:

Two patients with tissue defects on their feet were treated with SCIP flaps under local anesthesia. Fifteen milliliter of 0.5% bupivacaine was injected for ankle block. SCIP flaps were harvested after injecting 10 to 15 mL of 1% lidocaine combined with epinephrine around the flap incisions.

Outcomes:

No complications related to the use of local anesthesia developed during the operation or postoperatively. Two flaps survived and fully took without complications.

Lessons:

With proper local anesthesia, successful foot reconstruction with a free SCIP flap was possible. This method can be considered a sufficient option for foot reconstruction for patients unable to receive general anesthesia.
Qishenyiqi dripping pill improves ventricular remodeling and function in patients with chronic heart failure
Authors: Chang Mingzheng , Cheng Lei , Shen Yaqian , Zhang Ying , Zhang Zhongwen , Hao Panpan
Published: January 2019

Background:

Qishenyiqi dripping pill for chronic heart failure (CHF) remains controversial due to lack of high-quality trials. Therefore, we conduct this pooled-analysis to evaluate the efficacy and safety of Qishenyiqi in CHF patients.

Methods:

We searched for randomized clinical trials for Qishenyiqi dripping pill in treating CHF up to August 2018 through China National Knowledge Infrastructure (CNKI), the PubMed Database, the Wanfang Database, the China Scientific Journal Database (VIP), and the Chinese Biomedicine Literature Service System. RevMan 5.3 was used for pooled analyses. Based on the New York Heart Association (NYHA) classification, the clinical therapeutic effect was collected as the primary endpoint.

Results:

The efficacy and safety of Qishenyiqi combined with routine treatment significantly increased NYHA functional classification, left ventricular ejection fraction, cardiac index, and 6-minute walking test and decreased brain natriuretic peptide, left ventricular end-diastolic, and end-systolic dimensions with no obvious side effects in comparison with routine therapy alone.

Conclusions:

Together these results provide important insights into Qishenyiqi is effective and safe in improving ventricular remodeling and function of CHF patients.

PROSPERO registration number:

PROSPERO106695.
Hyperhomocysteinemia in men with a reproductive history of fetal neural tube defects
Authors: Yu Yang , Jia Chunshu , Shi Qingyang , Zhu Yueying , Liu Yanhong
Published: January 2019

Rationale:

Hereditary hyperhomocysteinemia results from a polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene that reduces folate metabolism. Mutations in the MTHFR gene are common in parents who have given birth to children with neural tube defects (NTDs). Most research has focused on the risk for fetal NTDs in women with hyperhomocysteinemia and MTHFR gene mutations. Studies investigating the association between hyperhomocysteinemia, MTHFR gene mutations, and the risk for fetal NTDs in men are scarce.

Patient concerns:

Here, we report on 3 men with hyperhomocysteinemia and the MTHFR C677T homozygous TT genotype that have reproductive histories of fetal NTDs.

Diagnosis:

these 3 men were diagnosed as hyperhomocysteinemia and MTHFR C677T homozygous TT genotype.

Interventions:

Three men received homocysteine-lowering therapy.

Outcomes:

The first man's wife became pregnant, and a healthy infant was spontaneously delivered at term, the other 2 men's wives are still not pregnant.

Lessons:

Findings from this case reports and published literature imply that hereditary hyperhomocysteinemia in men affects sperm quality and sperm DNA methylation and causes epigenetic modifications that can result in fetal NTDs. We recommend monitoring homocysteine and folate levels in men before conception and supplementing with folate as needed, especially in men with a reproductive history of fetuses with neural tube or other birth defects.
Acupuncture for perimenopausal depression
Authors: Xiao Xiao , Zhang Jiayuan , Jin Yuxia , Wang Yunxia , Zhang Qi
Published: January 2019

Background:

Depression is one of common disease in the female perimenopausal period. It deprives women of their right to work and live normally, and even destroys the happiness of their families. Acupuncture is a promising treatment for perimenopausal depression.

Methods:

Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, EMBASE, China National Knowledge Internet (CNKI), Chongqing VIP (CQVIP), Wanfang Data, and on-line trial registries such as ClinicalTrials.gov (ClinicalTrials.gov/), European Medicines Agency (EMA)(www.ema.europa.eu/ema/), WHO International Clinical Trials Registry Platform (www.who.int/ictrp) will be searched from establishment of the database until Oct. 2018. There are no restrictions on the language of publication. The randomized controlled trials of acupuncture (electroacupuncture and manual acupuncture) for perimenopausal depression will be included, and all articles will be screened and collected by 2 reviewers independently. Revman 5.3.5 software will be used for meta-analysis. The specific process will refer to the Cochrane Handbook for Systematic Review.

Results:

The efficacy and safety of acupuncture for perimenopausal depression will be comprehensively assessed from the outcomes, including the effective rate, HAMD score, estrogen level and incidence of adverse events.

Conclusion:

This systematic review will provide evidence for whether acupuncture can improve perimenopausal depression.

Ethics and dissemination:

There is no requirement of ethical approval, and the review will be reported in a peer-reviewed journal.
Prenatal sonographic characteristics and postnatal outcomes of umbilical-portal-systemic venous shunts under the new in-utero classification
Authors: Wu Haifang , Tao Guowei , Cong Xiang , Li Qi , Zhang Jing , Ma Zhe , Zhang Zhonglu
Published: January 2019

An in-utero re-classification of umbilical-portal-systemic venous shunt (UPSVS) has recently been proposed. We retrospectively reviewed the sonograms of a large cohort of fetuses, identified and analyzed UPSVS cases, and presented the prenatal sonographic characteristics, birth outcomes, and follow-up results following the new classification system.

Sonograms and clinical data of all participants who visited our departments from April 2016 to July 2018 were retrospectively reviewed. Identified cases of UPSVS were analyzed according to the new classification: Type I: umbilical-systemic shunt (USS); Type II: ductus venosus-systemic shunt (DVSS); Type IIIa: intrahepatic portal-systemic shunt (IHPSS) and Type IIIb: extrahepatic portal-systemic shunt (EHPSS). Postnatal follow-ups ranged from 3 months to 1 year.

A total of 10 UPSVS cases were identified in 61,082 fetuses: 4 with Type I, 3 with Type II and 3 with Type IIIa. All 4 cases of USS had complete agenesis of the portal venous system, and had the umbilical vein drained into the inferior vena cava. Two USS cases also had trisomy 21. Pregnancy was terminated in all cases with a Type I shunt. Two fetuses with DVSS had normal portal venous system and were born full term. The pregnancy of 1 DVSS case was terminated due to the detection of trisomy 21. Three cases were IHPSS with full-term birth. One had chromosomal abnormality and 1 had surgery to repair the shunt 12-days post birth. In the 2 cases that did not receive repair surgery, sonographic examination revealed the portal-hepatic venous shunt was not closed at the 6-month follow-up period. However, the 1 case that had repair surgery appeared healthy at the 3-month follow-up period.

UPSVS is extremely rare. Type I shunts have the poorest prognosis, and the presence of the intrahepatic portal venous system is key to live birth in UPSVS regardless of types. Chromosomal abnormalities and other organ anomalies can occur in any types of UPSVS. Therefore, karyotyping and examination of other organs should be performed once UPSVS is detected.
Clinical analysis of 17 cases of neonatal osteomyelitis
Authors: Zhan Canyang , Zhou Bo , Du Jing , Chen Lihua
Published: January 2019

Although acute osteomyelitis is rare in neonates, it might result in severe sequelae such as joint destruction and growth failure if it is not diagnosed and treated early. However, few studies have focused on the clinical features and treatment of this disease.

A retrospective review of 17 cases of neonatal osteomyelitis, for which the patients underwent medical treatment alone or combined with surgery at the Children's Hospital of Zhejiang University School of Medicine between January 2009 and September 2016, was conducted. Medical treatment included the use of antibiotics and supportive care. Surgery was performed in cases with subperiosteal abscess (>1 cm) or clinical deterioration despite antibiotic therapy.

All of the patients (11 men and 6 women) were term neonates. The main complaints were redness or swelling around the affected bone and fever. The most common sites were the femur (29.4%) and humerus (23.5%). There were 14 (82.35%) cases with positive cultures: Staphylococcus accounted for 71.43% (n = 10), followed by Salmonella (n = 1), Streptococcus pneumoniae (n = 1), Klebsiella pneumoniae (n = 1), and Escherichia coli (n = 1). X-rays (n = 14), ultrasound (n = 6), computed tomography (CT) (n = 5), or magnetic resonance imaging (MRI) (n = 7) were performed. Three of 14 x-rays were not pathological at the onset of the disease, while the positive rate of MRI in detecting osteomyelitis was 100%. Eleven of 17 cases underwent surgical drainage, and higher white blood cell (WBC) counts were found in patients requiring surgery (P < .05). The prognosis for all patients was good without severe sequelae with a mean follow-up period of 49.47 ± 23.43 months.

In conclusion, the prognosis of neonatal osteomyelitis with early active treatment is good. MRI is advocated for detecting early osteomyelitis. Additionally, neonates with higher WBC count together with osteomyelitis have an increased risk for surgery.
Could E-Cadherin and CD10 Expression be Used to Differentiate Between Atypical Endometrial Hyperplasia and Endometrial Carcinoma?
Authors: Youssef Mona Y. , Mohamed Mie A.
Published: January 2019

Endometrial carcinoma contributes to morbidity and mortality among female individuals worldwide. The role of E-cadherin expression, as an adhesion molecule, in endometrial carcinoma is controversial. Moreover, the role of CD10-expressing stromal cells in endometrial carcinoma is still unclear. The aim of this work was to evaluate E-cadherin and CD10 expression in normal endometrium, atypical endometrial hyperplasia, and endometrial carcinoma, and assess their role to differentiate atypical endometrial hyperplasia from endometrial carcinoma. The association of E-cadherin and CD10 expression with clinicopathologic parameters of endometrial carcinoma was also determined. This retrospective study was carried out on 80 cases including 36 cases of endometrial adenocarcinoma (all were of endometrioid type), 34 cases of atypical endometrial hyperplasia, and another 10 cases of normal endometrial tissue. Immunohistochemistry for E-cadherin and CD10 was conducted. The studied patients were in their sixth and seventh decades of life with a mean age of 60.97 yr. Most of the carcinoma cases (18 cases) were grade 1, 10 cases were grade 2, and only 2 cases were grade 3. With regard to International Federation of Gynecology and Obstetrics (FIGO) staging, 28 cases were stage I, and only 2 cases were stage II. E-cadherin in normal endometrial tissue and atypical hyperplastic endometrial tissue showed predominantly membranous homogenous reactivity, and CD10 was detected as membranocyptoplasmic staining. However, we noticed the subcellular change of E-cadherin reactivity to be heterogenous and predominantly membranocytoplasmic in endometrial carcinoma, whereas CD10 remained membranocytoplasmic. Concerning E-cadherin expression, there was a statistically significant relationship between E-cadherin expression, tumor grade and FIGO staging, whereas there was an insignificant relationship between E-cadherin expression and patients’ age, specimen type, tumor gross pattern, and histopathologic types. With regard to CD10 expression, there was a statistically significant relation between CD10 expression and tumor grade and FIGO staging with insignificant relation with patients’ age, tumor gross pattern, specimen type, and tumor histologic types (villoglandular vs. usual endometrial adenocarcinoma). There was also a highly statistically significant positive relationship between E-cadherin expression and CD10 expression. This study puts the spot light on their role in differentiating between atypical endometrial hyperplasia and endometrial carcinoma, which is often difficult.
Novel Three-Dimensional Morphometry to Reassess Orbit Deformities Associated With Orbital-Periorbital Plexiform Neurofibroma
Authors: Guo Chengrui , Chen Liangbo , Qu Yang , Hu Xiaojie
Published: January 2019

Background:

Orbit deformities are usually found in neurofibromatosis type 1 patients, especially those with orbital-periorbital plexiform neurofibroma (OPPN). Unfortunately, current morphometry is complicated and, in some cases, cannot be performed on the deformed orbit due to the destruction of landmarks. Herein, we present a novel 3-dimensional (3D) morphometry for these orbital measurements.

Methods:

We retrospectively reviewed 29 patients with OPPN, and another 29 disseminated cutaneous neurofibroma patients served as controls. All patients had undergone craniofacial computed tomography and 3D reconstruction. New morphometry was used to measure the area of the orbital rim (OR) and superior orbital fissure (SOF).

Results:

For the 29 patients with OPPN, the area of the OR at the affected side was 14.18 ± 3.50 cm2, while the OR at the nonaffected side was 12.32 ± 1.38 cm2. In addition, the area of the SOF at the affected side was 5.37 ± 5.75 cm2, while that at the nonaffected side was 1.27 ± 1.03 cm2. The OR and SOF at the affected side are more likely to become enlarged compared with those at the nonaffected side. Among the 29 patients with OPPN, the novel morphometry could be performed in 19 cases (65.5%) that cannot be measured by previous morphometry.

Conclusion:

The novel morphometry is convenient and reproducible, which optimizes its application in pathologic cases, especially those involving deformed orbits.
C-terminal HSP90 Inhibitors Block the HSP90:HIF-1α Interaction and Inhibit the Cellular Hypoxic Response
Authors: Kataria Nalin , Kerr Bernadette , Zaiter Samantha S. , McAlpine Shelli , Cook Kristina M
Published: January 2019

Hypoxia Inducible Factor (HIF) is a transcription factor activated by low oxygen, which is common in solid tumours. HIF controls the expression of genes involved in angiogenesis, chemotherapy resistance and metastasis. The chaperone HSP90 (Heat Shock Protein 90) stabilizes the subunit HIF-1α and prevents degradation. Previously identified HSP90 inhibitors bind to the N-terminal pocket of HSP90 which blocks binding to HIF-1α, and produces HIF-1α degradation. N-terminal inhibitors have failed in the clinic as single therapy treatments due in part because they induce a heat shock response, which increases chemotherapy resistance. SM molecules are HSP90 inhibitors that bind to the C-terminus and do not activate the heat shock response. The effects of C-terminal HSP90 inhibitors on HIF-1α are unreported. Herein we show that SM compounds block binding between HSP90 and HIF-1α, leading to HIF-1α degradation through the proteasome using the PHD/pVHL pathway in hypoxic conditions. The SM compounds decrease HIF-1α target gene expression at the mRNA and protein level under hypoxia in colorectal cancer cells, leading to cell death, without inducing a heat shock response. Our results suggest that targeting the C-terminus of HSP90 blocks the hypoxic response and may be an effective anti-cancer strategy.
Selective enrichment of A-to-I edited transcripts from cellular RNA using Endonuclease V
Authors: Knutson Steve D. , Heemstra Jennifer M.
Published: January 2019

Immunoprecipitation enrichment has significantly improved the sensitivity and accuracy of detecting RNA modifications in the transcriptome. However, there are no existing methods for selectively isolating adenosine-to-inosine (A-to-I) edited RNAs. Here we show thatEscherichia coliEndonuclease V (eEndoV), an inosine-cleaving enzyme, can be repurposed to bind and isolate A-to-I edited transcripts from cellular RNA through adjustment of cationic conditions. While Mg2+is required for eEndoV catalysis, it has also been shown that similar levels of Ca2+instead promote binding of inosine without cleavage. Leveraging these properties, we observe that Ca2+-supplemented eEndoV is highly specific for inosine in RNA and exhibits low nanomolar binding affinity. We then demonstrate EndoVIPER (EndonucleaseVinosine precipitationenrichment) as a facile and robust method to isolate A-to-I edited transcripts from cellular RNA. We envision the use of this approach as a straightforward and cost-effective strategy to enrich edited RNAs and detect A-to-I sites with improved sensitivity and fidelity.
Interspecies metabolite transfer and aggregate formation in a co-culture of Dehalococcoides and Sulfurospirillum dehalogenating tetrachloroethene to ethene
Authors: Kruse Stefan , Türkowsky Dominique , Birkigt Jan , Matturro Bruna , Franke Steffi , Jehmlich Nico , von Bergen Martin , Westermann Martin , Rossetti Simona , Nijenhuis Ivonne , Adrian Lorenz , Diekert Gabriele , Goris Tobias
Published: January 2019

Microbial communities involving dehalogenating bacteria assist in bioremediation of areas contaminated with halocarbons. To understand molecular interactions between dehalogenating bacteria, we co-cultured Sulfurospirillum multivorans, dechlorinating tetrachloroethene (PCE) to cis-1,2-dichloroethene (cDCE), and Dehalococcoides mccartyi strains BTF08 or 195, dehalogenating PCE to ethene. The co-cultures were cultivated with lactate as electron donor. In this co-culture, the bacterial cells formed aggregates and D. mccartyi established an unusual, barrel-like morphology. An extracellular matrix surrounding bacterial cells in the aggregates enhanced cell-to-cell contact. PCE was dehalogenated to ethene at least three times faster in the co-culture. The dehalogenation was carried out via PceA of S. multivorans, and PteA (a recently described PCE dehalogenase) and VcrA of D. mccartyi BTF08, as supported by protein abundance. The co-culture was not dependent on exogenous hydrogen and acetate, suggesting a syntrophic relationship in which the obligate hydrogen consumer D. mccartyi consumes hydrogen and acetate produced by S. multivorans. The cobamide cofactor of the reductive dehalogenase – mandatory for D. mccartyi – was also produced by S. multivorans. D. mccartyi strain 195 dechlorinated cDCE in the presence of norpseudo-B12 produced by S. multivorans, but D. mccartyi strain BTF08 depended on an exogenous lower cobamide ligand. This observation is important for bioremediation, since cofactor supply in the environment might be a limiting factor for PCE dehalogenation to ethene, described for D. mccartyi exclusively. The findings from this co-culture give new insights into aggregate formation and the physiology of D. mccartyi within a bacterial community.
Cortico-hippocampal network connections support the multidimensional quality of episodic memory
Authors: Cooper Rose A. , Ritchey Maureen
Published: January 2019

Episodic memories reflect a bound representation of multimodal features that can be reinstated with varying levels of precision. Yet little is known about how brain networks involved in memory, including the hippocampus and posterior-medial (PM) and anterior-temporal (AT) cortical systems, functionally interact to support the quality and the content of recollection. Participants learned color, spatial, and emotion associations of objects, later reconstructing the visual features using a continuous color spectrum and 360-degree panorama scenes. Behaviorally, dependencies in memory were observed for the gist but not precision of these event associations. Supporting this integration, hippocampus, AT, and PM regions showed increased inter-network connectivity and reduced modularity during retrieval compared to encoding. These network connections, particularly to hippocampus, tracked a multidimensional, continuous measure of objective memory quality. Moreover, distinct patterns of connectivity tracked item color precision and spatial memory precision. These findings demonstrate not only how hippocampal-cortical connections reconfigure during episodic retrieval, but how such dynamic interactions might flexibly support the multidimensional quality of remembered events.
Cell type composition and circuit organization of neocortical radial clones
Authors: Cadwell Cathryn R. , Scala Federico , Fahey Paul G. , Kobak Dmitry , Sinz Fabian H. , Johnsson Per , Li Shuang , Cotton R. James , Sandberg Rickard , Berens Philipp , Jiang Xiaolong , Tolias Andreas S.
Published: January 2019

Excitatory neurons arising from a common progenitor establish radially-oriented clonal units in the neocortex which have been proposed to serve as elementary information processing modules. To characterize the cell types and circuit diagram within these clonal units, we performed single-cell RNA-sequencing and multi-cell patch clamp recordings of neurons derived fromNestin-positive progenitors. We found that radial clones do not appear to be fate-restricted, but instead individual clones are composed of a random sampling of the transcriptomic cell types present in a particular cortical area. The effect of lineage on synaptic connectivity depends on the type of connection tested: pairs of clonally related neurons were more likely to be connected vertically, across cortical layers, but not laterally within the same layer, compared to unrelated pairs. We propose that integration of vertical input from related neurons with lateral input from unrelated neurons may represent a developmentally programmed motif for assembling neocortical circuits.
Intra-familial phenotypic heterogeneity and telomere abnormality in von Hippel-Lindau disease
Authors: Wang Jiangyi , Peng Xiang , Chen Cen , Ning Xianghui , Peng Shuanghe , Li Teng , Liu Shengjie , Hong Baoan , Zhou Jingcheng , Ma Kaifang , Cai Lin , Gong Kan
Published: January 2019

Von Hippel-Lindau (VHL) disease is a hereditary cancer syndrome with poor survival. The current recommendations have proposed uniform surveillance strategies for all patients, neglecting the obvious phenotypic varieties. In this study, we aim to confirm the phenotypic heterogeneity in VHL disease and the underlying mechanism. A total of 151 parent-child pairs were enrolled for genetic anticipation analysis, and 77 sibling pairs for birth order effect analysis. Four statistical methods were used to compare the onset age of patients among different generations and different birth orders. The results showed that the average onset age was 18.9 years earlier in children than in their parents, which was statistically significant in all of the four statistical methods. Furthermore, the first-born siblings were affected 8.3 years later than the other ones among the maternal patients. Telomere shortening was confirmed to be associated with genetic anticipation in VHL families, while it failed to explain the birth order effect. Moreover, no significant difference was observed for overall survival between parents and children (p=0.834) and between first-born patients and the other siblings (p=0.390). This study provides definitive evidence and possible mechanisms of intra-familial phenotypic heterogeneity in VHL families, which is helpful to the update of surveillance guidelines.
AirSurf-Lettuce: an aerial image analysis platform for ultra-scale field phenotyping and precision agriculture using computer vision and deep learning
Authors: Bauer Alan , Bostrom Aaron George , Ball Joshua , Applegate Christopher , Cheng Tao , Laycock Stephen , Rojas Sergio Moreno , Kirwan Jacob , Zhou Ji
Published: January 2019

Aerial imagery is regularly used by farmers and growers to monitor crops during the growing season. To extract meaningful phenotypic information from large-scale aerial images collected regularly from the field, high-throughput analytic solutions are required, which not only produce high-quality measures of key crop traits, but also support agricultural practitioners to make reliable management decisions of their crops. Here, we report AirSurf-Lettuce, an automated and open-source aerial image analysis platform that combines modern computer vision, up-to-date machine learning, and modular software engineering to measure yield-related phenotypes of millions of lettuces across the field. Utilising ultra-large normalized difference vegetation index (NDVI) images acquired by fixed-wing light aircrafts together with a deep-learning classifier trained with over 100,000 labelled lettuce signals, the platform is capable of scoring and categorising iceberg lettuces with high accuracy (>98%). Furthermore, novel analysis functions have been developed to map lettuce size distribution in the field, based on which global positioning system (GPS) tagged harvest regions can be derived to enable growers and farmers’ precise harvest strategies and marketability estimates before the harvest.
Removal of Spo11 from meiotic DNA breaksin vitrobut notin vivoby Tyrosyl DNA Phosphodiesterase 2
Authors: Johnson Dominic , Allison Rachal M , Cannavo Elda , Cejka Petr , Neale Matthew J
Published: January 2019

Meiotic recombination events are initiated by DNA double-strand breaks (DSBs) created by the topoisomerase-like protein, Spo11. Similar to type-II topoisomerases, Spo11 becomes covalently linked to the 5′ ends generated on each side of the DSB. Whilst Spo11-oligos—the product of nucleolytic removal by Mre11—have been detected in a number of biological systems, the lifetime of the covalent Spo11-DSB precursor has not been systematically determined and may be subject to alternative processing reactions. Here we explore the activity of human Tyrosyl DNA Phosphodiesterase, TDP2, on Spo11-DSBs isolated fromS. cerevisiaecells. We demonstrate that TDP2 can remove Spo11 from natural ssDNA-oligos, and dsDNA ends even when in the presence of excess competitor genomic DNA. Interestingly, TDP2-processed Spo11-DSBs are refractory to resection by Exo1, suggesting that ssDNA generated by Mre11 may be essentialin vivoto facilitate resection-dependent HR at Spo11-DSBs even if TDP2 were active. Moreover, although TDP2 can remove Spo11 peptidesin vitro, TDP2 was unable to remove Spo11in vivo—unlike during the repair of topoisomerase-induced DNA lesions. These results suggest that Spo11-DNA, but not topoisomerase-DNA cleavage complexes, are inaccessible to the TDP2 enzyme, perhaps due to occlusion by higher order protein complexes resident at sites of meiotic recombination.
Inferring phenotypic plasticity and local adaptation to climate across tree species ranges using forest inventory data
Authors: Fréjaville Thibaut , Fady Bruno , Kremer Antoine , Ducousso Alexis , Garzón Marta Benito
Published: January 2019

Aim

To test whether adaptive and plastic trait responses to climate across species distribution ranges can be untangled using field observations, under the rationale that, in natural forest tree populations, long-term climate shapes local adaptation while recent climate change drives phenotypic plasticity.

Location

Europe.

Time period

1901-2014.

Taxa

Silver fir (Abies alba Mill.) and sessile oak (Quercus petraea (Matt.) Liebl.).

Methods

We estimated the variation of individual tree height as a function of long-term and short-term climates to tease apart local adaptation, plasticity and their interaction, using mixed-effect models calibrated with National Forest Inventory data (in-situ models). To validate our approach, we tested the ability of in-situ models to predict independently tree height observations in common gardens where local adaptation to climate of populations and their plasticity can be measured and separated. In-situ model predictions of tree height variation among provenances (populations of different geographical origin) and among planting sites were compared to observations in common gardens and to predictions from a similar model calibrated using common garden data (ex-situ model).

Results

In Q. petraea, we found high correlations between in-situ and ex-situ model predictions of provenance and plasticity effects and their interaction on tree height (r > 0.80). We showed that the in-situ models significantly predicted tree height variation among provenances and sites for Abies alba and Quercus petraea. Spatial predictions of phenotypic plasticity across species distribution ranges indicate decreasing tree height in populations of warmer climates in response to recent anthropogenic climate warming.

Main conclusions

Our modelling approach using National Forest Inventory observations provides a new perspective for understanding patterns of intraspecific trait variation across species ranges. Its application is particularly interesting for species for which common garden experiments do not exist or do not cover the entire climatic range of the species.
Conduit integrity is compromised during acute lymph node expansion
Authors: Martinez Victor G. , Pankova Valeriya , Krasny Lukas , Singh Tanya , White Ian J. , Benjamin Agnesska C. , Dertschnig Simone , Horsnell Harry L. , Kriston-Vizi Janos , Burden Jemima J. , Huang Paul H. , Tape Christopher J. , Acton Sophie E.
Published: January 2019

Lymph nodes (LNs) work as filtering organs, constantly sampling peripheral cues. This is facilitated by the conduit network, a parenchymal tubular-like structure formed of bundles of aligned extracellular matrix (ECM) fibrils ensheathed by fibroblastic reticular cells (FRCs). LNs undergo 5-fold expansion with every adaptive immune response and yet these ECM-rich structures are not permanently damaged. Whether conduit integrity and filtering functions are affected during cycles of LN expansion and resolution is not known. Here we show that the conduit structure is disrupted during acute LN expansion but FRC-FRC contacts remain intact. In homeostasis, polarised FRCs adhere to the underlying substrate to deposit ECM ba-solaterally. ECM production by FRCs is regulated by the C-type lectin CLEC-2, expressed by dendritic cells (DCs), at transcriptional and secretory levels. Inflamed LNs maintain conduit size-exclusion, but flow becomes leaky, which allows soluble antigens to reach more antigen-presenting cells. We show how dynamic communication between peripheral tissues and LNs changes during immune responses, and describe a mechanism that enables LNs to prevent inflammation-induced fibrosis.

Highlights

FRCs use polarized microtubule networks to guide matrix deposition

CLEC-2/PDPN controls matrix production at transcriptional and post-transcriptional levels

FRCs halt matrix production and decouple from conduits during acute LN expansion

Conduits leak soluble antigen during acute LN expansion
Empirical and Computational Comparison of Alternative Therapeutic Exon Skip Repairs for Duchenne Muscular Dystrophy
Authors: Ma Krystal Manyuan , Thomas Evelyn S , Wereszczynski Jeff , Menhart Nick
Published: January 2019

Duchenne muscular dystrophy is a common and devastating genetic disease that is primarily caused by exon deletions that create a genetic frameshift in dystrophin. Exon skipping therapy seeks to correct this by masking an exon during the mRNA maturation process, which restores dystrophin expression, but creates an edited protein missing both the original defect and the therapeutically skipped region. Crucially, it is possible to correct many defects in alternative ways, by skipping an exon either before, or after the patient’s defect. This results in alternatively edited, hybrid proteins, of possibly different properties and therapeutic consequences. Here, we examined three such dystrophin exon skipped edits, comprising two pairs of alternative repairs of the same underlying DMD defect. We found that in both cases, one member of each alternative repair was more stable than the other by a variety of thermodynamic and biochemical measures. We also examined the origin of these differences by molecular dynamics simulations, which showed that these stability differences were the result of different types of structural perturbations. For example, in one edit there was partial unfolding at the edit site which caused domain-localized perturbations, while in another there was unfolding at the protein domain junctions distal to the edit site which increased molecular flexibility. These results demonstrate that alternative exon skip repairs of the same underlying defect can have very different consequences at the level of protein structure and stability, and furthermore that these can arise by different mechanisms, either locally, or by more subtle long-range perturbations.
Worldwide impacts of humans on animal genetic diversity
Authors: Millette K.L , Fugère V. , Debyser C. , Greiner A. , Chain F.J.J. , Gonzalez A
Published: January 2019

Human impacts on genetic diversity are poorly understood yet critical to understanding the evolutionary capacity of the world’s biodiversity. We used global maps of land use and human density to assess human impacts on the intraspecific genetic diversity of 15,946 species of birds, fishes, insects, and mammals over time and across four spatial scales worldwide. We analyzed 164,518 mitochondrial cytochromecoxidase subunit I (COI) sequences to quantify changes in genetic diversity between 1980-2016. We found temporal change in genetic diversity, with both increasing and decreasing trends observed. The magnitude and sign of human impacts on genetic diversity depended on scale and taxon. In contrast, latitude was a strong predictor of diversity in fish, insects, and mammals. Our analyses provide a first worldwide picture of human impacts on animal genetic diversity. A global effort to systematically monitor genetic diversity is needed to fill the gaps in taxonomic and geographic coverage in this dataset.