Representative Members Research Articles

Jacobs School of Medicine and Biomedical Sciences at University at Buffalo.

Jacobs School of Medicine and Biomedical Sciences at University at Buffalo.

Discovery of Potent and Orally Bioavailable Small Molecule Antagonists of Toll-like Receptors 7/8/9 (TLR7/8/9).

The toll-like receptor (TLR) family is an evolutionarily conserved component of the innate immune system, responsible for the early detection of foreign or endogenous threat signals. In the context of autoimmunity, the unintended recognition of self-motifs as foreign promotes initiation or propagation of disease. Overactivation of TLR7 and TLR9 have been implicated as factors contributing to autoimmune disorders such as psoriasis, arthritis, and lupus. In our search for small molecule antagonists of TLR7/9, 7f was identified as possessing excellent on-target potency for human TLR7/9 as well as for TLR8, with selectivity against other representative TLR family members. Good pharmacokinetic properties and a relatively balanced potency against TLR7 and TLR9 in mouse systems (systems which lack functional TLR8) made this an excellent in vivo tool compound, and efficacy from oral dosing in preclinical models of autoimmune disease was demonstrated.

New Insights from Chemical Biology: Molecular Basis of Transmission, Diagnosis, and Therapy of SARS-CoV-2

Coronavirus disease 2019 (COVID-19) is caused by a novel strain of coronavirus, designated as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has caused a global pandemic rapidly s...

Adiponectin and related C1q/TNF-related proteins bind selectively to anionic phospholipids and sphingolipids

Adiponectin (Acrp30) is an adipokine associated with protection from cardiovascular disease, insulin resistance, and inflammation. Although its effects are conventionally attributed to binding Adipor1/2 and T-cadherin, its abundance in circulation, role in ceramide metabolism, and homology to C1q suggest an overlooked role as a lipid-binding protein, possibly generalizable to other C1q/TNF-related proteins (CTRPs) and C1q family members. To investigate this, adiponectin, representative family members, and variants were expressed in Expi293 cells and tested for binding to lipids in liposomes using density centrifugation. Binding to physiological lipids were also analyzed using gradient ultracentrifugation, liquid chromatography-mass spectrometry, and shotgun lipidomics. Interestingly, adiponectin selectively bound several anionic phospholipids and sphingolipids, including phosphatidylserine, ceramide-1-phosphate, glucosylceramide, and sulfatide, via the C1q domain in an oligomerization-dependent fashion. Binding to lipids was observed in liposomes, low-density lipoproteins, cell membranes, and plasma. Other CTRPs and C1q family members (Cbln1, CTRP1, CTRP5, and CTRP13) also bound similar lipids. These findings suggest that adiponectin and CTRPs function not only as hormones, but also as lipid opsonins, as may other C1q family proteins.

Italian multi-society modified Delphi consensus on the definition and management of anastomotic leakage in colorectal surgery.

The incidence of anastomotic leak (AL) has not decreased over the past decades and some important grey areas remain in its definition, prevention, and management. The aim of this study was to reach a national consensus on the definition of AL and to identify key points to be applied in clinical practice. A 3-step modified Delphi method was used to establish consensus. Ten representative members of the major Italian surgical scientific societies with proven colorectal expertise were selected after a call to action. After a comprehensive literature search, each expert drew a list of evidence-based statements which were voted in round one by the scientific board. Panel members were asked to mark "totally disagree", "partially agree" or "totally agree" for each statement and provide comments. The same voting method was used for round 2. Round 3 consisted of a final face-to-face meeting. Thirty-three statements (clustered into 14 topics) were included in round 1. Following the third voting round, a final list of 16 items was formulated, which encompass the following 9 topics: AL definition, patient- and operative-related risk factors, prevention measures, bowel preparation, surgical technique, intraoperative assessment, early diagnosis, radiological diagnosis and management of specific patterns of AL. The overall response rate was 100% for all items in all the three rounds. This Delphi survey identified items that expert colorectal surgeons agreed were important to be applied in the prevention, diagnosis, and management of AL. This represents the first consensus involving all relevant national scientific societies, defining important and shared concepts in the diagnosis and management of AL.

Organization of Bone Sarcoma Care: A Cross-Sectional European Study.

ObjectiveTo assess organization of care in several bone sarcoma centers in Europe affiliated with the European Musculoskeletal Oncology Society (EMSOS) for comparison and to identify potential improvements in organization of care.MethodsData for this observational cross‐sectional study was obtained through healthcare professionals affiliated to EMSOS. The authors formulated 10 questions regarding organization of care. The questions were focused on guidance, multidisciplinary decision‐making, and data storage. A digital questionnaire was synthesized and included quality control. The digital questionnaire was sent to 54 representative members of EMSOS. We did not receive responses from 29 representative countries (53.7%) after one digital invitation and two digital reminders.ResultsWe received data from 25 representatives of bone sarcoma centers from 17 countries across Europe (46.3%). Authorization to perform oncological care in a bone sarcoma center was government issued in 41.2% of cases and based on expertise without governmental influence in 52.9% of cases. In 64.7% of the countries, a national bone tumor guideline regarding for diagnosis and treatment is used in oncological care. A national bone tumor board for extensive case evaluation including classification and advice for treatment is available for 47.1% of the countries. All participating bone sarcoma centers have a mandatory local multidisciplinary meeting before the start of treatment; in 84.0% this meeting takes place once a week. During this multidisciplinary meeting a median of 15 cases (range, 4–40 cases) are discussed. In terms of storage of oncological data, a local registry is used in eight countries (47.1%). A national registry is used in eight countries (47.1%).ConclusionsA national bone tumor board gives bone sarcoma centers with little adherence the opportunity to gain knowledge from a more experienced team. Centralization of care in a bone sarcoma center is important to lower incidences. The optimal size for a bone sarcoma center in terms of patient adherence is not known at present.

Ophiocordyceps desmidiospora, a basal lineage within the “Zombie-Ant Fungi” clade

ABSTRACT The genus Ophiocordyceps contains the most diverse assemblage of fungi that attack ants worldwide and are remarkably well adapted to the specific ecologies of their hosts. Desmidiospora myrmecophila Thaxt. is closely related to other ant-pathogenic species within Ophiocordyceps, possibly specific to queens, but the sheer infrequency of encounters and previously unsuccessful attempts to culture this fungus has precluded any meaningful assessment until now. A new record of Desmidiospora myrmecophila from Louisiana was found infecting a foundress Camponotus pennsylvanicus queen, the same host species favored by the more common and ubiquitous ant-pathogenic Ophiocordyceps unilateralis clade found in the same geographic locality. To evaluate a long-held assumption that these fungi represent synanamorphs of a single species, we sampled our Desmidiospora specimen along with the local O. unilateralis population for molecular comparison. We are able to present for the first time the in vitro characteristics and morphology of Desmidiospora myrmecophila, as well as a phylogenetic context for this fungus based on combined molecular analysis of representative members of the Ophiocordycipitaceae. Our results place the Desmidiospora myrmecophila lineage within the genus Ophiocordyceps, with a basal affiliation to the Ophiocordyceps unilateralis core clade; thus, in accordance to the “One Fungus–One Name” (1F1N) rule, we propose a new synonym to suppress Desmidiospora in protection of Ophiocordyceps, i.e., O. desmidiospora. These results further implicate this species as an important and quintessential example of cryptic diversity among an already taxonomically diverse and ecologically important group of fungi.

OP0161 ASSOCIATION OF BASELINE CYTOTOXIC GENE EXPRESSION WITH USTEKINUMAB RESPONSE IN SYSTEMIC LUPUS ERYTHEMATOSUS

Background:Systemic Lupus Erythematous (SLE) is a clinically and biologically diverse disease, for which only one new therapy has been approved in the past 60 years. In a phase 2 trial on patients with mild-to-moderate SLE, ustekinumab (UST) improved clinical and laboratory measures of disease activity compared with placebo (PBO).1Objectives:We previously reported an association of IFN-γ reduction with response to UST,2suggesting an impact on the IL12/Th1 axis. To extend these findings, we performed unbiased transcriptomic analysis from baseline whole blood samples to identify genes that discriminate UST responders (UST-R) from non-responders (UST-NR) using the primary endpoint of Systemic Lupus Erythematosus Responder Index (SRI)-4 at week 24 to define response.Methods:UST was studied in a Ph2 PBO-controlled study of 102 patients with seropositive SLE and active disease despite standard therapy. Patients were randomized 3:2 to receive IV UST 6 mg/kg or placebo followed by subcutaneous injections of UST 90 mg or PBO every 8 weeks. Whole blood gene expression at baseline was measured via microarray using RNA samples from 100 patients, as samples from 2 patients failed quality control. An unbiased approach was used to identify gene signatures present at baseline that associate with UST response. Recombinant IL-12 or IL-23 was incubatedin vitrowith whole blood from 6 healthy donors for 24h and RNA-Seq was performed to determine the effect of these treatments on representative genes comprising the UST response signature.Results:A non-biased machine learning algorithm identified a 9-gene whole blood signature composed primarily of cytotoxic cell-associated transcripts (PRF1, KLRD1, GZMH, NKG7, GNLY, FGFBP2, TRGC2, TARP, TRGV2) that was enriched at baseline in UST-R vs UST-NR. By Gene Set Variation Analysis, the cytotoxic signature enrichment in UST-NR was less at baseline than both UST-R and a healthy control cohort (P=0.0087, P=0.056, respectively), whereas UST-R cytotoxic gene enrichment was similar to healthy controls (P=0.31). No significant difference in cytotoxic signature enrichment was observed at baseline between PBO responders and PBO non-responders or healthy controls (Figure). Enrichment levels of the cytotoxic gene signature remained stable over time in PBO and UST-NR groups while a trend of decreased cytotoxic signature was observed in UST-R, although never reaching levels seen in UST-NR. To begin to understand the relationship between IL-12 and IL-23, the targets of UST, and the cytotoxic signature, whole blood was stimulated with these cytokinesin vitro. Recombinant IL-12, but not IL-23, resulted in increased expression of representative members of this cytotoxic gene signature.Conclusion:We identified a novel cytotoxic signature in baseline blood samples that associated with UST response in SLE. The observation that IL-12 can increase this signaturein vitroand that IL-12 is a robust inducer of cytotoxic cell activity3as well as IFN-γ3suggests an important role of IL-12 blockade in the mechanism of action of UST in SLE.

Diet Diversity in Andasibe, Madagascar

Abstract Objectives In Madagascar, over 75% of the population is impoverished and 50% of children experience stunted growth with lifelong health and developmental implications. Beyond inadequate energy intake, diet homogeneity contributes to macronutrient and micronutrient deficiencies underlying underdeveloped organ and skeletal system. Research measuring diet diversity of the rural Malagasy population is lacking. A pilot diet-diversity study was conducted in the rural village of Andasibe to identify specific dietary components missing from the Malagasy diet. Methods Diet diversity data were obtained using guidelines established by the Food and Agriculture Organization of the United Nations. Over a 6-week period, 24-hour dietary recalls were collected of 150 representative adult household members- typically the mother or father of the household. Subjects provided verbal accounts of food and beverages consumed the day prior. Researchers then guided participants through a list of foods to capture any forgotten items. Foods recorded in the dietary recalls were assigned to categories based on nutrients of interest related to malnutrition and other diseases of nutrition inadequacy. Diet diversity scores (DDS) were assigned corresponding to food categories included in the 24-hour recall. Results The average DDS of all surveys was 4 of a possible 9, corresponding to “medium” diet diversity. 37% of subjects received a “low” DDS and consumed between 1–3 food categories per day. 15% of participants received a “high” DDS and consumed between 6–8 categories per day. Categories unreported in the average recall were “legumes, nuts, and seeds”; “vitamin A-rich fruit and vegetable”; and “milk and milk products”. Animal protein from sources such as meat or fish, dairy products, or eggs was not reported in most recalls. Conclusions Low consumption of protein, vitamin A, and iron-containing items on a given day may be indicative of dietary inadequacies related to stunting and morbidity. Diet diversity data allows for basic quantification of the extent of dietary homogeneity in Andasibe, which likely mimics that of other Malagasy villages and identifies priority areas for future nutrition intervention. Funding Sources Funding was provided by Auburn University's Office of Undergraduate Research and the College of Human Sciences.

Activation and selectivity of OTUB-1 and OTUB-2 deubiquitinylases

The ovarian tumor domain (OTU) deubiquitinylating cysteine proteases OTUB1 and OTUB2 (OTU ubiquitin aldehyde binding 1 and 2) are representative members of the OTU subfamily of deubiquitinylases. Deubiquitinylation critically regulates a multitude of important cellular processes, such as apoptosis, cell signaling, and growth. Moreover, elevated OTUB expression has been observed in various cancers, including glioma, endometrial cancer, ovarian cancer, and breast cancer. Here, using molecular dynamics simulation approaches, we found that both OTUB1 and OTUB2 display a catalytic triad characteristic of proteases but differ in their configuration and protonation states. The OTUB1 protein had a prearranged catalytic site, with strong electrostatic interactions between the active-site residues His265 and Asp267 In OTUB2, however, the arrangement of the catalytic triad was different. In the absence of ubiquitin, the neutral states of the catalytic-site residues in OTUB2 were more stable, resulting in larger distances between these residues. Only upon ubiquitin binding did the catalytic triad in OTUB2 rearrange and bring the active site into a catalytically feasible state. An analysis of water access channels revealed only a few diffusion trajectories for the catalytically active form of OTUB1, whereas in OTUB2 the catalytic site was solvent-accessible, and a larger number of water molecules reached and left the binding pocket. Interestingly, in OTUB2, the catalytic residues His224 and Asn226 formed a stable hydrogen bond. We propose that the observed differences in activation kinetics, protonation states, water channels, and active-site accessibility between OTUB1 and OTUB2 may be relevant for the selective design of OTU inhibitors.

Small Molecule Inhibitors of the Response Regulator ArsR Exhibit Bactericidal Activity against Helicobacter pylori.

Helicobacter pylori is considered the most prevalent bacterial pathogen in humans. The increasing antibiotic resistance evolved by this microorganism has raised alarm bells worldwide due to the significant reduction in the eradication rates of traditional standard therapies. A major challenge in this antibiotic resistance crisis is the identification of novel microbial targets whose inhibitors can overcome the currently circulating resistome. In the present study, we have validated the use of the essential response regulator ArsR as a novel and promising therapeutic target against H. pylori infections. A high-throughput screening of a repurposing chemical library using a fluorescence-based thermal shift assay identified several ArsR binders. At least four of these low-molecular weight compounds noticeably inhibited the DNA binding activity of ArsR and showed bactericidal effects against antibiotic-resistant strains of H. pylori. Among the ArsR inhibitors, a human secondary bile acid, lithocholic acid, quickly destroyed H. pylori cells and exhibited partial synergistic action in combination with clarithromycin or levofloxacin, while the antimicrobial effect of this compound against representative members of the normal human microbiota such as Escherichia coli and Staphylococcus epidermidis appeared irrelevant. Our results enhance the battery of novel therapeutic tools against refractory infections caused by multidrug-resistant H. pylori strains.

PCR Detection of Oxacillinases in Bacteria.

Oxacillinases (OXA) have been mostly described in Enterobacteriaceae, Acinetobacter, and Pseudomonas species. Recent years have witnessed an increased prevalence of intrinsic and/or acquired β-lactamase-producing Acinetobacter in food-producing animals. This study was conducted to assess the prevalence of OXA among selected bacterial species and to characterize these enzymes by in silico analysis. Screening of OXA was performed by PCR amplification using specific pairs of oligonucleotides. Overall, 40 pairs of primers were designed, of which 6 were experimentally tested in vitro. Among 49 bacterial isolates examined, the presence of blaOXA-1-like genes was confirmed in 20 cases (41%; 19 times in Klebsiella pneumoniae and once in Enterobacter cloacae). No OXA were found in animal isolates. The study results confirmed the specificity of the designed oligonucleotide pairs. Furthermore, the designed primers were found to possess the ability to specifically detect 90.2% of all OXA. These facts suggest that the in silico and in vitro tested primers could be used for single or multiplex PCR to screen for the presence of OXA in various bacteria, as well as to monitor their spread. At the same time, the presence of conserved characteristic amino acids and motifs was confirmed by in silico analysis of sequences of representative members of OXA.

Building a Culture of Health at the Neighborhood Level Through Governance Councils

To explore facilitators and barriers to developing and sustaining collaboration among New York City Department of Health and Mental Hygiene’s Neighborhood Health Action Centers and co-located partners, who share information and decision-making through a Governance Council structure of representative members. Semi-structured interviews were conducted in 2018 with 43 Governance Council members across the three Action Centers of East Harlem (13), Tremont (15), and Brownsville (15), New York City. Governance Council members identified collaboration through information- and resource-sharing, consistent meetings and continuous communication as valuable for fostering a culture of health in their communities. Immediate benefits included building relationships, increased access to resources, and increased reach and access to community members. Challenges included difficulty building community trust, insufficient advertisement of services, and navigation of government bureaucracy. The Governance Councils forged collaborative relationships among local government, community-based organizations and clinical providers to improve health and well-being in their neighborhoods. Sharing space, resources and information is feasible with a movement towards shared leadership and decision-making. This may result in community-driven and tailored solutions to historical inequities. In shared leadership models, some internal reform by Government partners may be required.

Reconstitution of biosynthetic machinery of fungal natural products in heterologous hosts.

Ascomycota and basidiomycota fungi are prolific sources of biologically active natural products. Recent genomic data and bioinformatic analysis indicate that fungi possess a large number of biosynthetic gene clusters for bioactive natural products but more than 90% are silent. Heterologous expression in the filamentous fungi as hosts is one of the powerful tools to expression of the silent gene clusters. This review introduces recent studies on the total biosynthesis of representative family members via common platform intermediates, genome mining of novel di- and sesterterpenoids including detailed cyclization pathway, and development of expression host for basidiomycota genes with efficient genome editing method. In addition, this review will discuss the several strategies, for the generation of structural diversity, which are found through these studies.

Mitochondrial Membranes Involved in Apoptosis - the Bcl-2 Proteins

Removal of cells via programmed cell death (apoptosis) is an essential mechanism in life. Upon internal stress clearance of undesired cells is executed via intrinsic (mitochondrial) apoptosis, a pathway tightly controlled by the Bcl-2 protein family. Its pro- and anti-apoptotic members meet at the mitochondrial surface, more precisely at its outer membrane system, where they arbitrate a life or death (membrane permeabilization) decision. Failures cause pathological disorders including abnormal embryogenic development and cancer. However, how opposing Bcl-2 members meet and form a sophisticated regulative network there, is still poorly understood due to the lack of structural and functional information for these proteins acting at the the mitochondrial membraneous surface. To provide structural about this molecular regulation mechanism occurring at the mitochondrial outer membrane system, we apply solid-state/liquid NMR approaches together with neutron reflectometry on two representative Bcl-2 family members, namely the anti-apoptotic Bcl-2 protein itself which is an integral membrane protein, and its counterpart, the pro-apoptotic, membrane perforating Bax protein. i) Using MOM-like membranes doped with oxidized lipids to simulate apoptosis triggering oxidative stress, we investigate changes in the dynamic and structural organization of these membranes in the presence of Bax protein to identify the key structural elements which regulate Bax perforation activity in response to type and level of oxidative membrane damage. ii) The atomic structure of the Bcl-2 membrane protein is still undetermined, preventing a detailed mechanistic insight into its function, especially its loops as anti-apoptotic molecular switches. We are going to provide this information by combining liquid-state NMR on Bcl-2 in micelles with solid-state NMR on Bcl-2/lipid assemblies.

Using a Local Public Good to Attract Representative Creative Class Members: The Inefficient Equilibrium Case

Batabyal and Beladi [1] have recently analyzed a model of competition between two cities that use a local public good (LPG) to attract members of the creative class. The creative class consists of artists and engineers and they study the behavior of a representative artist and an engineer. In this note, we explore three implications of the use of this “representative artist and engineer” modeling strategy. First, we show that the use of such a strategy can lead one to study an inefficient equilibrium in the aggregate economy. Second, we point out that in this inefficient equilibrium, the beliefs of the representative artist and the engineer are inconsistent. Finally, we contend that if we depart from the “representative artist and engineer” construct and focus instead on the entire creative class population which we model as a continuum, then the inefficient equilibrium mentioned above can be turned into an efficient equilibrium.

The Importance of Good Working Relationships between Principals and School Board Members in Zambezi Region, Namibia

The purpose of this study was to establish the importance of a good working relationship between principals and school board members (SBMs) in Zambezi region. The study adopted a qualitative research design approach. The data was gathered using interviews. In this study, the researchers worked with principals and SBMs in Zambezi region, Namibia. For the purpose of the study, the researcher selected five principals, nine teacher SBMs, ten parent SBMs and four learners’ representative council members (LRCs) from primary, combined and senior secondary schools in the Zambezi region. The reason for selecting the twenty-eight participants was their involvement as members of school boards in the Zambezi region. A qualitative data analysis (QDA) was employed in this study. The findings derived from principals’ comments revealed that, when there was a good working relationship between principals and SBMs, it became easier to maintain discipline among learners at the school. Good performance and good academic results of learners could be achieved at the school. The majority of principals and teacher SBMs seemed to be working together in ensuring that the school achieved the targeted goals and objectives. Principals and SBMs are important partners when it comes to the smooth running of the school. It was revealed from the findings derived from the comments of principals that the importance of a good working relationship with SBMs was the development of unity and trust. It was revealed from the findings derived from the comments of principals, parent SBMs and LRCs serving on the school board that the importance of a good working relationship also related to consultations on matters regarding school development. From the findings of this paper, the researcher can confirm that, to work properly, principals and SBMs should have a healthy working relationship.

People & Culture: What Human Resources Strategy for a University Promoting a Sustainable World?

Universities are higher education institutions whose mission is to generate and transmit knowledge to the society through their research and teaching activities. An important question facing universities today is how they can evolve into institutions where excellence is not only focused on scientific results but also on the development of human capital and on the promotion of diversity, equality, inclusiveness. This requires a major change in the governance of universities, which, in terms of human resources (HR), must define their strategic directions and implement evidence-based management. The HR strategy is translated into policies that must be well identified and validated by community members. Action plans are based on three essential pillars: (i) a high-performing HR team that guarantees equal rules and best practices for each member of the University; (ii) an information system adapted to HR performance management with appropriate indicators; (iii) a strong managerial culture aimed at giving all managers, whether academic or administrative, the means to face cultural gap, to foster the development of everyone's skills and to identify talent. Sustainable implementation of these ambitions relies on iterative evaluations to progressively adjust these processes, for the benefit of the well-being of community members, the effectiveness of the various structures to which they belong, and the attractiveness of the University. The inclusion of women and representative members of minorities in the leadership of universities undoubtedly favors this transition, towards a working environment strongly imbued with the values of the University, enabling the shaping and dissemination of a similar corpus of good practices, based on the fundamental principles of work centered on respect, trust, a strong sense of public interest, collaboration and initiative.

Diagnosis and Treatment Before Assisted Reproductive Treatments. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Register Number 015-085, February 2019) - Part 2, Hemostaseology, Andrology, Genetics and History of Malignant Disease.

Introduction Supporting and counselling couples with fertility issues prior to starting ART is a multidisciplinary diagnostic and therapeutic challenge. The first German-language interdisciplinary S2k guideline on "Diagnosis and Therapy Before Assisted Reproductive Treatments (ART)" was published in February 2019. The guideline was developed in the context of the guidelines program of the German Society of Gynecology and Obstetrics (DGGG) in cooperation with the Swiss Society of Gynecology and Obstetrics (SGGG) and the Austrian Society of Gynecology and Obstetrics (OEGGG). Aim In one third of cases, the cause of involuntary childlessness remains unclear, even if the woman or man have numerous possible risk factors. Because the topic is still very much taboo, couples may be socially isolated and often only present quite late to a fertility center. There is no standard treatment concept for these patients at present, as there are currently no standard multidisciplinary procedures for the diagnostic workup and treatment of infertility. The aim of this guideline is to provide physicians with evidence-based recommendations for counselling, diagnosis and treatment. Methods This S2k guideline was developed on behalf of the Guidelines Commission of the DGGG by representative members from different professional medical organizations and societies using a structured consensus process. Recommendations This second part of the guideline describes the hematological workup for women as well as additional diagnostic procedures which can be used to investigate couples and which are carried out in cooperation with physicians working in other medical fields such as andrologists, geneticists and oncologists.

Diagnosis and Therapy Before Assisted Reproductive Treatments. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Register Number 015-085, February 2019) - Part 1, Basic Assessment of the Woman.

Introduction Supporting and counselling couples with fertility issues prior to starting ART is a multidisciplinary diagnostic and therapeutic challenge. The first German/Austrian/Swiss interdisciplinary S2k guideline on "Diagnosis and Therapy Before Assisted Reproductive Treatments (ART)" was published in February 2019. This guideline was developed in the context of the guidelines program of the German Society of Gynecology and Obstetrics (DGGG) in cooperation with the Swiss Society of Gynecology and Obstetrics (SGGG) and the Austrian Society of Gynecology and Obstetrics (OEGGG). Aims One third of the causes of involuntary childlessness are still unclear, even if the woman or man have numerous possible risk factors. Because the topic is still very much taboo, couples may be socially isolated and often only present quite late to a fertility center. At present, there is no standard treatment concept, as currently no standard multidisciplinary procedures exist for the diagnostic workup and treatment of infertility. The aim of this guideline is to provide physicians with evidence-based recommendations for counselling, diagnostic workup and treatment. Methods This S2k guideline was developed on behalf of the Guidelines Commission of the DGGG by representative members from different professional medical organizations and societies using a structured consensus process. Recommendations The first part of this guideline focuses on the basic assessment of affected women, including standard anatomical and endocrinological diagnostic procedures and examinations into any potential infections. Other areas addressed in this guideline are the immunological workup with an evaluation of the patient's vaccination status, an evaluation of psychological factors, and the collection of data relating to other relevant factors affecting infertility. The second part will focus on explanations of diagnostic procedures compiled in collaboration with specialists from other medical specialties such as andrologists, human geneticists and oncologists.