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Article ; Online: HIV-1 prehairpin intermediate inhibitors show efficacy independent of neutralization tier.

Bell, Benjamin N / Bruun, Theodora U J / Friedland, Natalia / Kim, Peter S

Proceedings of the National Academy of Sciences of the United States of America

2023 Volume 120, Issue 8, Page(s) e2215792120

Abstract: HIV-1 strains are categorized into one of three neutralization tiers based on the relative ease by which they are neutralized by plasma from HIV-1-infected donors not on antiretroviral therapy; tier-1 strains are particularly sensitive to neutralization ... ...

Abstract	HIV-1 strains are categorized into one of three neutralization tiers based on the relative ease by which they are neutralized by plasma from HIV-1-infected donors not on antiretroviral therapy; tier-1 strains are particularly sensitive to neutralization while tier-2 and tier-3 strains are increasingly difficult to neutralize. Most broadly neutralizing antibodies (bnAbs) previously described target the native prefusion conformation of HIV-1 Envelope (Env), but the relevance of the tiered categories for inhibitors targeting another Env conformation, the prehairpin intermediate, is not well understood. Here, we show that two inhibitors targeting distinct highly conserved regions of the prehairpin intermediate have strikingly consistent neutralization potencies (within ~100-fold for a given inhibitor) against strains in all three neutralization tiers of HIV-1; in contrast, best-in-class bnAbs targeting diverse Env epitopes vary by more than 10,000-fold in potency against these strains. Our results indicate that antisera-based HIV-1 neutralization tiers are not relevant for inhibitors targeting the prehairpin intermediate and highlight the potential for therapies and vaccine efforts targeting this conformation.
MeSH term(s)	Humans ; Antibodies, Neutralizing ; Broadly Neutralizing Antibodies ; env Gene Products, Human Immunodeficiency Virus ; HIV Antibodies ; HIV Infections/drug therapy ; HIV-1/drug effects ; Neutralization Tests
Chemical Substances	Antibodies, Neutralizing ; Broadly Neutralizing Antibodies ; env Gene Products, Human Immunodeficiency Virus ; HIV Antibodies
Language	English
Publishing date	2023-02-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.2215792120
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Article ; Online: Does acute normovolemic hemodilution shorten viscoelastic test clot initiation after cardiopulmonary bypass?

Kristobak, Benjamin M / Brooks, Daniel I / Bell, Austin G / Willett, Peter B / Lodico, Derek N

Journal of clinical anesthesia

2020 Volume 67, Page(s) 109983

MeSH term(s)	Cardiopulmonary Bypass/adverse effects ; Hemodilution ; Humans ; Preoperative Care ; Thrombosis
Language	English
Publishing date	2020-07-10
Publishing country	United States
Document type	Letter
ZDB-ID	1011618-7
ISSN	1873-4529 ; 0952-8180
ISSN (online)	1873-4529
ISSN	0952-8180
DOI	10.1016/j.jclinane.2020.109983
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Zs.A 2622: Show issues

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Article ; Online: Neutralizing antibodies targeting the SARS-CoV-2 receptor binding domain isolated from a naïve human antibody library.

Bell, Benjamin N / Powell, Abigail E / Rodriguez, Carlos / Cochran, Jennifer R / Kim, Peter S

Protein science : a publication of the Protein Society

2021 Volume 30, Issue 4, Page(s) 716–727

Abstract: Infection with SARS-CoV-2 elicits robust antibody responses in some patients, with a majority of the response directed at the receptor binding domain (RBD) of the spike surface glycoprotein. Remarkably, many patient-derived antibodies that potently ... ...

Abstract	Infection with SARS-CoV-2 elicits robust antibody responses in some patients, with a majority of the response directed at the receptor binding domain (RBD) of the spike surface glycoprotein. Remarkably, many patient-derived antibodies that potently inhibit viral infection harbor few to no mutations from the germline, suggesting that naïve antibody libraries are a viable means for discovery of novel SARS-CoV-2 neutralizing antibodies. Here, we used a yeast surface-display library of human naïve antibodies to isolate and characterize three novel neutralizing antibodies that target the RBD: one that blocks interaction with angiotensin-converting enzyme 2 (ACE2), the human receptor for SARS-CoV-2, and two that target other epitopes on the RBD. These three antibodies neutralized SARS-CoV-2 spike-pseudotyped lentivirus with IC
MeSH term(s)	Angiotensin-Converting Enzyme 2/metabolism ; Antibodies, Neutralizing/chemistry ; Antibodies, Neutralizing/metabolism ; Binding Sites ; COVID-19/metabolism ; Epitopes/chemistry ; Epitopes/metabolism ; Humans ; Molecular Docking Simulation ; Protein Binding ; Protein Interaction Domains and Motifs ; SARS-CoV-2/physiology ; Spike Glycoprotein, Coronavirus/chemistry ; Spike Glycoprotein, Coronavirus/metabolism
Chemical Substances	Antibodies, Neutralizing ; Epitopes ; Spike Glycoprotein, Coronavirus ; spike protein, SARS-CoV-2 ; ACE2 protein, human (EC 3.4.17.23) ; Angiotensin-Converting Enzyme 2 (EC 3.4.17.23)
Language	English
Publishing date	2021-02-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	1106283-6
ISSN	1469-896X ; 0961-8368
ISSN (online)	1469-896X
ISSN	0961-8368
DOI	10.1002/pro.4044
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Zs.A 3407: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Radiation-induced Fistulas in Patients With Prior Pelvic Radiotherapy for Prostate Cancer: A Systematic Review and Meta-analysis.

Sadighian, Michael / Hakam, Nizar / Amend, Gregory / Shaw, Nathan M / Tahir, Peggy / Allen, Isabel E / Nabavizadeh, Behnam / Holler, Jordan / Shibley, William / Li, Kevin D / Abbasi, Behzad / Bell, Alexander / Mohamad, Osama / Breyer, Benjamin N

Urology

2023 Volume 176, Page(s) 121–126

Abstract: Objective: To systematically aggregate and summarize existing data on fistula prevalence among patients with a history of pelvic radiotherapy for prostate cancer.: Materials and methods: We queried PubMed, Embase, and Web of Science on October 7, ... ...

Abstract	Objective: To systematically aggregate and summarize existing data on fistula prevalence among patients with a history of pelvic radiotherapy for prostate cancer. Materials and methods: We queried PubMed, Embase, and Web of Science on October 7, 2020 for peer-reviewed publications pertaining to radiation-induced fistulas in the pelvis. For meta-analysis, we used the random-effects model. We used the I Results: Our final meta-analysis included 6 cohort studies with a total of 7665 patients exposed to pelvic radiotherapy between 1967 and 2013. Median follow-up time was 35.5 months (IQR 33.5-57.5). Pooled prevalence of radiation-induced fistula across all 6 cohort studies was 0.2% (95% CI: 0.1-0.4, I Conclusion: There is limited published literature reporting fistula as an adverse event of prostate cancer radiotherapy, especially in the medium and long-term period. Patients undergoing pelvic radiotherapy for prostate cancer appear at low short-term risk for developing fistulas. Adverse event reporting in randomized controlled trials merits greater granularity where fistulas should be reported with specificity rather than aggregating into broad categories of genitourinary or gastrointestinal adverse events.
MeSH term(s)	Male ; Humans ; Pelvis ; Prostatic Neoplasms/radiotherapy ; Cohort Studies
Language	English
Publishing date	2023-03-23
Publishing country	United States
Document type	Meta-Analysis ; Systematic Review ; Journal Article
ZDB-ID	192062-5
ISSN	1527-9995 ; 0090-4295
ISSN (online)	1527-9995
ISSN	0090-4295
DOI	10.1016/j.urology.2023.03.015
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Zs.A 1142: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 275: Show issues

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Article: IgM N-glycosylation correlates with COVID-19 severity and rate of complement deposition.

Haslund-Gourley, Benjamin / Woloszcuk, Kyra / Hou, Jintong / Connors, Jennifer / Cusimano, Gina / Bell, Mathew / Taramangalam, Bhavani / Fourati, Slim / Mege, Nathan / Bernui, Mariana / Altman, Matthew / Krammer, Florian / van Bakel, Harm / Maecker, Holden / Wigdahl, Brian / Cairns, Charles / Haddad, Elias / Comunale, Mary

Research square

2023

Abstract: ... inducing cytokine production. However, the role of IgM N-glycosylation has not been studied during acute ...

Abstract	The glycosylation of IgG plays a critical role during human SARS-CoV-2, activating immune cells and inducing cytokine production. However, the role of IgM N-glycosylation has not been studied during acute viral infection in humans.
Language	English
Publishing date	2023-06-02
Publishing country	United States
Document type	Preprint
DOI	10.21203/rs.3.rs-2939468/v1
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Article ; Online: IgM N-glycosylation correlates with COVID-19 severity and rate of complement deposition.

Nature communications

2024 Volume 15, Issue 1, Page(s) 404

Abstract: ... However, the role of IgM N-glycosylation has not been studied during human acute viral infection. The analysis ... of IgM N-glycosylation from healthy controls and hospitalized coronavirus disease 2019 (COVID-19 ... These trends are confirmed within SARS-CoV-2-specific immunoglobulin N-glycan profiles. Moreover, the degree ...

Abstract	The glycosylation of IgG plays a critical role during human severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, activating immune cells and inducing cytokine production. However, the role of IgM N-glycosylation has not been studied during human acute viral infection. The analysis of IgM N-glycosylation from healthy controls and hospitalized coronavirus disease 2019 (COVID-19) patients reveals increased high-mannose and sialylation that correlates with COVID-19 severity. These trends are confirmed within SARS-CoV-2-specific immunoglobulin N-glycan profiles. Moreover, the degree of total IgM mannosylation and sialylation correlate significantly with markers of disease severity. We link the changes of IgM N-glycosylation with the expression of Golgi glycosyltransferases. Lastly, we observe antigen-specific IgM antibody-dependent complement deposition is elevated in severe COVID-19 patients and modulated by exoglycosidase digestion. Taken together, this work links the IgM N-glycosylation with COVID-19 severity and highlights the need to understand IgM glycosylation and downstream immune function during human disease.
MeSH term(s)	Humans ; COVID-19 ; Glycosylation ; SARS-CoV-2 ; Glycosyltransferases ; Complement System Proteins ; Immunoglobulin M
Chemical Substances	Glycosyltransferases (EC 2.4.-) ; Complement System Proteins (9007-36-7) ; Immunoglobulin M
Language	English
Publishing date	2024-01-09
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-44211-0
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Article ; Online: The association between SARS-CoV-2 RT-PCR cycle threshold and mortality in a community cohort.

Waudby-West, Rupert / Parcell, Benjamin J / Palmer, Colin N A / Bell, Samira / Chalmers, James D / Siddiqui, Moneeza K

The European respiratory journal

2021 Volume 58, Issue 1

MeSH term(s)	COVID-19 ; Cohort Studies ; Humans ; RNA, Viral ; Reverse Transcriptase Polymerase Chain Reaction ; SARS-CoV-2
Chemical Substances	RNA, Viral
Language	English
Publishing date	2021-07-20
Publishing country	England
Document type	Letter
ZDB-ID	639359-7
ISSN	1399-3003 ; 0903-1936
ISSN (online)	1399-3003
ISSN	0903-1936
DOI	10.1183/13993003.00360-2021
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Zs.A 2322: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
Zs.MO 292: Show issues

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Article: Time for Bed: Genetic Mechanisms Mediating the Circadian Regulation of Sleep.

Blum, Ian D / Bell, Benjamin / Wu, Mark N

Trends in genetics : TIG

2018 Volume 34, Issue 5, Page(s) 379–388

Abstract: Sleep is an evolutionarily conserved behavior that is increasingly recognized as important for human health. While its precise function remains controversial, sleep has been suggested to play a key role in a variety of biological phenomena ranging from ... ...

Abstract	Sleep is an evolutionarily conserved behavior that is increasingly recognized as important for human health. While its precise function remains controversial, sleep has been suggested to play a key role in a variety of biological phenomena ranging from synaptic plasticity to metabolic clearance. Although it is clear that sleep is regulated by the circadian clock, how this occurs remains enigmatic. Here we examine the genetic mechanisms by which the circadian clock regulates sleep, drawing on recent work in fruit flies, zebrafish, mice, and humans. These studies reveal that central and local clocks utilize diverse mechanisms to regulate different aspects of sleep, and a better understanding of this multilayered regulation may lead to a better understanding of the functions of sleep.
MeSH term(s)	Animals ; Circadian Clocks/genetics ; Circadian Clocks/physiology ; Circadian Rhythm/genetics ; Circadian Rhythm/physiology ; Drosophila/genetics ; Humans ; Mice ; Neuronal Plasticity/genetics ; Neuronal Plasticity/physiology ; Sleep/genetics ; Sleep/physiology ; Zebrafish/genetics
Language	English
Publishing date	2018-01-24
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	619240-3
ISSN	1362-4555 ; 0168-9525 ; 0168-9479
ISSN (online)	1362-4555
ISSN	0168-9525 ; 0168-9479
DOI	10.1016/j.tig.2018.01.001
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Article ; Online: 5-Alpha reductase inhibitor related litigation: A legal database review.

Low, Patrick / Li, Kevin D / Hakam, Nizar / Bell, Alexander / Abbasi, Behzad / Lui, Jason / Shaw, Nathan M / Breyer, Benjamin N

Andrology

2021 Volume 10, Issue 3, Page(s) 470–476

Abstract: ... criteria. Adverse events experienced by patients included medication side effects (n = 12, 66.7%), delayed ... cancer diagnosis (n = 3, 16.7%), and lack of symptom improvement (n = 3, 16.7%). The identity ... of the plaintiffs were most commonly patients themselves (n = 15, 83.3%). Defendants include pharmaceutical ...

Abstract	Background: 5α-reductase inhibitors are commonly prescribed medications with multiple side effects used in the treatment of male pattern hair loss and benign prostatic hyperplasia. These side effects including "post-finasteride syndrome" may result in lawsuits. Objectives: To characterize lawsuits involving the adverse side effects of 5α-reductase inhibitor to better understand drivers of litigation and outcomes. Methods: Legal cases were queried from Nexis Uni using the search terms "5-alpha reductase inhibitor" as well as specific agents "finasteride," "dutasteride" in combination with "malpractice," "negligence," "damage," "loss," "side effect," and "complication." Secondary review was performed with publicly available data on "In Re: Propecia." Relevant cases were reviewed and pertinent characteristics were extracted and summarized using descriptive statistics. Results: Our search yielded 156 unique legal cases in the Nexis Uni database from April 2003 to May 2021. Only 18 of these cases met the inclusion criteria. Adverse events experienced by patients included medication side effects (n = 12, 66.7%), delayed cancer diagnosis (n = 3, 16.7%), and lack of symptom improvement (n = 3, 16.7%). The identity of the plaintiffs were most commonly patients themselves (n = 15, 83.3%). Defendants include pharmaceutical companies (n = 6, 33.3%), a combination of parties (n = 5, 27.8%), and physicians (n = 5, 27.8%) alone. The allegations included sexual side effects such as erectile dysfunction (n = 6, 33.3%) and decreased libido (n = 4, 22.2%). These prescriptions were made for benign prostatic hyperplasia (n = 9, 50%), male pattern hair loss (n = 7, 38.9%), and feminizing hormone therapy (n = 2, 11.1%). Several of these cases involved the same plaintiffs in related cases. No verdicts were against physicians. We noted a largely settled lawsuit involving more than 1000 plaintiffs with limited data on harms alleged and a $4.3 million settled amount. Of the total cases that resulted in a verdict, 9/18 were within the last 3 years. Discussion: The most common complications experienced by patients in our legal review were those involving sexual dysfunction with erectile dysfunction and decreased libido. The growing number of cases in the later years of our review suggests litigation may continue to increase in the coming future. Our review did not identify any individual cases that resulted in a monetary payout beyond a $4.3 million settlement outside of court. Conclusion: 5α-reductase inhibitor was alleged to have sexual, mental, and physical side effects, resulting in legal litigation. Despite this, no judgment against a physician or pharmaceutical company was identified. We do note and discuss a large number of lawsuits settled out of court. Given the increase in the number of lawsuits resulting in verdicts over the last 3 years, we suspect that the frequency of litigation around 5α-reductase inhibitors will continue for the foreseeable future.
MeSH term(s)	5-alpha Reductase Inhibitors/adverse effects ; Dutasteride ; Erectile Dysfunction/chemically induced ; Erectile Dysfunction/drug therapy ; Finasteride/adverse effects ; Humans ; Male ; Malpractice
Chemical Substances	5-alpha Reductase Inhibitors ; Finasteride (57GNO57U7G) ; Dutasteride (O0J6XJN02I)
Language	English
Publishing date	2021-12-30
Publishing country	England
Document type	Journal Article
ZDB-ID	2696108-8
ISSN	2047-2927 ; 2047-2919
ISSN (online)	2047-2927
ISSN	2047-2919
DOI	10.1111/andr.13145
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Zs.A 6983: Show issues

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Article ; Online: Characterization of mWake expression in the murine brain.

Bell, Benjamin J / Wang, Annette A / Kim, Dong Won / Xiong, Jiali / Blackshaw, Seth / Wu, Mark N

The Journal of comparative neurology

2020 Volume 529, Issue 8, Page(s) 1954–1987

Abstract: Structure-function analyses of the mammalian brain have historically relied on anatomically-based approaches. In these investigations, physical, chemical, or electrolytic lesions of anatomical structures are applied, and the resulting behavioral or ... ...

Abstract	Structure-function analyses of the mammalian brain have historically relied on anatomically-based approaches. In these investigations, physical, chemical, or electrolytic lesions of anatomical structures are applied, and the resulting behavioral or physiological responses assayed. An alternative approach is to focus on the expression pattern of a molecule whose function has been characterized and then use genetic intersectional methods to optogenetically or chemogenetically manipulate distinct circuits. We previously identified WIDE AWAKE (WAKE) in Drosophila, a clock output molecule that mediates the temporal regulation of sleep onset and sleep maintenance. More recently, we have studied the mouse homolog, mWAKE/ANKFN1, and our data suggest that its basic role in the circadian regulation of arousal is conserved. Here, we perform a systematic analysis of the expression pattern of mWake mRNA, protein, and cells throughout the adult mouse brain. We find that mWAKE labels neurons in a restricted, but distributed manner, in multiple regions of the hypothalamus (including the suprachiasmatic nucleus, dorsomedial hypothalamus, and tuberomammillary nucleus region), the limbic system, sensory processing nuclei, and additional specific brainstem, subcortical, and cortical areas. Interestingly, mWAKE is also observed in non-neuronal ependymal cells. In addition, to describe the molecular identities and clustering of mWake
MeSH term(s)	Animals ; Brain/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Nerve Tissue Proteins/metabolism
Chemical Substances	Nerve Tissue Proteins ; Nmf9 protein, mouse
Language	English
Publishing date	2020-11-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3086-7
ISSN	1096-9861 ; 0021-9967 ; 0092-7317
ISSN (online)	1096-9861
ISSN	0021-9967 ; 0092-7317
DOI	10.1002/cne.25066
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